U.S. patent application number 17/178609 was filed with the patent office on 2021-06-10 for combination of bcl-2 inhibitor and mek inhibitor for the treatment of cancer.
The applicant listed for this patent is Board of Regents, The University of Texas System, Genentech, Inc.. Invention is credited to Lina Han, Marina Konopleva, Mark Merchant, Deepak Sampath.
Application Number | 20210169865 17/178609 |
Document ID | / |
Family ID | 1000005405955 |
Filed Date | 2021-06-10 |
United States Patent
Application |
20210169865 |
Kind Code |
A1 |
Merchant; Mark ; et
al. |
June 10, 2021 |
COMBINATION OF BCL-2 INHIBITOR AND MEK INHIBITOR FOR THE TREATMENT
OF CANCER
Abstract
The present invention is directed to a combination therapy
involving a selective Bcl-2 inhibitor and a MEK inhibitor for the
treatment of a patient in need of such a therapy. The patient in
need of the combination therapy is suffering from cancer, such as
acute myeloid leukemia.
Inventors: |
Merchant; Mark; (South San
Francisco, CA) ; Sampath; Deepak; (South San
Francisco, CA) ; Konopleva; Marina; (Houston, TX)
; Han; Lina; (Houston, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Genentech, Inc.
Board of Regents, The University of Texas System |
South San Francisco
Austin |
CA
TX |
US
US |
|
|
Family ID: |
1000005405955 |
Appl. No.: |
17/178609 |
Filed: |
February 18, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15767914 |
Apr 12, 2018 |
10959993 |
|
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PCT/US2016/060271 |
Nov 3, 2016 |
|
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17178609 |
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62263082 |
Dec 4, 2015 |
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62250231 |
Nov 3, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/02 20180101;
A61K 45/06 20130101; A61K 31/4523 20130101; A61K 2300/00 20130101;
A61K 31/496 20130101 |
International
Class: |
A61K 31/4523 20060101
A61K031/4523; A61K 45/06 20060101 A61K045/06; A61K 31/496 20060101
A61K031/496; A61P 35/02 20060101 A61P035/02 |
Claims
1.-16. (canceled)
17. A pharmaceutical product comprising (i) a first composition
comprising
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib) or a pharmaceutically
acceptable salt thereof, and (ii) a second composition comprising
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (ABT-199) or a
pharmaceutically acceptable salt thereof.
18. The pharmaceutical product of claim 17 wherein the first
composition further comprises a pharmaceutically acceptable
excipient.
19. The pharmaceutical product of claim 17 wherein the second
composition further comprises a pharmaceutically acceptable
excipient.
20. The pharmaceutical product of claim 17 wherein the first
composition and the second composition are the same.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional application of U.S.
application Ser. No. 15/767,914, filed Apr. 12, 2018, the contents
of which are hereby incorporated by reference as if set forth in
its entirety. U.S. application Ser. No. 15/767,914 is the 35 U.S.C.
.sctn. 371 national stage of International Application No.
PCT/US2016/060271, filed Nov. 3, 2016, the contents of which are
hereby incorporated by reference as if set forth in its entirety.
International Application No. PCT/US2016/060271 claims priority to
U.S. provisional application Ser. No. 62/250,231, filed Nov. 3,
2015, the contents of which are hereby incorporated by reference as
if set forth in its entirety. International Application No.
PCT/US2016/060271 claims priority to U.S. provisional application
Ser. No. 62/263,082, filed Dec. 4, 2015, the contents of which are
hereby incorporated by reference as if set forth in its
entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to a combination therapy
involving a selective Bcl-2 inhibitor and a MEK inhibitor for the
treatment of a patient in need of such a therapy, and more
particularly is directed to the combination of venetoclax
(ABT-199/GDC-0199) and cobimetinib (GDC-0973).
BACKGROUND OF THE INVENTION
[0003] Protein kinases are enzymes that catalyze the
phosphorylation of proteins, and in particular the hydroxy groups
on tyrosine, serine, and threonine residues of proteins. The
consequences of this seemingly simple activity are significant.
Cell differentiation and proliferation (i.e., virtually all aspects
of cell life, in one-way or another) depend on protein kinase
activity. Furthermore, abnormal protein kinase activity has been
related to a host of disorders, ranging from relatively non-life
threatening diseases, such as psoriasis, to extremely virulent
diseases, such as glioblastoma (brain cancer).
[0004] Protein kinases can be categorized as receptor type or
non-receptor type. Receptor-type tyrosine kinases have an
extracellular, a transmembrane, and an intracellular portion, while
non-receptor type tyrosine kinases are wholly intracellular. They
are comprised of a large number of transmembrane receptors with
diverse biological activity. In fact, about 20 different
subfamilies of receptor-type tyrosine kinases have been identified.
One tyrosine kinase subfamily, designated the HER subfamily, is
comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands of this
subfamily of receptors identified so far include epithelial growth
factor, TGF-alpha, amphiregulin, HB-EGF, betacellulin, and
heregulin. Another subfamily of these receptor-type tyrosine
kinases is the insulin subfamily, which includes INS-R, IGF-IR, and
IR-R. The PDGF subfamily includes the PDGF-alpha and beta
receptors, CSFIR, c-kit, and FLK-II. In addition, there is the FLK
family, which is comprised of the kinase insert domain receptor
(KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4),
and the fms-like tyrosine kinase-1 (flt-1). The PDGF and FLK
families are usually considered together due to the similarities of
the two groups. (For a detailed discussion of the receptor-type
tyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994,
which is hereby incorporated by reference.)
[0005] The non-receptor type of tyrosine kinases is also comprised
of numerous subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70,
Fes/Fps, Fak. Jak, Ack, and LIMK. Each of these subfamilies is
further sub-divided into varying receptors. For example, the Src
subfamily is one of the largest and includes Src, Yes, Fyn, Lyn,
Lck, Blk, Hck, Fgr, and Yrk. The Src subfamily of enzymes has been
linked to oncogenesis. (For a more detailed discussion of the
non-receptor type of tyrosine kinases, see Bolen, Oncogene,
8:2025-2031 (1993), which is hereby incorporated by reference.)
[0006] Since protein kinases and their ligands play critical roles
in various cellular activities, deregulation of protein kinase
enzymatic activity can lead to altered cellular properties, such as
uncontrolled cell growth associated with cancer. In addition to
oncological indications, altered kinase signaling is implicated in
numerous other pathological diseases. These include, but are not
limited to: immunological disorders, cardiovascular diseases,
inflammatory diseases, and degenerative diseases. Therefore, both
receptor and non-receptor protein kinases are attractive targets
for small molecule drug discovery.
[0007] One particularly attractive goal for therapeutic use of
kinase modulation relates to oncological indications. For example,
modulation of protein kinase activity for the treatment of cancer
has been demonstrated successfully with the FDA approval of
Gleevec.RTM. (imatinib mesylate, produced by Novartis
Pharmaceutical Corporation of East Hanover, N.J.) for the treatment
of Chronic Myeloid Leukemia (CML) and gastrointestinal stroma
cancers. Gleevec is a selective Abl kinase inhibitor.
[0008] Modulation (particularly inhibition) of cell proliferation
and angiogenesis, two key cellular processes needed for tumor
growth and survival (Matter A. Drug Disc Technol 20016, 1005-1024),
is an attractive goal for the development of small-molecule drugs.
Anti-angiogenic therapy represents a potentially important approach
for the treatment of solid tumors and other diseases associated
with dysregulated vascularization, including ischemic coronary
artery disease, diabetic retinopathy, psoriasis and rheumatoid
arthritis. Cell anti-proliferative agents are desirable to slow or
stop the growth of tumors.
[0009] One particularly attractive target for small-molecule
modulation, with respect to antiangiogenic and anti-proliferative
activity is MEK. Inhibition of MEK1 (MAPK/ERK Kinase) is a
promising strategy to control the growth of tumors that are
dependent on aberrant ERK/MAPK pathway signaling (Solit et al.,
2006; Wellbrock et al., 2004). The MEK-ERK signal transduction
cascade is a conserved pathway, which regulates cell growth,
proliferation, differentiation, and apoptosis in response to growth
factors, cytokines, and hormones. This pathway operates downstream
of Ras which is often upregulated or mutated in human tumors. It
has been demonstrated that MEK is a critical effector of Ras
function. The ERK/MAPK pathway is upregulated in 30% of all tumors
and oncogenic activating mutations in K-Ras and B-Raf have been
identified in 22% and 18% of all cancers respectively (Allen et
al., 2003; Bamford S, 2004. Davies et al., 2002; Malumbres and
Barbacid, 2003). It has been reported that a large portion of human
cancers, including 66% (B-Raf) of malignant melanomas, 60% (K-Ras)
and 4% (B-Raf) of pancreatic cancers, 50% of colorectal cancers
(colon, in particular, K-Ras: 30%, B-Raf 15%), 20% (K-Ras) of lung
cancers, 27% (B-Raf) papillary and anaplastic thyroid cancer, and
10-20% (B-Raf) of endometriod ovarian cancers, harbor activating
Ras and Raf mutations. It has been shown that inhibition of the ERK
pathway, and in particular inhibition of MEK kinase activity,
results in anti-metastatic and anti-angiogenic effects largely due
to a reduction of cell-cell contact and motility as well as
downregulation of vascular endothelial growth factor (VEGF)
expression. Furthermore, expression of dominant negative MEK, or
ERK reduced the transforming ability of mutant Ras as seen in cell
culture and in primary and metastatic growth of human tumor
xenografts in vivo. Therefore, the MEK-ERK signal transduction
pathway is an appropriate pathway to target for therapeutic
intervention.
[0010] The Bcl-2 family of proteins regulates programmed cell death
triggered by developmental cues and in response to multiple Stress
signals (Cory. S., and Adams, J. M., Nature Reviews Cancer 2 (2002)
647-656: Adams, Genes und Development 17 (2003) 2481-2495; Danial,
N. N., and Korsmeyer. S. J., Cell 116 (2004) 205-219). Whereas cell
survival is promoted by Bcl-2 itself and several close relatives
(Bcl-xL, Bcl-W. Mcl-1, and Al), which bear three or four conserved
Bcl-2 homology (BH) regions, apoptosis is driven by two other
subfamilies. The initial signal for cell death is conveyed by the
diverse group of BH3-only proteins, including Bad, Bid, Bim, Puma
and Noxa, which have in common only the small BH3 interaction
domain (Huang and Strasser, Cell 103 (2000) 839-842). However, Bax
or Bak, multi-domain proteins containing BH1-BH3, are required for
commitment to cell death (Cheng, et al., Molecular Cell 8 (2001)
705-711; Wei, M. C., et al., Science 292 (2001) 727-730; Zong, W.
X., et al., Genes and Development 15 148 (2001) 1-1486). When
activated, they can permeabilize the outer membrane of mitochondria
and release pro-apoptogenic factors (e.g., cytochrome C) needed to
activate the caspases that dismantle the cell (Wang, K., Genes and
Development 15 (2001) 2922-2933; (Adams, 2003 supra); Green, D. R.,
and Kroemer, G., Science 305 (2004) 626-629).
[0011] Interactions between members of these three factions of the
Bcl-2 family may dictate whether a cell lives or dies. When
BH3-only proteins have been activated, for example, in response to
DNA damage, they can bind via their BH3 domain to a groove on their
pro-survival relatives (Sattler, et al., Science 275 (1997)
983-986). How the BH3-only and Bcl-2-like proteins control the
activation of Bax and Bak, however, remains poorly understood
(Adams, 2003 supra). Most attention has focused on Bax. This
soluble monomeric protein (Hsu, Y. T., et al., Journal of
Biological Chemistry 272 (1997) 13289-13834; Wolter, K. G., et al.,
Journal of Cell Biology 139 (1997) 1281-92) normally has its
membrane targeting domain inserted into its groove, probably
accounting for its cytosolic localization (Nechushtan. A., et al.,
EMBO Journal 18 (1999) 2330-2341; Suzuki, et al., Cell 103 (2000)
645-654; Schinzel, A., et al., J Cell Biol 164 (2004) 1021-1032).
Several unrelated peptides/proteins have been proposed to modulate
Bax activity (see, e.g., Lucken-Ardjomande, S., and Martinou, J.
C., J Cell Sci 118 (2005) 473-483), but their physiological
relevance remains to be established. Alternatively, Bax may be
activated via direct engagement by certain BH3-only proteins
(Lucken-Ardjomande, S., and Martinou, J. C, 2005 supra), the best
documented being a truncated form of Bid, tBid (Wei, M. C., et al.,
Genes und Development 14 (2000) 2060-2071; Kuwana, T., et al., Cell
111 (2002) 331-342; Roucou, X., et al., Biochemical Journal 368
(2002) 915-921; Catron, P. F., et al., Mol Cell 16 (2004) 807-818).
As discussed elsewhere (Adams 2003 supra), the oldest model, in
which Bcl-2 directly engages Bax (Oltvai, Z. N., et al., Cell 74
(1993) 609-619), has become potentially problematic because Bcl-2
is membrane bound while Bax is cytosolic, and their interaction
seems highly dependent on the detergents used for cell lysis (Hsu,
Y. T., and Youle, 1997 supra). Nevertheless, it has been
established that the BH3 region of Bax can mediate association with
Bcl-2 (Zha, H. and Reed, J., Journal of Biological Chemistry 272
(1997) 31482-88; Wang, K., et al., Molecular and Cellular Biology
18 (1998) 6083-6089), and that Bcl-2 may prevent the
oligomerization of Bax, even though no heterodimers can be detected
(Mikhailov. V., et al., Journal of Biological Chemistry 276 (2001)
18361-18374). Thus, whether the pro-survival proteins restrain Bax
activation directly or indirectly remains uncertain.
[0012] Although Bax and Bak seem in most circumstances to be
functionally equivalent (Lindsten, T. et al., Molecular Cell 6
(2000) 1389-1399; Wei, M. C., et al., 2001 supra), substantial
differences in their regulation would be expected from their
distinct localization in healthy cells. Unlike Bax, which is
largely cytosolic, Bak resides in complexes on the outer membrane
of mitochondria and on the endoplasmic reticulum of healthy cells
(Wei, M. C., et al., 2000 supra; Zong, W. X., et al., Journal of
Cell Biology 162 (2003) 59-69). Nevertheless, on receipt of
cytotoxic signals, both Bax and Bak change conformation, and Bax
translocates to the organellar membranes, where both Bax and Bak
then form homo-oligomers that can associate, leading to membrane
permeabilization (Hsu. Y. T., et al., PNAS 94 (1997) 3668-3672;
Wolter, K. G., et al., 1997 supra; Antonsson, B., et al., Journal
of Biological Chemistry 276 (2001) 11615-11623; Nechushtan. A. et
al., Journal of Cell Biology 153 (2001) 1265-1276: Wei, M. C., et
al., 2001 supra; Mikhailov, V., et al., Journal of Biological
Chemistry 278 (2003) 5367-5376).
[0013] There exist various Bcl-2 inhibitors, which all have the
same property of inhibiting prosurvival members of the Bcl-2 family
of proteins and are therefore promising candidates for the
treatment of cancer. Such Bcl-2 inhibitors include, for example:
Oblimersen, SPC-2996, RTA-402, Gossypol, AT-101, Obatoclax
mesylate, A-371191, A-385358, A-438744, ABT-737, ABT-263, AT-101,
BL-11, BL-193, GX-15-003, 2-Methoxyantimycin A3, HA-14-1. KF-67544,
Purpurogallin, TP-TW-37, YC-137 and Z-24, and are described, for
example, in Zhai, D., et al., Cell Death and Differentiation 13
(2006) 1419-1421.
SUMMARY OF THE INVENTION
[0014] The present invention is directed to a method of treating a
proliferative disorder, the method comprising administering to a
mammal in need thereof a therapeutically effective amount of a
combination of a MEK inhibitor and a selective Bcl-2 inhibitor.
[0015] The present invention is further directed to a
pharmaceutical product comprising (i) a first composition
comprising
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib) or a pharmaceutically
acceptable salt thereof, and (ii) a second composition comprising
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (ABT-199) or a
pharmaceutically acceptable salt thereof.
[0016] Other objects and features will be in part apparent and in
part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIGS. 1A through 1L are graphs depicting in vitro
cytotoxicity of cobimetinib and venetoclax against AML cell lines.
(FIG. 1A) The AML cell lines were treated with cobimetinib or
venetoclax at 0.001, 0.01, 0.1 and 1.0 .mu.M for 72 hrs. Calcusyn
software was used to calculate the IC.sub.50 values and combination
index (CI) based on the luminescent intensity that correlated with
number of viable cells determined by the CellTiter-Glo assay. P-ERK
was determined using flow cytometry and relative median
fluorescence intensity (R-MFI) was determined using MFI of p-ERK.
Response patterns 1-5 were shown. (FIGS. 1B through 1L) Growth
curves of representative cell lines from each response pattern.
[0018] FIGS. 2A, 2B, and 2C. Anti-leukemia activities of
cobimetinib/venetoclax against primary AML blasts. (FIG. 2A)
Primary AML peripheral blood mononuclear cells were cultured in
serum-Free Expansion Medium (SFEM) supplemented with BIT 9500 Serum
Substitute and cytokines including stem cell factor (100 ng/ml),
Flt3 ligand (50 ng/ml), IL-3 (20 ng/ml) and G-CSF (20 ng/ml) as
well as SRI (1 .mu.M). After culture for 5 days, cells were stained
with CD45-PE. Annexin-V-APC and DAPI-. The apoptotic leukemia
blasts (CD45dimAnnexin-V+) were determined by flow cytometry.
Results were expressed as percentage of specific apoptosis
calculated by the formula: 100.times.(% apoptosis of treated
cells-% apoptosis of control cells)/(100-% apoptosis of control
cells), or % growth inhibition of control using the viable cell
counts determined by Annexin-/DAPI. (FIG. 2B) Representative data
from 3 AML samples were shown, for those displaying synergy. MNCs
isolated from patients with AML (100,000) or healthy donors
(50,000) were plated in methylcellulose medium (1 mL/well; Cat.
04435; STEMCELL Technologies Inc., Vancouver, BC, Canada) in
triplicate per condition. Colonies were scored after 2 weeks of
culture. (FIG. 2C). Clinical data and combination index values
based on viable cell count. **p<0.01, ***p<0.001.
[0019] FIGS. 3A, 3B, 3C, 3D, and 3E demonstrate a Pharmacodynamic
study of underlying mechanisms of cobimetinib/venetoclax
combination. (FIGS. 3A, 3B, 3C, and 3D) RPPA data demonstrate
proteins differentially expressed in sensitive or resistant AML
cell lines (to single drugs or combination) treated with
cobimetinib or/and venetoclax at 0.5.times., 1.times. and
2.times.IC.sub.50 values for 24 hrs. Representative proteins that
are differentially expressed between combination-sensitive and
combination-resistant cells were shown. (FIG. 3E) The Bcl-2:BIM
complex was measured by the MSD ELISA assay in AML cell lines,
untreated, treated with venetoclax alone, treated with cobimetinib
alone, or treated with cobimetinib/venetoclax at 1.times.IC.sub.50
values for 4 hrs.
[0020] FIGS. 4A, 4B, and 4C demonstrate Mass cytometry analysis of
intracellular proteins in cell sub-populations. Mononuclear cells
from primary AML were treated with cobimetinib at 1.0 .mu.M for 2
hrs followed by 10 minutes plus or minus stimulation with G-CSF
(100 ng/ml). The SPADE tree was generated using markers including
CD7, CD117, CD123, CD64, CD34, CD26, CD45, TIM3, CD33, CD19, CD56,
CD2, CD15, CD41, CD38, CD166, CD3, CD90, CD11b, CD135 and HLA-DR.
FIG. 4A depicts representative markers from among those markers
tested. The grey-scale color represents the expression levels of
each indicated protein. (FIG. 4A) Bcl-2 family members at baseline
in the gated stem/progenitor AML cell populations (AML4295468:
CD34+CD38+CD123+CD33+; AML 4366894: CD34+CD38-CD123+CD33+). (FIG.
4B) The median intensity of each protein in the gated cell
populations mentioned above. (FIG. 4C) The intracellular signaling
protein activation in the gated populations mentioned above.
[0021] FIGS. 5A, 5B, 5C, 5D, and 5E demonstrate Anti-leukemia
efficacy of cobimetinib and venetoclax in OCI-AML3 and MOLM13 AML
model in vivo. OCI-AML3/Luc/GFP cells (1.times.10.sup.6 per mouse)
were injected intravenously into NSG mice. (FIG. 5A) The luciferase
intensity was quantified by serial bioluminescence imaging from 8
representative mice from 4 groups at week 5 post injection. (FIG.
5B) Overall survival rate in each group was estimated by the
Kaplan-Meier method. 1.times.10.sup.6 MOLM13-luci-GFP cells were
injected into NSGS mice. Leukemia engraftment was confirmed on day
3 using Bioluminescence imaging (BLI). Mice were orally dosed daily
with cobimetinib (10 mg/kg) or venetoclax (100 mg/kg) or in
combination for 14 days. Luciferase intensity was shown on day 17
(FIG. 5C). Human CD45 engraftment in BM and spleen was determined
by CyTOF. (FIG. 5D). The viable cell count was measured using
Vi-Cell. (FIG. 5E). **P: 0.01; ***P: 0.001.
DESCRIPTION OF THE EMBODIMENT(S) OF THE INVENTION
[0022] The present invention is directed to a combination therapy
involving a selective Bcl-2 inhibitor and a MEK inhibitor for the
treatment of a mammal, e.g., a human patient, in need of such a
therapy. Pro-survival molecules including Bcl-2 play critical roles
in leukemia transformation and chemoresistance. ABT-199 (also known
as, and optionally referred to herein as, GDC-01'), or venetoclax)
is an orally available BH3-mimetic that binds with high affinity to
Bcl-2, but lacks affinity for Bcl-X.sub.L and Mcl-1. The
anti-leukemia potency of venetoclax in acute myeloid leukemia (AML)
models has recently been demonstrated (see, e.g., Pan et al.,
Cancer Discovery 2014). However, venetoclax poorly inhibits Mcl-1,
causing resistance in leukemia cells that rely on Mcl-1 for
survival. The RAF/MEK/ERK (MAPK) cascade is a major effector
pathway in AML that is activated by upstream mutant proteins such
as FLT3, KIT and RAS. Additionally, the MAPK pathway regulates
Bcl-2 family proteins by stabilizing anti-apoptotic Mcl-1 and
inactivating pro-apoptotic BIM. In some embodiments, the present
invention is directed to a combination therapy that combines the
anti-tumor effects of the concomitant Bcl-2 and MAPK blockade by
venetoclax in combination with MEK1/2 inhibitor cobimetinib.
[0023] In some embodiment, the mammal, e.g., a human patient, in
need of the combination therapy is suffering from cancer, such as
acute myeloid leukemia. In some embodiments, the combination
therapy involves administering a therapeutically effective amount
of a selective Bcl-2 inhibitor and a therapeutically effective
amount of a MEK inhibitor for the treatment of a mammal, e.g., a
human patient, in need of such a therapy.
[0024] In some embodiments, the mammal, e.g., a human patient, in
need of the combination therapy is suffering from cancer, such as
multiple myeloma. In some embodiments, the combination therapy
involves administering a therapeutically effective amount of a
selective Bcl-2 inhibitor and a therapeutically effective amount of
a MEK inhibitor for the treatment of a mammal, e.g., a human
patient, in need of such a therapy.
[0025] In some embodiments, the selective Bcl-2 inhibitor comprises
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (also known as,
and optionally referred to herein as, venetoclax, or ABT-199, or
GDC-0199) or a pharmaceutically acceptable salt thereof. In some
embodiments, the combination therapy of the present invention
involves administration of a therapeutically effective amount of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof to
a mammal, e.g., a human patient, in need thereof. Venetoclax has
the following structure:
##STR00001##
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl)piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-1-yloxy)benzamide
[0026] In some embodiments, the MEK inhibitor comprises
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (also known as, and optionally
referred to herein as, cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof. In some embodiments, the
combination therapy of the present invention involves
administration of a therapeutically effective amount of
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-pipe-
ridin-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof to a mammal, e.g., a human
patient, in need thereof. Cobimetinib has the following
structure
##STR00002##
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl](3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl)methanone
[0027] The name of this compound as generated using ACD/Labs naming
software 8.00 release, product version 8.08 is
1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S)-
-piperidin-2-yl]azetidin-3-ol.
[0028] In some embodiments, the combination therapy comprises
administering to a mammal, e.g., a human patient, in need of such a
therapy a therapeutically effective amount of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (ABT-199) or a
pharmaceutically acceptable salt thereof and a therapeutically
effective amount of
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2-
S)-piperidin-2-yl]azetidin-1-yl}methanone (cobimetinib) or a
pharmaceutically acceptable salt thereof. The patient in need of
the combination therapy of the invention may be suffering from
cancer. In some embodiments, the cancer is acute myeloid leukemia.
In some embodiments, the cancer is multiple myeloma.
I. Definitions
[0029] The term "mammal" includes, but is not limited to, humans,
mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs,
sheep, and poultry. The term patient refers to a mammal, and in one
embodiment, the patient is a human male or a human female.
[0030] Herein, a "patient" (interchangeably termed "individual") is
a human patient. The patient may be a "cancer patient", i.e. one
who is suffering or at risk for suffering from one or more symptoms
of cancer. A "subject" or an "individual" for purposes of treatment
refers to any animal classified as a mammal, including humans,
domestic and farm animals, and zoo, sports, or pet animals, such as
dogs, horses, cats, cows, etc. Preferably, the mammal is human.
[0031] A "population" of patients refers to a group of patients
with cancer, such as in a clinical trial, or as seen by oncologists
following FDA approval for a particular indication, such as
unresectable or metastatic melanoma cancer therapy.
[0032] A "disorder" is any condition that would benefit from
treatment including, but not limited to, chronic and acute
disorders or diseases including those pathological conditions which
predispose the mammal to the disorder in question.
[0033] The terms "cell proliferative disorder" and "proliferative
disorder" refer to disorders that are associated with some degree
of abnormal cell proliferation. In one embodiment, the cell
proliferative disorder is cancer. In one embodiment, the cell
proliferative disorder is a tumor.
[0034] "Tumor," as used herein, refers to all neoplastic cell
growth and proliferation, whether malignant or benign, and all
pre-cancerous and cancerous cells and tissues. The terms "cancer",
"cancerous", "cell proliferative disorder", "proliferative
disorder" and "tumor" are not mutually exclusive as referred to
herein.
[0035] The terms "cancer" and "cancerous" refer to or describe the
physiological condition in mammals that is typically characterized
by unregulated cell growth. Examples of cancer include but are not
limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or
lymphoid malignancies. More particular examples of such cancers
include, but not limited to, squamous cell cancer (e.g., epithelial
squamous cell cancer), lung cancer including small-cell lung
cancer, non-small cell lung cancer, adenocarcinoma of the lung and
squamous carcinoma of the lung, cancer of the peritoneum,
hepatocellular cancer, gastric or stomach cancer including
gastrointestinal cancer and gastrointestinal stromal cancer,
pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer,
liver cancer, bladder cancer, cancer of the urinary tract,
hepatoma, breast cancer, colon cancer, rectal cancer, colorectal
cancer, endometrial or uterine carcinoma, salivary gland carcinoma,
kidney or renal cancer, prostate cancer, vulval cancer, thyroid
cancer, hepatic carcinoma, anal carcinoma, penile carcinoma,
melanoma, superficial spreading melanoma, lentigo maligna melanoma,
acral lentiginous melanomas, nodular melanomas, multiple myeloma
and B-cell lymphoma (including low grade/follicular non-Hodgkin's
lymphoma (NHL); small lymphocytic (SL) NHL; intermediate
grade/follicular NHL; intermediate grade diffuse NHL; high grade
immunoblastic NHL; high grade lymphoblastic NHL; high grade small
non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma;
AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia);
chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia
(ALL); hairy cell leukemia; chronic myeloblastic leukemia; and
post-transplant lymphoproliferative disorder (PTLD), as well as
abnormal vascular proliferation associated with phakomatoses, edema
(such as that associated with brain tumors), Meigs' syndrome,
brain, as well as head and neck cancer, and associated metastases.
In certain embodiments, cancers that are amenable to treatment by
the antibodies of the invention include breast cancer, colorectal
cancer, rectal cancer, non-small cell lung cancer, glioblastoma,
non-Hodgkins lymphoma (NHL), renal cell cancer, prostate cancer,
liver cancer, pancreatic cancer, soft-tissue sarcoma, kaposi's
sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer,
mesothelioma, and multiple myeloma. In some embodiments, the cancer
is selected from: small cell lung cancer, glioblastoma,
neuroblastomas, melanoma, breast carcinoma, gastric cancer,
colorectal cancer (CRC), and hepatocellular carcinoma.
[0036] The term "treating" as used herein, unless otherwise
indicated, means reversing, alleviating, inhibiting the progress
of, or preventing, either partially or completely, the growth of
tumors, tumor metastases, or other cancer-causing or neoplastic
cells in a patient. The object is to prevent or slow down (lessen)
an undesired physiological change or disorder, such as the growth,
development or spread of cancer. For purposes of this invention,
beneficial or desired clinical results include, but are not limited
to, alleviation of symptoms, diminishment of extent of disease,
stabilized (i.e., not worsening) state of disease, delay or slowing
of disease progression, amelioration or palliation of the disease
state, and remission (whether partial or total), whether detectable
or undetectable.
[0037] As used herein, the term "treatment" refers to clinical
intervention designed to alter the natural course of the individual
or cell being treated during the course of clinical pathology.
Desirable effects of treatment include decreasing the rate of
disease progression, ameliorating or palliating the disease state,
and remission or improved prognosis. For example, an individual is
successfully "treated" if one or more symptoms associated with
cancer are mitigated or eliminated, including, but are not limited
to, reducing the proliferation of (or destroying) cancerous cells,
decreasing symptoms resulting from the disease, increasing the
quality of life of those suffering from the disease, decreasing the
dose of other medications required to treat the disease, and/or
prolonging survival of individuals. "Treatment" refers to both
therapeutic treatment and prophylactic or preventative measures.
"Treatment" can also mean prolonging survival as compared to
expected survival if not receiving treatment. Those in need of
treatment include those already having the condition or disorder,
e.g., a patient with cancer.
[0038] The term "a method of treating" or its equivalent, when
applied to, for example, cancer refers to a procedure or course of
action that is designed to reduce or eliminate the number of cancer
cells in a patient, or to alleviate the symptoms of a cancer. "A
method of treating" cancer or another proliferative disorder does
not necessarily mean that the cancer cells or other disorder will,
in fact, be eliminated, that the number of cells or disorder will,
in fact, be reduced, or that the symptoms of a cancer or other
disorder will, in fact, be alleviated. Often, a method of treating
cancer will be performed even with a low likelihood of success, but
which, given the medical history and estimated survival expectancy
of a patient, is nevertheless deemed to induce an overall
beneficial course of action. The terms "co-administration" or
"co-administering" refer to the administration of said MEK
inhibitor and said selective Bcl-2 inhibitor as two separate
formulations or within one single formulation. The
co-administration can be simultaneous or sequential in either
order. In one further embodiment, there is a time period while both
(or all) active agents simultaneously exert their biological
activities. Said MEK inhibitor and said selective Bcl-2 inhibitor
are co-administered either simultaneously or sequentially (e.g. via
an intravenous (i.v.) through a continuous infusion (one for the
MEK inhibitor and eventually one for the Bcl-2 inhibitor; or the
Bcl-2 inhibitor is administered orally). When both therapeutic
agents are co-administered sequentially the agents are administered
in two separate administrations that are separated by a "specific
period of time". The term specific period of time is meant anywhere
from 1 hour to 15 days. For example, one of the agents can be
administered within about 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4,
3, 2, or 1 day, or 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13,
12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 hour from the
administration of the other agent, and, in one embodiment, the
specific period time is 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day, or
24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8,
7, 6, 5, 4, 3, 2 or 1 hour.
[0039] To "inhibit" is to decrease or reduce an activity, function,
and/or amount as compared to a reference.
[0040] For the purposes herein, a "previously treated" cancer
patient has received prior cancer therapy. A "previously treated"
unresectable or metastatic melanoma patient has received prior
therapy for unresectable or metastatic melanoma.
[0041] A "cancer medicament" is a drug effective for treating
cancer.
[0042] The terms "orally deliverable". "oral administration" and
"orally administered" herein refer to administration to a subject
per os (p.o.), that is, administration wherein the composition is
immediately swallowed, for example with the aid of a suitable
volume of water or other potable liquid. "Oral administration" is
distinguished herein from intraoral administration, e.g.,
sublingual or buccal administration or topical administration to
intraoral tissues such as periodontal tissues, that does not
involve immediate swallowing of the composition.
[0043] The term "simultaneously" means at the same time or within a
short period of time, usually less than 1 hour.
[0044] A dosing period as used herein is meant a period of time,
during which each therapeutic agent has been administered at least
once. A dosing cycle is usually about 1, 2, 3, 4, 5, 6.7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18.19, 20, 21, 22, 23.24, 25, 26, 27,
28, 29, or 30 days, and, in one embodiment, 6, 7, 8, 9, 10, 11, 12,
13, or 14 days, for example, 7 or 14 days.
[0045] In certain embodiments, a dosing period is a dosing
cycle.
[0046] It is self-evident that the pharmaceutically active agents
are administered to the patient in a "therapeutically effective
amount" (or simply "effective amount") which is the amount of the
respective compound or combination that will elicit the biological
or medical response of a tissue, system, animal or human that is
being sought by the researcher, veterinarian, medical doctor or
other clinician. The administration of an effective amount of a
pharmaceutically active agent can be a single administration or
split dose administration. A "split dose administration" is meant
an effective amount is a split into multiple doses, preferably 2,
and administered within 1 or 2 days. For example, if 100 mg of a
selective Bcl-2 inhibitor is deemed effective, it can be
administered in one 100 mg administration or two 50 mg
administrations. Split dose administration is sometimes desirable
at the beginning of a dosing period to reduce side effects. When an
effective amount is administered in split dosing, it is still
considered one administration of an effective amount. For example,
when 100 mg is the effective amount of a selective Bcl-2 inhibitor
and that amount is administered in two 50 mg doses over a period of
time, e.g. 2 days, only one effective amount is administered during
that period of time.
[0047] The term "pharmaceutical formulation" refers to a sterile
preparation that is in such form as to permit the biological
activity of the medicament to be effective, and which contains no
additional components that are unacceptably toxic to a subject to
which the formulation would be administered.
[0048] As used herein, a "pharmaceutically acceptable carrier" is
intended to include any and all material compatible with
pharmaceutical administration including solvents, dispersion media,
coatings, antibacterial and antifungal agents, isotonic and
absorption delaying agents, and other materials and compounds
compatible with pharmaceutical administration. A non-limiting list
of exemplary pharmaceutically acceptable carriers is a buffer,
excipient, stabilizer, or preservative. Except insofar as any
conventional media or agent is incompatible with the active
compound, use thereof in the compositions of the invention is
contemplated. Supplementary active compounds can also be
incorporated into the compositions.
[0049] The phrase "pharmaceutically acceptable salt" as used
herein, refers to pharmaceutically acceptable organic or inorganic
salts of a compound. Exemplary salts include, but are not limited,
to bismesylate, sulfate, citrate, acetate, oxalate, chloride,
bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate,
isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate,
tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A
pharmaceutically acceptable salt may involve the inclusion of
another molecule such as an acetate ion, a succinate ion or other
counter ion. The counter ion may be any organic or inorganic moiety
that stabilizes the charge on the parent compound. Furthermore, a
pharmaceutically acceptable salt may have more than one charged
atom in its structure. Instances where multiple charged atoms are
part of the pharmaceutically acceptable salt can have multiple
counter ions. Hence, a pharmaceutically acceptable salt can have
one or more charged atoms and/or one or more counter ion.
[0050] The desired pharmaceutically acceptable salt may be prepared
by any suitable method available in the art. For example, treatment
of the free base with an inorganic acid, such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid,
phosphoric acid and the like, or with an organic acid, such as
acetic acid, maleic acid, succinic acid, mandelic acid, fumaric
acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,
salicylic acid, a pyranosidyl acid, such as glucuronic acid or
galacturonic acid, an alpha hydroxy acid, such as citric acid or
tartaric acid, an amino acid, such as aspartic acid or glutamic
acid, an aromatic acid, such as benzoic acid or cinnamic acid, a
sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic
acid, or the like. Acids which are generally considered suitable
for the formation of pharmaceutically useful or acceptable salts
from basic pharmaceutical compounds are discussed, for example, by
P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts.
Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge
et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1 19; P.
Gould, International J. of Pharmaceutics (1986) 33 201217; Anderson
et al, The Practice of Medicinal Chemistry (1996), Academic Press,
New York; Remington's Pharmaceutical Sciences, 18.sup.th ed.,
(1995) Mack Publishing Co., Easton Pa.; and in The Orange Book
(Food & Drug Administration, Washington, D.C, on their
website). These disclosures are incorporated herein by reference
thereto.
II. Selective Bcl-2 Inhibitor
[0051] The combination therapy of the present invention involves
the administration of a selective Bcl-2 inhibitor. Methods of
treatment using selective Bcl-2 inhibitors are disclosed in U.S.
Publication No. 2012/0129853, the disclosure of which is hereby
incorporated by reference as if set forth in its entirety. In this
regard, a selective Bcl-2 inhibitor is one which selectively binds
to a particular protein within the Bcl-2 family. In some
embodiments, the combination therapy of the present invention
involves the administration of a selective Bcl-2 inhibitor that
selectively inhibits Bcl-2 protein. For example,
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (also known as,
and optionally referred to as, venetoclax, or ABT-199/GDC-0199) is
an orally available, potent and highly selective inhibitor of
Bcl-2, a member of the Bcl-2 family of regulator proteins that
regulate apoptosis. ABT-199 selectively binds to and elicits a
response on Bcl-2 proteins at much lower concentrations than those
required to bind to and elicit a response on Bcl-x.sub.L. As such,
when ABT-199 is administered to the patient, the inhibitor is more
prone to inhibit Bcl-2, rather than Bcl-x.sub.L. ABT-199 tends to
have a competitive binding affinity (Ki) for Bcl-2 that is at least
about 500, at least about 1000, at least about 2000, at least about
2500, at least about 3000, at least about 3500, and at least about
4000 times less than the binding affinity for Bcl-x.sub.L. As such,
even at low concentrations (i.e., picomolar concentrations),
ABT-199 will bind to and inhibit the Bcl-2 protein.
[0052] In some embodiments, the selective Bcl-2 inhibitor comprises
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof. In
some embodiments, the combination therapy of the present invention
involves administration of a therapeutically effective amount of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof to
a mammal, e.g., a human patient, in need thereof. Venetoclax has
the following structure:
##STR00003##
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl)piperazin-
-1-yl)-N-((3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
[0053] Venetoclax (or ABT-199/GDC-0199) may be formulated in its
parent-compound form (i.e., as a free base), in a pharmaceutically
acceptable salt form of the compound, or a combination of the
parent-compound form and the pharmaceutically acceptable salt form.
Additional suitable forms include the hydrate or solvated forms of
ABT-199. In some embodiments, the ABT-199 may be a crystalline
polymorph suitable for incorporation into a pharmaceutical
composition further comprising a pharmaceutical acceptable
excipient. Salts and crystalline forms of ABT-199 are disclosed in
U.S. Publication No. 2012/0157470, the disclosure of which is
hereby incorporated by reference as if set forth in its entirety.
The phrase "pharmaceutically acceptable salt(s)", as used herein,
means those salts of ABT-199 that are safe and effective for
administration to a patient and that do not adversely affect the
therapeutic qualities of the compound. Pharmaceutically acceptable
salts include salts of acidic or basic groups present in compounds
of the invention. Salts of ABT-199 can be prepared during isolation
or following purification of the compounds.
[0054] Acid addition salts are those derived from reaction of
Venetoclax (or ABT-199/GDC-0199) with an acid. For example, salts
including the acetate, acid phosphate, adipate, alginate,
ascorbate, bicarbonate, citrate, aspartate, benzoate,
benzenesulfonate (besylate), bisulfate, bitartrate, butyrate,
camphorate, camphorsulfonate, citrate, digluconate,
ethanesulfonate, ethanedisulfonate, formate, fumarate, gentisinate,
glycerophosphate, gluconate, glucaronate, glutamate, hemisulfate,
heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide,
isonicotinate, 1-hydroxy-2-naphthoate, lactate, lactobionate,
malate, maleate, malonate, mesitylenesulfonate, methanesulfonate,
naphthalenesulfonate, nicotinate, nitrate, oxalate,
p-toluenesulfonate, pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate), pantothenate,
pectinate, persulfate, phosphate, picrate, propionate, saccharate,
salicylate, succinate, sulfate, tartrate, thiocyanate,
trichloroacetate, trifluoroacetate, para-toluenesulfonate and
undecanoate salts of a compound of ABT-199 can be used in a
composition of the invention. Basic addition salts, including those
derived from reaction of ABT-199 with the bicarbonate, carbonate,
hydroxide or phosphate of cations such as aluminum, lithium,
sodium, potassium, calcium, zinc, and magnesium, can likewise be
used. (For a review on pharmaceutically acceptable salts see, e.g.,
Berge et al., 66J. Pharm. Sci., 1-19 (1977), incorporated herein by
reference, in its entirety.)
[0055] Venetoclax (or ABT-199/GDC-0199) or a pharmaceutically
acceptable salt thereof may present in a dosage form in an amount
that can be therapeutically effective when the composition is
administered to a subject in need thereof according to an
appropriate regimen. Dosage amounts are expressed herein as
parent-compound-equivalent amounts unless the context requires
otherwise. Typically, a unit dose (the amount administered at a
single time), which can be administered at an appropriate
frequency, e.g., twice daily to once weekly, is about 10 to about
1,000 mg, depending on the compound in question. Where frequency of
administration is once daily (q.d.), unit dose and daily dose are
the same. Illustratively, the unit dose is typically about 25 to
about 1,000 mg, more typically about 50 to about 500 mg, for
example about 50, about 100, about 150, about 200, about 250, about
300, about 350, about 400, about 450 or about 500 mg. Where the
dosage form comprises a capsule shell enclosing the dosage form,
e.g., a solid dispersion, or a tablet wherein the dosage form
(e.g., a solid dispersion) is formulated with other ingredients, a
unit dose can be deliverable in a single dosage form or a plurality
of dosage forms, most typically 1 to about 10 dosage forms.
[0056] The "therapeutically effective amount" of the venetoclax (or
ABT-199/GDC-0199) or the pharmaceutically acceptable salt thereof
refers to that amount of the compound being administered sufficient
to prevent development of or alleviate to some extent one or more
of the symptoms of the condition or disorder being treated.
Therapeutically effective amounts of ABT-199 depend on the
recipient of the treatment, the disorder being treated and the
severity thereof, the composition containing the compound, the time
of administration, the route of administration, the duration of
treatment, the compound potency, its rate of clearance and whether
or not another drug is co-administered. Generally, the methods of
the current invention involve administering a dose of the selective
Bcl-2 inhibitor ranging from about 0.001 mg/kg to about 1000 mg/kg.
In one embodiment, the methods involve administering a dose of
selective Bcl-2 inhibitor ranging from about 0.01 mg/kg to about
500 mg/kg. In a further embodiment, the methods involve
administering a dose of ABT-199 ranging from about 0.1 mg/kg to
about 300 mg/kg.
[0057] The methods of the current invention may have illustrated
improved efficacy in treating disease states compared to methods
currently known within the art due to the fact that ABT-199 may
selectively inhibit the Bcl-2 protein. The Bcl-2 family of proteins
is a group of proteins that have regulatory effects on many
developmental and homeostasis functions, such as apoptosis
(programmed cell death). The Bcl-2 family includes other proteins
include Bcl-x.sub.L and Bcl-w. However, inhibition of the
Bcl-x.sub.L protein has been shown to have an adverse impact on
platelet counts, in some cases resulting in thrombocytopenia. The
selective Bcl-2 inhibitor compounds have shown a higher binding
affinity (as evidenced by lower Ki values) for Bcl-2 compared to
other Bcl-2 family proteins, such as Bcl-x.sub.L and Bcl-w. As
such, the methods of the current invention provide the advantages
of inhibition of the Bcl-2 protein, with a decreased risk of the
adverse effects associated with Bcl-x.sub.L and Bcl-w inhibition,
such as thrombocytopenia. This may allow for a more tolerable
combination with other drugs such as cobimetinib. Additionally,
ABT-199 is a more potent Bcl-2 inhibitor than some Bcl-2 inhibitors
known in the art. Finally, it has been observed that acute myeloid
leukemia cells are more dependent on Bcl-2 than Bcl-X.sub.L for
survival, which is an unexpected finding in this field. The
rationale of combination with cobimetinib is to treat tumors in
which Bcl-2 and Mcl-1 are co-expressed.
[0058] The binding affinity for the various proteins is measured as
a value of Ki, which represents the amount of the compound required
to inhibit a physiologic process or compound (such as a protein) by
50%. See U.S. Publication No. 2012/0129853, the disclosure of which
is hereby incorporated by reference as if set forth in its
entirety. The selective Bcl-2 compounds used in the methods of the
current invention generally have a binding affinity (Ki) of less
than about 1 micromolar, less than about 500 nanomolar, less than
about 400 nanomolar, less than about 300 nanomolar, less than about
200 nanomolar, less than about 100 nanomolar, less than about 50
nanomolar, less than about 25 nanomolar, less than about 10
nanomolar, less than about 5 nanomolar, less than about 1
nanomolar, less than about 900 picomolar, less than about 800
picomolar, less than about 700 picomolar, less than about 600
picomolar, less than about 500 picomolar, less than about 400
picomolar, less than about 300 picomolar, less than about 200
picomolar, and less than about 100 picomolar to Bcl-2.
III. Cobimetinib
[0059] Cobimetinib (also known as, and optionally referred to
herein as, GDC-0973) is an orally available, potent, and highly
selective inhibitor of MEK1 and MEK2. MEK1 and MEK2 are central
components of the RAS/RAF pathway. Selective MEK inhibitors,
including cobimetinib, are disclosed in U.S. Pat. No. 7,803,839,
the disclosure of which is hereby incorporated by reference as if
set forth in its entirety.
[0060] In some embodiments, the MEK inhibitor comprises
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof. In some embodiments, the
combination therapy of the present invention involves
administration of a therapeutically effective amount of
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof to a mammal, e.g., a human
patient, in need thereof. Cobimetinib has the following
structure.
##STR00004##
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl} methanone
[0061] Cobimetinib may be formulated in its parent-compound form
(i.e., as a free base), in a pharmaceutically acceptable salt form
of the compound, or a combination of the parent-compound form and
the pharmaceutically acceptable salt form. Additional suitable
forms include the hydrate or solvated forms of cobimetinib. In some
embodiments, the cobimetinib may be a crystalline polymorph
suitable for incorporation into a pharmaceutical composition
further comprising a pharmaceutical acceptable excipient. Salts and
crystalline forms of cobimetinib are disclosed in U.S. Pat. No.
7,803,839 and International Application No. PCT/EP2013/067050
(published as WO 2014/027056), the disclosures of which are hereby
incorporated by reference as if set forth in their entirety. The
phrase "pharmaceutically acceptable salt(s)", as used herein, means
those salts of cobimetinib that are safe and effective for
administration to a patient and that do not adversely affect the
therapeutic qualities of the compound. Pharmaceutically acceptable
salts include salts of acidic or basic groups present in compounds
of the invention. Salts of cobimetinib can be prepared during
isolation or following purification of the compounds.
[0062] Pharmaceutically acceptable salts are described herein and
known in the art. Exemplary salts include, but are not limited, to
sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,
nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,
lactate, salicylate, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucuronate, saccharate, formate,
benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A
pharmaceutically acceptable salt may involve the inclusion of
another molecule such as an acetate ion, a succinate ion or other
counter ion. The counter ion may be any organic or inorganic moiety
that stabilizes the charge on the parent compound. Furthermore, a
pharmaceutically acceptable salt may have more than one charged
atom in its structure. Instances where multiple charged atoms are
part of the pharmaceutically acceptable salt can have multiple
counter ions. Hence, a pharmaceutically acceptable salt can have
one or more charged atoms and/or one or more counter ion. If the
compound is a base, the desired pharmaceutically acceptable salt
may be prepared by any suitable method available in the art, for
example, treatment of the free base with an inorganic acid, such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
methanesulfonic acid, phosphoric acid and the like, or with an
organic acid, such as acetic acid, maleic acid, succinic acid,
mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic
acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as
glucuronic acid or galacturonic acid, an alpha hydroxy acid, such
as citric acid or tartaric acid, an amino acid, such as aspartic
acid or glutamic acid, an aromatic acid, such as benzoic acid or
cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or
ethanesulfonic acid, or the like. Acids which are generally
considered suitable for the formation of pharmaceutically useful or
acceptable salts from basic pharmaceutical compounds are discussed,
for example, by: P. Stahl et al, Camille G. (eds.) Handbook of
Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:
Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences
(1977) 66(1) 1 19; P. Gould, International J. of Pharmaceutics
(1986) 33 201217; Anderson et al, The Practice of Medicinal
Chemistry (1996), Academic Press, New York; Remington's
Pharmaceutical Sciences. 18th ed., (1995) Mack Publishing Co.,
Easton Pa.; and in The Orange Book (Food & Drug Administration.
Washington, D.C, on their website). If the compound is an acid, the
desired pharmaceutically acceptable salt may be prepared by any
suitable method, for example, treatment of the free acid with an
inorganic or organic base, such as an amine (primary, secondary or
tertiary), an alkali metal hydroxide or alkaline earth metal
hydroxide, or the like. Illustrative examples of suitable salts
include, but are not limited to, organic salts derived from amino
acids, such as glycine and arginine, ammonia, primary, secondary,
and tertiary amines, and cyclic amines, such as piperidine,
morpholine and piperazine, and inorganic salts derived from sodium,
calcium, potassium, magnesium, manganese, iron, copper, zinc,
aluminum and lithium.
[0063] Cobimetinib or a pharmaceutically acceptable salt thereof
may present in a dosage from in an amount that can be
therapeutically effective when the composition is administered to a
subject in need thereof according to an appropriate regimen. Dosage
amounts are expressed herein as parent-compound-equivalent amounts
unless the context requires otherwise. Typically, a unit dose (the
amount administered at a single time), which can be administered at
an appropriate frequency, e.g., twice daily to once weekly, is
about 10 to about 1,000 mg, depending on the compound in question.
Where frequency of administration is once daily (q.d.), unit dose
and daily dose are the same. Illustratively, the unit dose is
typically about 25 to about 1,000 mg, more typically about 50 to
about 500 mg, for example about 50, about 100, about 150, about
200, about 250, about 300, about 350, about 400, about 450 or about
500 mg. Where the dosage form comprises a capsule shell enclosing
the dosage form, e.g., a solid dispersion, or a tablet wherein the
dosage form, e.g., a solid dispersion is formulated with other
ingredients, a unit dose can be deliverable in a single dosage form
or a plurality of dosage forms, most typically 1 to about 10 dosage
forms.
[0064] The "therapeutically effective amount" of cobimetinib or the
pharmaceutically acceptable salt thereof refers to that amount of
the compound being administered sufficient to prevent development
of or alleviate to some extent one or more of the symptoms of the
condition or disorder being treated. Therapeutically effective
amounts of cobimetinib depend on the recipient of the treatment,
the disorder being treated and the severity thereof, the
composition containing the compound, the time of administration,
the route of administration, the duration of treatment, the
compound potency, its rate of clearance and whether or not another
drug is co-administered. Generally, the methods of the current
invention involve administering a dose of cobimetinib ranging from
about 0.001 mg/kg to about 1000 mg/kg. In one embodiment, the
methods involve administering a dose of cobimetinib ranging from
about 0.01 mg/kg to about 500 mg/kg. In a further embodiment, the
methods involve administering a dose of cobimetinib ranging from
about 0.1 mg/kg to about 300 mg/kg.
IV. Pharmaceutical Formulations
[0065] Typically, the concentration of drug or combination of drugs
in the pharmaceutical formulation is at least about 1%, e.g., about
1% to about 50%, by parent-compound-equivalent weight, but lower
and higher concentrations can be acceptable or achievable in
specific cases. Illustratively, the drug concentration in various
embodiments is at least about 2%, e.g., about 2% to about 50%, or
at least about 5%, e.g., about 5% to about 40%, for example about
5%, about 10%, about 15%, about 20%, about 25%, about 30%, about
35% or about 40%, by parent-compound-equivalent weight. In some
embodiments, the drug concentration may be between about 5% and
about 15%, such as between about 5% and about 12%, such as about
5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%,
or about 12%.
[0066] Orally deliverable solid dosage forms of the invention
include but are not limited to capsules, dragees, granules, pills,
powders and tablets. Excipients commonly used to formulate such
dosage forms include encapsulating materials or formulation
additives such as absorption accelerators, antioxidants, binders,
buffers, coating agents, coloring agents, diluents, disintegrating
agents, emulsifiers, extenders, fillers, flavoring agents,
humectants, lubricants, preservatives, propellants, releasing
agents, sterilizing agents, sweeteners, solubilizers and mixtures
thereof. Many excipients have two or more functions in a
pharmaceutical composition. Characterization herein of a particular
excipient as having a certain function, e.g., diluent,
disintegrant, binding agent, etc., should not be read as limiting
to that function. Further information on excipients can be found in
standard reference works such as Handbook of Pharmaceutical
Excipients, 3rd ed. (Kibbe, ed. (2000), Washington: American
Pharmaceutical Association).
[0067] In some embodiments, a suitable formulation may be prepared
as a solid dispersion, e.g., by a melting-extrusion process or by a
solvent evaporation process. The solid dispersion may be
administered to a patient in need thereof, or the solid dispersion
may be tabletted with further pharmaceutically acceptable
excipients.
[0068] The melting-extrusion process (meltrex) is disclosed in U.S.
Publication No. 2012/0108590, the disclosure of which is hereby
incorporated by reference as if set forth in its entirety. The
meltrex process comprises: (a) subjecting to elevated temperature
(i) an active pharmaceutical ingredient (API) or a pharmaceutically
acceptable salt thereof. (ii) a pharmaceutically acceptable
water-soluble polymeric carrier and (iii) a pharmaceutically
acceptable surfactant to provide an extrudable semi-solid mixture;
(b) extruding the semi-solid mixture, for example through a die;
and (c) cooling the resulting extrudate to provide a solid matrix
comprising the polymeric carrier and the surfactant and having the
compound or salt thereof dispersed in an essentially
non-crystalline form therein. A "melt" herein is a liquid or
semi-solid (e.g., rubbery) state induced by elevated temperature
wherein it is possible for a first component to become
homogeneously distributed in a matrix comprising a second
component. Typically, the second (matrix) component, for example a
polymeric carrier, is in such a state and other components, for
example including a compound of Formula I or a salt thereof,
dissolve in the melt, thus forming a solution. By "elevated
temperature" herein is meant a temperature above a softening point
of the polymeric carrier, as affected by other components if
present, such as plasticizers or surfactants.
[0069] The solvent evaporation process is disclosed in U.S.
Publication No. 20120277210, the disclosure of which is hereby
incorporated by reference as if set forth in its entirety. The
solvent evaporation process comprises: (a) dissolving (i) an active
pharmaceutical ingredient (API) or a pharmaceutically acceptable
salt thereof, (ii) a pharmaceutically acceptable water-soluble
polymeric carrier and (iii) a pharmaceutically acceptable
surfactant in a suitable solvent; and (b) removing the solvent to
provide a solid matrix comprising the polymeric carrier and the
surfactant and having the compound or salt thereof dispersed in an
essentially non-crystalline form therein.
[0070] Suitable diluents illustratively include, either
individually or in combination, lactose, including anhydrous
lactose and lactose monohydrate; lactitol; maltitol; mannitol;
sorbitol; xylitol; dextrose and dextrose monohydrate; fructose;
sucrose and sucrose-based diluents such as compressible sugar,
confectioner's sugar and sugar spheres; maltose; inositol
hydrolyzed cereal solids; starches (e.g., corn starch, wheat
starch, rice starch, potato starch, tapioca starch, etc.), starch
components such as amylose and dextrates, and modified or processed
starches such as pregelatinized starch; dextrins; celluloses
including powdered cellulose, microcrystalline cellulose,
silicified microcrystalline cellulose, food grade sources of
.alpha.- and amorphous cellulose and powdered cellulose, and
cellulose acetate; calcium salts including calcium carbonate,
tribasic calcium phosphate, dicalcium phosphate (e.g., dibasic
calcium phosphate dihydrate), monobasic calcium sulfate
monohydrate, calcium sulfate and granular calcium lactate
trihydrate; magnesium carbonate; magnesium oxide; bentonite;
kaolin; sodium chloride; and the like. Such diluents, if present,
typically constitute in total about 1% to about 95%, for example
about 5% to about 50%, or about 10% to about 30%, by weight of the
composition. The diluent or diluents selected preferably exhibit
suitable flow properties and, where tablets are desired,
compressibility.
[0071] Microcrystalline cellulose and silicified microcrystalline
cellulose are particularly useful diluents, and are optionally used
in combination with a water-soluble diluent such as mannitol.
Illustratively, a suitable weight ratio of microcrystalline
cellulose or silicified microcrystalline cellulose to mannitol is
about 10:1 to about 1:1, but ratios outside this range can be
useful in particular circumstances.
[0072] Suitable disintegrants include, either individually or in
combination, polymeric materials such as starches including
pregelatinized starch and sodium starch glycolate; clays; magnesium
aluminum silicate; cellulose-based disintegrants such as powdered
cellulose, microcrystalline cellulose, methylcellulose,
low-substituted hydroxypropylcellulose, carmellose, carmellose
calcium, carmellose sodium and croscarmellose sodium; alginates;
povidone; crospovidone; polacrilin potassium; gums such as agar,
guar, locust bean, karaya, pectin and tragacanth gums; colloidal
silicon dioxide; and the like. One or more disintegrants, if
present, typically constitute in total about 0.2% to about 30%, for
example about 0.5% to about 20%, or about 1% to about 10%, by
weight of the composition.
[0073] Sodium starch glycolate is a particularly useful
disintegrant, and typically constitutes in total about 1% to about
20%, for example about 2% to about 15%, or about 5% to about 10%,
by weight of the composition.
[0074] Binding agents or adhesives are useful excipients,
particularly where the composition is in the form of a tablet. Such
binding agents and adhesives should impart sufficient cohesion to
the blend being tableted to allow for normal processing operations
such as sizing, lubrication, compression and packaging, but still
allow the tablet to disintegrate and the composition to be absorbed
upon ingestion. Suitable binding agents and adhesives include,
either individually or in combination, acacia; tragacanth; glucose;
polydextrose; starch including pregelatinized starch; gelatin;
modified celluloses including methylcellulose, carmellose sodium,
hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose,
hydroxyethylcellulose and ethylcellulose; dextrins including
maltodextrin; zein; alginic acid and salts of alginic acid, for
example sodium alginate; magnesium aluminum silicate; bentonite:
polyethylene glycol (PEG); polyethylene oxide; guar gum;
polysaccharide acids; polyvinylpyrrolidone (povidone or PVP), for
example povidone K-15, K-30 and K-29/32; polyacrylic acids
(carbomers); polymethacrylates; and the like. One or more binding
agents and/or adhesives, if present, typically constitute in total
about 0.5% to about 25%, for example about 1% to about 15%, or
about 1.5% to about 10%, by weight of the composition.
[0075] Povidone and hydroxypropylcellulose, either individually or
in combination, are particularly useful binding agents for tablet
formulations, and, if present, typically constitute about 0.5% to
about 15%, for example about 1% to about 10%, or about 2% to about
8%, by weight of the composition.
[0076] Wetting agents, e.g., solubilizers, can be added to the
formulation if desired, in addition to the surfactant component of
the solid dispersion. Non-limiting examples of surfactants that can
be used as wetting agents include, either individually or in
combination, quaternary ammonium compounds, for example
benzalkonium chloride, benzethonium chloride and cetylpyridinium
chloride; dioctyl sodium sulfosuccinate; polyoxyethylene
alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10 and
octoxynol 9; poloxamers (polyoxyethylene and polyoxypropylene block
copolymers); polyoxyethylene fatty acid glycerides and oils, for
example polyoxyethylene (8) caprylic/capric mono- and diglycerides,
polyoxyethylene (35) castor oil and polyoxyethylene (40)
hydrogenated castor oil; polyoxyethylene alkyl ethers, for example
ceteth-10, laureth-4, laureth-23, oleth-2, oleth-10, oleth-20,
steareth-2, steareth-10, steareth-20, steareth-100 and
polyoxyethylene (20) cetostearyl ether; polyoxyethylene fatty acid
esters, for example polyoxyethylene (20) stearate, polyoxyethylene
(40) stearate and polyoxyethylene (100) stearate; sorbitan esters,
for example sorbitan monolaurate, sorbitan monooleate, sorbitan
monopalmitate and sorbitan monostearate; polyoxyethylene sorbitan
esters, for example polysorbate 20 and polysorbate 80; propylene
glycol fatty acid esters, for example propylene glycol laurate;
sodium lauryl sulfate; fatty acids and salts thereof, for example
oleic acid, sodium oleate and triethanolamine oleate; glyceryl
fatty acid esters, for example glyceryl monooleate, glyceryl
monostearate and glyceryl palmitostearate; .alpha.-tocopherol
polyethylene glycol (1000) succinate (TPGS); tyloxapol; and the
like. One or more wetting agents, if present, typically constitute
in total about 0.1% to about 15%, for example about 0.2% to about
10%, or about 0.5% to about 7%, by weight of the composition,
excluding surfactant present in the solid dispersion.
[0077] Nonionic surfactants, more particularly poloxamers, are
examples of wetting agents that can be useful herein.
Illustratively, a poloxamer such as Pluronic.TM. F127, if present,
can constitute about 0.1% to about 10%, for example about 0.2% to
about 7%, or about 0.5% to about 5%, by weight of the composition,
excluding surfactant present in the solid dispersion.
[0078] Lubricants reduce friction between a tableting mixture and
tableting equipment during compression of tablet formulations.
Suitable lubricants include, either individually or in combination,
glyceryl behenate; stearic acid and salts thereof, including
magnesium, calcium and sodium stearates; hydrogenated vegetable
oils; glyceryl palmitostearate; talc; waxes; sodium benzoate;
sodium acetate, sodium fumarate; sodium stearyl fumarate; PEGs
(e.g., PEG 4000 and PEG 6000), poloxamers; polyvinyl alcohol;
sodium oleate; sodium lauryl sulfate; magnesium lauryl sulfate; and
the like. One or more lubricants, if present, typically constitute
in total about 0.05% to about 10%, for example about 0.1% to about
5%, or about 0.2% to about 2%, by weight of the composition. Sodium
stearyl fumarate is a particularly useful lubricant.
[0079] Anti-adherents reduce sticking of a tablet formulation to
equipment surfaces. Suitable anti-adherents include, either
individually or in combination, talc, colloidal silicon dioxide,
starch, DL-leucine, sodium lauryl sulfate and metallic stearates.
One or more anti-adherents, if present, typically constitute in
total about 0.05% to about 10%, for example about 0.1% to about 7%,
or about 0.2% to about 5%, by weight of the composition. Colloidal
silicon dioxide is a particularly useful anti-adherent.
[0080] Glidants improve flow properties and reduce static in a
tableting mixture. Suitable glidants include, either individually
or in combination, colloidal silicon dioxide, starch, powdered
cellulose, sodium lauryl sulfate, magnesium trisilicate and
metallic stearates. One or more glidants, if present, typically
constitute in total about 0.05% to about 10%, for example about
0.1% to about 7%, or about 0.2% to about 5%, by weight of the
composition, excluding glidant present in the solid dispersion.
Colloidal silicon dioxide is a particularly useful glidant.
[0081] Other excipients such as buffering agents, stabilizers,
antioxidants, antimicrobials, colorants, flavors and sweeteners are
known in the pharmaceutical art and can be used in compositions of
the present invention. Tablets can be uncoated or can comprise a
core that is coated, for example with a nonfunctional film or a
release-modifying or enteric coating. Capsules can have hard or
soft shells comprising, for example, gelatin (in the form of hard
gelatin capsules or soft elastic gelatin capsules), starch,
carrageenan and/or HPMC, optionally together with one or more
plasticizers.
[0082] According to some embodiments of the present invention, a
pharmaceutical product is provided, the pharmaceutical product
comprising (i) a first composition comprising
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib) or a pharmaceutically
acceptable salt thereof, and (ii) a second composition comprising
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (ABT-199) or a
pharmaceutically acceptable salt thereof. As set forth above, in
some embodiments, the first composition further comprises a
pharmaceutically acceptable excipient. In some embodiments, the
second composition further comprises a pharmaceutically acceptable
excipient. In some embodiments, the first composition and the
second composition are the same. In some embodiments, the first
composition and the second composition are different.
V. Indications
[0083] In some embodiments, the method of the present invention
involves the administration to a mammal, e.g., a human patient, in
need of such a therapy a therapeutically effective amount of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof and
a therapeutically effective amount of
[3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof to treat a disease during
which is overexpressed one or more of antiapoptotic Bcl-2 protein,
antiapoptotic Bcl-X, protein and antiapoptotic Bcl-w protein.
[0084] In another embodiment, a composition of the invention is
administered in a therapeutically effective amount to a subject in
need thereof to treat a disease of abnormal cell growth and/or
dysregulated apoptosis.
[0085] Examples of such diseases include, but are not limited to,
cancer, mesothelioma, bladder cancer, pancreatic cancer, skin
cancer, cancer of the head or neck, cutaneous or intraocular
melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma
of the fallopian tubes, carcinoma of the endometrium, carcinoma of
the cervix, carcinoma of the vagina, carcinoma of the vulva, bone
cancer, colon cancer, rectal cancer, cancer of the anal region,
stomach cancer, gastrointestinal (gastric, colorectal and/or
duodenal) cancer, chronic lymphocytic leukemia, acute lymphocytic
leukemia, esophageal cancer, cancer of the small intestine, cancer
of the endocrine system, cancer of the thyroid gland, cancer of the
parathyroid gland, cancer of the adrenal gland, sarcoma of soft
tissue, cancer of the urethra, cancer of the penis, testicular
cancer, hepatocellular (hepatic and/or biliary duct) cancer,
primary or secondary central nervous system tumor, primary or
secondary brain tumor, Hodgkin's disease, chronic or acute
leukemia, chronic myeloid leukemia, lymphocytic lymphoma,
lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies
of T-cell or B-cell origin, melanoma, multiple myeloma, oral
cancer, non-small-cell lung cancer, prostate cancer, small-cell
lung cancer, cancer of the kidney and/or ureter, renal cell
carcinoma, carcinoma of the renal pelvis, neoplasms of the central
nervous system, primary central nervous system lymphoma,
non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma,
pituitary adenoma, adrenocortical cancer, gall bladder cancer,
cancer of the spleen, cholangiocarcinoma, fibrosarcoma,
neuroblastoma, retinoblastoma or a combination thereof.
[0086] In a more particular embodiment, the method of the present
invention involves the administration to a mammal, e.g., a human
patient, in need of such a therapy a therapeutically effective
amount of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof and
a therapeutically effective amount of
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof to treat to treat bladder
cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, chronic lymphocytic leukemia, acute lymphocytic leukemia,
colorectal cancer, esophageal cancer, hepatocellular cancer,
lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies
of T-cell or B-cell origin, melanoma, myelogenous leukemia,
myeloma, oral cancer, ovarian cancer, non-small-cell lung cancer,
prostate cancer, small-cell lung cancer or spleen cancer.
[0087] In a more particular embodiment, the method of the present
invention involves the administration to a mammal, e.g., a human
patient, in need of such a therapy a therapeutically effective
amount of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof and
a therapeutically effective amount of
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof to treat to treat acute
myeloid leukemia.
[0088] In a more particular embodiment, the method of the present
invention involves the administration to a mammal, e.g., a human
patient, in need of such a therapy a therapeutically effective
amount of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy) (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof and
a therapeutically effective amount of
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof to treat to treat multiple
myeloma.
[0089] For example, a method for treating mesothelioma, bladder
cancer, pancreatic cancer, skin cancer, cancer of the head or neck,
cutaneous or intraocular melanoma, ovarian cancer, breast cancer,
uterine cancer, carcinoma of the fallopian tubes, carcinoma of the
endometrium, carcinoma of the cervix, carcinoma of the vagina,
carcinoma of the vulva, bone cancer, colon cancer, rectal cancer,
cancer of the anal region, stomach cancer, gastrointestinal
(gastric, colorectal and/or duodenal) cancer, chronic lymphocytic
leukemia, acute lymphocytic leukemia, esophageal cancer, cancer of
the small intestine, cancer of the endocrine system, cancer of the
thyroid gland, cancer of the parathyroid gland, cancer of the
adrenal gland, sarcoma of soft tissue, cancer of the urethra,
cancer of the penis, testicular cancer, hepatocellular (hepatic
and/or biliary duct) cancer, primary or secondary central nervous
system tumor, primary or secondary brain tumor, Hodgkin's disease,
chronic or acute leukemia, chronic myeloid leukemia, lymphocytic
lymphoma, lymphoblastic leukemia, follicular lymphoma, lymphoid
malignancies of T-cell or B-cell origin, melanoma, multiple
myeloma, oral cancer, non-small-cell lung cancer, prostate cancer,
small-cell lung cancer, cancer of the kidney and/or ureter, renal
cell carcinoma, carcinoma of the renal pelvis, neoplasms of the
central nervous system, primary central nervous system lymphoma,
non-Hodgkin's lymphoma, spinal axis tumors, brain stem glioma,
pituitary adenoma, adrenocortical cancer, gall bladder cancer,
cancer of the spleen, cholangiocarcinoma, fibrosarcoma,
neuroblastoma, retinoblastoma or a combination thereof in a subject
comprises administering to the subject therapeutically effective
amounts of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof and
a therapeutically effective amount of
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof.
[0090] In another embodiment, the method of the present invention
involves the administration to a mammal, e.g., a human patient, in
need of such a therapy a therapeutically effective amount of
44-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-
-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-
-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (venetoclax, or
ABT-199/GDC-0199) or a pharmaceutically acceptable salt thereof and
a therapeutically effective amount of
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-piperid-
in-2-yl]azetidin-1-yl}methanone (cobimetinib, or GDC-0973) or a
pharmaceutically acceptable salt thereof to treat an immune or
autoimmune disorder. Such disorders include acquired
immunodeficiency disease syndrome (AIDS), autoimmune
lymphoproliferative syndrome, hemolytic anemia, inflammatory
diseases, thrombocytopenia, acute and chronic immune diseases
associated with organ transplantation, Addison's disease, allergic
diseases, alopecia, alopecia areata, atheromatous
disease/arteriosclerosis, atherosclerosis, arthritis (including
osteoarthritis, juvenile chronic arthritis, septic arthritis, Lyme
arthritis, psoriatic arthritis and reactive arthritis), autoimmune
bullous disease, abetalipoprotemia, acquired
immunodeficiency-related diseases, acute immune disease associated
with organ transplantation, acquired acrocyanosis, acute and
chronic parasitic or infectious processes, acute pancreatitis,
acute renal failure, acute rheumatic fever, acute transverse
myelitis, adenocarcinomas, aerial ectopic beats, adult (acute)
respiratory distress syndrome, AIDS dementia complex, alcoholic
cirrhosis, alcohol-induced liver injury, alcohol-induced hepatitis,
allergic conjunctivitis, allergic contact dermatitis, allergic
rhinitis, allergy and asthma, allograft rejection,
alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic
lateral sclerosis, anemia, angina pectoris, ankylosing
spondylitis-associated lung disease, anterior horn cell
degeneration, antibody mediated cytotoxicity, antiphospholipid
syndrome, anti-receptor hypersensitivity reactions, aortic and
peripheral aneurysms, aortic dissection, arterial hypertension,
arteriosclerosis, arteriovenous fistula, arthropathy, asthenia,
asthma, ataxia, atopic allergy, atrial fibrillation (sustained or
paroxysmal), atrial flutter, atrioventricular block, atrophic
autoimmune hypothyroidism, autoimmune haemolytic anaemia,
autoimmune hepatitis, type-1 autoimmune hepatitis (classical
autoimmune or lupoid hepatitis), autoimmune mediated hypoglycemia,
autoimmune neutropenia, autoimmune thrombocytopenia, autoimmune
thyroid disease, B-cell lymphoma, bone graft rejection, bone marrow
transplant (BMT) rejection, bronchiolitis obliterans, bundle branch
block, burns, cachexia, cardiac arrhythmias, cardiac stun syndrome,
cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation
response, cartilage transplant rejection, cerebellar cortical
degenerations, cerebellar disorders, chaotic or multifocal atrial
tachycardia, chemotherapy-associated disorders, chlamydia,
choleosatatis, chronic alcoholism, chronic active hepatitis,
chronic fatigue syndrome, chronic immune disease associated with
organ transplantation, chronic eosinophilic pneumonia, chronic
inflammatory pathologies, chronic mucocutaneous candidiasis,
chronic obstructive pulmonary disease (COPD), chronic salicylate
intoxication, colorectal common varied immunodeficiency (common
variable hypogammaglobulinemia), conjunctivitis, connective tissue
disease-associated interstitial lung disease, contact dermatitis.
Coombs-positive hemolytic anemia, cor pulmonale, Creutzfeldt-Jakob
disease, cryptogenic autoimmune hepatitis, cryptogenic fibrosing
alveolitis, culture-negative sepsis, cystic fibrosis, cytokine
therapy-associated disorders. Crohn's disease, dementia
pugilistica, demyelinating diseases, dengue hemorrhagic fever,
dermatitis, dermatitis scleroderma, dermatologic conditions,
dermatomyositis/polymyositis-associated lung disease, diabetes,
diabetic arteriosclerotic disease, diabetes mellitus, diffuse Lewy
body disease, dilated cardiomyopathy, dilated congestive
cardiomyopathy, discoid lupus erythematosus, disorders of the basal
ganglia, disseminated intravascular coagulation, Down's Syndrome in
middle age, drug-induced interstitial lung disease, drug-induced
hepatitis, drug-induced movement disorders induced by drugs which
block CNS dopamine receptors, drug sensitivity, eczema,
encephalomyelitis, endocarditis, endocrinopathy, enteropathic
synovitis, epiglottitis, Epstein-Barr virus infection,
erythromelalgia, extrapyramidal and cerebellar disorders, familial
hematophagocytic lymphohistiocytosis, fetal thymus implant
rejection, Friedreich's ataxia, functional peripheral arterial
disorders, female infertility, fibrosis, fibrotic lung disease,
fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis,
glomerular nephritis, glomerulonephritides, Goodpasture's syndrome,
goitrous autoimmune hypothyroidism (Hashimoto's disease), gouty
arthritis, graft rejection of any organ or tissue, graft versus
host disease, gram-negative sepsis, gram-positive sepsis,
granulomas due to intracellular organisms, group B streptococci
(GBS) infection, Graves' disease, hemosiderosis-associated lung
disease, hairy cell leukemia, Hallerrorden-Spatz disease,
Hashimoto's thyroiditis, hay fever, heart transplant rejection,
hemachromatosis, hematopoietic malignancies (leukemia and
lymphoma), hemolytic anemia, hemolytic uremic syndrome/thrombolytic
thrombocytopenic purpura, hemorrhage, Henoch-Schoenlein purpura,
hepatitis A, hepatitis B, hepatitis C. HIV infection/HIV
neuropathy, Hodgkin's disease, hypoparathyroidism, Huntington's
chorea, hyperkinetic movement disorders, hypersensitivity
reactions, hypersensitivity pneumonitis, hyperthyroidism,
hypokinetic movement disorders, hypothalamic-pituitary-adrenal axis
evaluation, idiopathic Addison's disease, idiopathic leucopenia,
idiopathic pulmonary fibrosis, idiopathic thrombocytopenia,
idiosyncratic liver disease, infantile spinal muscular atrophy,
infectious diseases, inflammation of the aorta, inflammatory bowel
disease, insulin dependent diabetes mellitus, interstitial
pneumonitis, iridocyclitis/uveitis/optic neuritis,
ischemia-reperfusion injury, ischemic stroke, juvenile pemicious
anemia, juvenile rheumatoid arthritis, juvenile spinal muscular
atrophy. Kaposi's sarcoma. Kawasaki's disease, kidney transplant
rejection, legionella, leishmaniasis, leprosy, lesions of the
corticospinal system, linear IgA disease, lipidema, liver
transplant rejection, Lyme disease, lymphederma, lymphocytic
infiltrative lung disease, malaria, male infertility idiopathic or
NOS, malignant histiocytosis, malignant melanoma, meningitis,
meningococcemia, microscopic vasculitis of the kidneys, migraine
headache, mitochondrial multisystem disorder, mixed connective
tissue disease, mixed connective tissue disease-associated lung
disease, monoclonal gammopathy, multiple myeloma, multiple systems
degenerations (Mencel, Dejerine-Thomas, Shy-Drager and
Machado-Joseph), myalgic encephalitis/Royal Free Disease,
myasthenia gravis, microscopic vasculitis of the kidneys,
Mycobacterium avium intracellulare, Mycobacterium tuberculosis,
myelodyplastic syndrome, myocardial infarction, myocardial ischemic
disorders, nasopharyngeal carcinoma, neonatal chronic lung disease,
nephritis, nephrosis, nephrotic syndrome, neurodegenerative
diseases, neurogenic I muscular atrophies, neutropenic fever,
non-alcoholic steatohepatitis, occlusion of the abdominal aorta and
its branches, occlusive arterial disorders, organ transplant
rejection, orchitis/epidydimitis, orchitis/vasectomy reversal
procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian
failure, pancreas transplant rejection, parasitic diseases,
parathyroid transplant rejection, Parkinson's disease, pelvic
inflammatory disease, pemphigus vulgaris, pemphigus foliaceus,
pemphigoid, perennial rhinitis, pericardial disease, peripheral
atherlosclerotic disease, peripheral vascular disorders,
peritonitis, pernicious anemia, phacogenic uveitis, Pneumocystis
carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin
changes syndrome), post-perfusion syndrome, post-pump syndrome,
post-MI cardiotomy syndrome, postinfectious interstitial lung
disease, premature ovarian failure, primary biliary cirrhosis,
primary sclerosing hepatitis, primary myxoedema, primary pulmonary
hypertension, primary sclerosing cholangitis, primary vasculitis,
progressive supranuclear palsy, psoriasis, psoriasis type 1,
psoriasis type 2, psoriatic arthropathy, pulmonary hypertension
secondary to connective tissue disease, pulmonary manifestation of
polyarteritis nodosa, post-inflammatory interstitial lung disease,
radiation fibrosis, radiation therapy, Raynaud's phenomenon and
disease, Raynoud's disease, Refsum's disease, regular narrow QRS
tachycardia, Reiter's disease, renal disease NOS, renovascular
hypertension, reperfusion injury, restrictive cardiomyopathy,
rheumatoid arthritis-associated interstitial lung disease,
rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,
scleroderma, senile chorea, senile dementia of Lewy body type,
sepsis syndrome, septic shock, seronegative arthropathies, shock,
sickle cell anemia, Sjogren's disease-associated lung disease,
Sjogren's syndrome, skin allograft rejection, skin changes
syndrome, small bowel transplant rejection, sperm autoimmunity,
multiple sclerosis (all subtypes), spinal ataxia, spinocerebellar
degenerations, spondyloarthropathy, sporadic polyglandular
deficiency type I, sporadic polyglandular deficiency type II,
Still's disease, streptococcal myositis, stroke, structural lesions
of the cerebellum, subacute sclerosing panencephalitis, sympathetic
ophthalmia, syncope, syphilis of the cardiovascular system,
systemic anaphylaxis, systemic inflammatory response syndrome,
systemic onset juvenile rheumatoid arthritis, systemic lupus
erythematosus, systemic lupus erythematosus-associated lung
disease, lupus nephritis, systemic sclerosis, systemic
sclerosis-associated interstitial lung disease. T-cell or FAB ALL,
Takaasu's disease/arteritis, telangiectasia, Th2-type and Th1-type
mediated diseases, thromboangitis obliterans, thrombocytopenia,
thyroiditis, toxicity, toxic shock syndrome, transplants,
trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody
hepatitis), type B insulin resistance with acanthosis nigricans,
type III hypersensitivity reactions, type IV hypersensitivity,
ulcerative colitic arthropathy, ulcerative colitis, unstable
angina, uremia, urosepsis, urticaria, uveitis, valvular heart
diseases, varicose veins, vasculitis, vasculitic diffuse lung
disease, venous diseases, venous thrombosis, ventricular
fibrillation, vitiligo acute liver disease, viral and fungal
infections, vital encephalitis/aseptic meningitis, vital-associated
hemaphagocytic syndrome, Wegener's granulomatosis,
Wernicke-Korsakoff syndrome. Wilson's disease, xenograft rejection
of any organ or tissue, yersinia and salmonella-associated
arthropathy and the like.
VI. Combination Dosing Regimens
[0091] The terms "orally deliverable", "oral administration" and
"orally administered" herein refer to administration to a subject
per os (p.o.), that is, administration wherein the composition is
immediately swallowed, for example with the aid of a suitable
volume of water or other potable liquid. "Oral administration" is
distinguished herein from intraoral administration, e.g.,
sublingual or buccal administration or topical administration to
intraoral tissues such as periodontal tissues, that does not
involve immediate swallowing of the composition.
[0092] The active ingredient form (e.g., parent compound or salt),
the polymeric carrier(s), surfactant(s) and other optional
ingredients should be selected, and relative amounts of these
components should be used, to provide a solid dispersion or dosage
form having acceptable bioabsorption when administered orally. Such
bioabsorption can be evidenced, for example, by the pharmacokinetic
(PK) profile of the solid dispersion or dosage form, more
particularly by the C.sub.max or AUC, for example AUC.sub.0-24 or
AUC.sub.0-.infin. at a particular dose or over a range of doses.
Illustratively, bioavailability can be expressed as a percentage,
for example using the parameter F, which computes AUC for oral
delivery of a test composition as a percentage of AUC for
intravenous (i.v.) delivery of the drug in a suitable solvent,
taking into account any difference between oral and i.v. doses.
[0093] Bioavailability can be determined by PK studies in humans or
in any suitable model species. For present purposes, a dog model is
generally suitable. In various illustrative embodiments,
compositions of the invention exhibit oral bioavailability of at
least about 15%, at least about 20%, at least about 25% or at least
about 30%, up to or exceeding about 50%, in a dog model, when
administered as a single dose of about 2.5 to about 10 mg/kg to
fasting or non-fasting animals.
[0094] Compositions embraced herein are useful for orally
delivering a drug or a pharmaceutically acceptable salt thereof to
a subject. Accordingly, a method of the invention for delivering
such a drug to a subject comprises orally administering a
composition as described above.
[0095] The subject can be human or non-human (e.g., a farm, zoo,
work or companion animal, or a laboratory animal used as a model)
but in an important embodiment the subject is a human patient in
need of the drug, for example to treat a disease characterized by
apoptotic dysfunction and/or overexpression of an anti-apoptotic
Bcl-2 family protein. A human subject can be male or female and of
any age. The patient is typically an adult, but a method of the
invention can be useful to treat a childhood cancer such as
leukemia, for example acute lymphocytic leukemia, in a pediatric
patient.
[0096] The composition is normally administered in an amount
providing a therapeutically effective daily dose of the drug. The
term "daily dose" herein means the amount of drug administered per
day, regardless of the frequency of administration. For example, if
the subject receives a unit dose of 150 mg twice daily, the daily
dose is 300 mg. Use of the term "daily dose" will be understood not
to imply that the specified dosage amount is necessarily
administered once daily. However, in a particular embodiment the
dosing frequency is once daily (q.d.), and the daily dose and unit
dose are in this embodiment the same thing.
[0097] What constitutes a therapeutically effective dose depends on
the particular compound, the subject (including species and body
weight of the subject), the disease (e.g., the particular type of
cancer) to be treated, the stage and/or severity of the disease,
the individual subject's tolerance of the compound, whether the
compound is administered in monotherapy or in combination with one
or more other drugs, e.g., other chemotherapeutics for treatment of
cancer, and other factors. Thus the daily dose can vary within wide
margins, for example from about 10 to about 1,000 mg. Greater or
lesser daily doses can be appropriate in specific situations. It
will be understood that recitation herein of a "therapeutically
effective" dose herein does not necessarily require that the drug
be therapeutically effective if only a single such dose is
administered; typically therapeutic efficacy depends on the
composition being administered repeatedly according to a regimen
involving appropriate frequency and duration of administration. It
is strongly preferred that, while the daily dose selected is
sufficient to provide benefit in terms of treating the cancer, it
should not be sufficient to provoke an adverse side-effect to an
unacceptable or intolerable degree. A suitable therapeutically
effective dose can be selected by the physician of ordinary skill
without undue experimentation based on the disclosure herein and on
art cited herein, taking into account factors such as those
mentioned above. The physician may, for example, start a cancer
patient on a course of therapy with a relatively low daily dose and
titrate the dose upwards over a period of days or weeks, to reduce
risk of adverse side-effects.
[0098] Illustratively, suitable doses are generally about 25 to
about 1,000 mg/day, more typically about 50 to about 500 mg/day or
about 200 to about 400 mg/day, for example about 50, about 100,
about 150, about 200, about 250, about 300, about 350, about 400,
about 450 or about 500 mg/day, administered at an average dosage
interval of about 3 hours to about 7 days, for example about 8
hours to about 3 days, or about 12 hours to about 2 days. In most
cases a once-daily (q.d.) administration regimen is suitable.
[0099] An "average dosage interval" herein is defined as a span of
time, for example one day or one week, divided by the number of
unit doses administered over that span of time. For example, where
a drug is administered three times a day, around 8 am, around noon
and around 6 pm, the average dosage interval is 8 hours (a 24-hour
time span divided by 3). If the drug is formulated as a discrete
dosage form such as a tablet or capsule, a plurality (e.g., 2 to
about 10) of dosage forms administered at one time is considered a
unit dose for the purpose of defining the average dosage
interval.
[0100] Where the composition is in the form of a capsule, one to a
small plurality of capsules can be swallowed whole, typically with
the aid of water or other imbibable liquid to help the swallowing
process. Suitable capsule shell materials include, without
limitation, gelatin (in the form of hard gelatin capsules or soft
elastic gelatin capsules), starch, carrageenan and HPMC.
[0101] Administration can be with or without food, i.e., in
anon-fasting or fasting condition. It is generally preferred to
administer the present compositions to a non-fasting patient.
VII. Additional Combinations
[0102] The combination therapy of the present invention may be
suitable for use in with other chemotherapeutics or with ionizing
radiation. Combination therapies illustratively include
administration of a combination therapy of the present invention
concomitantly with one or more of bortezomib, carboplatin,
cisplatin, cyclophosphamide, dacarbazine, dexamethasone, docetaxel,
doxorubicin, etoposide, fludarabine, irinotecan, paclitaxel,
rapamycin, rituximab, vincristine and the like, for example with a
polytherapy such as CHOP
(cyclophosphamide+doxorubicin+vincristine+prednisone), RCVP
(rituximab+cyclophosphamide+vincristine+prednisone), R-CHOP
(rituximab+CHOP) or DA-EPOCH-R (dose-adjusted etoposide,
prednisone, vincristine, cyclophosphamide, doxorubicin and
rituximab).
[0103] Additional examples of one or more therapeutic agents
include, but are not limited to, alkylating agents, angiogenesis
inhibitors, antibodies, antimetabolites, antimitotics,
antiproliferatives, antivirals, aurora kinase inhibitors, other
apoptosis inducing agents (for example, Bcl-xL, Bcl-w and Bfl-1
inhibitors), activators of a death receptor pathway, Bcr-Abl kinase
inhibitors, BiTE (bi-specific T-cell engager) antibodies,
antibody-drug conjugates, biological response modifiers,
cyclin-dependent kinase (CDK) inhibitors, cell cycle inhibitors,
cyclooxygenase-2 (COX-2) inhibitors, dual variable domain binding
proteins (DVDs), human epidermal growth factor receptor 2 (ErbB2 or
HER/2neu) receptor inhibitors, growth factor inhibitors, heat shock
protein (HSP)-90 inhibitors, histone deacetylase (HDAC) inhibitors,
hormonal therapies, immunologicals, inhibitors of apoptosis
proteins (IAPs), intercalating antibiotics, kinase inhibitors,
kinesin inhibitors. JAK2 inhibitors, mammalian target of rapamycin
(mTOR) inhibitors, microRNAs, mitogen-activated extracellular
signal-regulated kinase (MEK) inhibitors, multivalent binding
proteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly-ADP
(adenosine diphosphate)-ribose polymerase (PARP) inhibitors,
platinum chemotherapeutics, polo-like kinase (Plk) inhibitors,
phosphoinositide-3 kinase (PI3K) inhibitors, proteasome inhibitors,
purine analogs, pyrimidine analogs, receptor tyrosine kinase
inhibitors, retinoids, deltoids, plant alkaloids, small inhibitory
ribonucleic acids (siRNAs), topoisomerase inhibitors, ubiquitin
ligase inhibitors, and the like.
[0104] BiTE antibodies are bi-specific antibodies that direct
T-cells to attack cancer cells by simultaneously binding the two
cells. The T-cell then attacks the target cancer cell. Examples of
BiTE antibodies include, but are not limited to, adecatumumab
(Micromet MT201), blinatumomab (Micromet MT103) and the like.
Without being limited by theory, one of the mechanisms by which
T-cells elicit apoptosis of the target cancer cell is by exocytosis
of cytolytic granule components, which include perforin and
granzyme B. In this regard, Bcl-2 has been shown to attenuate the
induction of apoptosis by both perform and granzyme B. These data
suggest that inhibition of Bcl-2 could enhance the cytotoxic
effects elicited by T-cells when targeted to cancer cells (Sutton
et al. (1997) J. Immunol. 158:5783-5790).
[0105] siRNAs are molecules having endogenous RNA bases or
chemically modified nucleotides. The modifications do not abolish
cellular activity, but rather impart increased stability and/or
increased cellular potency. Examples of chemical modifications
include phosphorothioate groups, 2'-deoxynucleotide,
2'-OCH.sub.3-containing ribonucleotides, 2'-F-ribonucleotides,
2'-methoxyethyl ribonucleotides, combinations thereof and the like.
The siRNA can have varying lengths (e.g., 10-200 bps) and
structures (e.g., hairpins, single/double strands, bulges,
nicks/gaps, mismatches) and are processed in cells to provide
active gene silencing. A double-stranded siRNA (dsRNA) can have the
same number of nucleotides on each strand (blunt ends) or
asymmetric ends (overhangs). The overhang of 1-2 nucleotides can be
present on the sense and/or the antisense strand, as well as
present on the 5'- and/or the 3'-ends of a given strand. For
example, siRNAs targeting Mcl-1 have been shown to enhance the
activity of ABT-263 or ABT-737 in various tumor cell lines (Tse et
al. (2008) Cancer Res. 68:3421-3428 and references therein).
[0106] Multivalent binding proteins are binding proteins comprising
two or more antigen binding sites. Multivalent binding proteins are
engineered to have the three or more antigen binding sites and are
generally not naturally occurring antibodies. The term
"multispecific binding protein" means a binding protein capable of
binding two or more related or unrelated targets. Dual variable
domain (DVD) binding proteins are tetravalent or multivalent
binding proteins binding proteins comprising two or more antigen
binding sites. Such DVDs may be monospecific (i.e., capable of
binding one antigen) or multispecific (i.e., capable of binding two
or more antigens). DVD binding proteins comprising two heavy-chain
DVD polypeptides and two light-chain DVD polypeptides are referred
to as DVD g's. Each half of a DVD Ig comprises a heavy-chain DVD
polypeptide, a light-chain DVD polypeptide, and two antigen binding
sites. Each binding site comprises a heavy-chain variable domain
and a light-chain variable domain with a total of 6 CDRs involved
in antigen binding per antigen binding site.
[0107] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil. Cloretazine.TM. (laromustine, VNP
40101M), cyclophosphamide, dacarbazine, estramustine, fotemustine,
glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide,
melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard
N-oxide, ranimustine, temozolomide, thiotepa, treosulfan,
trofosfamide and the like.
[0108] Angiogenesis inhibitors include epidermal growth factor
receptor (EGFR) inhibitors, endothelial-specific receptor tyrosine
kinase (Tie-2) inhibitors, insulin growth factor-2 receptor
(IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors,
matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived
growth factor receptor (PDGFR) inhibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[0109] Antimetabolites include Alimta.TM. (pemetrexed disodium,
LY231514, MTA), 5-azacitidine, Xeloda.TM., (capecitabine),
carmofur, Leustat.TM. (cladribine), clofarabine, cytarabine,
cytarabine ocfosfate, cytosine arabinoside, decitabine,
deferoxamine, doxifluridine, eflornithine, EICAR
(5-ethynyl-1-.beta.-D-ribofuranosylimidazole-4-carboxamide),
enocitabine, ethenylcytidine, fludarabine, 5-fluorouracil (5-FU)
alone or in combination with leucovorin, Gemzar.TM. (gemcitabine),
hydroxyurea, Alkeran.TM. (melphalan), mercaptopurine,
6-mercaptopurine riboside, methotrexate, mycophenolic acid,
nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,
raltitrexed, ribavirin, S-1, triapine, trimetrexate, TS-1,
tiazofurin, tegafur, vidarabine, UFT and the like.
[0110] Antivirals include ritonavir, hydroxychloroquine and the
like.
[0111] Aurora kinase inhibitors include ABT-348, AZD-1152,
MLN-8054, VX-680, aurora A-specific kinase inhibitors, aurora
B-specific kinase inhibitors, pan-aurora kinase inhibitors and the
like.
[0112] Bcl-2 family protein inhibitors other than compounds of
Formula I herein include AT-101 ((-)gossypol), Genasense.TM.
Bcl-2-targeting antisense oligonucleotide (G3139 or oblimersen),
IPI-194, IPI-565, ABT-737, ABT-263, GX-070 (obatoclax) and the
like.
[0113] Bcr-Abl kinase inhibitors include dasatinib (BMS-354825),
Gleevec.TM. (imatinib) and the like.
[0114] CDK inhibitors include AZD-5438, BMI-1040, BMS-387032,
CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202 or R-roscovitine), ZK-304709 and the like.
[0115] COX-2 inhibitors include ABT-963, Arcoxia.TM. (etoricoxib).
Bextram.TM. (valdecoxib), BMS-347070, Celebrex.TM. (celecoxib),
COX-189 (lumiracoxib), CT-3, Deramaxx.TM. (deracoxib), JTE-522,
4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl)-1H-pyrrole,
MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125,
SD-8381, SVT-2016, 5-2474, T-614, Vioxx.TM. (rofecoxib) and the
like.
[0116] EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes,
EGF-vaccine, EMD-7200, Erbitux.TM. (cetuximab), HR3, IgA
antibodies, Iressa.TM. (gefitinib), Tarcevar.TM. (erlotinib or
OSI-774), TP-38, EGFR fusion protein, Tykerb.TM. (lapatinib) and
the like.
[0117] ErbB2 receptor inhibitors include CP-724714, CI-1033
(canertinib), Herceptin.TM. (trastuzumab), Tykerb.TM. (lapatinib),
Omnitarg.TM. (2C4, petuzumab), TAK-165, GW-572016 (ionafamib),
GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER2
vaccine), anti-HER/2neu bispecific antibody. B7.her2IgG3, AS HER2
trifunctional bispecific antibodies, mAB AR-209, mAB 2B-1 and the
like.
[0118] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[0119] HSP-90 inhibitors include 17AAG, CNF-101, CNF-1010,
CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, Mycograb.TM.
(human recombinant antibody to HSP-90), nab-17AAG, NCS-683664,
PU24FCl, PU-3, radicicol, SNX-2112, STA-9090, VER-49009 and the
like.
[0120] Inhibitors of apoptosis proteins include HGS-1029, GDC-0145,
GDC-0152, LCL-161, LBW-242 and the like.
[0121] Antibody-drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC,
MEDI-547, SGN-19A SGN-35, SGN-75 and the like.
[0122] Activators of death receptor pathway include TRAIL and
antibodies or other agents that target TRAIL or death receptors
(e.g., DR4 and DR5) such as apomab, conatumumab, ETR2-ST01, GDC0145
(lexatumumab), HGS-1029, LBY-135, PRO-1762, trastuzumab and the
like.
[0123] Kinesin inhibitors include Eg5 inhibitors such as AZD-4877
and ARRY-520 CENPE inhibitors such as GSK-923295A, and the
like.
[0124] JAK2 inhibitors include CEP-701 (lesaurtinib), XL019,
INCB-018424 and the like.
[0125] MEK inhibitors include ARRY-142886, ARRY-438162, PD-325901,
PD-98059 and the like.
[0126] mTOR inhibitors include AP-23573, CCI-779, everolimus,
RAD-001, rapamycin, temsirolimus, ATP-competitive TORC1/TORC2
inhibitors, including PI-103, PP242, PP30 and Torin 1, and the
like.
[0127] Non-steroidal anti-inflammatory drugs include Amigesic.TM.
(salsalate), Dolobid.TM. (diflunisal), Motrin.TM. (ibuprofen),
Orudis.TM. (ketoprofen), Relafen.TM. (nabumetone), Feldene.TM.
(piroxicam), ibuprofen cream. Aleve.TM. and Naprosyn.TM.
(naproxen), Voltaren.TM. (diclofenac), Indocin.TM. (indomethacin),
Clinoril.TM. (sulindac), Tolectin.TM. (tolmetin), Lodine.TM.
(etodolac), Toradol.TM. (ketorolac), Daypro.TM. (oxaprozin) and the
like.
[0128] PDGFR inhibitors include CP-673451, CP-868596 and the
like.
[0129] Platinum chemotherapeutics include cisplatin, Eloxatin.TM.
(oxaliplatin), eptaplatin, lobaplatin, nedaplatin, Paraplatin.TM.
(carboplatin), picoplatin, satraplatin and the like.
[0130] Polo-like kinase inhibitors include B1-2536 and the
like.
[0131] Phosphoinositide-3 kinase inhibitors include wortmannin,
LY-294002, XL-147. CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,
GDC-0941, BGT226, BEZ235, XL765 and the like.
[0132] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[0133] VEGFR inhibitors include Avastin.TM. (bevacizumab), ABT-869,
AEE-788, Angiozyme.TM. (a ribozyme that inhibits angiogenesis
(Ribozyme Pharmaceuticals (Boulder, Colo.) and Chiron (Emeryville.
Calif.)), axitinib (AG-13736), AZD-2171. CP-547632, IM-862,
Macugen.TM. (pegaptanib), Nexavar.TM. (sorafenib, BAY43-9006),
pazopanib (GW-786034), vatalanib (PTK-787 or ZK-222584), Sutent.TM.
(sunitinib or SU-11248), VEGF trap, Zactim.TM. (vandetanib or
ZD-6474) and the like.
[0134] Antibiotics include intercalating antibiotics such as
aclarubicin, actinomycin D, amrubicin, annamycin, Adriamycin.TM.
(doxorubicin), Blenoxane.TM. (bleomycin), daunorubicin, Caelyx.TM.
and Myocet.TM. (liposomal doxorubicin), elsamitrucin, epirubicin,
glarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
Valstar.TM. (valrubicin), zinostatin and the like.
[0135] Topoisomerase inhibitors include aclarubicin,
9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan,
BN-80915, Camptosar.TM. (irinotecan hydrochloride), camptothecin,
Cardioxane.TM. (dexrazoxane), diflomotecan, edotecarin, Ellence.TM.
and Pharmorubicin.TM. (epirubicin), etoposide, exatecan,
10-hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone,
orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38,
tafluposide, topotecan and the like.
[0136] Antibodies include Avastin.TM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, Erbitux.TM. (cetuximab),
Humax-CD4.TM. (zanolimumab), IGF1R-specific antibodies, lintuzumab,
Panorex.TM. (edrecolomab), Rencarex.TM. (WX G250), Rituxan.TM.
(rituximab), ticilimumab, trastuzumab, CD20 antibodies types I and
11 and the like.
[0137] Hormonal therapies include Arimidex.TM. (anastrozole),
Aromasin.TM. (exemestane), arzoxifene, Casodex.TM. (bicalutamide),
Cetrotide.TM. (cetrorelix), degarelix, deslorelin, Desopan.TM.
(trilostane), dexamethasone, Drogenil.TM. (flutamide), Evista.TM.
(raloxifene), Afema.TM. (fadrozole), Fareston.TM. (toremifene),
Faslodex.TM. (fulvestrant), Femara.TM. (letrozole), formestane,
glucocorticoids. Hectorol.TM. (doxercalciferol), Renagel.TM.
(sevelamer carbonate), lasofoxifene, leuprolide acetate, Megace.TM.
(megestrol), Mifeprex.TM. (mifepristone), Nilandron.TM.
(nilutamide), tamoxifen including Nolvadex.TM. (tamoxifen citrate),
Plenaxis.TM. (abarelix), prednisone, Propecia.TM. (finasteride),
rilostane, Suprefact.TM. (buserelin), luteinizing hormone releasing
hormone (LHRH) including Trelstar.TM. (triptorelin), histrelin
including Vantas.TM. (histrelin implant), Modrastane.TM.
(trilostane), Zoladex.TM. (goserelin) and the like.
[0138] Deltoids and retinoids include seocalcitol (EB1089 or
CB1093), lexacalcitol (KH1060), fenretinide, Panretin.TM.
(alitretinoin), tretinoin including Atragen.TM. (liposomal
tretinoin), Targretin.TM. (bexarotene), LGD-1550 and the like.
[0139] PARP inhibitors include ABT-888, olaparib, KU-59436,
AZD-2281, AG-014699, BSI-201. BGP-15, INO-1001, ONO-2231 and the
like.
[0140] Plant alkaloids include vincristine, vinblastine, vindesine,
vinorelbine and the like.
[0141] Proteasome inhibitors include Velcade.TM. (bortezomib),
MG132, NPI-0052, PR-171 and the like.
[0142] Examples of immunologicals include interferons and other
immune-enhancing agents. Interferons include interferon alpha,
interferon alpha-2a, interferon alpha-2b, interferon beta,
interferon gamma-1a. Actimmune.TM. (interferon gamma-1b),
interferon gamma-n1, combinations thereof and the like. Other
agents include Alfaferone (IFN-.alpha.), BAM-002 (oxidized
glutathione), Beromun.TM. (tasonermin), Bexxar.TM. (tositumomab),
Campath.TM. (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4),
dacarbazine, denileukin, epratuzumab, Granocyte.TM. (lenograstim),
lentinan, leukocyte alpha interferon, imiquimod, MDX-010
(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim,
Mylotarg.TM. (gemtuzumab ozogamicin), Neupogen.TM. (filgrastim),
OncoVAC-CL, Ovarex.TM. (oregovomab), pemtumomab (Y-muHMFG1),
Provenge.TM. (sipuleucel-T), sargaramostim, sizofiran, teceleukin
Theracys.TM. (BCG or Bacillus Calmette-Guerin), ubenimex,
Virulizin.TM. (immunotherapeutic, Lorus Pharmaceuticals), Z-100
(Specific Substance of Maruyama or SSM), WF-10
(tetrachlorodecaoxide or TCDO), Proleukin.TM. (aldesleukin),
Zadaxin.TM. (thymalfasin), Zenapax.TM. (daclizumab), Zevalin.TM.
(90Y-ibritumomab tiuxetan) and the like.
[0143] Biological response modifiers are agents that modify defense
mechanisms of living organisms or biological responses, such as
survival, growth or differentiation of tissue cells to direct them
to have anti-tumor activity, and include krestin, lentinan,
sizofiran, picibanil, PF-3512676 (CpG-8954), ubenimex and the
like.
[0144] Pyrimidine analogs include cytarabine (cytosine arabinoside,
ara C or arabinoside C), doxifluridine, Fludara.TM. (fludarabine),
5-FU (5-fluorouracil), floxuridine, Gemzar.TM. (gemcitabine),
Tomudex.TM. (raltitrexed), triacetluridine. Troxatvl.TM.
(troxacitabine) and the like.
[0145] Purine analogs include Lanvis.TM. (thioguanine),
Purinethol.TM. (mercaptopurine) and the like.
[0146] Antimitotic agents include batabulin, epothilone D
(KOS-862),
N-(2-((4-hydroxy-phenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,
ixabepilone (BMS-247550), paclitaxel, Taxotere.TM. (docetaxel),
larotaxel (PNU-100940, RPR-109881 or XRP-9881), patupilone,
vinflunine, ZK-EPO (synthetic epothilone) and the like.
[0147] Ubiquitin ligase inhibitors include MDM2 inhibitors such as
nutlins, NEDD8 inhibitors such as MLN4924, and the like.
[0148] The combination therapy of this present invention may also
be used as radiosensitizers that enhance the efficacy of
radiotherapy. Examples of radiotherapy include, but are not limited
to, external beam radiotherapy (XBRT), teletherapy, brachytherapy,
sealed-source radiotherapy, unsealed-source radiotherapy and the
like.
[0149] Additionally or alternatively, the combination therapy of
the present invention can be administered in combination therapy
with one or more antitumor or chemotherapeutic agents selected from
Abraxane.TM. (ABI-007), ABT-100 (famesyl transferase inhibitor),
Advexin.TM. (Ad5CMV-p53 vaccine or contusugene ladenovec),
Altocor.TM. or Mevacor.TM. (lovastatin), Ampligen.TM.
(poly(I)-poly(C12U), a synthetic RNA), Aptosyn.TM. (exisulind),
Aredia.TM. (pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), Avage.TM. (tazarotene),
AVE-8062 (combretastatin derivative), BEC2 (mitumomab), cachectin
or cachexin (tumor necrosis factor), Canvaxin.TM. (melanoma
vaccine), CeaVac.TM. (cancer vaccine), Celeuk.TM. (celmoleukin),
histamine including Ceplene.TM. (histamine dihydrochloride),
Cervarix.TM. (AS04 adjuvant-adsorbed human papilloma virus (HPV)
vaccine), CHOP (Cytoxan.TM. (cyclophosphamide)+Adriamycin.TM.
(doxorubicin)+Oncovin.TM. (vincristine)+prednisone), combretastatin
A4P, Cypat.TM. (cyproterone), DAB(389)EGF (catalytic and
translocation domains of diphtheria toxin fused via a His-Ala
linker to human epidermal growth factor), dacarbazine,
dactinomycin, Dimericine.TM. (T4N5 liposome lotion),
5,6-dimethylxanthenone-4-acetic acid (DMXAA), discodermolide,
DX-8951f (exatecan mesylate), eniluracil (ethynyluracil),
squalamine including Evizon.TM. (squalamine lactate), enzastaurin,
EPO-906 (epothilone B), Gardasil.TM. (quadrivalent human papilloma
virus (Types 6, 11, 16, 18) recombinant vaccine), Gastrimmune.TM.,
Genasense.TM. (oblimersen), GMK (ganglioside conjugate vaccine),
GVAX.TM. (prostate cancer vaccine), halofuginone, histerelin,
hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38,
IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin,
interferon-.alpha., interferon-.gamma., Junovan.TM. and Mepact.TM.
(mifamurtide), lonafamib, 5,10-methylenetetrahydrofolate,
miltefosine (hexadecylphosphocholine), Neovastat.TM. (AE-941),
Neutrexin.TM. (trimetrexate glucuronate), Nipent.TM. (pentostatin),
Onconase.TM. (ranpimase, a ribonuclease enzyme), Oncophage.TM.
(vitespen, melanoma vaccine treatment), OncoVAX.TM. (IL-2 vaccine),
Orathecin.TM. (rubitecan), Osidem.TM. (antibody-based cell drug),
Ovarex.TM. MAb (murine monoclonal antibody), paclitaxel
albumin-stabilized nanoparticle, paclitaxel, Pandimex.TM. (aglycone
saponins from ginseng comprising 20(S)-protopanaxadiol (aPPD) and
20(S)-protopanaxatriol (aPPT)), panitumumab, Panvac.TM.-VF
(investigational cancer vaccine), pegaspargase, peginterferon alfa
(PEG interferon A), phenoxodiol, procarbazine, rebimastat,
Removab.TM. (catumaxomab), Revlimid.TM. (lenalidomide), RSR13
(efaproxiral), Somatuline.TM. LA (lanreotide), Soriatane.TM.
(acitretin), staurosporine (Streptomyces staurospores), talabostat
(PT100), Targretin.TM. (bexarotene), Taxoprexin.TM.
(docosahexaenoic acid (DHA)+paclitaxel), Telcytar.TM.
(canfosfamide, TLK-286), Temodar.TM. (temozolomide), tesmilifene,
tetrandrine, thalidomide, Theratope.TM. (STn-KLH vaccine),
Thymitaq.TM. (nolatrexed dihydrochloride), TNFerade.TM.
(adenovector: DNA carrier containing the gene for tumor necrosis
factor-.alpha.), Tracleer.TM. or Zavesca.TM. (bosentan),
TransMID-107R.TM. (KSB-311, diphtheria toxins), tretinoin
(retin-A), Trisenox.TM. (arsenic trioxide), Ukrain.TM. (derivative
of alkaloids from the greater celandine plant), Virulizin.TM.,
Vitaxin.TM. (anti-.alpha.v.beta.3 antibody), Xcytrin.TM. (motexafin
gadolinium), Xinlay.TM. (atrasentan), Xyotax.TM. (paclitaxel
poliglumex) Yondelis.TM. (trabectedin), ZD-6126
(N-acetylcolchinol-O-phosphate), Zinecard.TM. (dexrazoxane),
zoledronic acid, zorubicin and the like.
[0150] Other objects and features will be in part apparent and in
part pointed out hereinafter.
EXAMPLES
[0151] The following non-limiting examples are provided to further
illustrate the present invention.
[0152] The activity of
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (ABT-199, or
venetoclax) and
[3,4-Difluoro-2-(2-fluoro-4-iodoanilino)phenyl]{3-hydroxy-3-[(2S)-pip-
eridin-2-yl]azetidin-1-yl}methanone (cobimetinib) was examined in a
panel of myeloid leukemia cell lines with diverse genetic
alterations. The IC.sub.50 values of cobimetinib ranged from
<0.01 .mu.M to >1 .mu.M after 72 hours of drug treatment but
did not correlate with the basal level of p-ERK1/2. (FIG. 1A). In 7
out of 11 cell lines, combination of the agents elicited
synergistic growth inhibition. Notably synergism of venetoclax with
cobimetinib was observed in venetoclax-resistant cell lines
(MOLM14, OCI-AML3, NB4 and THP1). (FIGS. 1B through 1L). In a
long-term culture of primary AML blasts, the combination of
venetoclax and cobimetinib predominantly suppressed cell
proliferation and induced distinct apoptotic cell death in a subset
of AML samples. The clonogenic potential of myeloid progenitors was
significantly suppressed by the combination, while the normal
progenitor function was minimally affected. (FIGS. 2A, 2B, and
2C).
[0153] Ongoing analysis of pharmacodynamic markers include
transcriptome assessment by RNA sequencing, functional proteomics
by reverse phase protein array (RPPA), and quantification of
Bcl-2:BIM and MCL-1:BIM complexes using the electrochemiluminescent
ELISA assay (Meso Scale Discovery, MSD-ELISA). RPPA is a
high-throughput technology that performs protein assays on
thousands of samples simultaneously. This protein array platform
measures levels of protein expression, as well as protein
modifications such as phosphorylation. RPPA data demonstrated
differentially expressed proteins in sensitive and resistant cell
lines to cobimetinib or venetoclax as single agents or in
combination. See the following Tables 1, 2, and 3.
TABLE-US-00001 TABLE 1 COBIMETINIB: SENSITIVE V. RESISTANT Protein
Pval Mean. Res Mean. Sens Bax 8.64E-15 1.010 1.307 Bim 2.87E-13
0.893 1.175 ERK 1/2 (T202/Y204) 1.47E-09 1.073 1.988 FLT3
(Y589/591) 1.71E-12 0.948 1.256 p16INK4a 6.56E-23 2.220 1.184
p38MAP (T180/Y182) 0.00174 0.983 1.275 p53 4.87E-10 0.939 1.373
PTEN 3.92E-18 1.013 1.361 PTEN (S380) 0.0003 1.049 1.335 RSK3
(T356/S360) 1.09E-15 0.859 1.495 S6 (S235/236) 0.00012 0.748
1.174
TABLE-US-00002 TABLE 2 VENETOCLAX: SENSITIVE V. RESISTANT Protein
Pval Mean. Res Mean. Sens bRaf (T401) 5.44E-10 1.263 0.927 Bax
1.48E-15 0.958 1.227 Bcl-2 1.28E-19 0.817 1.081 Bim 3.41E-20 1.143
0.811 p16INK4a 3.09E-06 1.989 1.593 PTEN 2.39E-20 0.704 1.495 PTEN
(S380) 1.88E-09 0.839 1.369 S6 (S240/244) 8.51E-05 1.918 1.571
TABLE-US-00003 TABLE 3 COMBINATION: SENSITIVE V. RESISTANT Protein
Pval Mean. Res Mean. Sens Bad 1.65E-07 1.232 0.923 Bad (S112)
3.26E-07 1.272 0.938 Bcl2 2.12E-22 0.373 1.051 Caspase 3 2.66E-16
1.526 0.998 Caspase 3 Cleaved D175 0.000127321 0.938 1.359 Caspase
7 Cleaved D198 5.53E-09 0.590 1.771 Caspase 8 Cleaved D391 2.19E-05
0.804 1.409 eIF2a (S51) 2.26E-08 1.393 0.850 ERK 1/2 9.81E-13 0.802
1.098 p16INK4a 1.03E-14 3.786 1.326 p70 p85 S6 (S371/S394) 1.84E-05
0.726 1.054 PARP Cleaved D214 9.37E-07 0.680 1.477 PTEN 2.39E-11
0.508 1.178 PTEN (S380) 9.64E-05 0.661 1.109 RSK3 (T356/S360)
8.80E-06 0.789 1.130
[0154] Representative proteins that are differentially expressed in
sensitive and resistant cell lines to the combination. (FIGS. 3A,
3B, 3C, and 3D). The preliminary MSD data revealed that Bcl-2:BIM
complex was disrupted by venetoclax in most cell lines and
accumulated following cobimetinib treatment in OCI-AML3 cells,
which may be due to the disruption of MCL-1:BIM complex by
inhibition of MEK releasing BIM to bind with Bcl-2. (FIG. 3E).
[0155] We next investigated signaling patterns and Bcl-2 family
protein expression in AML stem/progenitor cells using a 34-antibody
panel and time-of-flight mass cytometry (CyTOF). CyTOF is a
variation of flow cytometry in which antibodies are labeled with
heavy metal ion tags rather than fluorochromes. Readout is by
time-of-flight mass spectrometry. This allows for the combination
of many more antibody specificities in single samples, without
significant spillover between channels. In AML 4295468. Bcl-2 was
expressed in leukemia blasts, with enrichment in a progenitor AML
population phenotypically defined as CD45dimCD34+CD38+CD123+CD33+.
(FIG. 4A). The high expression level of Bcl-2 and low expression of
MCL-1 and BCL-XL may account for sensitivity to venetoclax in AML
4295468. A venetoclax-resistant AML (4366894) showed low expression
of Bcl-2 in CD45dimCD34+CD38-CD123+CD33+ population. (FIG. 4B). In
AML 4295468, both basal and G-CSF- or SCF-stimulated p-ERK was
efficiently down-regulated by cobimetinib; however, G-CSF-evoked
p-STAT3/5 and SCF-induced p-AKT were only slightly reduced. (FIG.
4C). Notably we observed increased phosphorylation of STAT5 pathway
upon treatment with cobimetinib, suggesting that active MAPK
signals inhibit phosphorylation of the JAK-STAT pathway, as
previously reported (Krasilnikov et al. Oncogene, 2003 and Lee at
al. Cancer Cell, 2014). In AML 4366894, p-ERK was also reduced,
however, G-CSF-induced p-STAT3/5 were not significantly changed. To
test the efficacy of both compounds in vivo, we injected NSG mice
with genetically engineered OCI-AML3/Luc/GFP cells. Bioluminescent
imaging (BLI) demonstrated significantly reduced leukemia burden in
treated groups compared to controls, more prominently in the
cobimetinib single agent and venetoclax plus cobimetinib co-treated
mice. (FIGS. 5A and 5B). To further explore the anti-leukemia
efficacy of both compounds, we injected NSGS mice with genetically
engineered MOLM3/Luc/GFP cells. Bioluminescent imaging demonstrated
significantly reduced leukemia burden in treated groups compared to
controls, more prominently in the venetoclax group and in
venetoclax plus cobimetinib co-treated mice. (FIG. 5C). Human CD45
engraftment and cell counts in both bone marrow and spleen
demonstrated a trend towards decreased tumor burden when venetoclax
was combined with cobimetinib in vivo. (FIGS. 5D and 5E).
[0156] In summary, the data demonstrate that combinatorial blockade
of MAPK and Bcl-2 pathways is synergistic in the majority of AML
cell lines tested and can overcome intrinsic resistance to
venetoclax. Further, cobimetinib/venetoclax combination inhibited
proliferation, induced apoptosis and reduced clonogenicity in a
subset of primary AML samples, but not in normal hematopoietic
precursors. In addition, differentially overexpressed proteins were
identified in cell lines sensitive or resistant to either single
agents or to cobimetinib/venetoclax combination. MSD assay revealed
that venetoclax but not cobimetinib disrupted the Bcl-2:BIM
complex. CyTOF mass cytometry enables measurements of intracellular
signaling pathways and Bcl-2 family members in antigen-defined AML
stem/progenitor cell populations. Finally, the combination of
venetoclax and cobimetinib reduces AML tumor burden and extends
survival in OCI-AML3 AML model and MOLM13 AML model in vivo.
[0157] When introducing elements of the present invention or the
preferred embodiments(s) thereof, the articles "a". "an", "the" and
"said" are intended to mean that there are one or more of the
elements. The terms "comprising", "including" and "having" are
intended to be inclusive and mean that there may be additional
elements other than the listed elements.
[0158] In view of the above, it will be seen that the several
objects of the invention are achieved and other advantageous
results attained.
[0159] As various changes could be made in the above compositions
and processes without departing from the scope of the invention, it
is intended that all matter contained in the above description and
shown in the accompanying drawings shall be interpreted as
illustrative and not in a limiting sense.
* * * * *