U.S. patent application number 15/253279 was filed with the patent office on 2017-07-27 for methods for inhibiting tie-2 kinase useful in the treatment of cancer.
The applicant listed for this patent is DECIPHERA PHARMACEUTICALS, LLC. Invention is credited to Daniel L. Flynn, Michael D. Kaufman, Marc Rudoltz, Brian D. Smith.
Application Number | 20170209428 15/253279 |
Document ID | / |
Family ID | 54006254 |
Filed Date | 2017-07-27 |
United States Patent
Application |
20170209428 |
Kind Code |
A1 |
Flynn; Daniel L. ; et
al. |
July 27, 2017 |
METHODS FOR INHIBITING TIE-2 KINASE USEFUL IN THE TREATMENT OF
CANCER
Abstract
The present invention relates to methods of inhibiting TIE2
kinase useful in the treatment of tumor growth, invasiveness,
intravasation, dissemination, metastasis, and immunosuppression.
Specifically, the invention relates to methods of using
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea and salts thereof of
Formula I.
Inventors: |
Flynn; Daniel L.; (Lawrence,
KS) ; Kaufman; Michael D.; (Lawrence, KS) ;
Smith; Brian D.; (Lawrence, KS) ; Rudoltz; Marc;
(West Orange, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DECIPHERA PHARMACEUTICALS, LLC |
Lawrence |
KS |
US |
|
|
Family ID: |
54006254 |
Appl. No.: |
15/253279 |
Filed: |
August 31, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14535900 |
Nov 7, 2014 |
9457019 |
|
|
15253279 |
|
|
|
|
61901316 |
Nov 7, 2013 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/337 20130101;
A61K 9/0019 20130101; A61K 31/337 20130101; A61K 31/357 20130101;
A61K 47/64 20170801; A61K 31/4709 20130101; A61K 31/185 20130101;
A61K 31/351 20130101; A61K 31/4709 20130101; C07D 401/14 20130101;
C07K 16/40 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 45/06 20130101; A61K 2300/00 20130101; A61K 31/357
20130101 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; A61K 31/185 20060101 A61K031/185; A61K 9/00 20060101
A61K009/00; A61K 31/357 20060101 A61K031/357; A61K 45/06 20060101
A61K045/06; A61K 31/337 20060101 A61K031/337 |
Claims
1. A method of blocking primary breast tumor growth and
invasiveness comprising administering to a patient in need thereof
an effective amount of a composition of Formula I ##STR00004##
wherein n is an integer from 0 to 7; X is the basic radical of a
pharmaceutically acceptable salt; provided that when n is 0, the
composition of Formula I is the parent free base; in a dosing
regimen sufficient to block TIE2 kinase in the tumor
microenvironment.
2. The method of claim 1, wherein the dosing regimen is
administered daily.
3. The method of claim 1, wherein the dosing regimen is
intermittent non-daily dosing, alternate daily dosing, every third
daily dosing, twice weekly dosing, or once weekly dosing.
4. The method of claim 1, wherein the dosing regimen is twice
weekly, once weekly, or on an alternately weekly dosing.
5. The method of claim 1, wherein the composition of Formula I is
used in combination with one or more agents taken from an
anti-tubulin agent.
6. The method of claim 1, wherein the composition of Formula I is
used in combination with paclitaxel.
7. The method of claim 1, wherein the composition of Formula I is
used in combination with paclitaxel protein-bound particles for
injectable suspension.
8. The method of claim 1, wherein the compound of Formula I is used
in combination with eribulin.
9. The method of claim 1, wherein the composition of Formula I is
used in combination with docetaxel, ixabepilone, or
vinorelbine.
10.-35. (canceled)
36. The method of claim 1, wherein the composition of Formula I is
the composition having Formula IL ##STR00005## and wherein Formula
II is used in combination with one or more agents taken from an
anti-tubulin agent comprising paclitaxel, paclitaxel protein-bound
particles for injectable suspension, eribulin, ixabepilone, and
vinorelbine.
37. (canceled)
38. A method of blocking breast cancer intravasation, dissemination
and metastasis, comprising administering to a patient in need
thereof an effective amount of a composition of Formula I
##STR00006## wherein n is an integer from 0 to 7; X is the basic
radical of a pharmaceutically acceptable salt; provided that when n
is 0, the composition of Formula I is the parent free base, in a
dosing regimen sufficient to block TIE2 kinase in tumor
microenvironment TIE2-expressing macrophages.
39. The method of claim 38, wherein the dosing regimen of is
administered daily.
40. The method of claim 38, wherein the dosing regimen is
intermittent non-daily dosing, alternate daily dosing, every third
daily dosing, twice weekly dosing, or once weekly dosing.
41. The method of claim 38, wherein the dosing regimen is twice
weekly, once weekly, or on an alternately weekly dosing.
42. The method of claim 38, wherein the composition of Formula I is
used in combination with one or more agents taken from an
anti-tubulin agent.
43. The method of claim 38, wherein the composition of Formula I is
used in combination with paclitaxel.
44. The method of claim 38, wherein the composition of Formula I is
used in combination with paclitaxel protein-bound particles for
injectable suspension.
45. The method of claim 38, wherein the composition of Formula I is
used in combination with eribulin.
46. The method of claim 38, wherein the composition of Formula I is
used in combination with docetaxel, ixabepilone, or
vinorelbine.
47.-219. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/535,900, filed on Nov. 7, 2014, which
claims the benefit of U.S. Provisional Patent Application No.
61/901,316, filed Nov. 7, 2013, entitled "METHODS FOR INHIBITING
TIE-2 KINASE USEFUL IN THE TREATMENT OF CANCER," which is
incorporated herein by reference in its entirety.
DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY
[0002] The contents of the text file submitted electronically
herewith are incorporated herein by reference in their entirety: A
computer readable format copy of the Sequence Listing (filename:
DECP_066_01US_SeqList_ST25.txt, date recorded: Nov. 7, 2014, file
size 6 kilobytes).
FIELD OF THE INVENTION
[0003] The present invention relates to methods of inhibiting TIE2
kinase useful in the treatment of tumor growth, tumor invasiveness,
tumor intravasation, tumor dissemination, tumor metastasis, and
tumor immunotolerance. Specifically, the invention relates to
methods of using compositions of Formula I herein described as
potent inhibitors of TIE2 for treating breast cancer growth,
invasiveness, intravasation dissemination, metastasis, and
immunotolerance.
BACKGROUND OF THE INVENTION
[0004] Tunica interna endothelial cell kinase-2 (TIE2) is largely
restricted to expression in endothelial cells of the vasculature,
and in a subset of bone marrow derived TIE2 expressing monocytes
(TEMs). TIE2 is the receptor for angiopoietin 1 (ANG1),
angiopoietin 2 (ANG2), and angiopoietin 4 (ANG4) and this signaling
system plays an important role in both angiogenesis (sprouting of
new vessels from existing vessels) and vasculogenesis (de novo new
vessel formation). TEMs are a subset of circulating monocytes and
tissue macrophages that have proangiogenic and provasculogenic
activity in tumor models (De Palma M D et al, Cancer Cell 2005;
8:211-226). TIE2 inhibition decreases the ability of TEMs to
associate with blood vessels (Mazzieri R, Cancer Cell 2011;
19:512-526) and markedly decreases the proangiogenic activity of
this macrophage subset (De Palma M, Clin Cancer Res 2011;
17(16):5226-5232).
[0005] Cytotoxic chemotherapy, radiation therapy, and
anti-angiogenic treatments damage the tumor-associated vasculature
thus leading to a hypoxic tumor environment. The hypoxic tumor
environment leads to rebound tumor vascularization by activating an
angiogenic switch from the vascular endothelial growth factor
(VEGF)/VEGFR2 pathway to the ANG/TIE2 pathway in vascular
endothelial cells. The recruitment of pro-vasculogenic TEMs from
the bone marrow to these hypoxic tumor sites facilitates this
revascularization by the association of TEMs with endothelial cells
within the tumor microenvironment. TEMs and TIE2-expressing
endothelial cells are thus believed to play an important role in
the revascularization of tumors after these treatments, leading to
progression due to the growth of residual tumor cells (De Palma M,
et al. Trends Immunol 2007; 28:519-524).
[0006] TIE2 is also a mediator of osteoclast differentiation, and
TIE2 inhibition led to decreased osteolytic bone invasion and
decreased tumor growth in the 4T1 mouse breast cancer model (Dales
J P, et al. Int J Oncol 2003; 22:391-397). Beyond the physiologic
expression of TIE2 on endothelial, monocyte/macrophage, and
osteoclast cells of the tumor microenvironment, TIE2 has also been
demonstrated to be present on breast cancer cells. Tumor cell
expression of TIE2 was associated with an elevated risk of
metastatic disease and an independent predictor of prognosis on
multivariate analysis (Min Y, et al. Cancer Res 2010;
70:2918-2828).
[0007] Significantly, a subset of TIE2-expressing tissue
macrophages are located within specialized vascular structures
known as tumor microenvironment for metastases (TMEMs). Recent
observations have linked TIE2-expressing macrophages within TMEM
structures as being essential for extravasation of breast cancer
cells into the vascular circulation and subsequent dissemination to
distal metastatic sites (Condeelis J, Pollard J W. Cell 2006;
124:263-6; Ginter P S, et al. Cancer Res 2012; 72(24
Suppl):Abstract #P6-02-04). Thus inhibition of TIE2, and of the
macrophages within TMEM structures, may lead to a decrease in new
metastases.
[0008] TIE2-expressing tissue macrophages (TEMs) have recently been
demonstrated to play a role in breast cancer immunotolerance. TEMs
from breast tumors are able to suppress tumor-specific immune
responses. Specifically, suppressive functions of TEMs are
similarly driven by TIE2 and VEGFR kinase activity. TEMs isolated
from breast cancer tissue can function as antigen-presenting cells
that elicit only a weak proliferation of T cells. Blocking TIE2 and
VEGFR kinase activity induced TEMs to change their phenotype into
cells with features of myeloid dendritic cells with robust
antigen-presentation. Immunosuppressive activity of TEMs is also
associated with high CD86 surface expression and extensive
engagement of T regulatory cells in breast tumors. TIE2 and VEGFR
kinase activities were required to maintain high CD86 surface
expression levels and to convert T cells into immunosuppressive
regulatory cells (Ibberson M, et al. Clin Cancer Res 2013;
19:3439-3449).
[0009] The polyoma middle-T antigen (PyMT) syngeneic mouse breast
cancer model utilizes the mouse mammary tumor virus (MMTV)
promoter, a breast specific promoter, to express PyMT in mouse
breast tissue. In this model, PyMT breast cancer cells are
implanted in the mouse mammary fat pad, and these cancers
metastasize and lead to the death of the mouse. Unlike xenograft
models, the PyMT model utilizes fully immunocompetent mice.
Metastasis in this model is known to be modulated by TIE2
expressing macrophages within TMEM vascular structures. Thus, there
is a need for new treatments for diseases assocaited with TIE2.
SUMMARY OF THE INVENTION
[0010] Methods of the present invention find utility in the
inhibition TIE2 kinase. As a result of this inhibition the present
invention is useful in the treatment or prophylaxis against of
tumor growth, invasiveness, intravasation, dissemination,
metastasis, and tumor immunotolerance. In particular, the invention
relates to methods of using compositions of Formula I, described
below, as potent inhibitors of TIE2 for treating breast cancer
growth, invasiveness, intravasation, dissemination, metastasis, and
immunotolerance:
##STR00001##
wherein [0011] n is an integer from 0 to 7; [0012] X is the basic
radical of a pharmaceutically acceptable salt; [0013] provided that
when n is 0, the composition of Formula I is the parent free base.
In some embodiments, HX is absent whereby the structure of Formula
I is the parent free base.
[0014] The compositions of Formula I also find utility in other
cancers wherein TIE2 expression, either in the tumor cell or in the
tumor microenvironment, causes tumor progression by mechanisms
mediating primary tumor growth, primary tumor invasiveness, tumor
intravasation into the blood stream, tumor cell dissemination,
tumor metastases to distal tissues, or tumor immunotolerance.
Inhibition of TIE2 kinase by the composition of Formula I therefore
finds utility in the treatment of cancer by inhibiting processes
including primary tumor growth, primary tumor invasiveness, tumor
intravasation into the blood stream, tumor cell dissemination,
tumor metastases to distal tissues, or tumor immunotolerance.
[0015] TIE2 kinase has been shown to be causative of cancer
progression in gliomas (Liu et al, Oncotarget (2010) 1: 700-709;
Brunckhorst et al, Cancer Research (2010) 70: 7283-7293), melanomas
(Helfrich et al, Clin Cancer Res (2009) 15: 1384-1392), ovarian
cancer (Karlan et al, J. Clinical Oncology (2012) 30: 362-370),
colorectal cancer (Ahmad et al, Cancer (2001) 92: 1138-1143;
Hashizume et al, Cancer Research (2010) 70: 2213-2223),
hepatocellular carcinoma (Matsubara et al, Hepatology (2013) 57:
1416-1425; Mitsuhashi et al, Hepatology (2003) 37: 1105-1113;
Tanaka et al, J. Clin Invest (1999) 103: 341-345), and
hematological cancers (Muller et al, Leukemia Research (2002) 26:
163-168; Hou et al, Leukemia Research (2008) 32: 904-912).
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] FIG. 1 shows the inhibition of primary PyMT tumor growth
using the composition of Formula II, paclitaxel, or a combination
thereof.
[0017] FIG. 2 shows the inhibition of PyMT tumor macrophage
accumulation using the composition of Formula II, paclitaxel, or a
combination thereof.
[0018] FIG. 3 shows the inhibition of PyMT tumor TIE2-expressing
cell accumulation using the composition of Formula II, paclitaxel,
or a combination thereof.
[0019] FIG. 4 shows the inhibition of lung metastases in the PyMT
breast cancer model using the composition of Formula II,
paclitaxel, or a combination thereof.
[0020] FIG. 5 shows the inhibition of lung metastases in the PyMT
breast cancer model comparing the activities of paclitaxel and the
combination of paclitaxel and the composition of Formula II.
[0021] FIG. 6 shows the inhibition of lung metastases in the PyMT
breast cancer model using eribulin as a single agent or in
combination with the composition of Formula II.
[0022] FIG. 7 shows enzymatic and in vivo activities of eribulin as
a single agent or in combination with the composition of Formula
II.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0023] The term "basic radical of a pharmaceutically acceptable
salt" in compositions of Formula I include, without limitation,
water-soluble and water-insoluble salts, such as substituted or
unsubstituted benzenesulfonate, the acetate, amsonate
(4,4-diaminostilbene-2, 2-disulfonate), benzonate, bicarbonate,
bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium
edetate, camsylate, carbonate, chloride, citrate, clavulariate,
dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate,
gluceptate, gluconate, glutamate, glycollylarsanilate,
hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,
lactobionate, laurate, magnesium, malate, maleate, mandelate,
mesylate, methylbromide, methylnitrate, methylsulfate, mucate,
napsylate, nitrate, N-methylglucamine ammonium salt,
3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate
(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,
phosphate/diphosphate, picrate, polygalacturonate, propionate,
p-toluenesulfonate, salicylate, stearate, subacetate, succinate,
sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,
tosylate, triethiodide, and valerate salts. Specific examples of
the basic radicals include para-toluene sulfonate, triflate, and
methanesulfonate.
[0024] The term "salt` refers to pharmaceutically acceptable
salts
[0025] The term "pharmaceutically acceptable salt" also refers to a
salt of the compositions of the present invention having an acidic
functional group, such as a carboxylic acid functional group, and a
base.
[0026] The term "treating" with regard to a subject, refers to
improving at least one symptom of the subject's disorder. Treating
can be curing, improving, or at least partially ameliorating the
disorder.
[0027] The term "administer", "administering", or "administration"
as used in this disclosure refers to either directly administering
a composition or pharmaceutically acceptable salt of the compound
or a composition to a subject, or administering a prodrug
derivative or analog of the composition or pharmaceutically
acceptable salt of the compound or composition to the subject,
which can form an equivalent amount of active compound within the
subject's body.
[0028] An "effective amount," when used in connection with medical
uses is an amount that is effective for providing a measurable
treatment, prevention, or reduction in the rate of pathogenesis of
a disease of interest.
[0029] The present invention relates to methods of the treatment
(blocking) or prophylaxis against tumor growth, invasiveness,
intravasation, dissemination, metastasis, and tumor
immunotolerance. The method comprises administering to a patient in
need of treatment or reduction of prophylactic effects of these
conditions an effective amount of a composition of Formula I herein
described in a dosing regimen that regulates TIE2 inhibition.
[0030] The amount of composition described herein needed for
achieving a therapeutic effect may be determined empirically in
accordance with conventional procedures for the particular purpose.
Generally, for administering therapeutic agents (e.g. compositions
of Formulae I or II (and/or additional agents) described herein)
for therapeutic purposes, the therapeutic agents are given at a
pharmacologically effective dose. A "pharmacologically effective
amount," "pharmacologically effective dose," "therapeutically
effective amount," or "effective amount" refers to an amount
sufficient to produce the desired physiological effect or amount
capable of achieving the desired result, particularly for treating
the disorder or disease. An effective amount as used herein would
include an amount sufficient to, for example, delay the development
of a symptom of the disorder or disease, alter the course of a
symptom of the disorder or disease (e.g., slow the progression of a
symptom of the disease), reduce or eliminate one or more symptoms
or manifestations of the disorder or disease, and reverse a symptom
of a disorder or disease. For example, administration of
therapeutic agents to a patient suffering from cancer provides a
therapeutic benefit not only when the underlying condition is
eradicated or ameliorated, but also when the patient reports a
decrease in the severity or duration of the symptoms associated
with the disease, e.g., a decrease in tumor burden, a decrease in
circulating tumor cells, an increase in progression free survival.
Therapeutic benefit also includes halting or slowing the
progression of the underlying disease or disorder, regardless of
whether improvement is realized.
[0031] In one embodiment of the invention, the composition of
Formula I is
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt of Formula II which is a potent inhibitor of TIE2, the
receptor tyrosine kinase for angiopoietin ligands.
##STR00002##
[0032] The compositions of Formula I find utility in cancers
wherein TIE2 expression, either in the tumor cell or in the tumor
microenvironment, causes tumor progression by mechanisms mediating
primary tumor growth, primary tumor invasiveness, tumor
intravasation into the blood stream, tumor cell dissemination,
tumor metastases to distal tissues, or tumor immunotolerance.
Inhibition of TIE2 kinase by the composition of Formula I therefore
finds utility in the treatment of cancer by inhibiting processes
including primary tumor growth, primary tumor invasiveness, tumor
intravasation into the blood stream, tumor cell dissemination,
tumor metastases to distal tissues, or tumor immunotolerance.
[0033] Therapeutic concentrations of the compositions of Formula I
block cells within the tumor microenvironment known to cause tumor
growth, invasion, intravasation, dissemination, metastases, of
tumor induced immunotolerance. Such cell types within the tumor
microenvironment include TIE2-expressing monocytes, TIE2-expressing
macrophages, and TIE2-expressing endothelial cells.
[0034] Tumors responsive to angiopoietin/TIE2 signaling include but
are not limited to breast cancer, ovarian cancer, hepatocellular
carcinoma, gliomas, colorectal cancer, and hematological
malignancies.
[0035] In another embodiment, the composition of Formula I when the
HX is absent is the free base compound
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea having the structure:
##STR00003##
[0036] The composition of Formula I may be administered as a single
agent or in combination with other therapeutic agents known to
treat cancers. Such other therapeutic agents include radiation
therapy, anti-tubulin agents, DNA alkylating agents, DNA
synthesis-inhibiting agents, DNA intercalating agents,
anti-estrogen agents, anti-androgens, steroids, anti-EGFR agents,
kinase inhibitors, topoisomerase inhibitors, Histone Deacetylase
(HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents,
anti-angiogenic agents, proteasome inhibitors, thalidomide,
lenalidomide, antibody-drug-conjugates (ADCs), immunomodulating
agents, or cancer vaccines.
[0037] Effective amounts, toxicity, and therapeutic efficacy can be
determined by standard pharmaceutical procedures in cell cultures
or experimental animals, e.g., for determining the LD50 (the dose
lethal to about 50% of the population) and the ED50 (the dose
therapeutically effective in about 50% of the population). The
dosage can vary depending upon the dosage form employed and the
route of administration utilized. The dose ratio between toxic and
therapeutic effects is the therapeutic index and can be expressed
as the ratio LD50/ED50. In some embodiments, compositions and
methods that exhibit large therapeutic indices are preferred. A
therapeutically effective dose can be estimated initially from in
vitro assays, including, for example, cell culture assays. Also, a
dose can be formulated in animal models to achieve a circulating
plasma concentration range that includes the IC50 as determined in
cell culture, or in an appropriate animal model. Levels of the
described compositions in plasma can be measured, for example, by
high performance liquid chromatography. The effects of any
particular dosage can be monitored by a suitable bioassay. The
dosage can be determined by a physician and adjusted, as necessary,
to suit observed effects of the treatment.
[0038] In certain embodiments, the prophylactic effect will result
in a quantifiable change of at least about 10%, at least about 20%,
at least about 30%, at least about 50%, at least about 70%, or at
least about 90%. In some embodiments, the effect will result in a
quantifiable change of about 10%, about 20%, about 30%, about 50%,
about 70%, or even about 90% or more. Therapeutic benefit also
includes halting or slowing the progression of the underlying
disease or disorder, regardless of whether improvement is
realized.
[0039] When the compositions of Formulae I or II are used in
combination with other anti-cancer agents, the other anti-cancer
agent may be dosed independently of the dosing schedule of the
composition of Formulae I or II. The other anti-cancer agent may be
dosed at its previously established therapeutic dose and dosing
schedule, or its dose and dosing schedule may be modified to
optimize efficacy, safety or tolerability when used in combination
with the compositions of Formulae I or II.
[0040] Further, any compositions of Formulae I or II (and/or
additional agents) described herein can be administered to a
subject as a component of a composition that comprises a
pharmaceutically acceptable carrier or vehicle. Such compositions
can optionally comprise a suitable amount of a pharmaceutically
acceptable excipient so as to provide the form for proper
administration.
[0041] Pharmaceutical excipients can be liquids, such as water and
oils, including those of petroleum, animal, vegetable, or synthetic
origin, such as peanut oil, soybean oil, mineral oil, sesame oil
and the like. The pharmaceutical excipients can be, for example,
saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal
silica, urea and the like. In addition, auxiliary, stabilizing,
thickening, lubricating, and coloring agents can be used. In one
embodiment, the pharmaceutically acceptable excipients are sterile
when administered to a subject. Water is a useful excipient when
any agent described herein is administered intravenously. Saline
solutions and aqueous dextrose and glycerol solutions can also be
employed as liquid excipients, specifically for injectable
solutions. Suitable pharmaceutical excipients also include starch,
glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,
silica gel, sodium stearate, glycerol monostearate, talc, sodium
chloride, dried skim milk, glycerol, propylene, glycol, water,
ethanol and the like. Any agent described herein, if desired, can
also comprise minor amounts of wetting or emulsifying agents, or pH
buffering agents.
[0042] The compositions of Formula I may be used in combination
with other agents including chemotherapeutic agents, targeted
therapeutics, biological agents, or radiotherapy.
[0043] The compositions of Formula I may be used in combination
with chemotherapeutic agents including but not limited to
anti-tubulin agents (paclitaxel, paclitaxel protein-bound particles
for injectable suspension, eribulin, docetaxel, ixabepilone,
vincristine), vinorelbine, DNA-alkylating agents (including
cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide,
temozolomide), DNA intercalating agents (including doxorubicin,
pegylated liposomal doxorubicin, daunorubicin, idarubicin, and
epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine,
5-aza cytadine, gemcitabine and methotrexate.
[0044] The compositions of Formula I may be used in combination
with kinase inhibitors including but not limited to erlotinib,
gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEE011,
PD 0332991, crizotinib, cabozantinib, sunitinib, pazopanib,
sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib,
vemurafenib, dabrafenib, trametinib, idelalisib, and
quizartinib.
[0045] The compositions of Formula I may be used in combination
with anti-estrogen agents including but not limited to tamoxifen,
fulvestrant, anastrozole, letrozole, and exemestane.
[0046] The compositions of Formula I may be used in combination
with anti-androgen agents including but not limited to abiraterone
acetate, enzalutamide, nilutamide, bicalutamide, flutamide,
cyproterone acetate.
[0047] The compositions of Formula I may be used in combination
with steroid agents including but not limited to prednisone and
dexamethazone.
[0048] The compositions of Formula I may be used in combination
with topoisomerase I inhibitors including but not limited to
irinotecan, camptothecin, and topotecan.
[0049] The compositions of Formula I may be used in combination
with topoisomerase II inhibitors including but not limited to
etoposide, etoposide phosphate, and mitoxantrone.
[0050] The compositions of Formula I may be used in combination
with Histone Deacetylase (HDAC) inhibitors including but not
limited to vorinostat, romidepsin, panobinostat, valproic acid, and
belinostat.
[0051] The compositions of Formula I may be used in combination
with DNA methylation inhibitors including but not limited to DZNep
and 5-aza-2'-deoxycytidine.
[0052] The compositions of Formula I may be used in combination
with proteasome inhibitors including but not limited to bortezomib
and carfilzomib.
[0053] The compositions of Formula I may be used in combination
with thalidomide, lenalidomide and pomalidomide.
[0054] The compositions of Formula I may be used in combination
with biological agents including but not limited to trastuzumab,
ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab,
anti-PD-1 agents including labrolizumab and nivolumab, anti-PD-L1
agents including MPDL3280A, anti-angiogenic agents including
bevacizumab and aflibercept, and antibody-drug-conjugates (ADCs)
including brentuximab vedotin and trastuzumab emtansine.
[0055] The compositions of Formula I may be used in combination
with radiotherapy.
[0056] The compositions of Formula I may be used in combination
with therapeutic vaccines including but not limited to
sipuleucel-T.
[0057] In some embodiments, the composition of Formula I or Formula
II can be used in combination with one or more of the other agents
described herein.
Methods for Blocking Primary Breast Tumor Growth and
Invasiveness:
[0058] A first aspect of the invention relates to a method of
blocking primary breast tumor growth and invasiveness which
comprises administering to a patient in need thereof an effective
amount of a composition of Formula I in a dosing regimen sufficient
to block TIE2 kinase in the tumor microenvironment.
[0059] In one embodiment of this aspect of the invention, the
dosing regimen of the composition of Formula I is a daily dosing
administration.
[0060] In another embodiment of this aspect of the invention the
dosing regimen of the composition of Formula I is a daily dosing
administration. The intermittent non-daily dosing regimen may
include, without limitation, alternate daily dosing, every
third-day dosing, twice weekly dosing, or once weekly dosing.
[0061] In another embodiment of this aspect of the invention, a
suitable dosing regimen of the composition of Formula I includes
administration twice weekly, once weekly, or alternate weekly.
[0062] In another embodiment of this aspect of the invention, the
dosing regimen of the composition of Formula I is twice weekly or
once weekly.
[0063] In other embodiments of this aspect of the invention, the
dosing regimen of the composition of Formula I is administration
twice weekly.
[0064] In yet another embodiment of the invention, the method of
blocking primary breast tumor growth and invasiveness comprises
administering a composition of Formula I in a dosing regimen
sufficient to block TIE2 kinase in the tumor microenvironment in
combination with one or more agents taken from an anti-tubulin
agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a
DNA intercalating agent, an anti-estrogen agent, an anti-HER2
agent, a kinase inhibitor or an anti-angiogenic agent.
[0065] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering a composition of Formula I in combination
with paclitaxel.
[0066] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering a composition of Formula I in combination
with paclitaxel protein-bound particles for injectable
suspension.
[0067] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering a composition of Formula I in combination
with docetaxel.
[0068] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with eribulin.
[0069] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with ixabepilone.
[0070] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with vinorelbine.
[0071] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with capecitabine.
[0072] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with gemcitabine.
[0073] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with 5-fluorouracil.
[0074] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with methotrexate.
[0075] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with cyclophosphamide.
[0076] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with cisplatin.
[0077] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with carboplatin.
[0078] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering of a composition of Formula I in
combination with doxorubicin.
[0079] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering of a composition of Formula I in
combination with pegylated liposomal doxorubicin.
[0080] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering of a compositionof Formula I in combination
with epirubicin.
[0081] In yet another embodiment of this aspect of the invention,
the method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with tamoxifen.
[0082] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with fulvestrant.
[0083] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with anastrozole.
[0084] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with letrozole.
[0085] \In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with exemestane.
[0086] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with trastuzumab.
[0087] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with ado-trastuzumab emtansine.
[0088] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering a composition of Formula I in combination
with pertuzumab.
[0089] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with lapatinib.
[0090] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with everolimus.
[0091] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with temsirolimus.
[0092] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with the CDK4/6 inhibitor LY2835219.
[0093] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with the CDK4/6 inhibitor LEE011.
[0094] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with the CDK4/6 inhibitor PD 0332991.
[0095] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with bevacizumab.
[0096] Another aspect of the invention relates to a method of
blocking primary breast tumor growth and invasiveness which
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment,
wherein the composition of Formula I is administered in an
intermittent non-daily dosing regimen. In some embodiments, the
intermittent non-daily dosing regimen, includes alternate daily
dosing, every third daily dosing, twice weekly dosing, and once
weekly dosing.
[0097] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment,
wherein the composition of Formula I is administered twice weekly,
once weekly, or alternate weekly.
[0098] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment,
wherein the composition of Formula I is administered twice weekly
or once weekly.
[0099] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment,
wherein the composition of Formula I is administered twice
weekly.
[0100] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment
wherein the composition of Formula I is administered in combination
with one or more agents taken from an anti-tubulin agent, a DNA
alkylating agent, a DNA synthesis-inhibiting agent, a DNA
intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a
kinase inhibitor or an anti-angiogenic agent.
[0101] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering a composition of Formula I in combination
with paclitaxel.
[0102] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering a composition of Formula I in combination
with paclitaxel protein-bound particles for injectable
suspension.
[0103] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering a composition of Formula I in combination
with docetaxel.
[0104] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with eribulin.
[0105] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with ixabepilone.
[0106] In another embodiment of this aspect of the invention, a
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with vinorelbine.
[0107] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with capecitabine.
[0108] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with gemcitabine.
[0109] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with 5-fluorouracil.
[0110] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with methotrexate.
[0111] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with cyclophosphamide.
[0112] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with cisplatin.
[0113] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with carboplatin.
[0114] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering of a composition of Formula I in
combination with doxorubicin.
[0115] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering of a composition of Formula I in
combination with pegylated liposomal doxorubicin.
[0116] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering of a composition of Formula I in
combination with epirubicin.
[0117] In yet another embodiment of this aspect of the invention,
the method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with tamoxifen.
[0118] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with fulvestrant.
[0119] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with anastrozole.
[0120] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with letrozole.
[0121] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with exemestane.
[0122] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with trastuzumab.
[0123] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with ado-trastuzumab emtansine.
[0124] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises administering a composition of Formula I in combination
with pertuzumab.
[0125] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
lapatinib.
[0126] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
everolimus.
[0127] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
temsirolimus.
[0128] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor LY2835219.
[0129] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor LEE011.
[0130] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor PD 0332991.
[0131] In another embodiment of this aspect of the invention, the
method of blocking primary breast tumor growth and invasiveness
comprises the administration of a composition of Formula I in
combination with bevacizumab.
Methods for Blocking Breast Cancer Intravasation, Dissemination and
Metastasis:
[0132] In yet another aspect of the invention a method of blocking
breast cancer intravasation, dissemination and metastasis is
provided which comprises administering to patient in need thereof
an effective amount of a composition of Formula I sufficient to
block TIE2 kinase in the tumor microenvironment.
[0133] In one embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering to patient in need thereof an
effective amount of a composition of Formula I in a dosing regimen
sufficient to block TIE2 kinase in the tumor microenvironment.
[0134] In another embodiment of this aspect of the invention, the
dosing regimen sufficient to block breast cancer intravasation,
dissemination and metastasis comprises the daily administration of
a composition of Formula I.
[0135] In another embodiment of this aspect of the invention, the
dosing regimen of a composition of Formula I is administered in an
intermittent non-daily dosing manner, including alternate daily
dosing, every third daily dosing, twice weekly dosing, or once
weekly dosing.
[0136] In another embodiment of this aspect of the invention, the
dosing regimen of a composition of Formula I is administered twice
weekly, once weekly, or alternate weekly.
[0137] In another embodiment of this aspect of the invention, the
dosing regimen of a composition of Formula I is twice weekly or
once weekly administration.
[0138] In another embodiment of this aspect of the invention, the
dosing regimen a composition of Formula I is administered twice
weekly.
[0139] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering to a patient in need thereof an
effective amount of a composition of Formula I in a dosing regimen
sufficient to block TIE2 kinase in the tumor microenvironment in
combination with one or more agents taken from an anti-tubulin
agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a
DNA intercalating agent, an anti-estrogen agent, an anti-HER2
agent, a kinase inhibitor or an anti-angiogenic agent.
[0140] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with paclitaxel.
[0141] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with paclitaxel protein-boundn particles for injectable
suspension.
[0142] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with docetaxel.
[0143] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with eribulin.
[0144] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises adminstering a composition of Formula I in
combination with ixabepilone.
[0145] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises adminstering a composition of Formula I in
combination with vinorelbine.
[0146] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with capecitabine.
[0147] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with gemcitabine.
[0148] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with 5-fluorouracil.
[0149] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with methotrexate.
[0150] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with cyclophosphamide.
[0151] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with cisplatin.
[0152] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with carboplatin.
[0153] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with doxorubicin.
[0154] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with epirubicin.
[0155] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with tamoxifen.
[0156] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with fulvestrant.
[0157] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with anastrozole.
[0158] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with letrozole.
[0159] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with exemestane.
[0160] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with trastuzumab.
[0161] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with ado-trastuzumab emtansine.
[0162] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with pertuzumab.
[0163] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with lapatinib.
[0164] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with everolimus.
[0165] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with temsirolimus.
[0166] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with the CDK4/6 inhibitor LY2835219.
[0167] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with the CDK4/6 inhibitor LEE011.
[0168] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with the CDK4/6 inhibitor PD 0332991.
[0169] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with bevacizumab.
[0170] In another aspect of the invention, a method of blocking
breast cancer intravasation, dissemination and metastasis comprises
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in the tumor microenvironment, wherein the dosing
regimen of the composition of Formula I is administered as
intermittent non-daily dosing. In some embodiments, the alternate
daily dosing includes every third daily dosing, twice weekly
dosing, or once weekly dosing.
[0171] In one embodiment of this aspect of the invention, a method
of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in the tumor
microenvironment, with the dosing regimen of the composition of
Formula I being administered twice weekly, once weekly, or
alternate weekly.
[0172] In another embodiment of this aspect of the invention, a
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in the tumor
microenvironment, with the dosing regimen of the composition of
Formula I being administered twice weekly or once weekly.
[0173] In another embodiment of this aspect of the invention, a
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in the tumor
microenvironment, with the dosing regimen of the composition of
Formula I being administered twice weekly.
[0174] In another embodiment of this aspect of the invention, a
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in the tumor
microenvironment administered in combination with one or more
agents taken from an anti-tubulin agent, a DNA alkylating agent, a
DNA synthesis-inhibiting agent, a DNA intercalating agent, an
anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an
anti-angiogenic agent.
[0175] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with paclitaxel.
[0176] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with paclitaxel protein-bound particles for injectable
suspension.
[0177] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with docetaxel.
[0178] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with eribulin.
[0179] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with ixabepilone.
[0180] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with vinorelbine.
[0181] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with capecitabine.
[0182] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with gemcitabine.
[0183] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with 5-fluorouracil.
[0184] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with methotrexate.
[0185] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with cyclophosphamide.
[0186] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with cisplatin.
[0187] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with carboplatin.
[0188] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering of a composition of Formula I in
combination with doxorubicin.
[0189] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering of a composition of Formula I in
combination with pegylated liposomal doxorubicin.
[0190] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering of a composition of Formula I in
combination with epirubicin.
[0191] In yet another embodiment of this aspect of the invention,
the method of blocking breast cancer intravasation, dissemination
and metastasis comprises the administration of a composition of
Formula I in combination with tamoxifen.
[0192] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with fulvestrant.
[0193] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with anastrozole.
[0194] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with letrozole.
[0195] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with exemestane.
[0196] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with trastuzumab.
[0197] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with ado-trastuzumab emtansine.
[0198] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises administering a composition of Formula I in
combination with pertuzumab.
[0199] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in tumor
microenvironment TIE2-expressing macrophages administered in
combination with lapatinib.
[0200] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in tumor
microenvironment TIE2-expressing macrophages administered in
combination with everolimus.
[0201] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in tumor
microenvironment TIE2-expressing macrophages administered in
combination with temsirolimus.
[0202] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in tumor
microenvironment TIE2-expressing macrophages administered in
combination with the CDK4/6 inhibitor LY2835219.
[0203] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in tumor
microenvironment TIE2-expressing macrophages administered in
combination with the CDK4/6 inhibitor LEE011.
[0204] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in tumor
microenvironment TIE2-expressing macrophages administered in
combination with the CDK4/6 inhibitor PD 0332991.
[0205] In another embodiment of this aspect of the invention, the
method of blocking breast cancer intravasation, dissemination and
metastasis comprises the administration of a composition of Formula
I in combination with bevacizumab.
Methods for Blocking Breast Cancer Immunotolerance:
[0206] Another aspect of the invention relates to a method of
blocking breast cancer immunotolerance. The method comprises
administering to a patient in need thereof an effective amount of a
composition of Formula I. In one embodiment, the dosing regimen of
the salt is sufficient to block TIE2 kinase in the tumor
microenvironment that mediates immunotolerance.
[0207] In one embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering to a patient in need thereof an effective amount of a
composition of Formula I in a dosing regimen sufficient to block
TIE2 kinase in the tumor microenvironment that mediates
immunotolerance.
[0208] In one embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I daily.
[0209] In another embodiment of this aspect of the invention, the
composition of Formula I is administered in an intermittent
non-daily manner. In some embodiments, the intermittent non-daily
manner includes alternate daily dosing, every third daily dosing,
twice weekly dosing, or once weekly dosing.
[0210] In another embodiment of this aspect of the invention,
administration of the composition of Formula I is twice weekly,
once weekly, or alternate weekly.
[0211] In another embodiment of this aspect of the invention, the
composition of Formula I is administered twice weekly or once
weekly.
[0212] In another embodiment of this aspect of the invention, the
composition of Formula I is administered twice weekly.
[0213] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering to a patient in need thereof an effective amount of a
composition of Formula I in a dosing regimen sufficient to block
TIE2 kinase in the tumor microenvironment in combination with one
or more agents taken from an anti-tubulin agent, a DNA alkylating
agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent,
an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an
anti-angiogenic agent, or an immunomodulating agent.
[0214] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
paclitaxel.
[0215] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
paclitaxel protein-bound particles for injectable suspension.
[0216] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
docetaxel.
[0217] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
eribulin.
[0218] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
ixabepilone.
[0219] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
vinorelbine.
[0220] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
capecitabine.
[0221] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
gemcitabine.
[0222] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
5-fluorouracil.
[0223] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
5-methotrexate.
[0224] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
cyclophosphamide.
[0225] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
cisplatin.
[0226] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
carboplatin.
[0227] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering of a composition of Formula I in combination with
doxorubicin.
[0228] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering of a composition of Formula I in combination with
pegylated liposomal doxorubicin.
[0229] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering of a composition of Formula I in combination with
epirubicin.
[0230] In yet another embodiment of this aspect of the invention,
the method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
tamoxifen.
[0231] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
fulvestrant.
[0232] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
anastrozole.
[0233] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
letrozole.
[0234] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
exemestane.
[0235] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
trastuzumab.
[0236] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
ado-trastuzumab emtansine.
[0237] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
pertuzumab.
[0238] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with lapatinib.
[0239] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with everolimus.
[0240] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with temsirolimus.
[0241] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with the CDK4/6 inhibitor
LY2835219.
[0242] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with the CDK4/6 inhibitor
LEE011.
[0243] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with the CDK4/6 inhibitor
PD 0332991.
[0244] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
bevacizumab.
[0245] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with an
anti-CTLA-4 agent.
[0246] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
ipilimumab.
[0247] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with an
anti-PD-1 agent.
[0248] In another embodiment of this aspect of the invention, a
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
lambrolizumab.
[0249] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with an
anti-PD L-1 agent.
[0250] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
MPDL3280A.
Methods for Blocking Breast Cancer Immunotolerance:
[0251] In another aspect of the invention, a method of blocking
breast cancer immunotolerance comprises the administration of a
composition of Formula I at doses sufficient to block TIE2 kinase
in the tumor microenvironment, wherein the dosing regimen of the
composition of Formula I is administered in an intermittent
non-daily dosing manner, including alternate daily dosing, every
third daily dosing, twice weekly dosing, or once weekly dosing.
[0252] In one embodiment of this aspect of the invention, a method
of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in the tumor microenvironment, wherein the
composition of Formula I is administered twice weekly, once weekly,
or alternate weekly.
[0253] In another embodiment of this aspect of the invention, a
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in the tumor microenvironment, wherein the
composition of Formula I is administered twice weekly or once
weekly.
[0254] In another embodiment of this aspect of the invention, a
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in the tumor microenvironment, wherein the
composition of Formula I is administered twice weekly.
[0255] In another embodiment of this aspect of the invention, a
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in the tumor microenvironment administered in
combination with one or more agents taken from an anti-tubulin
agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a
DNA intercalating agent, an anti-estrogen agent, an anti-HER2
agent, a kinase inhibitor, an anti-angiogenic agent, or an
immunomodulating agent.
[0256] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
paclitaxel.
[0257] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
paclitaxel protein-bound particles for injectable suspension.
[0258] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
docetaxel.
[0259] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
eribulin.
[0260] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
ixabepilone.
[0261] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
vinorelbine.
[0262] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
capecitabine.
[0263] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
gemcitabine.
[0264] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
5-fluorouracil.
[0265] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
methotrexate.
[0266] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
cyclophosphamide.
[0267] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
cisplatin.
[0268] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
carboplatin.
[0269] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering of a composition of Formula I in combination with
doxorubicin.
[0270] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering of a composition of Formula I in combination with
pegylated liposomal doxorubicin.
[0271] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering of a composition of Formula I in combination with
epirubicin.
[0272] In yet another embodiment of this aspect of the invention,
the method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
tamoxifen.
[0273] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
fulvestrant.
[0274] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
anastrozole.
[0275] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
letrozole.
[0276] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
exemestane.
[0277] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
trastuzumab.
[0278] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a a composition of Formula I in combination with
ado-trastuzumab emtansine.
[0279] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
pertuzumab.
[0280] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a a composition of Formula I at doses sufficient
to block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with lapatinib.
[0281] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with everolimus.
[0282] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with temsirolimus.
[0283] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with the CDK4/6 inhibitor
LY2835219.
[0284] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with the CDK4/6 inhibitor
LEE011.
[0285] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in tumor microenvironment TIE2-expressing
macrophages administered in combination with the CDK4/6 inhibitor
PD 0332991.
[0286] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises the
administration of a composition of Formula I in combination with
bevacizumab.
[0287] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with an
anti-CTLA-4 agent.
[0288] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
ipilimumab.
[0289] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with an
anti-PD-1 agent.
[0290] In another embodiment of this aspect of the invention, a
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
lambrolizumab.
[0291] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with an
anti-PD L-1 agent.
[0292] In another embodiment of this aspect of the invention, the
method of blocking breast cancer immunotolerance comprises
administering a composition of Formula I in combination with
MPDL3280A.
Methods for Increasing Overall Survival in Breast Cancer
Patients:
[0293] Another aspect of the invention relates to a method of
increasing overall survival in breast cancer patients compriseing
administering to a patient in need thereof an effective amount of a
composition of Formula I. In one embodiment, the dosing regimen is
sufficient to block TIE2 kinase in the tumor microenvironment.
[0294] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises a dosing regimen wherein the composition of Formula I
administered daily.
[0295] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises a composition of Formula I in a dosing regimen
administered in an intermittent non-daily manner, including
alternate daily dosing, every third daily dosing, twice weekly
dosing, or once weekly dosing.
[0296] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises a composition of Formula I in a dosing regimen
administered twice weekly, once weekly, or alternate weekly.
[0297] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients,
the dosing regimen of a composition of Formula I is administered
twice weekly or once weekly.
[0298] In another embodiment of this aspect of the invention, the
dosing regimen of a composition of Formula I is administered only
twice weekly.
[0299] Another embodiment of this aspect of the invention relates
to the method of increasing overall survival in breast cancer
patients which comprises administering a composition of Formula I
in a dosing regimen sufficient to block TIE2 kinase in the tumor
microenvironment in combination with one or more agents taken from
an anti-tubulin agent, a DNA alkylating agent, a DNA
synthesis-inhibiting agent, a DNA intercalating agent, an
anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an
anti-angiogenic agent, or an immunomodulating agent.
[0300] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with paclitaxel.
[0301] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with paclitaxel protein-bound particles for injectable
suspension.
[0302] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with docetaxel.
[0303] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with eribulin.
[0304] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with ixabepilone.
[0305] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with vinorelbine.
[0306] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with capecitabine.
[0307] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with gemcitabine.
[0308] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with 5-fluorouracil.
[0309] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with methotrexate.
[0310] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with cyclophosphamide.
[0311] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with cisplatin.
[0312] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with carboplatin.
[0313] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering of a composition of Formula I in
combination with doxorubicin.
[0314] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering of a composition of Formula I in
combination with pegylated liposomal doxorubicin.
[0315] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering of a composition of Formula I in
combination with epirubicin.
[0316] In yet another embodiment of this aspect of the invention,
the method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with tamoxifen.
[0317] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with fulvestrant.
[0318] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with anastrozole.
[0319] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with letrozole.
[0320] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with exemestane.
[0321] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with trastuzumab.
[0322] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with ado-trastuzumab emtansine.
[0323] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with pertuzumab.
[0324] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
lapatinib.
[0325] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
everolimus.
[0326] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
temsirolimus.
[0327] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor LY2835219.
[0328] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor LEE011.
[0329] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor PD 0332991.
[0330] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with bevacizumab.
[0331] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with an anti-CTLA-4 agent.
[0332] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with ipilimumab.
[0333] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with an anti-PD-1 agent.
[0334] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with lambrolizumab.
[0335] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with an anti-anti-PD L-1 agent.
[0336] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with MPDL3280A.
Methods for Increasing Overall Survival in Breast Cancer
Patients:
[0337] In another aspect of the invention, a method of increasing
overall survival in breast cancer patients comprises the
administration of a composition of Formula I at doses sufficient to
block TIE2 kinase in the tumor microenvironment, wherein a dosing
regimen of the composition of Formula I is intermittent non-daily
dosing administration, including alternate daily dosing, every
third daily dosing, twice weekly dosing, or once weekly dosing.
[0338] In one embodiment of this aspect of the invention, a method
of increasing overall survival in breast cancer patients comprises
the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment,
wherein a dosing regimen of the composition of Formula I is twice
weekly, once weekly, or alternate weekly, administration.
[0339] In another embodiment of this aspect of the invention, a
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment,
wherein a dosing regimen of the composition of Formula I is twice
weekly or once weekly administration.
[0340] In another embodiment of this aspect of the invention, a
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment, with
a dosing regimen of the composition of Formula I is twice weekly
administration.
[0341] In another embodiment of this aspect of the invention, a
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in the tumor microenvironment
administered in combination with one or more agents taken from an
anti-tubulin agent, a DNA alkylating agent, a DNA
synthesis-inhibiting agent, a DNA intercalating agent, an
anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an
anti-angiogenic agent, or an immunomodulating agent.
[0342] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
administering a composition of Formula I in combination with
paclitaxel.
[0343] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with paclitaxel protein-bound particles for injectable
suspension.
[0344] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with docetaxel.
[0345] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with eribulin.
[0346] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with ixabepilone.
[0347] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with vinorelbine.
[0348] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with capecitabine.
[0349] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with gemcitabine.
[0350] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with 5-fluorouracil.
[0351] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with methotrexate.
[0352] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with cyclophosphamide.
[0353] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with cisplatin.
[0354] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with carboplatin.
[0355] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering of a composition of Formula I in
combination with doxorubicin.
[0356] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering of a composition of Formula I in
combination with pegylated liposomal doxorubicin.
[0357] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering of a composition of Formula I in
combination with epirubicin.
[0358] In yet another embodiment of this aspect of the invention,
the method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with tamoxifen.
[0359] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with fulvestrant.
[0360] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with anastrozole.
[0361] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with letrozole.
[0362] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with exemestane.
[0363] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with trastuzumab.
[0364] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with ado-trastuzumab emtansine.
[0365] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with pertuzumab.
[0366] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
lapatinib.
[0367] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
everolimus.
[0368] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with
temsirolimus.
[0369] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor LY2835219.
[0370] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor LEE011.
[0371] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I at doses
sufficient to block TIE2 kinase in tumor microenvironment
TIE2-expressing macrophages administered in combination with the
CDK4/6 inhibitor PD 0332991.
[0372] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises the administration of a composition of Formula I in
combination with bevacizumab.
[0373] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with an anti-CTLA-4 agent.
[0374] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with ipilimumab.
[0375] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with an anti-PD-1 agent.
[0376] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with lambrolizumab.
[0377] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with an anti-anti-PD L-1 agent.
[0378] In another embodiment of this aspect of the invention, the
method of increasing overall survival in breast cancer patients
comprises administering a composition of Formula I in combination
with MPDL3280A.
Methods for Treating Breast Cancer Patients in a Neoadjuvant
Setting Prior to Surgical Resection of Tumor:
[0379] Another aspect of the invention relates to a method of
treating breast cancer patients in a neoadjuvant setting prior to
surgical resection of tumor, comprising administering to a patient
in need thereof and effective amount of a composition of Formula I,
a dosing regimen of the composition of Formula I is sufficient to
block TIE2 kinase in the tumor microenvironment.
[0380] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering to a
patient in need thereof an effective amount of a composition of
Formula I in a dosing regimen sufficient to block TIE2 kinase in
the tumor microenvironment.
[0381] In another embodiment of this aspect of the invention, a
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection comprises the administration of a
composition of Formula I at doses sufficient to block TIE2 kinase
in the tumor microenvironment, with a dosing regimen of the
composition of Formula I being administered daily.
[0382] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection comprises administering to a patient in
need thereof an effective amount of a composition of Formula I in a
dosing regimen sufficient to block TIE2 kinase in the tumor
microenvironment, with a dosing regimen of the composition of
Formula I administered in an intermittent non-daily manner,
including alternate daily dosing, every third daily dosing, twice
weekly dosing, or once weekly dosing.
[0383] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection comprises administering to a patient in
need thereof an effective amount of a composition of Formula I in a
dosing regimen administered twice weekly, once weekly, or alternate
weekly.
[0384] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection comprises the administration of a
composition of Formula I in a dosing regimen administered twice
weekly or once weekly.
[0385] In another embodiment of this aspect of the invention, the
dosing regimen of a composition of Formula I is administered twice
weekly.
[0386] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection comprises the administration of a
composition of Formula I in dosing regimen sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages in
combination with one or more agents taken from an anti-tubulin
agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a
DNA intercalating agent, an anti-estrogen agent, an anti-HER2
agent, a kinase inhibitor, an anti-angiogenic agent, or an
immunomodulating agent.
[0387] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with paclitaxel.
[0388] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with paclitaxel
protein-bound particles for injectable suspension.
[0389] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with docetaxel.
[0390] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with eribulin.
[0391] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with ixabepilone.
[0392] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with vinorelbine.
[0393] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with capecitabine.
[0394] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with gemcitabine.
[0395] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with
5-fluorouracil.
[0396] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with methotrexate.
[0397] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with
cyclophosphamide.
[0398] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with cisplatin.
[0399] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with carboplatin.
[0400] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering of a
composition of Formula I in combination with doxorubicin.
[0401] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering of a
composition of Formula I in combination with pegylated liposomal
doxorubicin.
[0402] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering of a
composition of Formula I in combination with epirubicin.
[0403] In yet another embodiment of this aspect of the invention,
the method of treating breast cancer patients in a neoadjuvant
setting prior to surgical resection of tumor comprises the
administration of a composition of Formula I in combination with
tamoxifen.
[0404] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with fulvestrant.
[0405] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with anastrozole.
[0406] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with letrozole.
[0407] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with exemestane.
[0408] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with trastuzumab.
[0409] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with ado-trastuzumab
emtansine.
[0410] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with pertuzumab.
[0411] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with lapatinib.
[0412] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with everolimus.
[0413] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with temsirolimus.
[0414] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with the CDK4/6 inhibitor
LY2835219.
[0415] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with the CDK4/6 inhibitor LEE011.
[0416] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with the CDK4/6 inhibitor PD
0332991.
[0417] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with bevacizumab.
[0418] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with an anti-CTLA-4
agent.
[0419] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with ipilimumab.
[0420] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with an anti-PD-1
agent.
[0421] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with lambrolizumab.
[0422] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with an anti-anti-PD L-1
agent.
[0423] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with MPDL3280A.
Methods for Treating Breast Cancer Patients in a Neoadjuvant
Setting Prior to Surgical Resection:
[0424] In another aspect of the invention, a method of treating
breast cancer patients in a neoadjuvant setting prior to surgical
resection comprises the administration of a composition of Formula
I at doses sufficient to block TIE2 kinase in the tumor
microenvironment, with a dosing regimen of the composition of
Formula I administered as intermittent non-daily dosing, including
alternate daily dosing, every third daily dosing, twice weekly
dosing, or once weekly dosing.
[0425] In one embodiment of this aspect of the invention, a method
of treating breast cancer patients in a neoadjuvant setting prior
to surgical resection comprises the administration of a composition
of Formula I at doses sufficient to block TIE2 kinase in the tumor
microenvironment, with a dosing regimen of the composition of
Formula I administered twice weekly, once weekly, or alternate
weekly.
[0426] In another embodiment of this aspect of the invention, a
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection comprises the administration of a
composition of Formula I at doses sufficient to block TIE2 kinase
in the tumor microenvironment, with a dosing regimen of the
composition of Formula I administered twice weekly or once
weekly.
[0427] In another embodiment of this aspect of the invention, a
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection comprises the administration of a
composition of Formula I at doses sufficient to block TIE2 kinase
in the tumor microenvironment, with a dosing regimen of the
composition of Formula I administered twice weekly.
[0428] In another embodiment of this aspect of the invention, a
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection comprises the administration of a
composition of Formula I at doses sufficient to block TIE2 kinase
in the tumor microenvironment administered in combination with one
or more
[0429] agents taken from an anti-tubulin agent, a DNA alkylating
agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent,
an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an
anti-angiogenic agent, or an immunomodulating agent.
[0430] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with paclitaxel.
[0431] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with paclitaxel
protein-bound particles for injectable suspension.
[0432] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with docetaxel.
[0433] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with eribulin.
[0434] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with ixabepilone.
[0435] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with vinorelbine.
[0436] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with capecitabine.
[0437] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with gemcitabine.
[0438] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with
5-fluorouracil.
[0439] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with
5-methotrexate.
[0440] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with
cyclophosphamide.
[0441] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with cisplatin.
[0442] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with carboplatin.
[0443] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering of a
composition of Formula I in combination with doxorubicin.
[0444] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering of a
composition of Formula I in combination with pegylated liposomal
doxorubicin.
[0445] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering of a
composition of Formula I in combination with epirubicin.
[0446] In yet another embodiment of this aspect of the invention,
the method of treating breast cancer patients in a neoadjuvant
setting prior to surgical resection of tumor comprises the
administration of a composition of Formula I in combination with
tamoxifen.
[0447] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with fulvestrant.
[0448] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with anastrozole.
[0449] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with letrozole.
[0450] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with exemestane.
[0451] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with trastuzumab.
[0452] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with ado-trastuzumab
emtansine.
[0453] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with pertuzumab.
[0454] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with lapatinib.
[0455] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with everolimus.
[0456] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with temsirolimus.
[0457] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with the CDK4/6 inhibitor
LY2835219.
[0458] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with the CDK4/6 inhibitor LEE011.
[0459] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I at doses sufficient to block TIE2
kinase in tumor microenvironment TIE2-expressing macrophages
administered in combination with the CDK4/6 inhibitor PD
0332991.
[0460] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises the administration
of a composition of Formula I in combination with bevacizumab.
[0461] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with an anti-CTLA-4
agent.
[0462] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with ipilimumab.
[0463] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with an anti-PD-1
agent.
[0464] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with lambrolizumab.
[0465] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with an anti-anti-PD L-1
agent.
[0466] In another embodiment of this aspect of the invention, the
method of treating breast cancer patients in a neoadjuvant setting
prior to surgical resection of tumor comprises administering a
composition of Formula I in combination with MPDL3280A.
[0467] Another aspect of the invention relates to a method of
treating ovarian cancer as TIE2 pathway signaling has been shown to
contribute to ovarian cancer progression (Karlan et al, J. Clinical
Oncology (2012) 30: 362-370). The method comprises administering to
a patient in need thereof an effective amount of a composition of
Formula I in a dosing regimen sufficient to block TIE2 kinase in
the tumor microenvironment. In one embodiment of this aspect of the
invention, a composition of Formula I is administered as a single
agent.
[0468] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
paclitaxel+carboplatin, doxetaxel+carboplatin,
paclitaxel+cisplatin, or other taxane+platinum drug regimens.
[0469] Another aspect of the invention relates to a method of
treating hepatocellular carcinoma as TIE2 pathway signaling has
been shown to contribute to hepatocellular cancer progression and
as a diagnostic marker (Matsubara et al, Hepatology (2013) 57:
1416-1425; Mitsuhashi et al, Hepatology (2003) 37: 1105-1113;
Tanaka et al, J. Clin Invest (1999) 103: 341-345). The method
comprises administering to a patient in need thereof an effective
amount of a composition of Formula I in a dosing regimen sufficient
to block TIE2 kinase in the tumor microenvironment.
[0470] In one embodiment of this aspect of the invention, a
composition of Formula I is administered as a single agent.
[0471] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with a
kinase inhibitor including sorafenib, crizotinib, cabozantinib,
sunitinib, pazopanib, sorafenib, regorafenib, or axitinib.
[0472] Another aspect of the invention relates to a method of
treating glioma as TIE2 pathway signaling has been shown to
contribute to glioma cancer progression (Liu et al, Oncotarget
(2010) 1: 700-709; Brunckhorst et al, Cancer Research (2010) 70:
7283-7293). The method comprises administering to a patient in need
thereof an effective amount of a composition of Formula I in a
dosing regimen sufficient to block TIE2 kinase in the tumor
microenvironment.
[0473] In one embodiment of this aspect of the invention, a
composition of Formula I is administered as a single agent.
[0474] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
radiotherapy.
[0475] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
temozolomide therapy.
[0476] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
radiotherapy and temozolomide therapy.
[0477] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
bevacizumab therapy.
[0478] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
radiotherapy and bevacizumab therapy.
[0479] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
temozolomide therapy and bevacizumab therapy.
[0480] Another aspect of the invention relates to a method of
treating melanoma as TIE2 pathway signaling has been shown to
contribute to melanoma progression (Helfrich et al, Clin Cancer Res
(2009) 15: 1384-1392; Peinado et al, Nature Medicine (2012) 18:
883-891). The method comprises administering to a patient in need
thereof an effective amount of a composition of Formula I in a
dosing regimen sufficient to block TIE2 kinase in the tumor
microenvironment.
[0481] In one embodiment of this aspect of the invention, a
composition of Formula I is administered as a single agent.
[0482] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
vemurafenib.
[0483] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
dabrafenib.
[0484] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
dabrafenib and trametinib.
[0485] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
temozolomide.
[0486] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
dacarbazine.
[0487] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
ipilimumab.
[0488] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
labrolizumab or nivolumab.
[0489] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
MPDL3280A.
[0490] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
imatinib.
[0491] Another aspect of the invention relates to a method of
treating colorectal cancer as TIE2 pathway signaling has been shown
to contribute to colorectal cancer progression (Ahmad et al, Cancer
(2001) 92: 1138-1143; Hashizume et al, Cancer Research (2010) 70:
2213-2223). The method comprises administering to a patient in need
thereof an effective amount of a composition of Formula I in a
dosing regimen sufficient to block TIE2 kinase in the tumor
microenvironment.
[0492] In one embodiment of this aspect of the invention, a
composition of Formula I is administered as a single agent.
[0493] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
mFOLFOX6 therapy (oxaplatin+leucovorin+5-fluorouracil).
[0494] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
mFOLFOX6 therapy and bevacizumab.
[0495] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
mFOLFOX6 therapy and panitumumab.
[0496] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
mFOLFOX6 therapy and cetuximab.
[0497] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
capecitabine.
[0498] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
capecitabine and bevacizumab.
[0499] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
FOLFIRI therapy (irinotecan+leucovorin+5-fluorouracil).
[0500] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
FOLFIRI therapy and bevacizumab.
[0501] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
FOLFIRI therapy and aflibercept.
[0502] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
FOLFIRI therapy and cetuximab.
[0503] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
FOLFIRI therapy and panitumumab.
[0504] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
panitumumab.
[0505] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
panitumumab and irinotecan.
[0506] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
cetuximab.
[0507] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
cetuximab and irinotecan.
[0508] Another aspect of the invention relates to a method of
treating acute myeloid leukemia as TIE2 pathway signaling has been
shown to contribute to acute myeloid leukemia progression (Muller
et al, Leukemia Research (2002) 26: 163-168; Hou et al, Leukemia
Research (2008) 32: 904-912). The method comprises administering to
a patient in need thereof an effective amount of a composition of
Formula I in a dosing regimen sufficient to block TIE2 kinase in
the tumor microenvironment.
[0509] In one embodiment of this aspect of the invention, a
composition of Formula I is administered as a single agent.
[0510] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
daunorubicin and cytarabine.
[0511] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
idarubicin and cytarabine.
[0512] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
mitoxantrone and cytarabine.
[0513] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
cytarabine.
[0514] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
5-azacytabine.
[0515] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
decitabine.
[0516] In another embodiment of this aspect of the invention, a
composition of Formula I is administered in combination with
quizartinib.
[0517] Another aspect of the invention relates to a method of
treating cancer. The method comprises administering an effective
amount of a composition of Formula I to a patient in need thereof.
In one embodiment the patient overexpresses Tunica interna
endothelial cell kinase 2 (TIE2) and the cancer is selected from
breast cancer, colorectal cancer, hepatocellular carcinoma, head
and neck cancer, bladder cancer, ovarian cancer, gliomas,
angiosarcomas, melanomas, or acute myeloid leukemia.
[0518] In certain embodiments of the invention of the treatment
regimen, the composition of Formula I is administered at a
frequency of daily.
[0519] In other embodiments of the invention of the treatment
regimen, the composition of Formula I is administered at a
frequency of non-daily intermittent.
[0520] In other embodiments of the invention of the treatment
regimen, the composition of Formula I is administered at a
frequency of three times weekly.
[0521] In other embodiments of the invention of the treatment
regimen, the composition of Formula I is administered at a
frequency of two times weekly.
[0522] In other embodiments of the invention of the treatment
regimen, the composition of Formula I is administered at a
frequency of one time weekly.
[0523] In other embodiments of the invention of the treatment
regimen, the composition of Formula I is administered at a
frequency of one time every two weeks.
[0524] In other embodiments the cancer is metastatic, triple
negative breast cancer (estrogen receptor negative, progesterone
receptor negative, HER2 negative).
[0525] In other embodiments the cancer is estrogen positive
(ER.sup.+) and HER2 receptor kinase negative (HER2.sup.-) breast
cancer.
[0526] In other embodiments the cancer is inflammatory breast
cancer.
[0527] In another embodiment, the method comprises the treatment of
preventing or reducing one or more of primary tumor growth, tumor
invasiveness, cancer intravasation, cancer dissemination,
metastasis, and tumor immunotolerance. In certain embodiments the
method increases patient survival rates.
Formulations, Administration, Dosing, and Treatment Regimens
[0528] The present invention includes the described salts of
Formulae I and/or II (and/or additional agents) in various
formulations. Any composition (and/or additional agents) described
herein can take the form of solutions, suspensions, emulsion,
drops, tablets, pills, pellets, capsules, capsules containing
liquids, powders, sustained-release formulations, suppositories,
emulsions, aerosols, sprays, suspensions, or any other form
suitable for use. In one embodiment, the composition is in the form
of a capsule (see, e.g., U.S. Pat. No. 5,698,155). Other examples
of suitable pharmaceutical excipients are described in Remington's
Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th
ed. 1995), incorporated herein by reference.
[0529] Where necessary, the salts herein described can also include
a solubilizing agent. Also, the agents can be delivered with a
suitable vehicle or delivery device as known in the art.
Combination therapies outlined herein can be co-delivered in a
single delivery vehicle or delivery device. Compositions for
administration can optionally include a local anesthetic such as,
for example, lignocaine to lessen pain at the site of the
injection.
[0530] In one embodiment, the salts of Formulae I and/or II (and/or
additional agents) described herein is formulated in accordance
with routine procedures as a composition adapted for a mode of
administration.
[0531] In certain embodiments, routes of administration include,
for example: intradermal, intramuscular, intraperitoneal,
intravenous, subcutaneous, intranasal, epidural, oral, sublingual,
intranasal, intracerebral, intravaginal, transdermal, rectally, by
inhalation, or topically, particularly to the ears, nose, eyes, or
skin. In some embodiments, the administering is effected orally or
by parenteral injection. The mode of administration can be left to
the discretion of the practitioner, and depend in-part upon the
site of the medical condition. In most instances, administration
results in the release of any agent described herein into the
bloodstream.
[0532] In specific embodiments, it may be desirable to administer
locally to the area in need of treatment or blocking.
[0533] In one embodiment, the salts (and/or additional agents)
described herein is formulated in accordance with routine
procedures as a composition adapted for oral administration to
humans. Compositions for oral delivery can be in the form of
tablets, lozenges, aqueous or oily suspensions, granules, powders,
emulsions, capsules, syrups, or elixirs, for example. Orally
administered compositions can comprise one or more agents, for
example, sweetening agents such as fructose, aspartame or
saccharin; flavoring agents such as peppermint, oil of wintergreen,
or cherry; coloring agents; and preserving agents, to provide a
pharmaceutically palatable preparation. Moreover, where in tablet
or pill form, the compositions can be coated to delay
disintegration and absorption in the gastrointestinal tract,
thereby providing a sustained action over an extended period of
time. Selectively permeable membranes surrounding an osmotically
active driving the salt of Formula I or II (and/or additional
agents) described herein are also suitable for orally administered
compositions. In these latter platforms, fluid from the environment
surrounding the capsule is imbibed by the driving composition,
which swells to displace the agent or agent composition through an
aperture. These delivery platforms can provide an essentially zero
order delivery profile as opposed to the spiked profiles of
immediate release formulations. A time-delay material such as
glycerol monostearate or glycerol stearate can also be useful. Oral
compositions can include standard excipients such as mannitol,
lactose, starch, magnesium stearate, sodium saccharin, cellulose,
and magnesium carbonate. In one embodiment, the excipients are of
pharmaceutical grade. Suspensions, in addition to the active
compositions, may contain suspending agents such as, for example,
ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters, microcrystalline cellulose, aluminum
metahydroxide, bentonite, agar-agar, tragacanth, etc., and mixtures
thereof.
[0534] Dosage forms suitable for parenteral administration (e.g.
intravenous, intramuscular, intraperitoneal, subcutaneous and
intra-articular injection and infusion) include, for example,
solutions, suspensions, dispersions, emulsions, and the like. They
may also be manufactured in the form of sterile solid compositions
(e.g. lyophilized composition), which can be dissolved or suspended
in sterile injectable medium immediately before use. They may
contain, for example, suspending or dispersing agents known in the
art.
[0535] The dosage of the salt of Formulae I and/or II (and/or
additional agents) described herein as well as the dosing schedule
can depend on various parameters, including, but not limited to,
the disease being treated, the subject's general health, and the
administering physician's discretion. Any agent described herein,
can be administered prior to (e.g., 5 minutes, 15 minutes, 30
minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours,
24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4
weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently
with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45
minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48
hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of
an additional therapeutic agent, to a subject in need thereof. In
various embodiments any agent described herein is administered 1
minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour
apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours
apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours
to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours
apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10
hours to 11 hours apart, or 11 hours to 12 hours apart.
[0536] The dosage of the salt of Formula I or II (and/or additional
agents) described herein can depend on several factors including
the severity of the condition, whether the condition is to be
treated or prevented, and the age, weight, and health of the
subject to be treated. Additionally, pharmacogenomic (the effect of
genotype on the pharmacokinetic, pharmacodynamic or efficacy
profile of a therapeutic) information about a particular subject
may affect dosage used. Furthermore, the exact individual dosages
can be adjusted somewhat depending on a variety of factors,
including the specific combination of the agents being
administered, the time of administration, the route of
administration, the nature of the formulation, the rate of
excretion, the particular disease being treated, the severity of
the disorder, and the anatomical location of the disorder. Some
variations in the dosage can be expected.
[0537] Generally, when orally administered to a mammal, the dosage
of any composition of Formula I (and/or additional agents)
described herein may be 0.001 mg/kg/day to 100 mg/kg/day, 0.01
mg/kg/day to 50 mg/kg/day, or 0.1 mg/kg/day to 10 mg/kg/day. When
orally administered to a human, the dosage of any agent described
herein is normally 0.001 mg to 1500 mg per day, 1 mg to 600 mg per
day, or 5 mg to 30 mg per day. In some embodiments, the dosage of
the salt (or agent) ranges from 57 mg to 1200 mg per day. In other
embodiments, the dosage of the agents or salt ranges from 100 mg to
200 mg per day.
[0538] For administration of the salts of Formulae I or II (and/or
additional agents) described herein by parenteral injection, the
dosage is normally 0.1 mg to 250 mg per day, 1 mg to 20 mg per day,
or 3 mg to 5 mg per day. Injections may be given up to four times
daily. Generally, when orally or parenterally administered, the
dosage of any agent described herein is normally 0.1 mg to 1500 mg
per day, or 0.5 mg to 10 mg per day, or 0.5 mg to 5 mg per day. A
dosage of up to 3000 mg per day can be administered.
[0539] Administration of the salts (and/or additional agents)
described herein can, independently, be one to four times daily.
Specifically, administration of the salt can be once a day at a
dosing regimen of the salt is from about 50 mg to 1500 mg. Suitable
daily dosage for the prophylactic effects sought is 57-1200 mg/day.
If administered twice daily, a suitable dosage is 100 mg to 200 mg
of the salt. Administration of the salt may also be intermittently
non-daily. In particular, administration of the salt may be done
one to four times per month or one to six times per year or once
every two, three, four or five years. In certain embodiments
administration of the salt is done weekly or bi-weekly. When
administered weekly or bi-weekly, a suitable salt dosing regimen
ranges from 50-200 mg/per administration. In certain weekly or
bi-weekly administrations, dosage is 200-400 mg/per administration.
Yet other mode of weekly or bi-weekly administration include
400-500 mg/per administration, 500-600 mg/per administration,
600-700 mg/per administration, 700-800 mg/per administration,
800-900 mg/per administration, 900-1000 mg/per administration,
1000-1100 mg/per administration, or 1100-1200 mg/per
administration. Administration can be for the duration of one day
or one month, two months, three months, six months, one year, two
years, three years, and may even be for the life of the subject.
Chronic, long-term administration will be indicated in many cases.
The dosage may be administered as a single dose or divided into
multiple doses. In general, the desired dosage should be
administered at set intervals for a prolonged period, usually at
least over several weeks or months, although longer periods of
administration of several months or years or more may be
needed.
EXAMPLES
Example 1. Biochemical Inhibition of Unphosphorylated TIE2 (uTIE2)
by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea
[0540] Biochemical Assay for uTIE2 (Seq. ID No. 1)
[0541] Activity of uTIE2 kinase was determined by following the
production of ADP from the kinase reaction through coupling with
the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler
et al. Science (2000) 289: 1938-1942). In this assay, the oxidation
of NADH (thus the decrease at A.sub.340 nm) was continuously
monitored spectrophotometrically. The reaction mixture (100 .mu.L)
contained TIE2 (SignalChem) (5.6 nM), BSA (0.004% (w/v)), polyEY
(1.5 mg/ml), MgCl.sub.2 (15 mM), DTT (0.5 mM), pyruvate kinase (4
units), lactate dehydrogenase (7 units), phosphoenol pyruvate (1
mM), and NADH (0.28 mM) and ATP (1.5 mM) in 90 mM Tris buffer
containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The inhibition
reaction was started by mixing serial diluted test composition with
the above reaction mixture. The absorption at 340 nm was monitored
continuously for 6 hours at 30.degree. C. on a plate reader
(BioTek). The reaction rate was calculated using the 5 to 6 h time
frame. Percent inhibition was obtained by comparison of reaction
rate with that of a control (i.e. with no test composition).
IC.sub.50 values were calculated from a series of percent
inhibition values determined at a range of inhibitor concentrations
using software routines as implemented in the GraphPad Prism
software package. The composition
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt (compound 1 as described in figures) exhibited an IC.sub.50
value of 3.5 nM.
TABLE-US-00001 uTIE2 protein sequence used for screening (Seq. ID
No. 1) QLKRANVQRRMAQAFQNVREEPAVQFNSGTLALNRKVKNNPDPTIYPVLD
WNDIKFQDVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDHRDFA
GELEVLCKLGHHPNIINLLGACEHRGYLYLAIEYAPHGNLLDFLRKSRVL
ETDPAFAIANSTASTLSSQQLLHFAADVARGMDYLSQKQFIHRDLAARNI
LVGENYVAKIADFGLSRGQEVYVKKTMGRLPVRWMAIESLNYSVYTTNSD
VWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKPLNCDDEVYDL
MRQCWREKPYERPSFAQILVSLNRMLEERKTYVNTTLYEKFTYAGIDCSA EEAA
Example 2. Biochemical Inhibition of Phosphorylated TIE2 (pTIE2) by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea
[0542] Biochemical Assay for pTIE2 (Seq. ID No. 2)
[0543] Activity of pTIE2 kinase was determined by following the
production of ADP from the kinase reaction through coupling with
the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler
et al. Science (2000) 289: 1938-1942). In this assay, the oxidation
of NADH (thus the decrease at A.sub.340 nm) was continuously
monitored spectrophotometrically. The reaction mixture (100 .mu.L)
contained TIE2 (Life Technologies) (6 nM), BSA (0.004% (w/v)),
polyEY (1.5 mg/ml), MgCl.sub.2 (15 mM), DTT (0.5 mM), pyruvate
kinase (4 units), lactate dehydrogenase (7 units), phosphoenol
pyruvate (1 mM), and NADH (0.28 mM) and ATP (1.5 mM) in 90 mM Tris
buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The
inhibition reaction was started by mixing serial diluted test
composition with the above reaction mixture. The absorption at 340
nm was monitored continuously for 6 hours at 30.degree. C. on a
plate reader (BioTek). The reaction rate was calculated using the 2
to 3 h time frame. Percent inhibition was obtained by comparison of
reaction rate with that of a control (i.e. with no test
composition). IC.sub.50 values were calculated from a series of
percent inhibition values determined at a range of inhibitor
concentrations using software routines as implemented in the
GraphPad Prism software package. When tested the compositions
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt and
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(-
methylcarbamoyl)pyridin-4-yloxy)phenyl)urea bis-hydrochloric acid
salt exhibited >50% inhibition of pTIE2 kinase at <0.1 .mu.M
concentration.
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt exhibited an IC.sub.50 value of 4.2 nM.
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea bis-hydrochloric acid salt
exhibited an IC.sub.50 value of 2.2 nM.
TABLE-US-00002 pTIE2 protein sequence used for screening (Seq. ID
No. 2) PVLDWNDIKFQDVIGEGNFGQVLKARIKKDGLRMDAAIKRMKEYASKDDH
RDFAGELEVLCKLGHHPNIINLLGACEHRGYLYLAIEYAPHGNLLDFLRK
SRVLETDPAFAIANSTASTLSSQQLLHFAADVARGMDYLSQKQFIHRDLA
ARNILVGENYVAKIADFGLSRGQEVYVKKTMGRLPVRWMAIESLNYSVYT
TNSDVWSYGVLLWEIVSLGGTPYCGMTCAELYEKLPQGYRLEKPLNCDDE
VYDLMRQCWREKPYERPSFAQILVSLNRMLEERKT
Example 3. Cellular Inhibition of TIE2 in CHO Cells by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea
CHO K1 Cell Culture
[0544] CHO-K1 cells (catalog #CCL-61) were obtained from the
American Type Culture Collection (ATCC, Manassas, Va.). Briefly,
cells were grown in F12K medium supplemented with 10% characterized
fetal bovine serum (Invitrogen, Carlsbad, Calif.), 100 units/mL
penicillin G, 100 .mu.g/ml streptomycin, and 0.29 mg/mL L-glutamine
(Invitrogen, Carlsbad, Calif.) at 37 degrees Celsius, 5% CO.sub.2,
and 95% humidity. Cells were allowed to expand until reaching
70-95% confluence at which point they were subcultured or harvested
for assay use.
TIE2-transfected CHO K1 Phospho-TIE2 Western Blot Assay
[0545] CHO K1 cells (1.times.10.sup.5 cells/well) were added to a
24-well tissue-culture treated plate in 1 mL of RPMI1640 medium
supplemented with 10% characterized fetal bovine serum and 1.times.
non-essential amino acids (Invitrogen, Carlsbad, Calif.). Cells
were then incubated overnight at 37 degrees Celsius, 5% CO.sub.2,
and 95% humidity. Medium was aspirated, and 0.5 mL of medium was
added to each well. Transfection-grade plasmid DNA (TIE2 gene
Gateway cloned into pcDNA3.2.TM./V5-DEST expression vector,
Invitrogen, Carlsbad, Calif.) was diluted to 5 .mu.g/mL in room
temperature Opti-MEM.RTM. I Medium without serum (Invitrogen,
Carlsbad, Calif.). Two .mu.L of Lipofectamine LTX Reagent
(Invitrogen, Carlsbad, Calif.) was added per 0.5 .mu.g of plasmid
DNA. The tube was mixed gently and incubated for 25 minutes at room
temperature to allow for DNA-Lipofectamine LTX complex formation.
100 .mu.L of the DNA-Lipofectamine LTX complex was added directly
to each well containing cells and mixed gently. Twenty-four hours
post-transfection, medium containing DNA-Lipofectamine complexes
was aspirated, cells were washed with PBS, and RPMI1640 medium
supplemented with 10% characterized fetal bovine serum (Invitrogen,
Carlsbad, Calif.), and 1.times. non-essential amino acids
(Invitrogen, Carlsbad, Calif.) was added. Test composition
(1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(met-
hylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt) or DMSO was added to the wells (0.5% final DMSO
concentration). The plates were then incubated for 4 hours at 37
degrees Celsius, 5% CO.sub.2, and 95% humidity. Following the
incubation, the media was aspirated and the cells were washed with
PBS. The cells were lysed using MPER lysis buffer (Pierce,
Rockford, Ill.) containing Halt Phosphatase and Protease Inhibitors
(Pierce, Rockford, Ill.) and Phosphatase inhibitor cocktail 2
(Sigma, St. Louis, Mo.) at 4.degree. C. for 10 minutes with
shaking. Cleared lysates were separated by SDS-PAGE on a 4-12%
Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, Calif.) and then
transferred to PVDF (Invitrogen, Carlsbad, Calif.). After transfer,
the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology,
Santa Cruz, Calif.) and then probed with an antibody for
phospho-TIE2 (Cell Signaling Technology, Beverly, Mass.). A
secondary anti-rabbit antibody conjugated to horseradish peroxidase
(Cell Signaling Technology, Beverly, Mass.) was used to detect
phospho-TIE2. ECL Plus (GE Healthcare, Piscataway, N.J.), a
substrate for horseradish peroxidase that generates a fluorescent
product, was added. Fluorescence was detected using a Storm 840
phosphorimager (GE Healthcare, Piscataway, N.J.) in fluorescence
mode. The 160 kDa phospho-TIE2 band was quantified using ImageQuant
software (GE Healthcare, Piscataway, N.J.). Data was analyzed using
Prism software (GraphPad Software, San Diego, Calif.) to calculate
IC.sub.50 values. The composition
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt exhibited an IC.sub.50 value of 2.0 nM.
Example 4. Cellular Inhibition of TIE2 in CHO Cells after Inhibitor
Wash-Out by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea
CHO K1 Cell Culture
[0546] CHO-K1 cells (catalog #CCL-61) were obtained from the
American Type Culture Collection (ATCC, Manassas, Va.). Briefly,
cells were grown in F12K medium supplemented with 10% characterized
fetal bovine serum (Invitrogen, Carlsbad, Calif.), 100 units/mL
penicillin G, 100 .mu.g/ml streptomycin, and 0.29 mg/mL L-glutamine
(Invitrogen, Carlsbad, Calif.) at 37 degrees Celsius, 5% CO.sub.2,
and 95% humidity. Cells were allowed to expand until reaching
70-95% confluence at which point they were subcultured or harvested
for assay use.
TIE2-Transfected CHO K1 Phospho-TIE2 Western Blot Composition
Washout Assay
[0547] CHO K1 cells (1.times.10.sup.5 cells/well) were added to a
24-well tissue-culture treated plate in 1 mL of RPMI1640 medium
supplemented with 10% characterized fetal bovine serum and 1.times.
non-essential amino acids (Invitrogen, Carlsbad, Calif.). Cells
were then incubated overnight at 37 degrees Celsius, 5% CO.sub.2,
and 95% humidity. Medium was aspirated, and 0.5 mL of medium was
added to each well. Transfection-grade plasmid DNA (TIE2 gene
Gateway cloned into pcDNA3.2.TM./V5-DEST expression vector,
Invitrogen, Carlsbad, Calif.) was diluted to 5 .mu.g/mL in room
temperature Opti-MEM.RTM. I Medium without serum (Invitrogen,
Carlsbad, Calif.). Two .mu.L of Lipofectamine LTX Reagent
(Invitrogen, Carlsbad, Calif.) was added per 0.5 .mu.g of plasmid
DNA. The tube was mixed gently and incubated for 25 minutes at room
temperature to allow for DNA-Lipofectamine LTX complex formation.
100 .mu.L of the DNA-Lipofectamine LTX complex was added directly
to each well containing cells and mixed gently. Approximately 18-24
hours post-transfection, medium containing DNA-Lipofectamine
complexes was aspirated, cells were washed with PBS, and RPMI1640
medium supplemented with 10% characterized fetal bovine serum
(Invitrogen, Carlsbad, Calif.), and 1.times. non-essential amino
acids (Invitrogen, Carlsbad, Calif.) was added. Test composition
(1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(met-
hylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt) or DMSO was added to the wells (0.5% final DMSO
concentration). The plates were then incubated for 2 hours at 37
degrees Celsius, 5% CO.sub.2, and 95% humidity. Following the
incubation, the media was aspirated and the cells were washed three
times with 1 mL media to wash out free composition. Next, 1 mL
fresh media was added and cells were incubated for specific times
points prior to lysis (i.e., 0, 1, 2, 4, 6, and 24 hours). The
cells were lysed using MPER lysis buffer (Pierce, Rockford, Ill.)
containing Halt Phosphatase and Protease Inhibitors (Pierce,
Rockford, Ill.) and Phosphatase inhibitor cocktail 2 (Sigma, St.
Louis, Mo.) at 4.degree. C. for 10 minutes with shaking. Cleared
lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris
gel (Invitrogen, Carlsbad, Calif.) and then transferred to PVDF
(Invitrogen, Carlsbad, Calif.). After transfer, the PVDF membrane
was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, Calif.)
and then probed with an antibody for phospho-TIE2 (Cell Signaling
Technology, Beverly, Mass.). A secondary anti-rabbit antibody
conjugated to horseradish peroxidase (Cell Signaling Technology,
Beverly, Mass.) was used to detect phospho-TIE2 ECL Plus (GE
Healthcare, Piscataway, N.J.), a substrate for horseradish
peroxidase that generates a fluorescent product, was added.
Fluorescence was detected using a Storm 840 phosphorimager (GE
Healthcare, Piscataway, N.J.) in fluorescence mode. PVDF membranes
were stripped and then re-probed with total TIE2 antibody (Santa
Cruz Biotechnology, Inc., Dallas, Tex.) as above. The 160 kDa
phospho-TIE2 and total TIE2 bands were quantified using ImageQuant
software (GE Healthcare, Piscataway, N.J.). Phospho-TIE2 levels
were normalized to total TIE2 levels, and data was plotted using
Prism software (GraphPad Software, San Diego, Calif.). When
incubated with TIE2-transfected CHO K1 cells for 2 hours at 0.1
.mu.M-1 .mu.M prior to being washed out, Composition
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt disclosed herein exhibited >50% inhibition of phospho-TIE2
levels for >24 hours.
Example 5. Cellular Inhibition of TIE2 in HUVEC Cells by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea
HUVEC Cell Culture
[0548] HUVEC (Human umbilical vein endothelial cells; Catalog
#CRL-1730) cells were obtained from the American Type Culture
Collection (ATCC, Manassas, Va.). Briefly, cells were grown in
EGM-2 (Lonza, Walkersville, Md.) at 37 degrees Celsius, 5%
CO.sub.2, and 95% humidity. Cells were allowed to expand until
reaching 90-95% saturation at which point they were subcultured or
harvested for assay use.
HUVEC Phospho-TIE2 Western Blot Assay
[0549] HUVEC cells (2.5.times.10.sup.5 cells/well) were added to a
24-well tissue-culture treated plate in 1 mL of EGM-2 culture
medium (Lonza, Walkersville, Md.). Cells were then incubated
overnight at 37 degrees Celsius, 5% CO.sub.2, and 95% humidity.
Media was then aspirated and 1 mL EBM-2 basal medium (Lonza,
Walkersville, Md.) supplemented with 2% FBS (Invitrogen, Carlsbad,
Calif.) was added. Test composition or DMSO was added to the wells
(0.5% final DMSO concentration). The plates were then incubated for
4 hours at 37 degrees Celsius, 5% CO.sub.2, and 95% humidity.
During the incubation, histidine-tagged angiopoietin 1 (ANG1)
growth factor (R&D Systems, Minneapolis, Minn.) was added to a
anti-polyhistidine antibody (R&D Systems, Minneapolis, Minn.)
for 30 minutes at room temperature to generate multimers of ANG1.
Following the four hour incubation of composition, cells were
stimulated with 800 ng/mL of the ANG1/anti-polyhistidine antibody
complex mixture for 15 minutes. The media was aspirated and the
cells were washed with PBS. The cells were lysed using MPER lysis
buffer (Pierce, Rockford, Ill.) containing Halt Phosphatase and
Protease Inhibitors (Pierce, Rockford, Ill.) and Phosphatase
inhibitor cocktail 2 (Sigma, St. Louis, Mo.) at 4.degree. C. for 10
minutes with shaking. Cleared lysates were separated by SDS-PAGE on
a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, Calif.)
and then transferred to PVDF (Invitrogen, Carlsbad, Calif.). After
transfer, the PVDF membrane was blocked with BSA (Santa Cruz
Biotechnology, Santa Cruz, Calif.) and then probed with an antibody
for phospho-TIE2 (Cell Signaling Technology, Beverly, Mass.). A
secondary anti-rabbit antibody conjugated to horseradish peroxidase
(Cell Signaling Technology, Beverly, Mass.) was used to detect
phospho-TIE2. ECL Plus (GE Healthcare, Piscataway, N.J.), a
substrate for horseradish peroxidase that generates a fluorescent
product, was added. Fluorescence was detected using a Storm 840
phosphorimager (GE Healthcare, Piscataway, N.J.) in fluorescence
mode. The 160 kDa phospho-TIE2 band was quantified using ImageQuant
software (GE Healthcare, Piscataway, N.J.). Data was analyzed using
Prism software (GraphPad Software, San Diego, Calif.) to calculate
IC.sub.50 values. The composition
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt disclosed herein exhibited an IC.sub.50 value of 0.018 nM.
Example 6. Inhibition of Angiopoietin 1 (ANG1) or Angiopoietin 2
(ANG2) Stimulated Capillary Tube Formation by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea
HMVEC Cell Culture
[0550] HMVEC (Human microvascular endothelial cells; Catalog
#PCS-110-010) cells were obtained from the American Type Culture
Collection (ATCC, Manassas, Va.). Briefly, cells were grown in
EGM-2 MV (Lonza, Walkersville, Md.) at 37 degrees Celsius, 5%
CO.sub.2, and 95% humidity. Cells were allowed to expand until
reaching 90-95% saturation at which point they were subcultured or
harvested for assay use.
HMVEC Capillary Tube Formation Assay
[0551] HMVEC cells (1.5.times.10.sup.4 cells/well) mixed with test
composition or DMSO control and the appropriate growth factor (ANG1
or ANG2) or control were added to a 96-well tissue-culture treated
plate coated with growth-factor reduced Matrigel in 0.1 mL of EBM-2
basal medium (Lonza, Walkersville, Md.). Cells were then incubated
for 18 hours at 37 degrees Celsius, 5% CO.sub.2, and 95% humidity.
Media was then gently aspirated and wells were gently washed with
0.1 mL EBM-2 basal medium. Media was again aspirated and 1 .mu.M
Calcein AM solution (Invitrogen, Carlsbad, Calif.) in basal medium
was added to each well to fluorescently label live cells. Cells
were then incubated for 30 minutes at 37 degrees Celsius, 5%
CO.sub.2, and 95% humidity. Media was aspirated and wells were
gently washed with phosphate-buffered saline twice. Images of each
well were acquired with a fluorescent microscope and processed
using ImagePro Analyzer (Media Cybernetics, Inc., Rockville, Md.)
using an automated macro that measures total capillary tube length.
Data was analyzed using Prism software (GraphPad Software, San
Diego, Calif.) to calculate IC.sub.50 values. The composition
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid
salt disclosed herein exhibited an IC.sub.50 value of 6.9 nM for
inhibition of ANG1-stimulated HMVEC capillary tube formation. The
composition of Formula I disclosed herein exhibited an IC.sub.50
value of 34 nM for inhibition of ANG2-stimulated HMVEC capillary
tube formation.
Example 7. Inhibition of In Vivo Primary Tumor Growth and
Invasiveness in the Murine PyMT Breast Cancer Model by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a Single Agent and in
Combination with Paclitaxel
PyMT Syngeneic Breast Cancer Model Primary Tumor Growth
[0552] The PyMT syngeneic breast cancer implant mouse model was
used to evaluate in vivo activity of compound 1. Briefly,
1.times.10.sup.6 cells (dissociated from PyMT tumor fragments) in
0.1 mL total volume were implanted into the fourth mammary fat pad
on the left side of female mice (FVB/NJ, JAWEST:RB05 mice from
Jackson Labs). A total of 10 mice were implanted in each group.
Molecular Imaging, Inc.'s Animal Care and Use Committee approved
all the experimental protocols and conducted experiments in
compliance with all the laws, regulations and guidelines of the
National Institutes of Health (NIH). Treatment was initiated by
oral administration (gavage) of Compound 1 twice daily or vehicle
(0.4% hydroxypropylmethylcellulose in water) and/or intravenous
administration (IV) of paclitaxel every five days or vehicle (10%
ethanol, 10% Cremophor EL and 80% saline) according to individual
body weight on the day of treatment at 0.2 mL per 20 g when tumor
size reached approximately 850 mg. Animals were dosed for 21 days.
Body weights and tumor measurements were recorded three times
weekly. Tumor burden (mg) was estimated from caliper measurements
by the formula for the volume of a prolate ellipsoid assuming unit
density as: Tumor burden (mg)=(L.times.W.sup.2)/2, where L and W
are the respective orthogonal tumor length and width measurements
(mm). In the PyMT model, both Compound 1 and paclitaxel groups
evidenced tumor growth inhibition. Compound 1 in combination with
paclitaxel demonstrated additive activity (FIG. 1). These data
evidence in vivo activity by Compound 1 and show correlation to
enzymatic and cell data.
Example 8. Inhibition of In Vivo Primary Tumor Macrophage
Accumulation in the Murine PyMT Breast Cancer Model by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a Single Agent and in
Combination with Paclitaxel
PyMT Syngeneic Breast Cancer Model Primary Tumor Macrophage
Accumulation
[0553] The PyMT syngeneic breast cancer implant mouse model was
used to evaluate in vivo activity of compound 1. Briefly,
1.times.10.sup.6 cells (dissociated from PyMT tumor fragments) in
0.1 mL total volume were implanted into the fourth mammary fat pad
on the left side of female mice (FVB/NJ, JAWEST:RB05 mice from
Jackson Labs). A total of 10 mice were implanted in each group.
Molecular Imaging, Inc.'s Animal Care and Use Committee approved
all the experimental protocols and conducted experiments in
compliance with all the laws, regulations and guidelines of the
National Institutes of Health (NIH). Treatment was initiated by
oral administration (gavage) of Compound 1 twice daily or vehicle
(0.4% hydroxypropylmethylcellulose in water) and/or intravenous
administration (IV) of paclitaxel every five days or vehicle (10%
ethanol, 10% Cremophor EL and 80% saline) according to individual
body weight on the day of treatment at 0.2 mL per 20 g when tumor
size reached approximately 850 mg. Animals were dosed for 21 days.
Body weights and tumor measurements were recorded three times
weekly.
[0554] At the end of study, tumors were excised and placed in
formalin. Formalin-fixed tumor samples were then placed in paraffin
blocks. Formalin fixed-paraffin embedded tissue slides were
deparaffinized with xylene and hydrated to distilled water through
a graduated series of alcohol rinses. Antigenic retrieval was
performed using Dako's PT Link Module with a Tris/EDTA buffer
target retrieval solution at 95.degree. C. for 20 minutes. Once the
slides cooled down, they were loaded onto a Dako
AutostainerPlusLink for immunohistochemical staining at room
temperature with F4/80 and CD31 antibodies, to stain for
macrophages and endothelial cells, respectively. Endogenous
peroxidase and alkaline phosphatase activity in the tissues was
quenched with a Dual Endogenous Enzyme Block solution (Dako, S2003)
for 5 minutes. Non-specific protein binding was blocked with serum
free Protein Block (Dako, X0909) for 5 minutes. The rat anti mouse
CD31 primary antibody was then incubated on the experimental tissue
sections for 30 minutes at an immunogenic concentration of 1:100.
The primary antibody was then conjugated with a rabbit anti rat
immunoglobulin secondary antibody (Dako, E0468). The secondary
antibody was then amplified with a goat anti rabbit peroxidase
labeled polymer (Dako, K4003) for 30 minutes. Enzymatic staining
was developed with substrate-chromogen DAB+(Dako, K3468) for 5
minutes. Excess rat IgG components were further blocked with Rodent
Block Rat (Biocare Medical, RBR962H) for 5 minutes. The rat anti
mouse F4/80 primary antibody was incubated on the experimental
tissue sections for 30 minutes. The F4/80 was then conjugated with
a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468).
The secondary antibody was then amplified with a goat anti rabbit
alkaline phosphatase labeled polymer, (Biocare RALP525) for 30
minutes. Enzymatic staining was developed with substrate chromogen
WARP Red (Biocare WR806). The counter staining was performed with
automation hematoxylin for 10 minutes. The tissue slides were then
air dried and cleared to xylene for glass cover slipping. Slides
were scored for F4/80 staining using a scale of 0, no visible
staining; 1, weak staining; 2, moderate staining; 3 strong
staining. In the PyMT model, Compound 1 evidenced a decrease in
macrophage accumulation at the primary tumor, whereas paclitaxel
did not decrease macrophage accumulation. Compound 1 in combination
with paclitaxel demonstrated similar activity to Compound 1
single-agent treatment (FIG. 2). These data evidence in vivo
activity by Compound 1 and show correlation to enzymatic and cell
data.
Example 9. Inhibition of In Vivo Primary Tumor TIE2 Cell
Accumulation in the Murine PyMT Breast Cancer Model by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a Single Agent and in
Combination with Paclitaxel
PyMT Syngeneic Breast Cancer Model Primary Tumor Macrophage
Accumulation
[0555] The PyMT syngeneic breast cancer implant mouse model was
used to evaluate in vivo activity of compound 1. Briefly,
1.times.10.sup.6 cells (dissociated from PyMT tumor fragments) in
0.1 mL total volume were implanted into the fourth mammary fat pad
on the left side of female mice (FVB/NJ, JAWEST:RB05 mice from
Jackson Labs). A total of 10 mice were implanted in each group.
Molecular Imaging, Inc.'s Animal Care and Use Committee approved
all the experimental protocols and conducted experiments in
compliance with all the laws, regulations and guidelines of the
National Institutes of Health (NIH). Treatment was initiated by
oral administration (gavage) of Compound 1 twice daily or vehicle
(0.4% hydroxypropylmethylcellulose in water) and/or intravenous
administration (IV) of paclitaxel every five days or vehicle (10%
ethanol, 10% Cremophor EL and 80% saline) according to individual
body weight on the day of treatment at 0.2 mL per 20 g when tumor
size reached approximately 850 mg. Animals were dosed for 21 days.
Body weights and tumor measurements were recorded three times
weekly.
[0556] At the end of study, tumors were excised and placed in
formalin. Formalin-fixed tumor samples were then placed in paraffin
blocks. The experimental formalin fixed-paraffin embedded tissue
slides were deparaffinized with xylene and hydrated to distilled
water through a graduated series of alcohol rinses. Antigenic
retrieval was performed using Dako's PT Link Module with a Citrate
pH 6 buffer target retrieval solution at 95.degree. C. for 20
minutes. Once the slides cooled down, they were loaded onto a Dako
AutostainerPlusLink for immunohistochemical staining at room
temperature with both TIE2 and CD31 antibodies. Endogenous
peroxidase and alkaline phosphatase activity in the tissues was
quenched with a Dual Endogenous Enzyme Block solution (Dako, S2003)
for 5 minutes. Non-specific protein binding was blocked with serum
free Protein Block (Dako, X0909) for 5 minutes. The rat anti mouse
CD31 primary antibody was then incubated on the experimental tissue
sections for 30 minutes at an immunogenic concentration of 1:100.
The primary antibody was then conjugated with a rabbit anti rat
immunoglobulin secondary antibody (Dako, E0468). The secondary
antibody was then amplified with a goat anti rabbit peroxidase
labeled polymer (Dako, K4003) for 30 minutes. Enzymatic staining
was developed with substrate-chromogen DAB+(Dako, K3468) for 5
minutes. Excess protein components were further blocked with
Protein Block (Dako, X0909) for 5 minutes. The rabbit anti TIE2
primary antibody was incubated on the experimental tissue sections
for 30 minutes. The TIE2 antibody was then conjugated with an
alkaline phosphatase labeled goat anti rabbit polymer for 30
minutes. Enzymatic staining was developed with substrate chromogen
WARP Red (Biocare WR806). The counter staining was performed with
automation hematoxylin for 10 minutes. The tissue slides were then
air dried and cleared to xylene for glass cover slipping. Slides
were scored for TIE2 staining using a scale of 0, no visible
staining; 1, weak staining; 2, moderate staining; 3 strong
staining. In the PyMT model, Compound 1 evidenced a decrease in
TIE2-expressing cell accumulation at the primary tumor, whereas
paclitaxel did not decrease TIE2-expressing cell accumulation.
Compound 1 in combination with paclitaxel demonstrated enhanced
activity compared to Compound 1 single-agent treatment (FIG. 3).
These data evidence in vivo activity by Compound 1 and show
correlation to enzymatic and cell data.
Example 10. Inhibition of In Vivo Lung Metastases in the Murine
PyMT Breast Cancer Model by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a Single Agent and in
Combination with Paclitaxel
PyMT Syngeneic Breast Cancer Model Lung Metastasis Evaluation
[0557] The PyMT syngeneic breast cancer implant mouse model was
used to evaluate in vivo activity of compound 1. Briefly,
1.times.10.sup.6 cells (dissociated from PyMT tumor fragments) in
0.1 mL total volume were implanted into the fourth mammary fat pad
on the left side of female mice (FVB/NJ, JAWEST:RB05 mice from
Jackson Labs). A total of 10 mice were implanted in each group.
Molecular Imaging, Inc.'s Animal Care and Use Committee approved
all the experimental protocols and conducted experiments in
compliance with all the laws, regulations and guidelines of the
National Institutes of Health (NIH). Treatment was initiated by
oral administration (gavage) of Compound 1 twice daily or vehicle
(0.4% hydroxypropylmethylcellulose in water) and/or intravenous
administration (IV) of paclitaxel every five days or vehicle (10%
ethanol, 10% Cremophor EL and 80% saline) according to individual
body weight on the day of treatment at 0.2 mL per 20 g when tumor
size reached approximately 850 mg. Animals were dosed for 21 days.
Body weights and tumor measurements were recorded three times
weekly.
[0558] At the end of study, lung tissues were excised and placed in
formalin. Formalin-fixed lung samples were then placed in paraffin
blocks. Each lung block had three slides with two levels per slide
cut and stained with Hematoxylin and Eosin. Metastatic lung nodules
were counted via microscopy. In the PyMT model, both Compound 1 and
paclitaxel evidenced a similar decrease in lung metastasis.
Compound 1 in combination with paclitaxel demonstrated additive
activity compared to single-agent treatments (FIG. 4). These data
evidence in vivo activity by Compound 1 and show correlation to
enzymatic and cell data.
Example 11. Inhibition of In Vivo Lung Metastases in the Murine
PyMT Breast Cancer Model by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea Dosed Intermittently
(Non-Daily) in Combination with Paclitaxel
PyMT Syngeneic Breast Cancer Model Lung Metastasis Evaluation
[0559] The PyMT syngeneic breast cancer implant mouse model was
used to evaluate in vivo activity of compound 1. Briefly,
1.times.10.sup.6 cells (dissociated from PyMT tumor fragments and
stored frozen in cell-freezing medium) in 0.1 mL total volume were
implanted into the fourth mammary fat pad on the left side of
female mice (FVB/NJ, JAWEST:RB05 mice from Jackson Labs). A total
of three mice were implanted in each group. Molecular Imaging,
Inc.'s Animal Care and Use Committee approved all the experimental
protocols and conducted experiments in compliance with all the
laws, regulations and guidelines of the National Institutes of
Health (NIH). Treatment was initiated by oral administration
(gavage) of Compound 1 twice weekly or vehicle (0.4%
hydroxypropylmethylcellulose in water) and/or intravenous
administration (IV) of paclitaxel every five days or vehicle (10%
ethanol, 10% Cremophor EL and 80% saline) according to individual
body weight on the day of treatment at 0.2 mL per 20 g when tumor
size reached approximately 600 mg. Animals were dosed for 12 days.
Body weights and tumor measurements were recorded three times
weekly.
[0560] At the end of study, lung tissues were excised and placed in
formalin. Formalin-fixed lung samples were then placed in paraffin
blocks. Each lung block had three slides with two levels per slide
cut and stained with Hematoxylin and Eosin. Metastatic lung nodules
were counted via microscopy. In the PyMT model, paclitaxel
evidenced a decrease in lung metastasis. Compound 1 in combination
with paclitaxel demonstrated additive activity compared to
single-agent treatment (FIG. 5). These data evidence in vivo
activity by Compound 1 and show correlation to enzymatic and cell
data.
Example 12. Inhibition of In Vivo Lung Metastases in the Murine
PyMT Breast Cancer Model by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(meth-
ylcarbamoyl)pyridin-4-yloxy)phenyl)urea Dosed Intermittently
(Non-Daily) in Combination with Eribulin
PyMT Syngeneic Breast Cancer Model Lung Metastasis Evaluation
[0561] The PyMT syngeneic breast cancer implant mouse model was
used to evaluate in vivo activity of compound 1. Briefly,
1.times.10.sup.6 cells (dissociated from PyMT tumor fragments and
stored frozen in cell-freezing medium) in 0.1 mL total volume were
implanted into the fourth mammary fat pad on the left side of
female mice (FVB/NJ, JAWEST:RB05 mice from Jackson Labs). A total
of three mice were implanted in each group. Molecular Imaging,
Inc.'s Animal Care and Use Committee approved all the experimental
protocols and conducted experiments in compliance with all the
laws, regulations and guidelines of the National Institutes of
Health (NIH). Treatment was initiated by oral administration
(gavage) of Compound 1 twice weekly or vehicle (0.4%
hydroxypropylmethylcellulose in water) and/or intravenous
administration (IV) of eribulin three times weekly or vehicle (80%
saline) according to individual body weight on the day of treatment
at 0.2 mL per 20 g when tumor size reached approximately 600 mg.
Animals were dosed for 12 days. Body weights and tumor measurements
were recorded three times weekly.
[0562] At the end of study, lung tissues were excised and placed in
formalin. Formalin-fixed lung samples were then placed in paraffin
blocks. Each lung block had three slides with two levels per slide
cut and stained with Hematoxylin and Eosin. Metastatic lung nodules
were counted via microscopy. In the PyMT model, eribulin evidenced
a decrease (or increase at low dose) in lung metastasis. Compound 1
in combination with eribulin demonstrated additive activity
compared to single-agent treatment (FIG. 6). These data evidence in
vivo activity by Compound 1 and show correlation to enzymatic and
cell data.
Example 13. Increase in Overall Survival in the Murine PyMT Breast
Cancer Model by
1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-
-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea Dosed
Intermittently (Non-Daily) in Combination with Eribulin
PyMT Syngeneic Breast Cancer Model Survival Evaluation
[0563] The PyMT syngeneic breast cancer implant mouse model was
used to evaluate in vivo activity of compound 1. Briefly,
1.times.10.sup.6 cells (dissociated from PyMT tumor fragments and
stored frozen in cell-freezing medium) in 0.1 mL total volume were
implanted into the fourth mammary fat pad on the left side of
female mice (FVB/NJ, JAWEST:RB05 mice from Jackson Labs). A total
of ten mice were implanted in each group. Molecular Imaging, Inc.'s
Animal Care and Use Committee approved all the experimental
protocols and conducted experiments in compliance with all the
laws, regulations and guidelines of the National Institutes of
Health (NIH). Treatment was initiated by oral administration
(gavage) of Compound 1 once or twice weekly or vehicle (0.4%
hydroxypropylmethylcellulose in water) and/or intravenous
administration (IV) of eribulin three times weekly or vehicle (80%
saline) according to individual body weight on the day of treatment
at 0.2 mL per 20 g when tumor size reached approximately 850 mg.
Tumors were then resected three days after treatment began. Animals
were then dosed for the duration of the survival experiment. Body
weights and tumor measurements were recorded three times weekly. In
the PyMT model, eribulin at 0.1 mg/kg evidenced no increase in
survival. Compound 1 in combination with eribulin demonstrated
significant increases in survival (FIG. 7). These data evidence in
vivo activity by Compound 1 and show correlation to enzymatic and
cell data.
[0564] The present invention is not to be limited in scope by the
specific embodiments disclosed in the examples which are intended
as illustrations of a few aspects of the invention and any
embodiments that are functionally equivalent are within the scope
of this invention. Indeed, various modifications of the invention
in addition to those shown and described herein will become
apparent to those skilled in the art and are intended to fall
within the scope of the appended claims.
EQUIVALENTS
[0565] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described specifically
herein. Such equivalents are intended to be encompassed in the
scope of the following claims.
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