U.S. patent application number 16/517936 was filed with the patent office on 2019-11-14 for pharmaceutical combinations for treating cancer.
The applicant listed for this patent is Purdue Pharmaceutical Products L.P.. Invention is credited to Thomas Mehrling, Enrique Maria Ocio.
Application Number | 20190343807 16/517936 |
Document ID | / |
Family ID | 51177574 |
Filed Date | 2019-11-14 |
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United States Patent
Application |
20190343807 |
Kind Code |
A1 |
Mehrling; Thomas ; et
al. |
November 14, 2019 |
PHARMACEUTICAL COMBINATIONS FOR TREATING CANCER
Abstract
The present invention is directed to a combination comprising a
proteasome inhibitor and a compound of formula I or a
pharmaceutically acceptable salt thereof: ##STR00001## to a
pharmaceutical composition and to a kit both comprising said
combination, to the combination, composition or kit for use in the
treatment of cancer, and to a method of treatment of cancer in a
patient in need thereof comprising administering to said patient an
effective amount of said combination, composition or kit.
Inventors: |
Mehrling; Thomas; (Basel,
CH) ; Ocio; Enrique Maria; (Salamanca, ES) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Purdue Pharmaceutical Products L.P. |
Stamford |
CT |
US |
|
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Family ID: |
51177574 |
Appl. No.: |
16/517936 |
Filed: |
July 22, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15985097 |
May 21, 2018 |
10406138 |
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16517936 |
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15314162 |
Nov 28, 2016 |
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PCT/EP2015/061571 |
May 26, 2015 |
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15985097 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/573 20130101;
A61K 31/4184 20130101; A61P 25/00 20180101; A61K 45/06 20130101;
A61P 35/00 20180101; A61P 17/00 20180101; A61K 31/69 20130101; A61K
31/407 20130101; A61K 38/06 20130101; A61K 38/05 20130101; A61P
15/00 20180101; A61K 31/427 20130101; A61K 31/5377 20130101; A61P
35/02 20180101; A61P 19/00 20180101; A61P 43/00 20180101; A61P
11/00 20180101; A61K 31/55 20130101; A61K 39/3955 20130101; A61P
35/04 20180101; A61K 31/58 20130101; A61K 31/502 20130101; A61K
31/69 20130101; A61K 2300/00 20130101; A61K 31/5377 20130101; A61K
2300/00 20130101; A61K 31/407 20130101; A61K 2300/00 20130101; A61K
31/427 20130101; A61K 2300/00 20130101; A61K 31/573 20130101; A61K
2300/00 20130101; A61K 31/58 20130101; A61K 2300/00 20130101; A61K
31/4184 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/4184 20060101
A61K031/4184; A61K 38/05 20060101 A61K038/05; A61K 31/69 20060101
A61K031/69; A61K 31/58 20060101 A61K031/58; A61K 31/573 20060101
A61K031/573; A61K 31/5377 20060101 A61K031/5377; A61K 31/502
20060101 A61K031/502; A61K 31/407 20060101 A61K031/407; A61K 38/06
20060101 A61K038/06; A61K 45/06 20060101 A61K045/06; A61K 39/395
20060101 A61K039/395; A61K 31/55 20060101 A61K031/55; A61K 31/427
20060101 A61K031/427 |
Foreign Application Data
Date |
Code |
Application Number |
May 28, 2014 |
GB |
1409471.8 |
Claims
1. A combination comprising a proteasome inhibitor and a compound
of formula I or a pharmaceutically acceptable salt thereof:
##STR00008##
2. The combination according to claim 1, wherein the
pharmaceutically acceptable salt of the compound of formula I is a
hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate,
sulfamate, nitrate, phosphate, citrate, methanesulfonate,
trifluoroacetate, glutamate, glucuronate, glutarate, malate,
maleate, succinate, fumarate, tartrate, tosylate, salicylate,
lactate, naphthalenesulfonate or acetate salt.
3. The combination according to claim 1, wherein the proteasome
inhibitor is selected from the group consisting of bortezomib,
carfilzomib, marizomib, delanzomib (CEP-18770), oprozomib (ONX
0912), ixazomib (MLN-9708), LU-102, and a pharmaceutically
acceptable salt thereof.
4. The combination according to claim 1, wherein the proteasome
inhibitor is selected from bortezomib, carfilzomib and LU-102.
5. The combination according to claim 1, further comprising a
glucocorticoid.
6. The combination according to claim 1, further comprising a
glucocorticoid selected from the group consisting of dexamethasone,
fluocinolone acetonide and prednisone.
7. The combination according to claim 1, further comprising the
glucocorticoid dexamethasone.
8. The combination according to claim 1, further comprising one or
more additional pharmaceutically active agents.
9. The combination according to claim 1, wherein the proteasome
inhibitor, the compound of formula I or pharmaceutically acceptable
salt thereof and, an optional glucocorticoid, are adapted for
administration concurrently, sequentially or separately.
10. The combination according to claim 1, wherein the proteasome
inhibitor, the compound of formula I or pharmaceutically acceptable
salt thereof and, an optional glucocorticoid, are adapted for
administration concurrently.
11. The combination according to claim 1, wherein the molar ratio
of the proteasome inhibitor to the compound of formula I or
pharmaceutically acceptable salt thereof in said combination is
from 1:1000 to 1000:1.
12. The combination according to claim 1, wherein the molar ratio
of the proteasome inhibitor to the compound of formula I or
pharmaceutically acceptable salt thereof in said combination is
from 1:1000 to 10:1.
13. The combination according to claim 1, wherein the molar ratio
of the proteasome inhibitor to the compound of formula I or
pharmaceutically acceptable salt thereof in said combination is
from 1:800 to 1:200.
14. The combination according to claim 1, wherein the molar ratio
of the proteasome inhibitor to the compound of formula I or
pharmaceutically acceptable salt thereof in said combination is
from 1:700 to 1:400.
15. The combination according to claim 1, wherein the molar ratio
of the proteasome inhibitor to the compound of formula I or
pharmaceutically acceptable salt thereof in said combination is
from 1:3 to 1:0.5.
16. The combination according to claim 1, comprising the compound
of formula I or the acetate salt thereof, and wherein the
proteasome inhibitor is selected from bortezomib and carfilzomib,
wherein the molar ratio of the proteasome inhibitor selected from
bortezomib and carfilzomib to the compound of formula I or
pharmaceutically acceptable salt thereof in said combination is
from 1:700 to 1:400.
17. The combination according to claim 1, comprising the compound
of formula I or the acetate salt thereof and the proteasome
inhibitor LU-102, wherein the molar ratio of LU-102 to the compound
of formula I or pharmaceutically acceptable salt thereof in said
combination is from 1:3 to 1:0.5.
18. The combination according to claim 1, comprising the proteasome
inhibitor and the compound of formula I or pharmaceutically
acceptable salt thereof, wherein the proteasome inhibitor and the
compound of formula I or the pharmaceutically acceptable salt
thereof form a synergistic combination.
19. The combination according to claim 1, further comprising a
glucocorticoid wherein the molar ratio of the proteasome inhibitor
to the compound of formula I or pharmaceutically acceptable salt
thereof to the glucocorticoid in said combination is from 1:1000:10
to 1000:1:20.
20. The combination according to claim 1, further comprising a
glucocorticoid wherein the molar ratio of the proteasome inhibitor
to the compound of formula I or pharmaceutically acceptable salt
thereof to the glucocorticoid used in said combination is from
1:1000:10 to 1:100:2.
21. The combination according to claim 1, further comprising a
glucocorticoid wherein the molar ratio of the proteasome inhibitor
to the compound of formula I or pharmaceutically acceptable salt
thereof to the glucocorticoid used in said combination is from
1:700:4 to 1:400:3.
22. The combination according to claim 1, comprising a proteasome
inhibitor selected from bortezomib and carfilzomib, the compound of
formula I or the acetate salt thereof and dexamethasone, wherein
the molar ratio of the proteasome inhibitor selected from
bortezomib and carfilzomib to the compound of formula I or the
acetate salt thereof to dexamethasone in said combination is from
1:700:4 to 1:400:3.
23. The combination according to claim 1, comprising the proteasome
inhibitor LU-102, the compound of formula I or the acetate salt
thereof and dexamethasone, wherein the molar ratio of LU-102 to the
compound of formula I or the acetate salt thereof to dexamethasone
in said combination is from 1:3:4 to 1:0.5:3.
24. The combination according to claim 1, comprising the proteasome
inhibitor, the compound of formula I or pharmaceutically acceptable
salt thereof and a glucocorticoid, wherein the proteasome
inhibitor, the compound of formula I or the pharmaceutically
acceptable salt thereof and the glucocorticoid form a synergistic
combination.
25. A pharmaceutical composition comprising a pharmaceutically
acceptable diluent or carrier and a combination according to claim
1.
26. A kit comprising a combination according to claim 1, and
optionally, instructions for treating a patient.
27. A method of treating cancer in a patient in need thereof
comprising administering to said patient a combination according to
claim 1.
28. The method according to claim 27, wherein said cancer is
selected from a hematologic cancer and breast cancer.
29. The method according to claim 27, wherein said cancer is a
hematologic cancer selected from multiple myeloma, lymphoma and
leukemia.
30. The method according to claim 27, wherein said cancer is
multiple myeloma selected from active myeloma, plasmacytoma, light
chain myeloma and non-secretory myeloma.
31. The method according to claim 27, wherein said cancer is
lymphoma selected from Hodgkin lymphoma and non-Hodgkin
lymphoma.
32. The method according to claim 27, wherein said cancer is
leukemia selected from acute lymphoblastic leukemia (ALL), chronic
lymphocytic leukemia (CLL), acute myeloid leukemia (AML), chronic
myeloid leukemia (CML), hairy cell leukemia (HCL), T-cell
prolymphocytic leukemia (T-PLL), large granular lymphocytic
leukemia and T-cell acute lymphoblastic leukemia.
33. The method according to claim 27, wherein said cancer is breast
cancer selected from claudin-low tumors, basal-like tumors, human
epidermal growth factor receptor 2 (HER2) positive tumors, luminal
A tumors and luminal B tumors.
34. The method according to claim 27, wherein said cancer is a
triple-negative breast cancer.
35. The method according to claim 27, wherein in said method the
proteasome inhibitor, the compound of formula I or pharmaceutically
acceptable salt thereof and, an optional glucocorticoid, are
administered concurrently, sequentially or separately.
36. The method according to claim 27, wherein in said method the
proteasome inhibitor, the compound of formula I or pharmaceutically
acceptable salt thereof and, an optional glucocorticoid, are
administered concurrently.
37. The method according to claim 27, wherein the compound of
formula I or pharmaceutically acceptable salt thereof is
administered to the patient in need thereof at a dosage range of 10
to 100 mg/kg body weight patient.
38. The method according to claim 27, wherein the compound of
formula I or pharmaceutically acceptable salt thereof is
administered to the patient in need thereof at a dosage range of 40
to 80 mg/kg body weight patient.
39. The method according to claim 27, wherein the proteasome
inhibitor is administered to the patient at a dosage range of 0.01
to 0.3 mg/kg body weight patient.
40. The method according to claim 27, wherein the proteasome
inhibitor is administered to the patient at a dosage range of 0.05
to 0.15 mg/kg body weight patient.
41. The method according to claim 27, wherein the combination
further comprises a glucocorticoid, and wherein in the method, the
glucocorticoid is administered at a dosage range of from 0.1 to 1.0
mg/kg body weight patient.
42. The method according to claim 27, wherein the combination
further comprises a glucocorticoid, and wherein in the method, the
glucocorticoid is administered at a dosage range of from 0.3 to 0.5
mg/kg body weight patient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 15/985,097, filed on May 21, 2018,
which is a continuation of U.S. patent application Ser. No.
15/314,162, filed on Nov. 28, 2016, which is a U.S. national stage
filing under 35 U.S.C. .sctn. 371(c), of International Application
No. PCT/EP2015/061571, filed on May 26, 2015, which claims foreign
priority of U.K. Patent Application No. 1409471.8, filed on May 28,
2014. The entire contents of each of the aforementioned
applications, including original claims and drawings, are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to combinations and
compositions that are of use in the treatment of cancer, for
example in the treatment of breast cancer or of hematologic cancers
such as multiple myeloma, lymphoma or leukemia.
BACKGROUND TO THE INVENTION
[0003] Cancer is one of the most life threatening diseases. Cancer
is a condition in which cells in a part of the body experience
out-of-control growth. According to latest data from American
Cancer Society, it is estimated there will be 1.67 million new
cases of cancer in USA in 2014. Cancer is the second leading cause
of death in the United States (second only to heart disease) and
will claim more than 585,000 lives in 2014. In fact, it is
estimated that 50% of all men and 33% of all women living in the
United States will develop some type of cancer in their lifetime.
Therefore cancer constitutes a major public health burden and
represents a significant cost in the United States. These figures
are reflected elsewhere across most countries globally, although
the types of cancer and relative proportions of the population
developing the cancers vary depending upon many different factors
such including genetics and diet.
[0004] For decades surgery, chemotherapy, and radiation were the
established treatments for various cancers. Patients usually
receive a combination of these treatments depending upon the type
and extent of their disease. But chemotherapy is the most important
option for cancer patients when surgical treatment (i.e. the
removal of diseased tissue) is impossible. While surgery is
sometimes effective in removing tumors located at certain sites,
for example, in the breast, colon, and skin, it cannot be used in
the treatment of tumors located in other areas, such as the
backbone, nor in the treatment of disseminated hematologic cancers
include cancers of the blood and blood-forming tissues (such as the
bone marrow). They include multiple myeloma, lymphoma and leukemia.
Radiation therapy involves the exposure of living tissue to
ionizing radiation causing death or damage to the exposed cells.
Side effects from radiation therapy may be acute and temporary,
while others may be irreversible. Chemotherapy involves the
disruption of cell replication or cell metabolism. It is used most
often in the treatment of breast, lung, and testicular cancer. One
of the main causes of failure in this treatment of cancer is the
development of drug resistance by the cancer cells, a serious
problem that may lead to recurrence of disease or even death. Thus,
more effective cancer treatments are needed.
[0005] Multiple myeloma is a significant and growing problem. It is
a cancer arising from plasma cells. Normal plasma cells produce
immunoglobulins to fight infection. In myeloma, the plasma cells
become abnormal, multiply uncontrollably and release only one type
of antibody--known as paraprotein--which has no useful function. It
tends to accumulate in the bone marrow and circulate in the blood
and can be detected in the urine as well. It affects multiple sites
in the body (hence `multiple` myeloma) where bone marrow is
normally active in adults. The main forms of multiple myeloma (or
myeloma as it is also referred to) are active myeloma,
plasmacytoma, light chain myeloma and non-secretory myeloma. The
number of new cases of myeloma in the US in 2011 was 6.1 per
100,000 men and women per year and the percentage survival rate
beyond five years was 45%. It is estimated that the number of new
cases in the US in 2014 will be over 24,000 (1.4% of all cancer
cases), while the number of deaths in 2014 will be just over 11,000
(1.9% of all cancer cases).
[0006] In WO-A-2010/085377, the compound of formula I was shown to
have excellent in vitro activity against multiple myeloma cell
lines, with activities in the range of .times.35-100 greater than
the activity shown by bendamustin.
[0007] Leukemia is a type of cancer of the blood or bone marrow
characterized by an abnormal increase of immature white blood cells
called "blasts". Instead of producing normal, functioning white
blood cells to fight infection the body produces large numbers of
these non-functional blasts. Leukemia is a broad term covering a
spectrum of diseases. In turn, it is part of the even broader group
of diseases affecting the blood, bone marrow and lymphoid system,
which are all known as hematological neoplasms. The most common
forms are acute lymphoblastic leukemia (ALL), chronic lymphocytic
leukemia (CLL), acute myeloid leukemia (AML) and chronic myeloid
leukemia (CML), with less common forms including hairy cell
leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large
granular lymphocytic leukemia and T-cell acute lymphoblastic
leukemia. It is estimated that the number of new cases in the
United States in 2014 will be over 52,000 (3.1% of all new cancers
in the US) with over 24,000 deaths (4.1% of all cancer deaths in
the US). The percentage survival rate over five years is currently
57.2%, a figure significantly lower than for many other cancers,
with the survival rate over five years for acute myeloid leukemia
being particularly low at only 20%.
[0008] Lymphoma is a cancer of the lymphatic system. There are two
main types of lymphoma, namely Hodgkin lymphoma and non Hodgkin
lymphoma.
[0009] Non Hodgkin lymphoma is the more common form of lymphoma.
The lymphatic system runs throughout the body, and it is therefore
possible to find non Hodgkin lymphoma in almost all parts of the
body. In patients with non Hodgkin lymphoma, some of their white
blood cells (lymphocytes) divide abnormally. They do not have any
resting time like normal cells and they start to divide
continuously, so too many are produced. They do not naturally die
off as they usually do. These cells start to divide before they are
fully mature and therefore cannot fight infection as normal white
blood cells do. All the abnormal lymphocytes start to collect in
the lymph nodes or other places such as the bone marrow or spleen.
They can then grow into tumours and begin to cause problems within
the lymphatic system or the organ in which they are growing. For
example, if a lymphoma starts in the thyroid gland it can affect
the normal production of thyroid hormones. There are many different
types of non Hodgkin lymphoma. They can be classified in several
different ways. One way is by the type of cell affected. In non
Hodgkin lymphoma two types of lymphocyte can be affected--B cells
and T cells. This is classified as B cell lymphoma or a T cell
lymphoma. Most people with non Hodgkin lymphoma have B cell
lymphomas. T cell lymphomas are more common in teenagers and young
adults.
[0010] The cells of Hodgkin lymphoma have a particular appearance
under the microscope. These cells are called Reed Sternberg cells.
Non Hodgkin lymphomas do not have Reed Sternberg cells. It is
important for doctors to be able to tell the difference between
Hodgkin lymphoma and non Hodgkin lymphoma cells as they are two
different diseases. In Hodgkin lymphoma, it is cells in the lymph
nodes that have become cancerous.
[0011] The % survival rate over 5 years in 2009 for patients with
non Hodgkin lymphoma was 63%, while the survival rate for those
with Hodgkin lymphoma over the same period was 83%.
[0012] Breast cancer is a cancer that forms in tissues of the
breast. The most common type of breast cancer is ductal carcinoma,
which begins in the lining of the milk ducts (thin tubes that carry
milk from the lobules of the breast to the nipple). Another type of
breast cancer is lobular carcinoma, which begins in the lobules
(milk glands) of the breast. Breast cancers can be classified into
sub-groups as claudin-low tumors, basal-like tumors, human
epidermal growth factor receptor 2 (HER2) positive tumors, luminal
A tumors and luminal B tumors. Invasive breast cancer is breast
cancer that has spread from where it began in the breast ducts or
lobules to surrounding normal tissue. Breast cancer occurs in both
men and women, although male breast cancer is rare. In 2014, it is
estimated that there will be nearly 233,00 new cases in women and
2,400 in men, with 40,00 female deaths and just over 400 male
deaths.
[0013] Approximately 15 out of every 100 women with breast cancer
have triple-negative breast cancer, i.e. are estrogen negative, are
progesterone negative and are HER2 negative. Recurrent
triple-negative breast cancer is a condition of high unmet medical
need, due to its aggressive biology, fast development of drug
resistance and lack of molecular targets. Until now, chemotherapy
remains the standard of care for advanced triple-negative breast
cancer with a poor median overall survival.
[0014] In WO-A-2010/085377, the compound of formula I below is
disclosed. It is a first-in-class dual-functional alkylating-HDACi
fusion molecule which potently inhibits the HDAC pathway.
##STR00002##
[0015] Biological assays showed that the compound of formula I
potently inhibits HDAC enzyme (HDAC1 IC.sub.50 of 9 nM) and it has
been shown to have excellent in vitro activity against multiple
myeloma cell lines.
[0016] There is a need for more effective cancer treatments,
including the treatment of breast cancer and of hematologic cancers
such as multiple myeloma, lymphoma or leukemia. Currently, these
conditions affect many people and the medium to long-term prognosis
is not good for many of these conditions.
SUMMARY OF THE INVENTION
[0017] In a first aspect of the present invention there is provided
a combination comprising a proteasome inhibitor and a compound of
formula I or a pharmaceutically acceptable salt thereof:
##STR00003##
[0018] It has surprisingly been discovered that combinations of a
compound of formula I or a pharmaceutically acceptable salt thereof
and a proteasome inhibitor such as carfilzomib or bortezomib are
particularly effective in the treatment of cancers including
hematologic cancers such as multiple myeloma, lymphoma and
leukemia, and breast cancer, such that they are highly promising in
efforts to address the problem of finding more effective treatments
for cancer. The combinations may optionally further comprise a
glucocorticoid such as dexamethasone. These further combinations
are also particularly effective in the treatment of cancer.
[0019] In a second aspect of the present invention, there is
provided a pharmaceutical composition comprising a pharmaceutically
acceptable diluent or carrier and a combination according to the
first aspect of the invention.
[0020] In a third aspect of the present invention, there is
provided a kit comprising a combination according to the first
aspect of the present invention and, optionally, instructions for
treating a patient.
[0021] In a fourth aspect of the present invention, there is
provided a combination, composition or kit according to the first,
second or third aspect of the present invention for use in the
treatment of cancer.
[0022] In a fifth aspect of the present invention, there is
provided a method of treating cancer in a patient in need thereof
comprising administering to said patient a combination, composition
or kit according to the first, second or third aspect of the
present invention.
[0023] In a sixth aspect of the present invention, there is
provided a compound of formula (I) or a pharmaceutically acceptable
salt thereof for use in the treatment of relapsed/refractory
multiple myeloma. In one embodiment, the compound of formula (I) or
the pharmaceutically acceptable salt thereof is for use in the
treatment of relapsed/refractory multiple myeloma in combination
with a proteasome inhibitor and optionally further in combination
with a glucocorticoid.
[0024] In a seventh aspect of the present invention, there is
provided a method of treatment of relapsed/refractory multiple
myeloma in a patient in need thereof comprising administering to
said patient a compound of formula (I) or the pharmaceutically
acceptable salt thereof. In one embodiment, the compound of formula
(I) or the pharmaceutically acceptable salt thereof is administered
in combination with a proteasome inhibitor and may further
optionally be administered in combination with a glucocorticoid as
well.
DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is a plot of the % surviving in vitro MM1S multiple
myeloma cells as a % of control versus concentration for different
tested compounds after 48 hours incubation, for single compounds
and as combinations (double and triple);
[0026] FIG. 2 is a plot of the % surviving in vitro MM1S multiple
myeloma cells as a % of control versus concentration for different
tested compounds after 72 hours incubation, for single compounds
and as combinations (double and triple);
[0027] FIG. 3 is a plot of tumour growth (mm.sup.3) against the
number of days of study for different tested compounds for
CB17-SCID mice subcutaneously inoculated into the right flank with
3.times.10.sup.6 MM1S cells, for single compounds and as
combinations;
[0028] FIG. 4 is a plot of the % surviving in vitro RPM18226
multiple myeloma cells as a % of control versus concentration for
different tested compounds after 48 hours incubation, for single
compounds and as combinations (double);
[0029] FIG. 5 is a plot of the % surviving in vitro 2013-10-16 MTS
AMO abzb multiple myeloma cells as a % of control versus
concentration for different tested compounds after 48 hours
incubation, for single compounds and as combinations (double);
[0030] FIG. 6 is a plot of the % surviving in vitro 2014-01-15 MTS
Jeko mantle cell lymphoma cells as a % of control versus
concentration for different tested compounds after 48 hours
incubation, for single compounds and as combinations (double);
[0031] FIG. 7 is a plot of the % surviving in vitro 2014-01-15 MTS
Granta mantle cell lymphoma cells as a % of control versus
concentration for different tested compounds after 48 hours
incubation, for single compounds and as combinations (double);
[0032] FIG. 8 is a plot of the % surviving in vitro 2014-02-21 MTS
MTS MDA-MB468 basal like breast cancer cells as a % of control
versus concentration for different tested compounds after 48 hours
incubation, for single compounds and as combinations (double);
[0033] FIG. 9 is a plot of the % surviving in vitro MTS HL-60
promyelocytic leukemia cells as a % of control versus concentration
for different tested compounds after 48 hours incubation, for
single compounds and as combinations (double);
[0034] FIG. 10 is a plot of the % surviving in vitro MTS U937 acute
myeloid leukemia cells as a % of control versus concentration for
different tested compounds after 48 hours incubation, for single
compounds and as combinations (double);
[0035] FIG. 11 is a plot of the % surviving in vitro BJAB (germinal
center line) B cell lymphoma cells as a % of control versus
concentration for different tested compounds after 48 hours
incubation, for single compounds and as combinations (double);
[0036] FIG. 12 is a plot of the % surviving in vitro OciLy3
(ABC-type) B cell lymphoma cells as a % of control versus
concentration for different tested compounds after 48 hours
incubation, for single compounds and as combinations (double);
[0037] FIG. 13 is a plot of the % surviving in vitro TMD8
(ABC-type) B cell lymphoma cells as a % of control versus
concentration for different tested compounds after 48 hours
incubation, for single compounds and as combinations (double);
[0038] FIG. 14 is a plot of the % surviving in vitro BT-549 triple
negative breast cancer cells as a % of control versus concentration
for different tested compounds after 48 hours incubation, for
single compounds and as combinations (double); and
[0039] FIG. 15 is a plot of % surviving fraction of in vitro T98G,
U251 MG and U87MG glioblastoma cell lines against dose of
radiotherapy (Gy) in combination with two different concentrations
of the compound of formula I (EDO-S101) against a control with
radiotherapy alone.
DETAILED DESCRIPTION OF THE INVENTION
[0040] In the present application, a number of general terms and
phrases are used, which should be interpreted as follows.
[0041] "Animal" includes humans, non-human mammals (e.g., dogs,
cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the
like) and non-mammals (e.g., birds, and the like).
[0042] "Pharmaceutically acceptable salts" means salts of compounds
of the present invention which are pharmaceutically acceptable, as
defined above, and which possess the desired pharmacological
activity. Such salts include acid addition salts formed with
inorganic acids, or with organic acids. Pharmaceutically acceptable
salts also include base addition salts which may be formed when
acidic protons present are capable of reacting with inorganic or
organic bases. Generally, such salts are, for example, prepared by
reacting the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or
in an organic solvent or in a mixture of the two. Generally,
non-aqueous media like ether, ethyl acetate, ethanol, isopropanol
or acetonitrile are preferred. Examples of the acid addition salts
include mineral acid addition salts such as, for example,
hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate,
sulfamate, nitrate, phosphate, and organic acid addition salts such
as, for example, acetate, trifluoroacetate, maleate, fumarate,
citrate, oxalate, succinate, tartrate, salicylate, tosylate,
lactate, naphthalenesulphonae, malate, mandelate, methanesulfonate
and p-toluenesulfonate. Examples of the alkali addition salts
include inorganic salts such as, for example, sodium, potassium,
calcium and ammonium salts, and organic alkali salts such as, for
example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine,
triethanolamine and basic aminoacids salts.
[0043] It has surprisingly been discovered that combinations of a
compound of formula I or a pharmaceutically acceptable salt thereof
and a proteasome inhibitor such as carfilzomib or bortezomib are
particularly effective in the treatment of cancers including
hematologic cancers such as multiple myeloma, leukemia and
lymphoma, and breast cancer such that they are highly promising in
efforts to address the problem of finding more effective treatments
for cancer. The combinations may optionally further comprise a
glucocorticoid such as dexamethasone. These further combinations
are also particularly effective in the treatment of cancer.
[0044] In the combination of the present invention, the
pharmaceutically acceptable salt of the compound of formula I may
preferably be the hydrochloride, hydrobromide, hydroiodide,
sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate,
methanesulfonate, trifluoroacetate, glutamate, glucuronate,
glutarate, malate, maleate, succinate, fumarate, tartrate,
tosylate, salicylate, lactate, naphthalenesulfonate or acetate, and
more preferably the acetate.
[0045] In the combination of the present invention, the proteasome
inhibitor may preferably be selected from the group consisting of
bortezomib, carfilzomib, marizomib, delanzomib (CEP-18770),
oprozomib (ONX 0912), ixazomib (MLN-9708) and LU-102, or a
pharmaceutically acceptable salt thereof. Particularly preferably,
the proteasome inhibitor may be selected from bortezomib,
carfilzomib and LU-102.
[0046] The structures of these proteasome inhibitors are as
follows:
##STR00004## ##STR00005##
[0047] The combination of the present invention may further
comprise a glucocorticoid. In this embodiment of the combination of
the present invention, the glucocorticoid may preferably be
selected from the group consisting of dexamethasone, fluocinolone
acetonide and prednisone, and it is most preferably
dexamethasone.
[0048] In one further preferred combination of the present
invention comprising a compound of formula I or a pharmaceutically
acceptable salt thereof, a proteasome inhibitor and optionally a
glucocorticoid, said combination may further comprise one or more
additional pharmaceutically active agents. Particularly suitable
pharmaceutically active agents are anti-tumor agents having a
different mode of action to the compound of formula I or a
pharmaceutically acceptable salt thereof, the proteasome inhibitor
and the glucocorticoid, e.g. alkylating agents such as nitrosureas,
ethylenimines, alkylsulfonates, hydrazines and triazines, and
platinum based agents; plant alkaloids, taxanes, vinca alkaloids;
anti-tumor antibiotics such as chromomycins, anthracyclines, and
miscellaneous antibiotics such as Mitomycin and Bleomycin;
anti-metabolites such as folic acid antagonists, pyrimidine
antagonists, purine antagonists and adenosine deaminase inhibitors;
topoisomerase inhibitors such as topoisomerase I inhibitors,
topoisomerase II inhibitors, miscellaneous anti-neoplastics such as
ribonucleotide reductase inhibitors, adrenocortical steroid
inhibitor, anti-microtubule agents, and retinoids; protein kinases;
heat shock proteins, poly-ADP (adenosine diphosphate)-ribose
polymerase (PARP), hypoxia-inducible factors(HIF), proteasome,
Wnt/Hedgehog/Notch signaling proteins, TNF-alpha, matrix
metalloproteinase, farnesyl transferase, apoptosis pathway, histone
deacetylases (HDAC), histone acetyltransferases (HAT), and
methyltransferase; hormonal therapies, vascular disrupting agent,
gene therapy, RNAi cancer therapy, chemoprotective agents, antibody
conjugate, cancer immunotherapy such as Interleukin-2, cancer
vaccines or monoclonal antibodies; and preferably DNA damaging
agents, anti-metabolites, topoisomerase inhibitors,
anti-microtubule agents, EGFR inhibitors, HER2 inhibitors, VEGFR2
inhibitors, BRAF inhibitors, Bcr-Abl inhibitors, PDGFR inhibitors,
ALK inhibitors, PLK inhibitors, MET inhibitors, epigenetic agents,
HSP90 inhibitors, PARP inhibitors, CHK inhibitors, aromatase
inhibitor, estrogen receptor antagonist, and antibodies targeting
VEGF, HER2, EGFR, CD50, CD20, CD30, CD33, etc.
[0049] In one preferred embodiment of the combination of the
present invention, the proteasome inhibitor, the compound of
formula I or a pharmaceutically acceptable salt thereof and, if
present, the glucocorticoid are adapted for administration
concurrently, sequentially or separately. Preferably, the
proteasome inhibitor, the compound of formula I or a
pharmaceutically acceptable salt thereof and, if present, the
glucocorticoid are adapted for administration concurrently.
[0050] In one preferred embodiment of the combination of the
present invention, the proteasome inhibitor is selected from
bortezomib, carfilzomib and LU-102 and the compound of formula I or
a pharmaceutically acceptable salt thereof is
##STR00006##
[0051] or the acetate salt thereof. In one embodiment of this
combination, the combination may further comprise a glucocorticoid
wherein said glucocorticoid is dexamethasone.
[0052] In one preferred embodiment of the combination of the the
present invention, the molar ratio of proteasome inhibitor to
compound of formula I or a pharmaceutically acceptable salt thereof
in said combination is from 1:1000 to 1000:1. Preferably, the molar
ratio of proteasome inhibitor to compound of formula I or a
pharmaceutically acceptable salt thereof in said combination is
from 1:1000 to 10:1, more preferably from 1:800 to 1:200 or from
1:5 to 1:0.5, and most preferably it is from 1:700 to 1:400 or from
1:3 to 1:0.5, e.g. 1:1000, 1:900, 1:800, 1:700, 1:600, 1:500,
1:400, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1 or 1:0.5.
[0053] One particularly preferred combination of present invention
comprises the compound of formula I or the acetate salt thereof and
a proteasome inhibitor selected from bortezomib and carfilzomib,
wherein the molar ratio of the proteasome inhibitor selected from
bortezomib and carfilzomib to the compound of formula I or a
pharmaceutically acceptable salt thereof in said combination is
from 1:700 to 1:400, e.g. 1:700, 1:600, 1:500 or 1:400. Another
particularly preferred combination of the first aspect of the
present invention comprises the compound of formula I or the
acetate salt thereof and a proteasome inhibitor selected from
LU-102, wherein the molar ratio of LU-102 to the compound of
formula I or a pharmaceutically acceptable salt thereof in said
combination is from 1:3 to 1:0.5, e.g. 1:3, 1:2, 1:1 or 1:0.5.
[0054] It has been surprisingly found that combinations comprising
a proteasome inhibitor and a compound of formula I or a
pharmaceutically acceptable salt thereof are synergistic
combinations. In other words, the potency of the combinations was
measured with the Calcusyn software (biosoft, Ferguson, Mo., USA),
which is based on the Chou Talay method (Chou et al., Adv. Enzyme
Regul., 22, 27-55 (1984)), that calculates a combination index (CI)
with the following interpretation: [0055] CI 1>1: antagonist
effect, CI=1: additive effect and CI<1 synergistic effect.
[0056] It was found in the present work that for many of the dual
combinations of the invention comprising a proteasome inhibitor and
a compound of formula I or a pharmaceutically acceptable salt, CI
has been found to be less than 1, indicating synergy.
[0057] Another preferred embodiment of the combination of the
present invention further comprises a glucocorticoid in addition to
the proteasome inhibitor and the compound of formula I or a
pharmaceutically acceptable salt thereof, wherein the molar ratio
of proteasome inhibitor to the compound of formula I or a
pharmaceutically acceptable salt thereof to the glucocorticoid in
said combination is from 1:1000:20 to 1000:1:20. Preferably, the
molar ratio of proteasome inhibitor to the compound of formula I or
a pharmaceutically acceptable salt thereof to the glucocorticoid in
said combination is from 1:1000:10 to 1:100:2. Preferably, the
molar ratio of proteasome inhibitor to the compound of formula I or
a pharmaceutically acceptable salt thereof to the glucocorticoid
used in said combination is from 1:1000:5 to 1:200:2, more
preferably 1:700:4 to 1:400:3, e.g. 1:1000:5, 1:900:5, 1:800:4,
1:700:4, 1:600:4, 1:500:3 or 1:400:3.
[0058] One particularly preferred combination of the the present
invention comprises a proteasome inhibitor selected from bortezomib
and carfilzomib, a compound of formula I or the acetate salt
thereof and dexamethasone, wherein the molar ratio of the
proteasome inhibitor selected from bortezomib and carfilzomib to
the compound of formula I or the acetate salt thereof to
dexamethasone in said combination is from 1:700:4 to 1:400:3, e.g.
1:700:4, 1:700:3, 1:600:4, 1:600:3, 1:500:3 or 1:400:3. Another
particularly preferred combination of the first aspect of the
present invention comprises a proteasome inhibitor selected from
LU-102, the compound of formula I or the acetate salt thereof and
dexamethasone, wherein the molar ratio of LU-102 to the compound of
formula I or the acetate salt thereof to dexamethasone in said
combination is from 1:3:4 to 1:0.5:3, e.g. 1:3:4, 1:3:3, 1:2:4,
1:2:3, 1:1:4, 1:1:3 or 1:0.5:3.
[0059] It has also been surprisingly discovered that many of the
triple combinations of the present invention comprising a
proteasome inhibitor, a compound of formula I or a pharmaceutically
acceptable salt thereof and a glucocorticoid are also synergistic
combinations, i.e. the combination index CI has been found to be
less than 1.
[0060] The pharmaceutical composition according to the second
aspect of the present invention comprises a pharmaceutically
acceptable diluent or carrier and a combination according to the
first aspect of the present invention. Preferred compositions of
the second invention include those comprising the preferred
combinations of the present invention as described and exemplified
above. The pharmaceutically acceptable diluent or carrier of the
pharmaceutical composition according to the second aspect of the
present can be any suitable dispersant, excipient, adjuvant, or
other material which acts as a carrier for the active agents of the
combination of the present invention and which does not interfere
with the active agents present in said combination. Examples of
typical pharmaceutically acceptable carriers and diluents may be
found in "Remington's Pharmaceutical Sciences" by E. W. Martin and
these include water, saline, dextrose solution, serum solution,
Ringer's solution, polyethylene glycol (e.g PEG400), a surfactant
(e.g Cremophor), a cyclopolysaccharide (e.g
hydroxypropyl-.beta.-cyclodextrin or sulfobutyl ether
.beta.-cyclodextrins), a polymer, a liposome, a micelle, a
nanosphere, etc.
[0061] In the third aspect of the present invention, there is
provided a kit comprising a combination according to the first
aspect of the present invention and, optionally, instructions for
treating a patient. Typically, a kit can comprise a compound of
formula I or pharmaceutically acceptable salt thereof, a proteasome
inhibitor, and a glucocorticoid together with instructions for
treating a patient. Each active agent can be provided in a suitable
container. The kit may further comprise a delivery system, e.g. for
the compound of formula I or pharmaceutically acceptable salt
thereof, the proteasome inhibitor or the glucocorticoid or any
combination thereof.
[0062] The instructions may advise administering the proteasome
inhibitor, the compound of formula I or a pharmaceutically
acceptable salt thereof and, if present, the glucocorticoid of the
combination concurrently, sequentially or separately according to
variables such as the specific condition being treated, the state
of that condition, the activity of the specific compounds employed;
the specific combination employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compounds employed; the duration of the treatment; drugs used in
combination or contemporaneously with the specific compounds
employed; and like factors well known in the medical arts.
Preferred kits according to the third aspect of the present
invention include those comprising the preferred combinations of
the present invention as described and exemplified above.
[0063] In the fourth aspect of the present invention, there is
provided the combination, composition or kit according to the
first, second or third aspect of the present invention for use in
the treatment of cancer.
[0064] In the fifth aspect of the present invention, there is
provided a method of treating cancer in a patient in need thereof
comprising administering to said patient the combination,
composition or kit according to the first, second or third aspect
of the present invention.
[0065] It has been found that the combinations, compositions and
kits of the present invention are highly active both in vitro and
in vivo against a wide variety of tumour cell types. The
anti-tumour activity shown by these double and triple combinations
of the present invention, and by the combinations in the
compositions and kits of the present invention is, in many cases,
more than merely additive, showing combination indexes CI of
significantly less than 1, indicating synergy for these
combinations. This surprising finding is a further support for the
particular effectiveness of the combinations,compositions and kits
of the present invention in the treatment of cancer.
[0066] Examples of cancers which are treatable by the combinations,
compositions and kits of the present invention include hematologic
cancers such as multiple myeloma, lymphoma and leukemia, breast
cancer, lung cancer, colorectal cancer, prostate cancer, testicular
cancer, pancreatic cancer, liver cancer, stomach cancer, biliary
tract cancer, esophageal cancer, gastrointestinal stromal tumor,
cervical cancer, ovarian cancer, uterine cancer, renal cancer,
melanoma, basal cell carcinoma, squamous cell carcinoma, bladder
cancer, sarcoma, mesothelioma, thymoma, myelodysplastic syndrome,
glioblastoma and myeloproliferative disease. In particular, the
combinations, compositions and kits of the present invention are
effective against hematologic cancer such as multiple myeloma,
lymphoma and leukemia, and breast cancer.
[0067] In one embodiment of the combination, composition or kit for
use in the treatment of a cancer according to the fourth aspect of
the present invention or the method of treatment in accordance with
the fifth aspect of the present invention, the cancer is selected
from a hematologic cancer and breast cancer.
[0068] Where the combination, composition or kit of the present
invention is for use in the treatment of a hematologic cancer, this
may preferably be selected from multiple myeloma (e.g. active
myeloma, plasmacytoma, light chain myeloma or non-secretory
myeloma, with all forms being treatable in all phases including
relapsed and refractory phases), lymphoma (e.g. Hodgkin lymphoma or
non-Hodgkin lymphoma) and leukemia [acute lymphoblastic leukemia
(ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia
(AML, including myeloblastic leukemia, acute promyelocytic
leukemia, acute myelomonocytic leukemia, acute monocytic leukemia,
acute erythroleukemia and acute megakaryotic leukemia, with all
forms being treatable in all phases including relapsed and
refractory phases), chronic myeloid leukemia (CML), hairy cell
leukemia (HCL), T-cell prolymphocytic leukemia (T-PLL), large
granular lymphocytic leukemia or T-cell acute lymphoblastic
leukemia].
[0069] Where the combination, composition or kit of the present
invention is for use in the treatment of breast cancer, the breast
cancer may typically be selected from claudin-low tumors,
basal-like tumors, human epidermal growth factor receptor 2 (HER2)
positive tumors, luminal A tumors and luminal B tumors, and it is
preferably a triple-negative breast cancer.
[0070] In one preferred embodiment of the combination, composition
or kit for use in the treatment of cancer according to the present
invention and the method of treatment of cancer according to the
present invention, the proteasome inhibitor, the compound of
formula I or a pharmaceutically acceptable salt thereof and, if
present, the glucocorticoid are administered concurrently,
sequentially or separately. More preferably, the proteasome
inhibitor, the compound of formula I or a pharmaceutically
acceptable salt thereof and, if present, the glucocorticoid are
administered concurrently.
[0071] In the combination for use in the treatment of cancer and
the method of treatment of cancer in accordance with the present
invention, the compound of formula I or a pharmaceutically
acceptable salt thereof is typically administered to the patient in
need thereof at a dosage range of 10 to 100 mg/kg body weight
patient, and preferably at a dosage range of 40 to 80 mg/kg body
weight patient. Typically, the proteasome inhibitor is administered
to the patient in need thereof at a dosage range of 0.01 to 0.3
mg/kg body weight patient, more preferably at a dosage range of
0.05 to 0.15 mg/kg body weight patient. Where a glucocorticoid is
also administered in the combination, the glucocorticoid is
typically administered at a dosage range of from 0.1 to 1 mg/kg
body weight patient. Preferably, it is administered at a dosage
range of from 0.3 to 0.5 mg/kg body weight patient.
[0072] The therapeutically effective amount of a combination,
composition or kit according to the present invention is an amount
of the combination, composition or kit which confers a therapeutic
effect in accordance with the fourth and fifth aspects of the
present invention on the treated subject, at a reasonable
benefit/risk ratio applicable to any medical treatment. The
therapeutic effect may be objective (i.e. measurable by some test
or marker) or subjective (i.e. subject gives an indication of or
feels an effect). An effective amount of the combination,
composition or kit according to the present invention is believed
to be one wherein the compound of formula I or a salt thereof is
included in the combination at a dosage range of from 10 to 100
mg/kg body weight patient (e.g. 40 to 80 mg/kg body weight such as
40, 50, 60, 70 or 80 mg/kg body weight), the proteasome inhibitor
is included at a dosage range of from 0.01 to 0.3 mg/kg body weight
patient (e.g. 0.1 to 1 mg/kg such as 0.1, 0.2, 0.3, 0.4 or 0.5
mg/kg body weight) and the glucocorticoid is included at a dosage
range of from 0.03 to 1 mg/kg body weight patient (e.g. 0.3 to 0.5
mg/kg body weight patient, such as 0.3, 0.4 or 0.5 mg/kg body
weight patient).
[0073] Effective doses will vary depending on route of
administration, as well as the possibility of co-usage with other
active agents. It will be understood, however, that the total daily
usage of the combinations, compositions and kits of the present
invention will be decided by the attending physician within the
scope of sound medical judgment. The specific therapeutically
effective dose level for any particular patient will depend upon a
variety of factors including the disorder being treated and the
severity of the disorder; the activity of the specific compound
employed; the specific composition employed; the age, body weight,
general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of
the specific compound employed; the duration of the treatment;
drugs used in combination or contemporaneously with the specific
compound employed; and like factors well known in the medical
arts.
[0074] The present invention is also directed to the use of a
combination, composition or kit according to the first, second or
third aspect of the present invention in the manufacture of a
medicament for the treatment of cancer, e.g. for the treatment of a
hematologic cancer or breast cancer.
[0075] Suitable examples of the administration form of the
combination, composition or kit of the present invention include
without limitation oral, topical, parenteral, sublingual, rectal,
vaginal, ocular, and intranasal. Parenteral administration includes
subcutaneous injections, intravenous, intramuscular, intrasternal
injection or infusion techniques. Preferably, the combinations,
compositions and kits are administered parenterally. Combinations
and compositions of the invention can be formulated so as to allow
a combination or composition of the present invention to be
bioavailable upon administration of the combination or composition
to an animal, preferably human. Compositions can take the form of
one or more dosage units, where for example, a tablet can be a
single dosage unit, and a container of a combination or composition
of the present invention in aerosol form can hold a plurality of
dosage units.
[0076] Preferably the combinations of the present invention are
provided in the form of kits. Typically, a kit includes a
proteasome inhibitor, a compound of formula I or a pharmaceutically
acceptable salt thereof and, optionally, a glucocorticoid. In
certain embodiments, a kit can include one or more delivery
systems, e.g. the proteasome inhibitor, the compound of formula I
or a pharmaceutically acceptable salt thereof and, optionally, a
glucocorticoid, or any combination thereof, and directions for the
use of the kit (e.g. instructions for treating a subject). These
directions/instructions may advise administering the proteasome
inhibitor, the compound of formula I or a pharmaceutically
acceptable salt thereof and, if present, the glucocorticoid of the
combination concurrently, sequentially or separately according to
variables such as the specific condition being treated, the state
of that condition, the activity of the specific compounds employed;
the specific combination employed; the age, body weight, general
health, sex and diet of the patient; the time of administration,
route of administration, and rate of excretion of the specific
compounds employed; the duration of the treatment; drugs used in
combination or contemporaneously with the specific compounds
employed; and like factors well known in the medical arts.
[0077] The pharmaceutically acceptable diluent or carrier can be
particulate, so that the compositions are, for example, in tablet
or powder form. The carrier(s) can be liquid, with the
combinations, compositions or kits being, for example, an oral
syrup or injectable liquid. In addition, the carrier(s) can be
gaseous, so as to provide an aerosol composition useful in, for
example, inhalatory administration. Such pharmaceutical carriers
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
carriers can be 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, when administered to an animal, the
combination, composition or kit of the present invention and the
pharmaceutically acceptable carriers are sterile. Water is a
preferred carrier when the combination or composition of the
present invention is administered intravenously. Saline solutions
and aqueous dextrose and glycerol solutions can also be employed as
liquid carriers, particularly for injectable solutions. Suitable
pharmaceutical carriers also include excipients such as 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. The present compositions, if desired, can
also contain minor amounts of wetting or emulsifying agents, or pH
buffering agents.
[0078] When intended for oral administration, the combination,
composition or kit may be in solid or liquid form, where
semi-solid, semi-liquid, suspension and gel forms are included
within the forms considered herein as either solid or liquid.
[0079] As a solid composition for oral administration, the
combination, composition or kit can be formulated into a powder,
granule, compressed tablet, pill, capsule, chewing gum, wafer or
the like form. Such a solid composition typically contains one or
more inert diluents, either as a single tablet comprising all
active agents or as a number of separate solid compositions, each
comprising a single active agent of the combination of the present
invention (in the case of the kit). In addition, one or more of the
following can be present: binders such as carboxymethylcellulose,
ethyl cellulose, microcrystalline cellulose, or gelatin; excipients
such as starch, lactose or dextrins, disintegrating agents such as
alginic acid, sodium alginate, corn starch and the like; lubricants
such as magnesium stearate; glidants such as colloidal silicon
dioxide; sweetening agents such as sucrose or saccharin; a
flavoring agent such as peppermint, methyl salicylate or orange
flavoring; and a coloring agent.
[0080] When the combination or composition is in the form of a
capsule (e. g. a gelatin capsule), it can contain, in addition to
materials of the above type, a liquid carrier such as polyethylene
glycol, cyclodextrin or a fatty oil.
[0081] The combination, composition or kit can be in the form of a
liquid, e. g. an elixir, syrup, solution, emulsion or suspension.
The liquid can be useful for oral administration or for delivery by
injection. When intended for oral administration, a combination,
composition or kit can comprise one or more of a sweetening agent,
preservatives, dye/colorant and flavor enhancer. In a combination
or composition for administration by injection, one or more of a
surfactant, preservative, wetting agent, dispersing agent,
suspending agent, buffer, stabilizer and isotonic agent can also be
included. In the kit of the present invention, the liquid
components comprising one or more of the active agents of the
composition may either be combined prior to administration and
administered concurrently or each active agent may be administered
sequentially or separately.
[0082] The preferred route of administration is parenteral
administration including, but not limited to, intradermal,
intramuscular, intraperitoneal, intravenous, subcutaneous,
intranasal, epidural, intranasal, intracerebral, intraventricular,
intrathecal, intravaginal or transdermal. The preferred mode of
administration is left to the discretion of the practitioner, and
will depend in part upon the site of the medical condition (such as
the site of cancer). In a more preferred embodiment, the present
combinations, compositions and kits of the present invention are
administered intravenously.
[0083] The liquid combinations, compositions and kits of the
invention, whether they are solutions, suspensions or other like
form, can also include one or more of the following: sterile
diluents such as water for injection, saline solution, preferably
physiological saline, Ringer's solution, isotonic sodium chloride,
fixed oils such as synthetic mono or digylcerides, polyethylene
glycols, glycerin, or other solvents; antibacterial agents such as
benzyl alcohol or methyl paraben; and agents for the adjustment of
tonicity such as sodium chloride or dextrose. A parenteral
combination or composition can be enclosed in an ampoule, a
disposable syringe or a multiple-dose vial made of glass, plastic
or other material. Physiological saline is a preferred
adjuvant.
[0084] For administration (e.g. intravenous) the combination,
composition or kit may typically comprise the compound of formula I
or a salt thereof at a dosage range of from 10 to 100 mg/kg body
weight patient, the proteasome inhibitor at a dosage range of from
0.01 to 0.3 mg/kg body weight patient and the glucocorticoid at a
dosage range of from 0.03 to 1 mg/kg body weight patient. More
preferably, the combination, composition or kit may typically
comprise the compound of formula I or a salt thereof at a dosage
range of from 40 to 80 mg/kg body weight patient, the proteasome
inhibitor at a dosage range of from 0.05 to 0.15 mg/kg body weight
patient and the glucocorticoid at a dosage range of from 0.3 to 0.5
mg/kg body weight patient.
[0085] The combinations of the inventions may be formulated such
that the proteasome inhibitor, the compound of formula I or a
pharmaceutically acceptable salt thereof and, if present, the
optional glucocorticoid of the combination are adapted for
administration concurrently, sequentially or separately.
Preferably, they are administered concurrently.
[0086] The combination, composition or kit of the present invention
can be administered by any convenient route, for example by
infusion or bolus injection, by absorption through epithelial or
mucocutaneous linings.
[0087] In specific embodiments, it can be desirable to administer
one or more combinations, compositions or kits of the present
invention or combinations, compositions or kits locally to the area
in need of treatment. In one embodiment, administration can be by
direct injection at the site (or former site) of a cancer, tumor or
neoplastic or pre-neoplastic tissue.
[0088] Pulmonary administration can also be employed, e. g. by use
of an inhaler or nebulizer, and formulation with an aerosolizing
agent, or via perfusion in a fluorocarbon or synthetic pulmonary
surfactant. In certain embodiments, the combination, composition or
kit of the present invention or compositions can be formulated as a
suppository, with traditional binders and carriers such as
triglycerides.
[0089] The present combination, composition or kit can take the
form of solutions, suspensions, emulsion, tablets, pills, pellets,
capsules, capsules containing liquids, powders, sustained-release
formulations, suppositories, emulsions, aerosols, sprays,
suspensions, or any other form suitable for use. Other examples of
suitable pharmaceutical carriers are described in "Remington's
Pharmaceutical Sciences" by E. W. Martin.
[0090] The pharmaceutical combinations, compositions and kits can
be prepared using methodology well known in the pharmaceutical art.
For example, a composition intended to be administered by injection
can be prepared by combining the components of a kit of the present
invention with water so as to form a solution. A surfactant can be
added to facilitate the formation of a homogeneous solution or
suspension.
[0091] The combinations, compositions and kits of the present
invention are particularly effective in the treatment of
cancer.
[0092] The combinations of the present invention have been shown to
have excellent activity against a wide variety of tumor cell types
both in vitro and in vivo, making them particularly interesting for
development for use in the treatment of cancer, e.g. hematologic
cancer and breast cancer.
[0093] It has also discovered in the present work that the compound
of formula I or a salt thereof can be administered in combination
with radiotherapy in the treatment of glioblastoma. Both in vitro
and in vivo studies showed that a combination of the compound of
formula I or a salt thereof together with radiotherapy was far more
effective than radiotherapy alone. There is a prior disclosure in
WO 2013/113838 of data for the compound of formula I tested in the
CNS Cancer (Glioma) cell lines SF-268, SF-295, SF-539, SNB-19,
SNB-75 and U-251. These suggest activity for the compound of
formula I against glioblastoma when used on its own.
EXAMPLES
[0094] In the following examples, the compound having the following
formula I is referred to as EDO-S101 (or EDO in the Figures):
##STR00007##
Example 1
EDO-S101 Combinations In Vitro--Multiple Myeloma MM1S Cell Line
[0095] EDO-S101 was combined in vitro with bortezomib and
dexamethasone in the multiple myeloma MM1S cell line kindly
provided by Steven Rosen at Northwestern University, Chicago, Ill.,
USA. Activity was measured by the MTT assay that is based on the
metabolic bromide reduction from
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazole (MTT), which is
produced by the mitochondrial enzyme succinate-dehydrogenase,
turned to a blue-colored compound named formazan. The mitochondrial
functionality of the treated cells is then determined. This method
has been extensively used to measure cell proliferation and
survival capacities. The remaining living cells are proportional to
the amount of formazan produced.
[0096] In brief the methodology was as follows: [0097] 30,000 MM1S
cells per well were plated into the 96-well microtiter plates.
[0098] EDO-S101 and PI dilutions were prepared in DMSO and
dexamethasone in ethanol and added into the wells to the final
concentrations indicated in the experiment. [0099] Plates were
incubated for 24-48-72 hours in the incubator at 37.degree. C. in a
humidified atmosphere in the presence of 5% CO.sub.2/95% air.
[0100] After the incubation 10 .mu.L of MTT solution were added in
each well and incubated for 2 hours to allow formazan crystal
formation. [0101] 100 .mu.l of a mix solution with SDS plus HCl (10
.mu.L of HCl for each 12 mL of SDS) was added to dissolve the
formazan crystals. [0102] Absorbance was read at 570 nm OD and use
a reference wavelength of 650 nm. [0103] Cell viability
(percentage) was obtained as follows: % Viability=OD treated
cells.times.100/OD control cells. [0104] Each dose was tested in
quadruplicate and each experiment was performed at least twice.
[0105] The concentrations for the different drugs were ratio
constant for all the experiments. EDO-S101 at 500 nM, 1 .mu.M, 2.5
.mu.M; dexamethasone at 2.5 nM; 5 nM; 10 nM; and bortezomib at 0.75
nM, 1.5 nM, 3 nM.
[0106] The results are as shown in Table 1 below and FIG. 1.
TABLE-US-00001 TABLE 1 48 H Cl For experimental values Dexa 48 h
EDO 48 h (nM) (nM) Fa Cl 2.5 500 0.43453 0.851 5 1000 0.56838 0.761
10 2000 0.683802 0.765 Cl For experimental values Bortz 48 h EDO 48
h (nM) (nM) Fa Cl 0.75 500 0.247333 1.087 1.5 1000 0.452958 1.230 3
2000 0.918526 0.627 Cl For experimental values DOBLE Dexa 48 h
Bortz 48 h (nM) (nM) Fa Cl 2.5 0.75 0.413191 1.105 5 1.5 0.620757
0.879 10 3 0.935984 0.494 Cl For experimental values Dexa 48 h
Bortz 48 h EDO 48 h (nM) (nM) (nM) Fa Cl 2.5 0.75 150 0.455868
0.958 5 1.5 300 0.673133 0.789 10 3 600 0.962173 0.404
[0107] The potency of the combination was quantitated with the
Calcusyn software (biosoft, Ferguson, Mo., USA), which is based on
the Chou Talay method (Chou et al., Adv. Enzyme Regul., 22, 27-55
(1984)), that calculates a combination index (CI) with the
following interpretation: [0108] CI 1>1: antagonist effect,
CI=1: additive effect and CI<1 synergistic effect.
[0109] It can be seen from the FIG. 1 and from above that EDO-S101
shows synergy with both bortezomib and also shows synergy in a
triple combination with bortezomib and dexamethasone.
[0110] In a further experiment, the same constant dose of these
drugs was incubated for 72 hours instead of 48 hours. The results
are as shown in Table 2 below and FIG. 2
TABLE-US-00002 TABLE 2 72 H Cl For experimental values DEXA EDO
(nM) (nM) Fa Cl 2.5 500 0.576413 0.682 5 1000 0.69365 0.836 10 2000
0.828332 0.829 Cl For experimental values BORTZ EDO (nM) (nM) Fa Cl
0.75 500 0.310537 1.336 1.5 1000 0.780181 1.166 3 2000 0.999302
0.489 Cl For experimental values DEXA BORTZ (nM) (nM) Fa Cl 2.5
0.75 0.411026 1.441 5 1.5 0.865318 0.876 10 3 1 0.017 Cl For
experimental values DEXA BORTZ EDO (nM) (nM) (nM) Fa Cl 2.5 0.75
500 0.607118 1.115 5 1.5 1000 0.923936 0.845 10 3 2000 1 0.017
[0111] Again, it can be seen from FIG. 2 and the above results in
Table 2 that EDO-S101 shows synergy with bortezomib and also shows
synergy in a triple combination with bortezomib and
dexamethasone.
Example 2
EDO-S101 Combinations In Vivo Against a Xenograft of Subcutaneous
Plasmacytoma
[0112] CB17-SCID mice (obtained from The Jackson Laboratory, Bar
Harbor, Me.) were subcutaneously inoculated into the right flank
with 3.times.10.sup.6 multiple myeloma MM1S cells kindly provided
by Steven Rosen at Northwestern University, Chicago, Ill., USA in
100 .mu.L RPMI 1640 medium and 100 .mu.L of Matrigel (BD
Biosciences). When tumours became palpable, mice were randomized to
8 groups of treatment with 5 mice in each one.
[0113] The groups were: [0114] Control (group treated with vehicle
alone) [0115] Bortezomib 1 mg/kg twice weekly intraperitoneal for
three weeks [0116] Dexamethasone 0.5 mg twice weekly intravenously
for three weeks [0117] EDO-S101 intravenously at doses of 30 mg/kg
once weekly for 3 doses, [0118] Bortezomib plus dexamethasone
[0119] Bortezomib plus EDO-S101 [0120] EDO-S101 plus dexamethasone
[0121] Triple combination of EDO-S101 plus Bortezomib and
dexamethasone
[0122] Caliper measurements of the tumor diameters were performed
every day, and the tumor volume was estimated as the volume of an
ellipse using the following formula:
V=4/3.pi..times.(a/2).times.(b/2)2, where "a" and "b" correspond to
the longest and shortest diameter, respectively.
[0123] The tumour growth results are as shown in FIG. 3 in a plot
of tumour growth (mm.sup.3) against the number of days of study. It
can be seen that the combination of EDO-S101 and bortezomib results
in tumour volumes lower than that seen with either agent alone
while the triple combination of EDO-S101, bortezomib and
dexamethasone shows very significantly lower tumour volumes by the
end of the study than any of the active agents individually.
Example 3
EDO-S101 Combinations In Vitro--Multiple Myeloma RPMI 8226 Cell
Line
[0124] Using the same test procedure as described in Example 1, but
using the multiple myeloma RPMI 8226 cell line (obtained from DMSZ)
in place of the MM1S cell line, combinations of EDO-S101 with
bortezomib, carfilzomib and LU-102 were tested for activity in
turn. The concentrations for the different drugs were ratio
constant for all the experiments. EDO-S101 at a concentration of 0,
2, 4, 8 .mu.M; each of bortezomib and carfilzomib at a
concentration of 0, 5, 10, 20 nM; and LU-102 at a concentration of
0, 1, 3.3, 10 .mu.M. Controls with bendamustin were also
performed.
[0125] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 4. The figure
shows clear synergy for each of the three combinations with
EDO-S101 in vitro against multiple myeloma RPMI 8226. The CI at 4
.mu.M EDO-S101 and 20 nm carfilzomib was 0.019 and the CI at 4
.mu.M EDO-S101 and 3 .mu.M LU-102 was 0.109.
Example 4
EDO-S101 Combinations In Vitro--Multiple Myeloma Cell Line
2013-10-16 MTS AMO abzb
[0126] Using the same test procedure as described in Example 1, but
using the bortezomib resistant multiple myeloma 2013-10-16 MTS AMO
abzb cell line (generated at the Department of Oncology and
Hematology of the Kantonsspital St. Gallen by Prof. Dr. med. C.
Driessen) in place of the MM1S cell line, combinations of EDO-S101
with bortezomib, carfilzomib and LU-102 were tested for activity in
turn. The concentrations for the different drugs were ratio
constant and were 0, 2, 4, 8 .mu.M for EDO-S101; 0, 1.25, 2.5, 5,
10, 20 nM for each of bortezomib and carfilzomib; and 0, 1, 3.3, 10
for LU-102.
[0127] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 5. The figure
shows clear synergy for the combinations of carflizomib and LU-102
with EDO-S101 in vitro against the bortezomib resistant multiple
myeloma 2013-10-16 MTS AMO abzb. The CI for the combinations of
EDO-S101 and carfilzomib against this cell line was 0.11 and that
for EDO-S101 and LU-102 was 0.25.
Example 5
EDO-S101 Combinations In Vitro--Mantle Cell Lymphoma Cell Line
2014-01-15 MTS Jeko
[0128] Using the same test procedure as described in Example 1, but
using the mantle cell lymphoma cell line 2014-01-15 MTS Jeko
(obtained from LGC Standards S.a.r.l., 6, rue Alfred Kastler, BP
83076, F-67123 Molsheim Cedex, France) in place of the MM1S cell
line, combinations of EDO-S101 with bortezomib, carfilzomib and
LU-102 were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and the
same as in Example 3.
[0129] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 6. The figure
shows clear synergy for each of the three combinations with
EDO-S101 in vitro against mantle cell lymphoma cell line 2014-01-15
MTS Jeko. The CI at 2 .mu.M EDO-S101 and 20 nm bortezomib was
0.292; the CI at 2 .mu.M EDO-S101 and 20 nm carfilzomib was 0.206;
and the CI at 2 .mu.M EDO-S101 and 10 .mu.M LU-102 was 0.204.
Example 6
EDO-S101 Combinations In Vitro--Mantle Cell Lymphoma Cell Line
2014-01-15 MTS Granta
[0130] Using the same test procedure as described in Example 1, but
using the mantle cell lymphoma cell line 2014-01-15 MTS Granta
(obtained from LGC Standards S.a.r.l., 6, rue Alfred Kastler, BP
83076, F-67123 Molsheim Cedex, France) in place of the MM1S cell
line, combinations of EDO-S101 with bortezomib, carfilzomib and
LU-102 were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and the
same as in Example 3.
[0131] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 7. The figure
shows clear synergy for each of the three combinations with
EDO-S101 in vitro against mantle cell lymphoma cell line 2014-01-15
MTS Granta. The CI at 0.5 .mu.M EDO-S101 and 8 nm bortezomib was
0.025; the CI at 0.5 .mu.M EDO-S101 and 8 nm carfilzomib was 0.089;
and the CI at 1 .mu.M EDO-S101 and 3 .mu.M LU-102 was 0.078.
Example 7
EDO-S101 Combinations In Vitro--Basal Like Breast Cancer Cell Line
MTS MDA-MB468
[0132] Using the same test procedure as described in Example 1, but
using the basal like breast cancer cell line MTS MDA-MB468
(obtained from LGC Standards S.a.r.l., 6, rue Alfred Kastler, BP
83076, F-67123 Molsheim Cedex, France) in place of the MM1S cell
line, combinations of EDO-S101 with bortezomib, carfilzomib and
LU-102 were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and
were 0, 2, 4, 8 and 16 .mu.M for EDO-S101; 0, 8, 16 and 32 nM for
each of bortezomib and carfilzomib; and 0, 1, 3.3 and 10 .mu.M for
LU-102.
[0133] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 8. The figure
shows clear synergy for each of the three combinations with
EDO-S101 in vitro against this triple negative breast cancer cell
line MTS MDA-MB468.
Example 8
EDO-S101 Combinations In Vitro--Promyelocytic Leukemia Cell Line
HL-60
[0134] Using the same test procedure as described in Example 1, but
using the promyelocytic leukemia cell line HL-60 (obtained from LGC
Standards S.a.r.l., 6, rue Alfred Kastler, BP 83076, F-67123
Molsheim Cedex, France) in place of the MM1S cell line,
combinations of EDO-S101 with bortezomib, carfilzomib and LU-102
were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and
were 0, 1, 2 and 4 .mu.M for EDO-S101; 0, 5, 10, 20 nM for
bortezomib and carfilzomib; and LU-102 for 0, 1, 3.3, 10 .mu.M.
[0135] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 9. The figure
shows clear synergy for each of the three combinations with
EDO-S101 in vitro against promyelocytic leukemia cell line HL-60.
The CI at 1 .mu.M EDO-S101 and 20 nm bortezomibzomib was 0.051; the
CI at 1 .mu.M EDO-S101 and 20 nm carfilzomib was 0.073; and the CI
at 1 .mu.M EDO-S101 and 3 .mu.M LU-102 was 0.387.
Example 9
EDO-S101 Combinations In Vitro--Acute Myeloid Leukemia Cell Line
U937
[0136] Using the same test procedure as described in Example 1, but
using the acute myeloid leukemia cell line U937 (obtained from LGC
Standards S.a.r.l., 6, rue Alfred Kastler, BP 83076, F-67123
Molsheim Cedex, France) in place of the MM1S cell line,
combinations of EDO-S101 with bortezomib, carfilzomib and LU-102
were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and
were the same as in Example 8.
[0137] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 10. The figure
shows clear synergy for each of the three combinations with
EDO-S101 in vitro against basal like acute myeloid leukemia cell
line U937. The CI at 2 .mu.M EDO-S101 and 10 nm bortezomib was
0.285; the CI at 2 .mu.M EDO-S101 and 10 nm carfilzomib was 0.272;
and the CI at 2 .mu.M EDO-S101 and 3 .mu.M LU-102 was 0.095.
Example 10
EDO-S101 Combinations In Vitro--B Cell Lymphoma Cell Line BJAB
[0138] Using the same test procedure as described in Example 1, but
using the B cell lymphoma cell line BJAB (germinal center line)
(obtained from LGC Standards S.a.r.l., 6, rue Alfred Kastler, BP
83076, F-67123 Molsheim Cedex, France) in place of the MM1S cell
line, combinations of EDO-S101 with bortezomib, carfilzomib and
LU-102 were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and
were the same as in Example 8.
[0139] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 11. The figure
shows strong synergy for the combination of EDO-S101 and
carfilzomib in particular in vitro against B cell lymphoma cell
line BJAB (germinal center line), while the combination of EDO-S101
and bortezomib also showed synergy. The CI for the combination of
EDO-S101 and carfilzomib was 0.09, while the CI for the combination
of EDO-S101 and bortezomib was 0.62.
Example 11
EDO-S101 Combinations In Vitro--B Cell Lymphoma Cell Line
OciLy3
[0140] Using the same test procedure as described in Example 1, but
using the B cell lymphoma cell line OciLy3 (ABC-type) (obtained
from LGC Standards S.a.r.l., 6, rue Alfred Kastler, BP 83076,
F-67123 Molsheim Cedex, France) in place of the MM1S cell line,
combinations of EDO-S101 with bortezomib, carfilzomib and LU-102
were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and
were 0, 0.5, 1 and 2 .mu.M for EDO-S101, 0, 5, 10 and 20 nM for
bortezomib and carfilzomib and 0, 1, 3.3 and 10 .mu.M for
LU-102.
[0141] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 12. The figure
shows strong synergy for the combination of EDO-S101 and bortezomib
in particular in vitro against B cell lymphoma cell line OciLy3
(ABC-type), while the combination of EDO-S101 and carfilzomib also
showed synergy. The CI for the combination of EDO-S101 and
carfilzomib was 0.59, while the CI for the combination of EDO-S101
and bortezomib was 0.21.
Example 12
EDO-S101 Combinations In Vitro--B Cell Lymphoma Cell Line TMD8
[0142] Using the same test procedure as described in Example 1, but
using the B cell lymphoma cell line TMD8 (ABC-type) (obtained from
LGC Standards S.a.r.l., 6, rue Alfred Kastler, BP 83076, F-67123
Molsheim Cedex, France) in place of the MM1S cell line,
combinations of EDO-S101 with bortezomib, carfilzomib and LU-102
were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and
were the same as in Example 11.
[0143] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 13. The figure
shows strong synergy for all combinations of EDO-S101 and
proteasome inhibitor tested. The CI for the combination of EDO-S101
and carfilzomib was 0.17, the CI for the combination of EDO-S101
and bortezomib was 0.14 and the CI for the combination of EDO-S101
and LU-102 was 0.63.
Example 13
EDO-S101 Combinations In Vitro--Triple Negative Breast Cancer Cell
Line BT-549
[0144] Using the same test procedure as described in Example 1, but
using the triple negative breast cancer cell line BT-549 (obtained
from LGC Standards S.a.r.l., 6, rue Alfred Kastler, BP 83076,
F-67123 Molsheim Cedex, France) in place of the MM1S cell line,
combinations of EDO-S101 with bortezomib, carfilzomib and LU-102
were tested for activity in turn. The concentrations for the
different drugs were ratio constant for all the experiments and
were 0, 1, 2 and 4 .mu.M for EDO-S101; 0, 5, 10 and 20 nM for each
of bortezomib and carfilzomib; and 0, 1, 3.3 and 10 .mu.M for
LU-102.
[0145] The cell viability as a percentage of the untreated control
was measured and the results are as shown in FIG. 14. The figure
shows clear synergy for each of the three combinations with
EDO-S101 in vitro against triple negative breast cancer cell line
BT-549. The CI for the combination of EDO-S101 and bortezomib was
0.14, the CI for the combination of EDO-S101 and carfilzomib was
0.05 and the CI for the combination of EDO-S101 and LU-102 was
0.38.
Example 14
Combinations of Radiotherapy and EDO-S101 Against Glioblastoma Cell
Lines In Vitro
[0146] For the U251 MG glioblastoma cell line, the IC.sub.50 was
measured to be 6.60 .mu.M for EDO-S101 (compared to 30 .mu.M for
bendamustin and 20 for temozolamide).
[0147] For the U87G glioblastoma cell line, the IC.sub.50 was
measured to be 1.36 .mu.M for EDO-S101 (compared to 50 .mu.M for
bendamustin and 20 for temozolamide).
[0148] For the T98G glioblastoma cell line, the IC.sub.50 was
measured to be 7.70 .mu.M for EDO-S101 (compared to 52 .mu.M for
bendamustin and >100 for temozolamide).
[0149] As can be seen from FIG. 15, the % survival rate for the
glioblstoma cells was considerably reduced when radiotherapy was
used in combination with a dose of EDO-S101 (5 .mu.M or 10 .mu.M)
compared to radiotherapy alone.
Example 15
Combinations of Radiotherapy and EDO-S101 Against Glioblastoma Cell
Lines In Vivo
[0150] U87MG, U251 MG and T98G
[0151] Subcutaneously Inoculated Xenografts
[0152] Treatments and Doses [0153] Vehicle (control) [0154]
Radiotherapy (2Gy/5 consecutive days) [0155] Temozolamide (16 mg/Kg
for 5 consecutive days, po) [0156] Temozolamide+radiotherapy [0157]
EDO-S101 (60 mg/Kg at day 1, 8 and 15 every 28 days, iv) [0158]
EDO-S101+radiotherapy
[0159] It was found that the time to progression of the tumours was
increased from approximately 17-18 days for the control for the
U251 MG mouse xenograft model, to 42 days with a combination of
radiotherapy and temozolamide to over 50 days for EDO-S101 alone
(significance P=0.924) to significantly over 50 days for a
combination of EDO-S101 and radiotherapy (significance
P=0.0359).
[0160] It was found that the time to progression of the tumours was
increased from approximately 15 days for the control for the U87MG
mouse xenograft model, to 35 days with a combination of
radiotherapy and temozolamide to 40 days for EDO-S101 alone
(significance P=2372) to significantly over 50 days for a
combination of EDO-S101 and radiotherapy (significance
P=0.0001).
Example 16
Activity of EDO-S101 Against Relapsed/Refractory Multiple Myeloma
Models
[0161] A genetic rearrangement of the MYC locus, resulting in
dysregulated expression of MYC, is the most common mutation in
human multiple myeloma. The genetically engineered Vk*MYC mouse
model is based on dysregulation of MYC, and has been extensively
validated as a clinically and biologically faithful model of
untreated multiple myeloma. Nine drugs or classes of drugs (DNA
alkylators, glucocorticoids, proteasome inhibitors, IMiDs,
nab-paclitaxel, histone deacetylase inhibitors, TACI-Ig, perifosine
and SNS-032, a CDK2,7,9 inhibitor) have been previously reported
with more than a 20% partial response rate in Vk*MYC MM. Among
those, the first five also have greater than 20% PR in patients
with multiple myeloma for a positive predictive value of 56%.
[0162] EDO-S101 induced a high rate of response in Vk*MYC multiple
myeloma that was sustained for more than three months in mice
receiving only two doses, one week apart. Remarkably EDO-S101 is
the only drug that was identified with single agent activity in the
very aggressive, multi-drug resistant Vk12653 transplant model of
relapsed/refractory multiple myeloma.
[0163] In conclusion, it can be seen that the compound of formula I
(EDO-S101) show excellent activity in combination with proteasome
inhibitors in acting both in vitro and in vivo against a wide range
of myeloma, lymphoma, leukemia and breast cell lines. Furthermore,
it can be seen that the activity of many of these combinations is
surprisingly synergistic, and in many cases to a very significant
degree. Yet further, it is seen in Examples 1 and 2 that triple
combinations comprising the compound of formula I, a proteasome
inhibitor and a glucocorticoid such as dexamethasone showed
particularly strong synergy.
[0164] As a result, it is to be expected that combinations of the
compound of formula I of the present invention with a proteasome
inhibitor, optionally comprising a glucocorticoid, will be of use
in the treatment of cancer, particularly hematologic cancers and
breast cancer.
* * * * *