U.S. patent application number 17/553612 was filed with the patent office on 2022-07-07 for use of an rxr agonist in treating her2+ cancers.
The applicant listed for this patent is Board of Regents, The University of Texas System, Io Therapeutics, Inc. Invention is credited to Powel H. Brown, Martin E. Sanders.
Application Number | 20220211652 17/553612 |
Document ID | / |
Family ID | |
Filed Date | 2022-07-07 |
United States Patent
Application |
20220211652 |
Kind Code |
A1 |
Sanders; Martin E. ; et
al. |
July 7, 2022 |
USE OF AN RXR AGONIST IN TREATING HER2+ CANCERS
Abstract
The present specification provides combinations of active agents
for the improved treatment of Her2.sup.+ cancers and associated
methods of treatments. The combinations comprise and RXR agonist
and a Her2-targeted therapeutic agent and may optionally further
comprise thyroid hormone.
Inventors: |
Sanders; Martin E.; (Spring,
TX) ; Brown; Powel H.; (Houston, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Io Therapeutics, Inc
Board of Regents, The University of Texas System |
Spring
Austin |
TX
TX |
US
US |
|
|
Appl. No.: |
17/553612 |
Filed: |
December 30, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17126347 |
Dec 18, 2020 |
11224583 |
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17553612 |
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16898230 |
Jun 10, 2020 |
10966950 |
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17126347 |
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62860133 |
Jun 11, 2019 |
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International
Class: |
A61K 31/216 20060101
A61K031/216; A61K 39/395 20060101 A61K039/395; A61P 35/00 20060101
A61P035/00; A61K 31/4709 20060101 A61K031/4709; A61K 38/24 20060101
A61K038/24; A61K 31/517 20060101 A61K031/517 |
Goverment Interests
STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH
[0002] This invention was made with government support under grant
number HHSN261201500018I awarded by the National Institutes of
Health. The government has certain rights in the invention.
Claims
1. A method of treating a patient with Her2.sup.+ breast cancer
comprising administering a RXR agonist of Formula I, ##STR00019##
wherein R is H, or lower alkyl of 1 to 6 carbons; or a
pharmaceutically-acceptable salt thereof, to the patient, wherein
the patient is receiving a Her2-targeted therapeutic agent.
2. The method of claim 1, wherein the Her2-targeted therapeutic
agent consists of means for therapeutically targeting Her2.
3. The method of claim 2, wherein the means for therapeutically
targeting Her2 consists of means for inhibiting Her2.sup.+ tumor
cell proliferation.
4. The method of claim 2, wherein the means for therapeutically
targeting Her2 consists of small molecule means for inhibiting Her2
kinase activity.
5. A method of treating a patient with Her2.sup.+ breast cancer
undergoing treatment with a Her2-targeted therapeutic agent,
wherein there is evidence of therapeutic effect that is less than a
complete response, comprising continuing treatment with the Her2
kinase inhibitor and initiating treatment with a RXR agonist of
Formula I, ##STR00020## wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof.
6. The method of claim 5, wherein the Her2-targeted therapeutic
agent consists of means for therapeutically targeting Her2.
7. The method of claim 6, wherein the means for therapeutically
targeting Her2 consists of means for inhibiting Her2.sup.+ tumor
cell proliferation.
8. The method of claim 6, wherein the means for therapeutically
targeting Her2 consists of small molecule means for inhibiting Her2
kinase activity.
9. A method of treating a patient with Her2.sup.+ breast cancer
comprising administering means for activating RXR/Nurr1
heterodimeric receptors, wherein the patient is receiving a
Her2-targeted therapeutic agent.
10. The method of claim 9, wherein the Her2-targeted therapeutic
agent comprises a therapeutic anti-Her2 antibody.
11. The method of claim 9, wherein the Her2-targeted therapeutic
agent is a small organic molecule inhibitor of Her2 kinase
activity.
12. The method of claim 1, further comprising administering thyroid
hormone in conjunction with the RXR agonist.
13. The method of claim 5, further comprising administering thyroid
hormone in conjunction with the RXR agonist.
14. The method of claim 9, further comprising administering thyroid
hormone in conjunction with the means for activating RXR/Nurr1
heterodimeric receptors.
15. The method of claim 1, wherein the inhibition of tumor cell
growth by the combination of the Her2-targeted therapeutic and the
RXR agonist is greater than additive effects of each of the
Her2-targeted therapeutic and the RXR agonist alone.
16. The method of claim 5, wherein the inhibition of tumor cell
growth by the combination of the Her2-targeted therapeutic and the
RXR agonist is greater than additive effects of each of the
Her2-targeted therapeutic and the RXR agonist alone.
17. The method of claim 9, wherein the inhibition of tumor cell
growth by the combination of the Her2-targeted therapeutic and the
means for activating RXR/Nurr1 heterodimeric receptors is greater
than additive effects of each of the Her2-targeted therapeutic and
the means for activating RXR/Nurr1 heterodimeric receptors alone.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 17/126,347, filed Dec. 18, 2020, now U.S. Pat.
No. 11,______, which is a divisional of U.S. patent application
Ser. No. 16/898,230, filed Jun. 10, 2020, now U.S. Pat. No
10,966,950, which claims the benefit of U.S. Provisional
Application No. 62/860,133, filed Jun. 11, 2019, the entire
contents of which are each incorporated by reference herein.
BACKGROUND
[0003] Compounds which have retinoid-like biological activity are
well known in the art and are described in numerous United States
patents including, but not limited to, U.S. Pat. Nos. 5,466,861;
5,675,033 and 5,917,082, all of which are herein incorporated by
reference. Preclinical studies with rexinoids suggest that
selective activation of retinoid X receptors (RXR), which modulate
functions associated with differentiation, inhibition of cell
growth, apoptosis and metastasis, may be useful in treating a
variety of diseases associated with the biochemical functions
modulated by RXR.
[0004] For example, TARGRETIN.RTM. (bexarotene), which is a
retinoid X receptor (RXR) agonist with retinoic acid receptor (RAR)
agonist activity as well, was approved by the U.S. Food and Drug
Administration for the treatment, both oral and topical, of
cutaneous manifestations of cutaneous T cell lymphoma in patients
who are refractory to at least one prior systemic therapy.
Encouraging results were obtained with TARGRETIN.RTM. in several
Phase II studies in NSCLC. However, the pivotal Phase III clinical
study did not show increased survival. One possible explanation for
the limited success of bexarotene is that its activation of RAR
decreases its efficacy as an anticancer agent. Thus, more selective
RXR agonists may hold greater promise.
[0005] Agents targeting human epidermal growth factor receptor 2
(Her2), both anti-Her2 antibodies and inhibitors of the tyrosine
kinase activity of Her2, have had significant, but not universal
success in treating Her2.sup.+ cancers, particularly Her2.sup.+
breast cancers.
[0006] Treatments for cancer are ever evolving, gaining in
specificity and sophistication. Early non-surgical cancer
treatments generally targeted rapidly dividing cells which were
more sensitive to radiological and chemical assault. Over time,
more specific and less generally toxic treatments have been
developed. Some treatments appear to have broad applicability, for
example immune checkpoint inhibitors or rexinoids. Others are
targeted to cancers that express a particular antigen or other
biomarker involved in the regulation of proliferation or
differentiation; including many monoclonal antibodies and kinase
inhibitors. Yet as the variety of cancer treatments has grown, it
has become ever harder to determine which treatments might be
productively combined and for what indications.
SUMMARY
[0007] Herein disclosed are improved methods of treatment of
Her2.sup.+ cancers comprising treating a patient having a
Her2.sup.+ tumor with a combination of a Her2-targeting therapeutic
agent and a RXR agonist capable of inhibiting cancer growth. In
some embodiments the treatment combination further comprises
thyroid hormone.
[0008] In some embodiments, the RXR agonist is capable of
activating RXR/Nurr1 heterodimeric receptors. In some embodiments
the RXR agonist is a compound of Formula I as disclosed herein
below, or a pharmaceutically-acceptable salt thereof. In some
embodiments the RXR agonist is a compound of Formula II as
disclosed herein below, or a pharmaceutically-acceptable salt
thereof. In some embodiments, compounds of Formula I and Formula
II, and their pharmaceutically-acceptable salts, are referred to as
means for activating RXR/Nurr1 heterodimeric receptors or rexinoid
means for inhibiting tumor growth.
[0009] In some embodiments, Her2-targeting therapeutic agent is an
inhibitor of Her2 kinase activity or Her2-mediated signaling. In
some embodiments Her2-targeting therapeutic agent is therapeutic
anti-Her2 antibody. Therapeutic antibodies may mediate
antibody-dependent cellular cytotoxicity (ADCC) instead of, or in
addition to, inhibiting signaling (kinase activity). Trastuzumab
and pertuzumab are examples of therapeutic anti-Her2 antibodies, as
disclosed herein below. In some embodiments such antibodies are
referred to as immunoglobulin means for inhibiting Her2.sup.+ tumor
cell proliferation, means for mediating ADCC of Her2.sup.+ tumor
cells, or immunoglobulin means for inhibiting Her2 signaling.
[0010] In some embodiments, a Her2-targeting therapeutic agent is
an antibody-drug conjugate comprising an anti-Her2 antibody. In
some embodiments, the anti-Her2 antibody has therapeutic activity
alone, while in other embodiments it does not, merely serving to
deliver a cytotoxic agent to Her2.sup.+ cells. Ado-trastuzumab
emtansine is an example of a Her2-targeting antibody-drug
conjugate, as disclosed herein below. In some embodiments such
antibody-drug conjugates are referred to as means for delivering a
cytotoxic agent to Her2.sup.+ cells.
[0011] In some embodiments, the inhibitor of Her2 kinase activity
or Her2-mediated signaling is a small organic molecule (small drug)
inhibitor of Her2 kinase activity. Lapatinib and neratinib are
examples of Her2 kinase inhibitors as disclosed herein below. In
some embodiments such small drug inhibitor of Her2 kinase activity
are referred to as small molecule means for inhibiting Her2 kinase
activity.
[0012] In some embodiments, the Her2.sup.+ cancer is a Her2.sup.+
breast cancer. In some embodiments the Her2.sup.+ cancer is a
Her2.sup.+ ovarian cancer, stomach cancer, adenocarcinoma of the
lung, uterine cancer (such as serous endometrial carcinoma),
gastric cancer, or salivary duct carcinoma.
[0013] In some embodiments, the herein disclosed treatments are
carried out concurrently with other pharmaceutical therapies or
radiotherapies. In alternative embodiments, the herein disclosed
treatments are the exclusive therapy in the time interval in which
they are conducted. In some embodiments, the herein disclosed
treatments serve as a debulking treatment in preparation for
subsequent surgical removal of tumor. In some embodiments, the
herein disclosed treatments are applied as adjuvant therapy
subsequent to surgical removal of tumor to address any residual
disease or potential recurrent disease.
[0014] Other embodiments include combination drug compositions or
formulations comprising at least one Her2-targeting therapeutic
agent and at least one RXR agonist capable of inhibiting cancer
growth. In other embodiments the combination (used for treatment)
may include more than one agent in one or the other classification
(Her2 targeting agent and/or RXR agonist). In still other
embodiments the combination may further include thyroid hormone. In
some embodiments the thyroid hormone is thyroxine.
BRIEF DESCRIPTION OF DRAWINGS
[0015] FIGS. 1A-B are three-dimensional plots depicting the growth
inhibitory effects of IRX4204 and trastuzumab, alone and in
combination, on breast cancer cell lines: MCF7 cells (FIG. 1 A) and
SkBr3 cells (FIG. 1B).
[0016] FIGS. 2A-D are three-dimensional plots depicting the growth
inhibitory effects of IRX4204 and lapatinib, alone and in
combination, on breast cancer cell lines: MCF7 cells (FIG. 2A),
SkBr3 cells (FIG. 2B), BT474 cells (FIG. 2C), and MDA-MB-361 cells
(FIG. 2D).
[0017] FIGS. 3A-D are three-dimensional plots depicting the growth
inhibitory effect of IRX4204 and neratinib, alone and in
combination, on breast cancer cell lines: MCF7 cells (FIG. 3A),
SkBr3 cells (FIG. 3B), BT474 cells (FIG. 3C), and MDA-MB-361 cells
(FIG. 3D).
DESCRIPTION
[0018] The herein disclosed embodiments include methods of treating
Her2.sup.+ cancers, such as Her2.sup.+ carcinoma of the breast,
with a combination a retinoid X (rexinoid) receptor (RXR) agonist
and a Her2-targeted anticancer agent. Some embodiment further
comprise administration of thyroid hormone in conjunction with the
RXR agonist. Embodiments include a RXR agonist for use in
combination with a Her2-targeted anticancer agent, or a thyroid
hormone and a Her2-targeted anticancer agent, in the treatment of
Her2.sup.+ cancers. In some embodiments the Her2.sup.+ cancer is
Her2.sup.+ breast cancer.
[0019] The methods of treatment involve the administration of a
combination of two, three, or more therapeutic agents. Moreover,
the administration of one of these agents may be described as being
done in coordination or conjunction with another of these agents.
By such combination, or administration of in coordination or in
conjunction with, it is meant that the manner of administration of
each of these agents is such that the physiologic effects of the
agents overlap in time. This does not require that the agents be
contained in the same composition or formulation, or that they be
administered as separate compositions at the same time, by the same
route of administration, or on the same schedule, though in some
embodiments any of the foregoing may be the case. Indeed, while it
is possible to administer RXR agonists, thyroid hormone, and Her2
kinase inhibitors on a daily schedule, antibodies are more
typically administered at intervals measured in weeks.
[0020] Among the earlier successful targeted cancer therapies are
those targeting human epidermal growth factor receptor 2 (Her2).
Her2-targeted treatments include monoclonal antibodies (mAbs), such
as trastuzumab and pertuzumab, and inhibitors of Her2 kinase
activity, such as lapatinib, neratinib, and afatinib (which all
also inhibit epidermal growth factor receptor (EGFR)). The rexinoid
IRX4204 has shown activity against a variety of cancers in model
systems (see for example, U.S. Patent Pub. 2008-0300312, which is
incorporated herein by reference in its entirety for all that it
teaches about the use of RXR agonists for the treatment of cancer)
especially when used in combination with thyroid hormone (see for
example, U.S. Patent Pub. 2008-0300312, which is incorporated
herein by reference in its entirety for all that it teaches about
the use of RXR agonists for the treatment of cancer). It is
disclosed herein that the combination of IRX4204 and a
Her2-targeted therapeutic agent are particularly effective against
Her2.sup.+ cancers, such as Her2.sup.+ breast cancer. Thus various
embodiments are combinations of IRX4204 and a Her2-targeted
therapeutic agent, and methods of treatment involving
administration of both IRX4204 and a Her2-targeted therapeutic
agent. Some embodiments further include thyroid hormone or the
administration of thyroid hormone. Other embodiments exclude
thyroid hormone or the administration of thyroid hormone.
[0021] A Her2-targeted therapeutic agent as used herein is a
therapeutic agent that inhibits growth of cancer cells by
inhibiting Her2 function. Such agents include mAbs that bind to
Her2, antibody-drug conjugates comprising such mAbs, and inhibitors
of Her2 tyrosine kinase activity. Collectively, such agents can be
referred to as means for therapeutically targeting Her2. Some
embodiments specifically include or are limited to one or more of
these classes of agent, or one or more species within one or more
of these classes of agent. Some embodiments specifically exclude
one or more of these classes of agent, or one or more species
within one or more of these classes of agent. Thus, means for
therapeutically targeting Her2 are mAbs that bind to Her2,
antibody-drug conjugates comprising mAbs that bind to Her2, and
inhibitors or Her2 tyrosine kinase activity. In some embodiments,
the mAb in an antibody-drug conjugate has therapeutic activity by
itself, in other embodiments it does not.
[0022] Many embodiments comprise administration of a single
anti-Her2 mAb, but some embodiments comprise administration of
multiple anti-Her2 mAbs, for example, trastuzumab and pertuzumab.
While the disclosed embodiments are generally described as using
anti-Her2 mAbs, further embodiments can substitute anti-Her2
polyclonal antiserum for anti-Her2 mAb. Some embodiments can
comprise administration of additional mAbs targeting other
antigens, some embodiments specifically exclude administration of
other antibodies.
Anti-Her2 Antibodies
[0023] Her2 is a growth factor receptor found on, and implicated
in, a variety of cancers, especially breast cancer but also, for
example, gastroesophageal cancer, ovarian cancer, stomach cancer,
adenocarcinoma of the lung, uterine cancer (such as serous
endometrial carcinoma), or salivary duct carcinoma. Anti-Her2
antibodies are believed to work as anticancer agents through a
combination of mechanisms: inhibition of signaling through Her2,
antibody-dependent cellular cytotoxicity (ADCC), and mediating
presentation of tumor antigen by antigen presenting cells (APC),
such as macrophages; additional mechanisms may also exist. The best
understood and most clinically advanced anti-Her2 antibodies are
trastuzumab, pertuzumab, and margetuximab.
[0024] In some embodiments, these antibodies are administered by
intravenous infusion. In exemplary embodiments infusions may be
done over 30-90 minutes and may occur at intervals of 1-3 weeks for
as long as a year. In some such embodiments, the antibody is
administered at an initial higher dose and a subsequent lower dose.
In some such embodiments, the initial higher dosage is twice the
subsequent lower dosage. In some such embodiments, the initial dose
is single administration. In other such embodiments the initial
dosage is administered multiple times before switching to the lower
subsequent dosage. Specific examples of dosages and dose regimens
can be found in the prescribing information for HERCEPTIN.RTM. and
PERJETA.RTM., which are incorporated herein by reference in their
entireties.
[0025] Trastuzumab (sold as HERCEPTIN.RTM.) binds to domain IV of
the extracellular segment of Her2. Trastuzumab inhibits the
proliferation of cells that overexpress Her2 and mediates ADCC.
Biosimilar antibodies to trastuzumab have been developed and are
marketed in some jurisdictions.
[0026] Pertuzumab (sold as PERJETA.RTM.) recognizes the
extracellular dimerization domain (domain II) of Her2, a different
epitope than trastuzumab. By preventing ligand dependent
dimerization, it inhibits signaling through Her2, leading to cell
growth arrest and apoptosis. Pertuzumab also mediates ADCC.
Pertuzumab augmented the activity of trastuzumab in tumor xenograft
models that over express Her2.
[0027] Margetuximab (currently still in clinical development)
recognizes the same epitope as trastuzumab, but possesses an
engineered Fc region designed to increase Fc-dependent mechanisms
of immune attack, such as ADCC. The engineered Fc region confers
increased binding to activating Fc-y receptors (CD16A) and reduced
binding to inhibitory Fc-y receptors (CD16B) on immune effector
cells, including monocytes, macrophages, dendritic cells and
natural killer (NK) cells.
[0028] Further anti-Her2 mAbs include TrasGEX.RTM., HM2,
hertuzumab, and HT-19. TrasGEX.RTM. and HM2 are being developed as
"biobetters" of trastuzumab, while the other two are independently
derived. in HM2 a metal-binding motif has been incorporated into
trastuzumab to aid conjugation. TrasGEX.RTM. is a
glycosylation-optimized version of trastuzumab. Hertuzumab had a
higher ELISA-based affinity for Her2 than trastuzumab. HT-19 is an
IgG1 antibody that is non-competitive for HER2 binding with
trastuzumab and pertuzumab; that is, it binds a different epitope
than either of those two mAbs.
[0029] Many embodiments comprise administration of a single
anti-Her2 mAb, but some embodiments comprise administration of
multiple anti-Her2 mAbs, for example, trastuzumab and pertuzumab.
While the disclosed embodiments are generally described as using
anti-Her2 mAbs, further embodiments can substitute anti-Her2
polyclonal antiserum for anti-Her2 mAb.
Antibody-Drug Conjugates
[0030] In addition to use of anti-Her2 mAbs themselves as
therapeutic agents, anti-Her2 mAbs have also been incorporated into
antibody-drug conjugates. One example is ado-trastuzumab emtansine
(sold as KADCYLA.RTM.). Further examples include A166, ALT-P7
(trastuzumab biobetter HM2 conjugated in a site-specific manner to
monomethyl auristatin E), ARX788 (a monoclonal HER2 targeting
antibody site-specifically conjugated, via a non-natural amino acid
linker para-acetyl-phenylalanine (pAcF), to monomethyl auristatin
F), DHES0815A (a monoclonal HER-2 targeting antibody linked to
pyrrolo[2,1-c][1,4]benzodiazepine monoamide), DS-8201a (trastuzumab
deruxtecan; trastuzumab, an enzymatically cleavable maleimide
glycynglycyn-phenylalanyn-glycyn (GGFG) peptide linker and a
topoisomerase I inhibitor, fam-trastuzumab deruxtecan (sold as
ENHERTU.RTM.), RC48 (humanized anti-HER2 antibody hertuzumab
conjugated with monomethyl auristatin E (MMAE) via a cleavable
linker), SYD985 (([vic-]trastuzumab duocarmazine; trastuzumab
linked via a cleavable valine-citrulline peptide to the synthetic
duocarmycin analog seco DUocarmycin hydroxyBenzamide Azaindole),
MEDI4276 (HER2-bispecific antibody targeting two different epitopes
on HER2, site-specifically conjugated via a maleimidocaproyl linker
to the potent tubulysin-based microtubule inhibitor AZ13599185) and
XMT-1522 (TAK-522; HT-19 conjugated with the DOLAFLEXIN.RTM.
platform to auristatin F-hydroxypropylamide).
[0031] In some embodiments, the Her2-targeting component comprises,
or is, an antibody-drug conjugate comprising an anti-Her2
antibody.
Her2 Kinase Inhibitors
[0032] Her2 and EGFR are closely related protein tyrosine kinases
and many drugs developed as an inhibitor of one also inhibit the
other. At least four drugs that are irreversible inhibitors of
these kinases are now marketed as a cancer treatment, though the
indications vary: lapatinib, neratinib, afatinib, and dacomitinib.
It should be noted that not all EGFR inhibitors are irreversible
inhibitors or are known to cross-inhibit Her2. EGFR inhibitors that
do not--or are not known to--inhibit Her2 should not be considered
Her2 inhibitors as the term is used herein. In some embodiments,
the Her2 inhibitor is an irreversible inhibitor. In some
embodiments, the Her2 inhibitor is not a reversible inhibitor.
[0033] Lapatinib (sold as TYKERB.RTM.) (CAS No. 231277-92-2),
typically provided as Lapatinib Ditosylate (CAS No. 388082-77-7) or
the monohydrate thereof, can be administered, according to its
prescribing instructions which are incorporated herein by reference
in their entirety, on a 21 day treatment cycle, at 1250 or 1500 mg
once daily, depending on indication. Lapatinib plus capecitabine is
taken on days 1 to 14. Lapatinib alone is taken on days 15 to 21.
At the end of the 21 days, the treatment cycle should be repeated
until disease progression or unacceptable toxicity occurs.
Capecitabine is administered orally in two doses approximately 12
hours apart at a dosage of 2000 mg/m.sup.2/day.
[0034] Neratinib (sold as NERLYNX.RTM.) (CAS No. 698387-09-6) can
be administered, according to its prescribing instructions which
are incorporated herein by reference in their entirety, with food
at an initial dose of 240 mg/day and taken daily for a year. If
toxicity exceeds grade 1, the dose can be reduced by 40 mg/day in
stepwise fashion until toxicity is grade 1 or less. If the dose has
been reduced to 120 mg/day and toxicity remains greater than grade
1, treatment with Neratinib should be discontinued.
[0035] Afatnib (sold as GILOTRIF.RTM.) (CAS No. 850140-72-6) can be
administered, according to its prescribing instructions which are
incorporated herein by reference in their entirety, orally without
food once daily at 40 mg/day until disease progression or no longer
tolerated by the patient.
[0036] Dacomitinib (sold as VIZIMPRO.RTM.) (CAS No. 1110813-31-4)
can be administered, according to its prescribing instructions
which are incorporated herein by reference in their entirety,
orally with or without food, once daily at 45 mg/day until disease
progression or unacceptable toxicity occurs. Upon occurrence of
unacceptable toxicity, the dosage can be reduced in stepwise
fashion to 30 or 15 mg/day.
[0037] Tucatinib (sold as TUKYSA.RTM.) (CAS No. 937263-43-9) can be
administered, according to its prescribing instructions which are
incorporated herein by reference in their entirety, orally with or
without food, 300 mg twice daily (12 hours apart) in combination
with trastuzumab and capecitabine until disease progression or
unacceptable toxicity. Upon occurrence of unacceptable toxicity,
the dosage can be reduced in stepwise fashion, 50 mg per step, to
150 mg, twice daily.
[0038] The above dosing information, in addition to disclosing
specific embodiments in which these Her2 kinase inhibitors may be
used in combination with an RXR agonist, provides general guidance
as to dosing practices with such drugs. The disclosed embodiments
are not necessarily limited to these specific dosing regimens and
it is within the skill of the physician to modify these regimens
for individual patients. Due to the improved and synergistic effect
of these drugs when used in combination with a RXR agonist,
unacceptable toxicity may be avoided by use of lower dosages of the
kinase inhibitor while still achieve beneficial therapeutic
effect.
[0039] Other Her2 kinase inhibitors include canertinib (CAS No.
267243-28-7), sapitinib (CAS No. 848942-61-0), CP-724714 (CAS No.
537705-08-1), and CUDC-101 (CAS No. 1012054-59-9).
RXR Agonists
[0040] Preclinical studies with rexinoids suggest that selective
activation of Retinoid X Receptors (RXR), which modulate functions
associated with differentiation, inhibition of cell growth,
apoptosis and metastasis, may be useful in treating a variety of
diseases associated with the biochemical functions modulated by
RXR.
[0041] The Retinoic Acid Receptors (RARs) and RXRs and their
cognate ligands function by distinct mechanisms. The term "RAR" as
used herein refers to one or more of RAR.alpha., RAR.beta., or
RAR.gamma.. The term "RXR" as used herein refers to one or more of
RXR.alpha., RXR.beta., or RXR.gamma.. A RAR biomarker is a
distinctive biological, biochemical or biologically derived
indicator that signifies patient RAR activity. RAR biomarkers
include, but are not limited to, CYP26 levels, CRBPI levels, and
the like, and combinations thereof.
[0042] In some embodiments, the RAR activation threshold means one
or more of a CYP26 level which is 25% increased over baseline and a
CRBPI level 25% increased over baseline. The RARs form heterodimers
with RXRs and these RAR/RXR heterodimers bind to specific response
elements in the promoter regions of target genes. The binding of
RAR agonists to the RAR receptor of the heterodimer results in
activation of transcription of target genes leading to retinoid
effects. On the other hand, the disclosed RXR agonists do not
activate RAR/RXR heterodimers. RXR heterodimer complexes like
RAR/RXR can be referred to as non-permissive RXR heterodimers as
activation of transcription due to ligand-binding occurs only at
the non-RXR protein (e.g., RAR); activation of transcription does
not occur due to ligand binding at the RXR.
[0043] RXRs also interact with nuclear receptors other than RARs
and RXR agonists may elicit some of its biological effects by
binding to such RXR/receptor complexes. These RXR/receptor
complexes can be referred to as permissive RXR heterodimers as
activation of transcription due to ligand-binding could occur at
the RXR, the other receptor, or both receptors. Examples of
permissive RXR heterodimers include, without limitation, peroxisome
proliferator activated receptor/RXR (PPAR/RXR), farnesyl X
receptor/RXR (FXR/RXR), nuclear receptor related-1 protein
(Nurr1/RXR) and liver X receptor/RXR (LXR/RXR). Alternately, RXRs
may form RXR/RXR homodimers which can be activated by RXR agonists
leading to rexinoid effects. Also, RXRs interact with proteins
other than nuclear receptors and ligand binding to an RXR within
such protein complexes can also lead to rexinoid effects. Due to
these differences in mechanisms of action, RXR agonists and RAR
agonists elicit distinct biological outcomes and even in the
instances where they mediate similar biological effects, they do so
by different mechanisms. Moreover, the unwanted side effects of
retinoids, such as pro-inflammatory responses or mucocutaneous
toxicity, are mediated by activation of one or more of the RAR
receptor subtypes. Stated another way, biological effects mediated
via RXR pathways would not induce pro-inflammatory responses, and
thus, would not result in unwanted side effects.
[0044] Thus, aspects of the present specification provide, in part,
a RXR agonist. As used herein, the term "RXR agonist", is
synonymous with "selective RXR agonist" and refers to a compound
that selectively binds to one or more RXR receptors like a
RXR.alpha., a RXR.beta., or a RXR.gamma. in a manner that elicits
gene transcription via an RXR response element. As used herein, the
term "selectively binds," when made in reference to a RXR agonist,
refers to the discriminatory binding of a RXR agonist to the
indicated target receptor like a RXR.alpha., a RXR.beta., or a
RXR.gamma. such that the RXR agonist does not substantially bind
with non-target receptors like a RAR.alpha., a RAR.beta. or a
RAR.gamma.. In some embodiments, the term "RXR agonist" includes
esters of RXR agonist.
[0045] For each of the herein disclosed embodiments the RXR
agonists can be compounds having the structure of Formula I
##STR00001##
wherein R is H, or lower alkyl of 1 to 6 carbons; or the agonist is
a pharmaceutically acceptable salt of the compounds.
[0046] Also disclosed herein are esters of RXR agonists. An ester
may be derived from a carboxylic acid of C1, or an ester may be
derived from a carboxylic acid functional group on another part of
the molecule, such as on a phenyl ring. While not intending to be
limiting, an ester may be an alkyl ester, an aryl ester, or a
heteroaryl ester. The term alkyl has the meaning generally
understood by those skilled in the art and refers to linear,
branched, or cyclic alkyl moieties. C.sub.1-6 alkyl esters are
particularly useful, where alkyl part of the ester has from 1 to 6
carbon atoms and includes, but is not limited to, methyl, ethyl,
propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl
isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, and combinations thereof having from 1-6 carbon atoms,
etc. In some embodiments the RXR agonist is the ethyl ester of
formula I.
[0047] In some embodiments the RXR agonist is
3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-
-aphth-7-yl]2(E), 4(E) heptadienoic acid, also known as IRX4204,
and has the following chemical structure:
##STR00002##
[0048] Pharmaceutically acceptable salts of RXR agonists can also
be used in the disclosed embodiments. Compounds disclosed herein
which possess a sufficiently acidic, a sufficiently basic, or both
functional groups, and accordingly can react with any of a number
of organic or inorganic bases, and inorganic and organic acids, to
form a salt.
[0049] Acids commonly employed to form acid addition salts from RXR
agonists with basic groups are inorganic acids such as hydrochloric
acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric
acid, and the like, and organic acids such as p-toluenesulfonic
acid, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic
acid, carbonic acid, succinic acid, citric acid, benzoic acid,
acetic acid, and the like. Examples of such salts include the
sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate,
pyrophosphate, chloride, bromide, iodide, acetate, propionate,
decanoate, caprylate, acrylate, formate, isobutyrate, caproate,
heptanoate, propiolate, oxalate, malonate, succinate, suberate,
sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,
benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,
xylenesulfonate, phenylacetate, phenylpropionate, phenyl butyrate,
citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate,
methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,
naphthalene-2-sulfonate, mandelate, and the like.
[0050] Bases commonly employed to form base addition salts from RXR
agonists with acidic groups include, but are not limited to,
hydroxides of alkali metals such as sodium, potassium, and lithium;
hydroxides of alkaline earth metal such as calcium and magnesium;
hydroxides of other metals, such as aluminum and zinc; ammonia, and
organic amines, such as unsubstituted or hydroxy-substituted mono-,
di-, or trialkylamines; dicyclohexylamine; tributyl amine;
pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine;
mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), such as mono-,
bis-, or tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy
lower alkyl)-amines, such as N,N-dimethyl-N-(2- hydroxyethyl)amine,
or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids
such as arginine, lysine, and the like.
[0051] IRX4204, like some other RXR ligands, does not activate
non-permissive heterodimers such as RAR/RXR. However, IRX4204, is
unique in that it specifically activates the Nurr1/RXR heterodimer
and does not activate other permissive RXR heterodimers such as
PPAR/RXR, FXR/RXR, and LXR/RXR. Other RXR ligands generally
activate these permissive RXR heterodimers. Thus, all RXR ligands
cannot be classified as belonging to one class. IRX4204 belongs to
a unique class of RXR ligands which specifically activate RXR
homodimers and only one of the permissive RXR heterodimers, namely
the Nurr1/RXR heterodimer.
[0052] In one embodiment, the selective RXR agonist does not
activate to any appreciable degree the permissive heterodimers
PPAR/RXR, FXR/RXR, and LXR/RXR. In another embodiment, the
selective RXR agonist, activates the permissive heterodimer
Nurr1/RXR. One example of such a selective RXR agonist is
3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydron-
aphth-7-yl]2(E),4(E) heptadienoic acid (IRX4204) disclosed herein,
the structure of which is shown in Formula II. In other aspects of
this embodiment, the RXR agonists activates the permissive
heterodimers PPAR/RXR, FXR/RXR, or LXR/RXR by 1% or less, 2% or
less, 3% or less, 4% or less, 5% or less, 6% or less, 7% or less,
8% or less, 9% or less, or 10% or less relative to the ability of
activating agonists to the non-RXR receptor to activate the same
permissive heterodimer. Examples of RXR agonists, which activates
one or more of PPAR/RXR, FXR/RXR, or LXR/RXR include LGD1069
(bexarotene) and LGD268.
[0053] Binding specificity is the ability of a RXR agonist to
discriminate between a RXR receptor and a receptor that does not
contain its binding site, such as a RAR receptor.
[0054] Particular embodiments provide methods of treating cancer
comprising administering to a patient in need of such treatment a
RXR agonist at a level below an RAR activating threshold and at or
above an RXR activating threshold.
[0055] For IRX4204, the RAR EC.sub.10 (the concentration effective
to cause a 10% of maximal activation of the RAR) is 300 nM for the
.alpha. isoform and 200 nM for the .beta. and .gamma. isoforms.
Thus, in some embodiments, concentrations not exceeding 200 nM are
considered to be below an RAR activating concentration. For
IRX4204, the RXR EC.sub.90 (the concentration effective to cause a
90% of maximal activation of the RXR) is 0.1 nM for the .alpha. and
.gamma. isoforms and 1 nM for the isoform. Thus, in some
embodiments concentrations of at least 0.1 nM are considered to be
above an RXR activating threshold. Based on studies in humans, oral
dosages of IRX4204 of 20 mg/m.sup.2/day will produce systemic
concentrations that remain below 200 nM. Similarly, it is estimated
that an oral dosage in the range of 0.01 to 0.02 mg/m.sup.2/day
will produce systemic concentrations of 0.1 nM or greater. Thus, in
various individual embodiments a dosage of IRX4204 is at least
0.01, 0.02, 0.03, 0.05, 0.1, 0.3, 0.5, 1, 3 or 5 mg/m.sup.2/day and
does not exceed 150, 200, or 300 mg/m.sup.2/day, or any range bound
by a pair of these values.
[0056] In other embodiments, the dosage for a human adult of the
RXR agonist, for example IRX4204, is from 0.2 to 300 mg/day, such
as in individual embodiments, from 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,
or 10 mg/day, but not to exceed 10, 15, 20, 50, or 100 mg/day, or
any range bound by a pair of these values.
[0057] The RXR agonist can be administered to a mammal using
standard administration techniques, including parenteral, oral,
intravenous, intraperitoneal, subcutaneous, pulmonary, transdermal,
intramuscular, intranasal, buccal, sublingual, or suppository
administration. The term "parenteral," as used herein, includes
intravenous, intramuscular, subcutaneous, rectal, vaginal, and
intraperitoneal administration. The RXR agonist preferably is
suitable for oral administration, for example as a pill, tablet or
capsule. Administration may be continuous or intermittent. In
certain embodiments, the total daily dosage of RXR agonist can be
administered as a single dose or as two doses administered with a
24 hour period spaced 8 to 16, or 10 to 14, hours apart.
Thyroid Hormone
[0058] Both biologically sourced and synthetic thyroid hormones
have been used in medicine. The major forms of thyroid hormone are
referred to a T.sub.3 (triiodothyronine) and T.sub.4 (thyroxine).
Thyroxine is less active but has a longer half-life and is
sometimes considered a prohormone of triiodothyronine. As used
herein, the term "thyroid hormone" refers to thyroxine and
triiodothyronine. Thyroxine (thyroid hormone T.sub.4, levothyroxine
sodium) is a tyrosine-based hormone produced by the thyroid gland
and is primarily responsible for regulation of metabolism. Both
have wide commercial availability and are suitable for use in the
herein disclosed embodiments. However, the synthetic form of
T.sub.4, levothyroxine, is much more commonly utilized (except in
patients unable to convert T.sub.4 into T.sub.3) as its longer
half-life in the body facilitates once-daily administration. In
some embodiments, the administered thyroid hormone is specifically
thyroxine. In some embodiments, the administered thyroid hormone is
triiodothyronine.
[0059] Administration of RXR agonists, or esters thereof, may lead
to the suppression of serum thyroid hormones and possibly to
clinical hypothyroidism and related conditions. However, in some
embodiments thyroid hormone is not co-administered (or is not
primarily co-administered) to remediate a suppression of serum
thyroid hormone levels. Co-administration of thyroid hormone with
an RXR agonist improves the RXR agonist's anti-cancer efficacy, as
compared to the effect of the RXR agonist alone, likely through
multiple mechanisms of action. The co-administered thyroid hormone
can also mitigate the hypothyroid-inducing effects of the RXR
agonist, thereby improving the clinical safety and tolerability of
the treatment. Thus, in preferred embodiments, thyroid hormone is
co-administered with an RXR agonist to improve the efficacy of the
treatment, whether or not administration of the RXR agonist has
caused, or is expected to cause, clinical hypothyroidism. By
administration of thyroid hormone in coordination or in conjunction
with the RXR agonist it is meant that the manner of administration
of each of these two agents is such that the physiologic effects of
the two agents overlap in time. This does not require that the RXR
agonist and thyroid hormone be contained in the same composition or
formulation, or that they be administered as separate compositions
at the same time, by the same route of administration, or on the
same schedule, though in some embodiments any of the foregoing may
be the case.
[0060] Suitable thyroxine doses are generally from about 5
.mu.g/day to about 250 .mu.g/day orally initially with an increase
in dose every 2-4 weeks as needed. In other embodiments, the
suitable thyroxine dose is from about 5 .mu.g/day to about 225
.mu.g/day, from about 7.5 .mu.g/day to about 200 .mu.g/day, from
about 10 .mu.g/day to about 175 .mu.g/day, from about 12.5
.mu.g/day to about 150 .mu.g/day, from about 15 .mu.g/day to about
125 .mu.g/day, from about 17.5 .mu.g/day to about 100 .mu.g/day,
from about 20 .mu.g/day to about 100 .mu.g/day, from about 22.5
.mu.g/day to about 100 .mu.g/day, from about 25 .mu.g/day to about
100 .mu.g/day, from about 5 .mu.g/day to about 200 .mu.g/day, from
about 5 .mu.g/day to about 100 .mu.g/day, from about 7.5 .mu.g/day
to about 90 .mu.g/day, from about 10 .mu.g/day to about 80
.mu.g/day, from about 12.5 .mu.g/day to about 60 .mu.g/day, or from
about 15 .mu.g/day to about 50 .mu.g/day. Increases in dose are
generally made in increments of about 5 .mu.g/day, about 7.5
.mu.g/day, about 10 .mu.g/day, about 12.5 .mu.g/day, about 15
.mu.g/day, about 20 .mu.g/day, or about 25 .mu.g/day. In certain
embodiments, the suitable thyroid hormone dose is a dose able to
produce serum levels of T.sub.4 in the top 50%, the top 60%, the
top 70%, the top 80%, or the top 90% of the normal range for the
testing laboratory. As the normal range of T.sub.4 levels may vary
by testing laboratory, the target T.sub.4 levels are based on
normal ranges determined for each particular testing
laboratory.
[0061] For each embodiment involving a combination of RXR agonist
and Her2-targeting therapeutic agent, there is a parallel
embodiment in which the combination further comprises thyroid
hormone.
Pharmaceutical Compositions and Formulations
[0062] The various component active agents used in the herein
described treatments will typically exist as pharmaceutical
compositions or formulations. Such compositions or formulations may
be a liquid formulation, semi-solid formulation, or a solid
formulation. A formulation disclosed herein can be produced in a
manner to form one phase, such as, e.g., an oil or a solid.
Alternatively, a formulation disclosed herein can be produced in a
manner to form two phases, such as, e.g., an emulsion. A
pharmaceutical composition disclosed herein intended for such
administration may be prepared according to any method known to the
art for the manufacture of pharmaceutical compositions.
[0063] Liquid formulations suitable for parenteral injection or for
nasal sprays may comprise physiologically acceptable sterile
aqueous or nonaqueous solutions, dispersions, suspensions or
emulsions and sterile powders for reconstitution into sterile
injectable solutions or dispersions. Formulations suitable for
nasal administration may comprise physiologically acceptable
sterile aqueous or nonaqueous solutions, dispersions, suspensions
or emulsions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols
(propylene glycol, polyethyleneglycol (PEG), glycerol, and the
like), suitable mixtures thereof, vegetable oils (such as olive
oil) and injectable organic esters such as ethyl oleate. Proper
fluidity can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersions and by the use of surfactants.
[0064] A pharmaceutical composition disclosed herein can optionally
include a pharmaceutically acceptable carrier that facilitates
processing of an active compound into pharmaceutically acceptable
compositions. As used herein, the term "pharmaceutically
acceptable" refers to those compounds, materials, compositions,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem complications commensurate with a reasonable
benefit/risk ratio. (This definition is also application to the
phrase "pharmaceutically-acceptable salts"). As used herein, the
term "pharmacologically acceptable carrier" is synonymous with
"pharmacological carrier" and refers to any carrier that has
substantially no long term or permanent detrimental effect when
administered and encompasses terms such as "pharmacologically
acceptable vehicle, stabilizer, diluent, additive, auxiliary, or
excipient." Such a carrier generally is mixed with an active
compound or permitted to dilute or enclose the active compound and
can be a solid, semi-solid, or liquid agent. It is understood that
the active compounds can be soluble or can be delivered as a
suspension in the desired carrier or diluent. Any of a variety of
pharmaceutically acceptable carriers can be used including, without
limitation, aqueous media such as, e.g., water, saline, glycine,
hyaluronic acid and the like; solid carriers such as, e.g., starch,
magnesium stearate, mannitol, sodium saccharin, talcum, cellulose,
glucose, sucrose, lactose, trehalose, magnesium carbonate, and the
like; solvents; dispersion media; coatings; antibacterial and
antifungal agents; isotonic and absorption delaying agents; or any
other inactive ingredient. Selection of a pharmacologically
acceptable carrier can depend on the mode of administration. Except
insofar as any pharmacologically acceptable carrier is incompatible
with the active compound, its use in pharmaceutically acceptable
compositions is contemplated. Non-limiting examples of specific
uses of such pharmaceutical carriers can be found in Pharmaceutical
Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al.,
eds., Lippincott Williams & Wilkins Publishers, 7.sup.th ed.
1999); Remington: The Science and Practice of Pharmacy (Alfonso R.
Gennaro ed., Lippincott, Williams & Wilkins, 20.sup.th ed.
2000); Goodman & Gilman's The Pharmacological Basis of
Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill
Professional, 10.sup.th ed. 2001); and Handbook of Pharmaceutical
Excipients (Raymond C. Rowe et al., APhA Publications, 4.sup.th
edition 2003). These protocols are routine and any modifications
are well within the scope of one skilled in the art and from the
teaching herein.
[0065] A pharmaceutical composition disclosed herein can optionally
include, without limitation, other pharmaceutically acceptable
components (or pharmaceutical components), including, without
limitation, buffers, preservatives, tonicity adjusters, salts,
antioxidants, osmolality adjusting agents, physiological
substances, pharmacological substances, bulking agents, emulsifying
agents, wetting agents, sweetening or flavoring agents, and the
like. Various buffers and means for adjusting pH can be used to
prepare a pharmaceutical composition disclosed herein, provided
that the resulting preparation is pharmaceutically acceptable. Such
buffers include, without limitation, acetate buffers, borate
buffers, citrate buffers, phosphate buffers, neutral buffered
saline, and phosphate buffered saline. It is understood that acids
or bases can be used to adjust the pH of a composition as needed.
Pharmaceutically acceptable antioxidants include, without
limitation, sodium metabisulfite, sodium thiosulfate,
acetylcysteine, butylated hydroxyanisole, and butylated
hydroxytoluene. Useful preservatives include, without limitation,
benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric
acetate, phenylmercuric nitrate, a stabilized oxy chloro
composition, such as, e.g., sodium chlorite and chelants, such as,
e.g., DTPA or DTPA-bisamide, calcium DTPA, and CaNaDTPA-bisamide.
Tonicity adjustors useful in a pharmaceutical composition include,
without limitation, salts such as, e.g., sodium chloride, potassium
chloride, mannitol or glycerin and other pharmaceutically
acceptable tonicity adjustor. The pharmaceutical composition may be
provided as a salt and can be formed with many acids, including but
not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric,
malic, succinic, etc. Salts tend to be more soluble in aqueous or
other protonic solvents than are the corresponding free base forms.
It is understood that these and other substances known in the art
of pharmacology can be included in a pharmaceutical composition
useful in the invention.
[0066] Pharmaceutical formulations suitable for administration by
inhalation include fine particle dusts or mists, which may be
generated by means of various types of metered, dose pressurized
aerosols, nebulizers, or insufflators.
[0067] Semi-solid formulations suitable for topical administration
include, without limitation, ointments, creams, salves, and gels.
In such solid formulations, the active compound may be admixed with
at least one inert customary excipient (or carrier) such as, a
lipid and/or polyethylene glycol.
[0068] Solid formulations suitable for oral administration include
capsules, tablets, pills, powders and granules. In such solid
formulations, the active compound may be admixed with at least one
inert customary excipient (or carrier) such as sodium citrate or
dicalcium phosphate or (a) fillers or extenders, as for example,
starches, lactose, sucrose, glucose, mannitol and silicic acid, (b)
binders, as for example, carboxymethylcellulose, alignates,
gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants,
as for example, glycerol, (d) disintegrating agents, as for
example, agar-agar, calcium carbonate, potato or tapioca starch,
alginic acid, certain complex silicates and sodium carbonate, (e)
solution retarders, as for example, paraffin, (f) absorption
accelerators, as for example, quaternary ammonium compounds, (g)
wetting agents, as for example, cetyl alcohol and glycerol
monostearate, (h) adsorbents, as for example, kaolin and bentonite,
and (i) lubricants, as for example, talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate or mixtures thereof. In the case of capsules, tablets and
pills, the dosage forms may also comprise buffering agents.
[0069] The small molecule components of the various embodiments,
that is, the RXR agonist, thyroid hormone, and Her2 kinase
inhibitors are capable of being formulated in solid, oral dosage
forms. The antibody components are generally formulated as liquids
typically for intravenous infusion. In alternative embodiments the
antibody components may be supplied in lyophilized form for
reconstitution as a liquid locally at the site of treatment, where
they are also typically infused intravenously into the patient.
While intravenous infusion is typical, in alternative embodiments
the antibody may be administered by another route of
administration, such as subcutaneous injection or infusion.
Treatment
[0070] As used herein, the terms "treatment," "treating," and the
like refer to obtaining a desired pharmacologic and/or physiologic
effect. This may be observed directly as a slowing of tumor growth,
stabilization of disease, or a partial or complete response (that
is, tumor regression or elimination of tumors), or extended overall
or disease-free survival. Treatment may also be observed as an
amelioration or reduction of symptoms related to the underlying
cancer. However, as cancer treatment, the disclosed embodiments'
aim and mechanism is directed to inhibiting, stabilizing, or
reducing tumor growth (including metastases), or partially or
completely eliminating tumors, or extending overall or disease-free
survival; effects on other cancer symptoms are secondary. Direct
treatment of such other symptoms (for example, pain, nausea, loss
of appetite, etc.) is not within the scope of treating cancer as
used herein. That is, treating a symptom, for example, cachexia in
a cancer patient is not treating cancer. However, an agent that
treats cancer (e.g., has an impact on the growth and/or spread of
cancer) may also ameliorate a symptom, such as cachexia, either
indirectly, through its effect on the cancer, or directly, through
a pleiotropic effect. A "therapeutically effective amount" refers
to an amount effective, at dosages and for periods of time
necessary, to achieve a desired therapeutic result. The
therapeutically effective amount may vary according to factors such
as the disease state, age, sex, and weight of the individual, and
the ability of the Her2-targeted therapy, RXR agonist, and if used,
thyroid hormone, to elicit a desired response in the
individual.
[0071] However, the dose administered to a mammal, particularly a
human, in the context of the present methods, should be sufficient
to effect a therapeutic response in the mammal over a reasonable
timeframe. One skilled in the art will recognize that the selection
of the exact dose and composition and the most appropriate delivery
regimen will also be influenced by inter alia the pharmacological
properties of the formulation, the nature and severity of the
condition being treated, and the physical condition and mental
acuity of the recipient, as well as the potency of the specific
compound, the age, condition, body weight, sex and response of the
patient to be treated, and the stage/severity of the disease.
[0072] Treatment activity includes the administration of the
medicaments, dosage forms, and pharmaceutical compositions
described herein to a patient, especially according to the various
methods of treatment disclosed herein, whether by a healthcare
professional, the patient his/herself, or any other person.
Treatment activities include the orders, instructions, and advice
of healthcare professionals such as physicians, physician's
assistants, nurse practitioners, and the like that are then acted
upon by any other person including other healthcare professionals
or the patient his/herself. In some embodiments, treatment activity
can also include encouraging, inducing, or mandating that a
particular medicament, or combination thereof, be chosen for
treatment of a condition--and the medicament is actually used--by
approving insurance coverage for the medicament, denying coverage
for an alternative medicament, including the medicament on, or
excluding an alternative medicament, from a drug formulary, or
offering a financial incentive to use the medicament, as might be
done by an insurance company or a pharmacy benefits management
company, and the like. In some embodiments, treatment activity can
also include encouraging, inducing, or mandating that a particular
medicament be chosen for treatment of a condition--and the
medicament is actually used--by a policy or practice standard as
might be established by a hospital, clinic, health maintenance
organization, medical practice or physicians group, and the
like.
[0073] To benefit from the combined effect of a RXR agonist of
Formula I (or pharmaceutically acceptable salt thereof) and
Her2-targeted therapeutics, embodiments include methods of
treatment comprising or consisting of administering RXR agonist of
Formula I (or pharmaceutically acceptable salt thereof) and a
Her2-targeted therapeutic to a patient having a Her2.sup.+ cancer.
Some embodiments further comprise administration of thyroid hormone
in coordination with administration of the RXR agonist. In some
embodiments the Her2.sup.+ cancer is a Her2.sup.+ breast cancer. In
some embodiments the Her2.sup.+ cancer is a Her2.sup.+
gastroesophageal cancer, ovarian cancer, stomach cancer,
adenocarcinoma of the lung, uterine cancer (such as serous
endometrial carcinoma), or salivary duct carcinoma. Some
embodiments specifically include one or more of these cancers.
Other embodiments specifically exclude one or more of these
cancers.
[0074] In various embodiments the herein disclosed treatments may
be applied as a primary therapy, as a debulking therapy prior to
surgical removal of tumor, or as an adjuvant therapy subsequent to
any mode of primary therapy (especially surgery) to address
residual disease and/or lower the risk of recurrent cancer.
[0075] In some embodiments the patient having a Her2.sup.+ cancer
has not been previously treated with either RXR agonist of Formula
I (or pharmaceutically acceptable salt thereof) or a Her2-targeted
therapeutic. In some embodiments the patient has been previously
treated with RXR agonist of Formula I (or pharmaceutically
acceptable salt thereof) and has achieved stable disease or a
partial response (in some embodiments, as defined by RECIST or
iRECIST criteria)--that is, the cancer is sensitive to RXR agonist
of Formula I (or pharmaceutically acceptable salt thereof)--and a
Her2-targeted therapeutic is added to the treatment regimen. In
some embodiments the patient has been previously treated with a
Her2-targeted therapeutic and has achieved stable disease or a
partial response (in some embodiments, as defined by RECIST or
iRECIST criteria)--that is, the cancer is sensitive to a
Her2-targeted therapeutic--and RXR agonist of Formula I (or
pharmaceutically acceptable salt thereof) is added to the treatment
regimen.
[0076] Thus some embodiments entail administration of an RXR
agonist to a patient with a Her2.sup.+ tumor who has received, is
receiving, or is scheduled to receive, a Her2-targeted therapeutic
agent. Some embodiments entail administration of an RXR agonist to
a patient in whom a Her2-targeted therapeutic agent has had some
therapeutic effect (less than a complete response), that is
administration of the RXR agonist is added to the therapeutic
regimen for the Her2-targeted therapeutic agent. Some embodiments
entail administration of a Her2-targeted therapeutic agent to a
patient in whom an RXR agonist (or RXR agonist in conjunction with
thyroid hormone) has had some therapeutic effect (less than a
complete response), that is administration of the Her2-targeted
therapeutic agent is added to the therapeutic regimen for the RXR
agonist.
[0077] Therapeutic efficacy can be monitored by periodic assessment
of treated patients. For repeated administrations over several days
or longer, the treatment can be repeated until a desired
suppression of disease or disease symptoms occurs. However, other
dosage regimens may be useful and are within the scope of the
present disclosure. Antibodies typically have a much longer
half-life in the body than the other active agents used in these
methods and therefore there will typically be substantially longer
intervals (measured in weeks) between administrations.
[0078] The effectiveness of cancer therapy is typically measured in
terms of "response." The techniques to monitor responses can be
similar to the tests used to diagnose cancer such as, but not
limited to: [0079] A lump or tumor involving some lymph nodes can
be felt and measured externally by physical examination. [0080]
Some internal cancer tumors will show up on an x-ray or CT scan and
can be measured with a ruler. [0081] Blood tests, including those
that measure organ function can be performed. [0082] A tumor marker
test can be done for certain cancers.
[0083] Regardless of the test used, whether blood test, cell count,
or tumor marker test, it is repeated at specific intervals so that
the results can be compared to earlier tests of the same type.
[0084] Response to cancer treatment is defined several ways: [0085]
Complete response--all of the cancer or tumor disappears; there is
no evidence of disease. Expression level of tumor marker (if
applicable) may fall within the normal range. [0086] Partial
response--the cancer has shrunk by a percentage but disease
remains. Levels of a tumor marker (if applicable) may have fallen
(or increased, based on the tumor marker, as an indication of
decreased tumor burden) but evidence of disease remains. [0087]
Stable disease--the cancer has neither grown nor shrunk; the amount
of disease has not changed. A tumor marker (if applicable) has not
changed significantly. [0088] Disease progression--the cancer has
grown; there is more disease now than before treatment. A tumor
marker test (if applicable) shows that a tumor marker has
risen.
[0089] Other measures of the efficacy of cancer treatment include
intervals of overall survival (that is time to death from any
cause, measured from diagnosis or from initiation of the treatment
being evaluated)), cancer-free survival (that is, the length of
time after a complete response cancer remains undetectable), and
progression-free survival (that is, the length of time after
disease stabilization or partial response that resumed tumor growth
is not detectable).
[0090] There are two standard methods for the evaluation of solid
cancer treatment response with regard to tumor size (tumor burden),
the WHO and RECIST standards. These methods measure a solid tumor
to compare a current tumor with past measurements or to compare
changes with future measurements and to make changes in a treatment
regimen. In the WHO method, the solid tumor's long and short axes
are measured with the product of these two measurements is then
calculated; if there are multiple solid tumors, the sum of all the
products is calculated. In the RECIST method, only the long axis is
measured. If there are multiple solid tumors, the sum of all the
long axes measurements is calculated. However, with lymph nodes,
the short axis is measured instead of the long axis. There is also
a variation of the RECIST method for immunotherapies (iRECIST)
which takes into account distinctive behaviors linked to these
types of therapeutics, such as delayed responses after
pseudoprogression. Both the RECIST 1.1 guidelines and the iRecist
guidelines are incorporated by reference herein in their
entirety.
[0091] In some embodiments of the herein disclosed methods, the
tumor burden of a treated patient is reduced by about 5%, about
10%, about 15%, about 20%, about 25%, about 30%, about 35%, about
40%, about 45%, about 50%, about 55% about 60%, about 65%, about
70%, about 75%, about 80%, about 90%, about 95%, about 100%, or any
range bound by these values.
[0092] In other embodiments, the 1-year survival rate of treated
subjects is increased by about 5%, about 10%, about 15%, about 20%,
about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,
about 55% about 60%, about 65%, about 70%, about 75%, about 80%,
about 90%, about 95%, about 100%, or any range bound by these
values.
[0093] In other embodiments, the 5-year survival rate of treated
subjects is increased by about 5%, about 10%, about 15%, about 20%,
about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,
about 55% about 60%, about 65%, about 70%, about 75%, about 80%,
about 90%, about 95%, about 100%, or any range bound by these
values.
[0094] In other embodiments, the 10-year survival rate of treated
subjects is increased by about 5%, about 10%, about 15%, about 20%,
about 25%, about 30%, about 35%, about 40%, about 45%, about 50%,
about 55% about 60%, about 65%, about 70%, about 75%, about 80%,
about 90%, about 95%, about 100%, or any range bound by these
values.
[0095] In yet other embodiments, the subject has a sustained
remission of at least 6 months, at least 7 months, at least 8
months, at least 9 months, at least 10 months, at least 11 months,
at least 12 months, at least 14 months, at least 16 months, at
least 18 months, at least 20 months, at least 22 months, at least
24 months, at least 27 months, at least 30 months, at least 33
months, at least 36 months, at least 42 months, at least 48 months,
at least 54 months, or at least 60 months or more.
[0096] In other embodiments, the methods may additionally help to
treat or alleviate conditions, symptoms, or disorders related to
cancer. In some embodiments, these conditions or symptoms may
include, but are not limited to, anemia, asthenia, cachexia,
Cushing's Syndrome, fatigue, gout, gum disease, hematuria,
hypercalcemia, hypothyroidism, internal bleeding, hair loss,
mesothelioma, nausea, night sweats, neutropenia, paraneoplastic
syndromes, pleuritis, polymyalgia rheumatica, rhabdomyolysis,
stress, swollen lymph nodes, thrombocytopenia, Vitamin D
deficiency, or weight loss. While a cancer treatment may reduce or
treat associated symptoms, treating symptoms associated with
cancer, is not treating cancer if there is no expectation that
tumor will be reduced or eliminated or their growth or spread will
be inhibited.
[0097] Toxicities and adverse events are sometimes graded according
to a 5 point scale. A grade 1 or mild toxicity is asymptomatic or
induces only mild symptoms; may be characterized by clinical or
diagnostic observations only; and intervention is not indicated. A
grade 2 or moderate toxicity may impair activities of daily living
(such as preparing meals, shopping, managing money, using the
telephone, etc.) but only minimal, local, or non-invasive
interventions are indicated. Grade 3 toxicities are medically
significant but not immediately life-threatening; hospitalization
or prolongation of hospitalization is indicated; activities of
daily living related to self-care (such as bathing, dressing and
undressing, feeding oneself, using the toilet, taking medications,
and not being bedridden) may be impaired. Grade 4 toxicities are
life-threatening and urgent intervention is indicated. Grade 5
toxicity produces an adverse event-related death. Thus in various
embodiments, use of an RXR agonist, or RXR agonist and thyroid
hormone, reduces the grade of a toxicity that would otherwise be
associated with use of the Her2-targeted therapy, by allowing a
lower dose to be used without substantial sacrifice of efficacy. In
some embodiments, use of an RXR agonist, or RXR agonist and thyroid
hormone, in combination with the Her2-targeted therapeutic agent
limits a toxicity to grade 1 or less, or produces no observation of
the toxicity, without substantial reduction of efficacy as would be
expected from the Her2-targeted therapeutic agent alone. In some
embodiments, the combined use of the Her2-targeted therapeutic
agent and the RXR agonist, or RXR agonist and thyroid hormone,
allows continued use of the Her2-targeted therapeutic agent at a
lower dosage with therapeutic effect in instances where treatment
with the Her2-targeted therapeutic agent would have had to have
been discontinued due to unacceptable toxicity. In some of these
embodiments, the Her2-targeted therapeutic agent comprises a Her2
kinase inhibitor.
[0098] The combination of the disclosed RXR agonists and the Her2
targeted therapeutics are synergistic in effect. That is, they
interact in a positive manner to produce a greater inhibition of
tumor cell growth, than would be expected from the independent
(non-interacting) effects of the two. Thus, some embodiments
produce improved efficacy. Other embodiments allow for the
reduction of dosage in order to reduce toxicity while still
achieving at least similar efficacy as provided by an individual
therapeutic agent. In some embodiments, both reduced toxicity and
improved efficacy (as compared to the more toxic single agent) is
achieved.
[0099] For each method of treatment there are further parallel
embodiments related to the foregoing methods directed to use of the
RXR agonist in conjunction with a Her2-targeted therapeutic agent,
or a Her2-targeted therapeutic agent and thyroid hormone, to treat
Her2.sup.+ cancer; directed to use of the RXR agonist in the
manufacture of a medicament for use in combination with a
Her2-targeted therapeutic agent, or a Her2-targeted therapeutic
agent and thyroid hormone, to treat Her2.sup.+ cancer.
[0100] Further embodiments include a combination comprising a RXR
agonist as herein described and a Her2-targeted therapeutic agent.
Some embodiments further comprise a thyroid hormone. In some
embodiments, the Her2-targeted therapeutic agent is an anti-Her2
antibody. In some embodiments the Her2-targeted therapeutic agent
is a Her2 kinase inhibitor.
[0101] Further embodiments include kits comprising the above
combinations. The kits may additionally comprise solvents,
diluents, injectors, and the like that may facilitate
administration of one or more of the therapeutic agents. The kits
may further comprise instructions for the coordinated use of the
therapeutic agents utilized in the disclosed methods, whether or
not any particular agent is supplied in the kit.
List of Particular Embodiments
[0102] The following listing of embodiments is illustrative of the
variety of embodiments with respect to breadth, combinations and
sub-combinations, class of invention, etc., elucidated herein, but
is not intended to be an exhaustive enumeration of all embodiments
finding support herein.
[0103] Embodiment 1. A method of treating a patient with Her2.sup.+
cancer comprising administering a RXR agonist of Formula I,
##STR00003## [0104] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, to the
patient, [0105] wherein the patient has received, is receiving, or
is scheduled to receive a Her2-targeted therapeutic agent.
[0106] Embodiment 2. A method of treating a patient with Her2+
cancer comprising administering a RXR agonist of Formula I,
##STR00004## [0107] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, and a
Her2-targeted therapeutic agent.
[0108] Embodiment 3. A method of treating a patient with Her2+
cancer undergoing treatment with a RXR agonist of Formula I,
##STR00005## [0109] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, [0110]
wherein there is evidence of therapeutic effect that is less than a
complete response, comprising continuing treatment with the RXR
agonist and initiating treatment with a Her2-targeted therapeutic
agent.
[0111] Embodiment 4. A method of treating a patient with Her2+
cancer undergoing treatment with a Her2-targeted therapeutic agent,
wherein there is evidence of therapeutic effect that is less than a
complete response, comprising continuing treatment with the
Her2-targeted therapeutic agent and initiating treatment with a RXR
agonist of Formula I,
##STR00006## [0112] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof.
[0113] Embodiment 5. A method of treating a patient with Her2.sup.+
cancer comprising administering a RXR agonist of Formula I,
##STR00007## [0114] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, to the
patient, [0115] wherein the patient has received, is receiving, or
is scheduled to receive means for therapeutically targeting
Her2.
[0116] Embodiment 6. The method of Embodiment 5, wherein the means
for therapeutically targeting Her2 are: [0117] means for inhibiting
Her2.sup.+ tumor cell proliferation, [0118] means for mediating
ADCC of Her2.sup.+ tumor cells, [0119] immunoglobulin means for
inhibiting Her2 signaling, [0120] means for delivering a cytotoxic
agent to Her2.sup.+ cells, or [0121] small molecule means for
inhibiting Her2 kinase activity.
[0122] Embodiment 7. A method of treating a patient with Her2.sup.+
cancer comprising administering means for activating RXR/Nurr1
heterodimeric receptors or rexinoid means for inhibiting tumor
growth, wherein the patient has received, is receiving, is
scheduled to receive a Her2-targeted therapeutic agent.
[0123] Embodiment 8. The method of any one of Embodiments 1-7,
further comprising administering thyroid hormone in conjunction
with the RXR agonist.
[0124] Embodiment 9. The method of Embodiment 8, wherein the
thyroid hormone is thyroxine.
[0125] Embodiment 10. The method of any one of Embodiments 1-9,
wherein the RXR agonist, the means for activating RXR/Nurr1
heterodimeric receptors, or the rexinoid means for inhibiting tumor
growth, is a compound of Formula I.
[0126] Embodiment 11. The method of any one of Embodiments 1-9,
wherein the RXR agonist, the means for activating RXR/Nurr1
heterodimeric receptors, or the rexinoid means for inhibiting tumor
growth, is a pharmaceutically-acceptable salt of a compound of
Formula I.
[0127] Embodiment 12. The method of any one of Embodiments 1-9,
wherein the RXR agonist, the means for activating RXR/Nurr1
heterodimeric receptors, or the rexinoid means for inhibiting tumor
growth, is a compound of Formula II
##STR00008##
[0128] Embodiment 13. The method of any one of Embodiments 1-12,
wherein: [0129] the Her2-targeted therapeutic agent, [0130] the
means for inhibiting Her2.sup.+ tumor cell proliferation, [0131]
the means for mediating ADCC of Her2.sup.+ tumor cells, [0132] the
immunoglobulin means for inhibiting Her2 signaling, or [0133] the
means for delivering a cytotoxic agent to Her2.sup.+ cells, [0134]
comprises an anti-Her2 therapeutic antibody.
[0135] Embodiment 14. The method of Embodiment 13, wherein the
therapeutic antibody is trastuzumab or pertuzumab.
[0136] Embodiment 15. The method of Embodiment 13, wherein the
therapeutic antibody is margetuximab, TrasGEX, HM2, hertuzumab, or
HT-19
[0137] Embodiment 16. The method of any one of Embodiments 1-13,
wherein the Her2-targeted therapeutic agent, the means for
inhibiting Her2.sup.+ tumor cell proliferation, or the
immunoglobulin means for inhibiting Her2 signaling, comprises an
antibody-drug conjugate wherein the antibody is an anti-Her2
antibody.
[0138] Embodiment 17. The method of Embodiment 16, wherein the
antibody-drug conjugate or the means for delivering a cytotoxic
agent to Her2.sup.+ cells, is ado-trastuzumab emtansine.
[0139] Embodiment 18. The method of Embodiment 16, wherein the
antibody-drug conjugate or the means for delivering a cytotoxic
agent to Her2.sup.+ cells, is A166, ALT-P7, ARX788, DHES0815A,
DS-8201a, RC48, SYD985, MED14276, or XMT-1522.
[0140] Embodiment 19. The method of any one of Embodiments 1-12,
wherein the Her2-targeted therapeutic agent, or the small molecule
means for inhibiting Her2 kinase activity, comprises a Her2 kinase
inhibitor.
[0141] Embodiment 20. The method of Embodiment 19, wherein the Her2
kinase inhibitor is lapatinib or neratinib.
[0142] Embodiment 21. The method of Embodiment 19, wherein the Her2
kinase inhibitor is afatinib or dacomitinib.
[0143] Embodiment 22. The method of any one of Embodiments 1-21,
wherein the treatment is applied as a debulking therapy.
[0144] Embodiment 23. The method of any one of Embodiments 1-21,
wherein the treatment is applied as adjuvant therapy.
[0145] Embodiment 24. The method of any one of Embodiments 1-23,
wherein the Her2.sup.+ cancer is Her2.sup.+ breast cancer.
[0146] Embodiment 25. The method of any one of Embodiments 1-23,
wherein the Her2.sup.+ cancer is Her2.sup.+ gastroesophageal
cancer, ovarian cancer, stomach cancer, adenocarcinoma of the lung,
uterine cancer (such as serous endometrial carcinoma), or salivary
duct carcinoma.
[0147] Embodiment 26. The method of any one of Embodiments 1-25,
wherein a therapeutic response to the RXR agonist and the
Her2-targeted therapeutic agent is greater than to the response to
either of the agents alone.
[0148] Embodiment 27. The method of Embodiment 26, wherein the
greater therapeutic response is a slowing of tumor growth,
stabilization of disease, a partial response, a complete response,
extended overall survival, or disease-free survival.
[0149] Embodiment 28. The method of Embodiment 26 or 27, wherein
response is evaluated according to RECIST or iRECIST criteria.
[0150] Embodiment 29. The method of any one of Embodiments 26-28,
comprising a reduction or amelioration of secondary symptoms.
[0151] Embodiment 30. A combination comprising a Her2-targeted
therapeutic agent, or means for therapeutically targeting Her2, and
a RXR agonist of Formula I,
##STR00009## [0152] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof.
[0153] Embodiment 31. The combination of Embodiment 30, wherein the
Her2-targeted therapeutic agent, or means for therapeutically
targeting Her2, comprises: [0154] means for inhibiting Her2.sup.+
tumor cell proliferation, [0155] means for mediating ADCC of
Her2.sup.+ tumor cells, [0156] immunoglobulin means for inhibiting
Her2 signaling, [0157] means for delivering a cytotoxic agent to
Her2.sup.+ cells, or [0158] small molecule means for inhibiting
Her2 kinase activity.
[0159] Embodiment 32. The combination of Embodiment 30 or 31,
further comprising thyroid hormone.
[0160] Embodiment 33. The combination of any one of Embodiments
30-32, wherein the RXR agonist is a compound of Formula II
##STR00010##
[0161] Embodiment 34. The combination of any one of Embodiments
30-33, wherein: [0162] the Her2-targeted therapeutic agent, [0163]
the means for inhibiting Her2.sup.+ tumor cell proliferation,
[0164] the means for mediating ADCC of Her2.sup.+ tumor cells,
[0165] the immunoglobulin means for inhibiting Her2 signaling, or
[0166] the means for delivering a cytotoxic agent to Her2.sup.+
cells, [0167] comprises an anti-Her2 therapeutic antibody.
[0168] Embodiment 35. The combination of Embodiment 34, wherein the
therapeutic antibody is trastuzumab or pertuzumab.
[0169] Embodiment 36. The combination of any one of Embodiments
30-34, wherein the Her2-targeted therapeutic agent, the means for
inhibiting Her2.sup.+ tumor cell proliferation, or the
immunoglobulin means for inhibiting Her2 signaling, comprises an
antibody-drug conjugate wherein the antibody is an anti-Her2
antibody.
[0170] Embodiment 37. The combination of Embodiment 36, wherein the
antibody-drug conjugate is ado-trastuzumab emtansine.
[0171] Embodiment 38. The combination of any one of Embodiments
30-33, wherein the Her2-targeted therapeutic agent, or the small
molecule means for inhibiting Her2 kinase activity, comprises a
Her2 kinase inhibitor.
[0172] Embodiment 39. The combination of Embodiment 38, wherein the
Her2 kinase inhibitor is lapatinib or neratinib.
[0173] Embodiment 40. A kit comprising the combination of any one
of Embodiments 30-39.
[0174] Embodiment 41. A RXR agonist of Formula I,
##STR00011## [0175] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, for use in
treating a patient with Her2.sup.+ cancer, wherein the patient has
received, is receiving, or is scheduled to receive a Her2-targeted
therapeutic agent.
[0176] Embodiment 42. A RXR agonist of Formula I,
##STR00012## [0177] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, and a
Her2-targeted therapeutic agent for use in combination in treating
a patient with Her2.sup.+ cancer.
[0178] Embodiment 43. A combination of a RXR agonist of Formula
I,
##STR00013## [0179] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, and a
Her2-targeted therapeutic agent for use in treating a patient with
Her2.sup.+ cancer.
[0180] Embodiment 44. A pharmaceutical combination for treating
Her2.sup.+ cancer comprising a RXR agonist of Formula I,
##STR00014## [0181] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, and a
Her2-targeted therapeutic agent.
[0182] Embodiment 45. A RXR agonist of Formula I,
##STR00015## [0183] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, for use in
manufacturing a medicament for treating Her2.sup.+ cancer, in a
patient who has received, is receiving, or is scheduled to receive
a Her2-targeted therapeutic agent.
[0184] Embodiment 46. A RXR agonist of Formula I,
##STR00016## [0185] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, and a
Her2-targeted therapeutic agent, for use in manufacturing
medicaments for use together to treat Her2.sup.+ cancer.
[0186] Embodiment 47. A Her2-targeted therapeutic agent for
treating Her2+ cancer in a patient with Her2.sup.+ cancer, with a
therapeutic response less than a complete response to treatment
with a RXR agonist of Formula I,
##STR00017## [0187] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, [0188] in
combination with the RXR agonist.
[0189] Embodiment 48. A RXR agonist of Formula I,
##STR00018## [0190] wherein R is H, or lower alkyl of 1 to 6
carbons; or a pharmaceutically-acceptable salt thereof, for
treating Her2+ cancer in a patient with Her2+ cancer, with a
therapeutic response less than a complete response to treatment
with a Her2-targeted therapeutic agent, [0191] in combination with
the Her2-targeted therapeutic agent.
[0192] It should be manifest that each or Embodiments 41-48 can be
modified in a manner similar to the modification of Embodiments 1-5
and 7 by Embodiments 5 and 8-29.
EXAMPLES
[0193] The following non-limiting examples are provided for
illustrative purposes only in order to facilitate a more complete
understanding of representative embodiments now contemplated. These
examples should not be construed to limit any of the embodiments
described in the present specification,
Example 1
Inhibition of Breast Cancer Cell Growth by IRX4204 plus
Trastuzumab
[0194] Two breast cancer cell lines, MCF7 and SkBr3 were cultured
in the presence of 0, 10, 100, or 1000 nM IRX4204 and 0, 0.1, 1, or
10 .mu.g/ml trastuzumab. MCF7 is an ER.sup.+ PR.sup.+ Her2.sup.-
cell line. SkBr3 is an ER.sup.- PR.sup.- Her2.sup.+ cell line.
Cells were plated in 96 well optical plates and IRX-4204 and
trastuzumab were added 24 hours after cell plating. After a further
6 days, the cells were fixed with 4% paraformaldehyde in phosphate
buffered saline (PBS). Nuclei were then stained with DAPI and
imaged with the MetaXpress.RTM. microscope (Molecular Devices, San
Jose, Calif.). Cell nuclei were segmented then counted by defining
pixel intensity over background and object size, using the
algorithm of the MetaXpress.RTM. image analysis software.
Experimental data points were performed at a minimum of
quadruplicate, and results were reported as average cell count
.+-.standard deviation (SD). As seen in FIG. 1A, neither agent had
more than marginal effect on the Her2.sup.- MCF7 cell line. As seen
in FIG. 1B, both agents individually have a moderate growth
inhibitory effect on the Her2.sup.+ SkBr3 cell line, and had a very
substantial, growth inhibitory effect when used in combination,
even at the lowest concentrations tested.
[0195] To assess if this improved growth inhibition effect was
synergistic, the percent inhibition observed for the highest
concentrations of the combined therapeutic agents was compared to
the percent inhibition that would be expected for the combination
based on the observed inhibition of the therapeutic agents used
alone, if the agents acting independently, that is, without
interaction (see Table 1). That is,
PAE=(FE1+((1-FE1).times.FE2)).times.100, where PAE is the predicted
additive effect, FE1 is the observed fractional effect of a 1st
treatment, and FE2 is the observed fractional effect of a 2nd
treatment.
TABLE-US-00001 TABLE 1 Synergistic Effect of the Combination of
IRX4204 and Trastuzumab on the Inhibition of the Growth of SkBr3
Cells. DAPI Nuclei Treatment Count % Inhibition Control 25958
IRX4204 1000 nM 18274 29.4 If Additive = 68.5% Herceptin 1000 ng
11582 55.4 IRX4204 + Herceptin 2946 88.7
[0196] Whereas the combined inhibitory effect of IRX4204 and
trastuzumab would be predicted to be 68.5% if there was no
interaction between the effects of the two agents, in fact the
observed degree of inhibition was 88.7%, clearly indicating that
IRX4204 and trastuzumab interact in a synergistic manner.
Example 2
Inhibition of Breast Cancer Cell Growth by IRX4204 plus Lapatinib
or Neratinib
[0197] The experiment of Example 1 was repeated using the Her2
kinase inhibitors lapatinib or neratinib instead of trastuzumab at
0, 0.1, 1, or 10 nM. Additionally the panel of breast cancer cell
lines was expanded to also include the ER.sup.+ PR.sup.+ Her2.sup.+
cell line BT.sub.474 and the ER.sup.+ PR.sup.- Her2.sup.+ cell line
MDA-MB-361. The general pattern seen above, that the Her2.sup.-
MCF7 cell line showed generally marginal response to the treatments
and that the Her.sup.+ cell lines exhibited a greater degree of
inhibition to the combination than either agent alone, was again
observed (see FIGS. 2 and 3).
[0198] To assess if this improved growth inhibition effect was
synergistic, the percent inhibition observed for the highest
concentrations of the combined therapeutic agents was compared to
the percent inhibition that would be expected for the combination
based on the observed inhibition of the therapeutic agents used
alone, if the agents acting independently, that is, without
interaction (see Tables 2-4).
TABLE-US-00002 TABLE 2 Synergistic Effect of the Combination of
IRX4204 and Lapatinib or Neratinib on the Inhibition of the Growth
of SkBr3 Cells. DAPI Nuclei Treatment Count % Inhibition Control
19855 IRX4204 1000 nM 18906 4.8 If Additive = 89.4% Lapatinib 1000
nM 2211 88.9 IRX4204 + Lapatinib 743 96.3 Control 6696 IRX4204 1000
nM 5218 22.1 If Additive = 89.5% Neratinib 1000 nM 903 86.5 IRX4204
+ Neratinib 329 95.1
TABLE-US-00003 TABLE 3 Synergistic Effect of the Combination of
IRX4204 and Lapatinib or Neratinib on the Inhibition of the Growth
of BT474 Cells. DAPI Nuclei Treatment Count % Inhibition Control
2937 1RX4204 1000 nM 3399 -15.7* If Additive = 58.8% Lapatinib 1000
nM 1211 58.8 IRX4204 + Lapatinib 813 72.3 Control 2192 1RX4204 1000
nM 2043 6.8 If Additive = 92.4% Neratinib 1000 nM 180 91.8 IRX4204
+ Neratinib 130 94.1 *Zero inhibition used in calculation of
predicted additive effect
TABLE-US-00004 TABLE 4 Synergistic Effect of the Combination of
IRX4204 and Lapatinib or Neratinib on the Inhibition of the Growth
of MDA-MB-361 Cells. DAPI Nuclei Treatment Count % Inhibition
Control 6696 IRX4204 1000 nM 5218 22.1 If Additive = 89.5%
Lapatinib 1000 nM 903 86.5 IRX4204 + Lapatinib 329 95.2 Control
5297 IRX4204 1000 nM 2459 43.6 If Additive = 97.3% Neratinib 1000
nM 249 95.3 IRX4204 + Neratinib 57 98.9
[0199] In each case the observed degree of inhibition exceeded that
predicted if there was no interaction between the effects of the
two agents, even though in some cases the individual therapeutic
agents were quite effective alone, leaving little room for synergy
to be observed. These data also clearly indicate that IRX4204 and
the small molecule Her2 kinase inhibitors interact in a synergistic
manner.
[0200] In closing, it is to be understood that although aspects of
the present specification are highlighted by referring to specific
embodiments, one skilled in the art will readily appreciate that
these disclosed embodiments are only illustrative of the principles
of the subject matter disclosed herein. Therefore, it should be
understood that the disclosed subject matter is in no way limited
to a particular methodology, protocol, and/or reagent, etc.,
described herein. As such, various modifications or changes to or
alternative configurations of the disclosed subject matter can be
made in accordance with the teachings herein without departing from
the spirit of the present specification. Lastly, the terminology
used herein is for the purpose of describing particular embodiments
only, and is not intended to limit the scope of the present
invention, which is defined solely by the claims. Accordingly, the
present invention is not limited to that precisely as shown and
described.
[0201] Certain embodiments of the present invention are described
herein, including the best mode known to the inventors for carrying
out the invention. Of course, variations on these described
embodiments will become apparent to those of ordinary skill in the
art upon reading the foregoing description. The inventor expects
skilled artisans to employ such variations as appropriate, and the
inventors intend for the present invention to be practiced
otherwise than specifically described herein. Accordingly, this
invention includes all modifications and equivalents of the subject
matter recited in the claims appended hereto as permitted by
applicable law. Moreover, any combination of the above-described
embodiments in all possible variations thereof is encompassed by
the invention unless otherwise indicated herein or otherwise
clearly contradicted by context.
[0202] Groupings of alternative embodiments, elements, or steps of
the present invention are not to be construed as limitations. Each
group member may be referred to and claimed individually or in any
combination with other group members disclosed herein. It is
anticipated that one or more members of a group may be included in,
or deleted from, a group for reasons of convenience and/or
patentability. When any such inclusion or deletion occurs, the
specification is deemed to contain the group as modified thus
fulfilling the written description of all Markush groups used in
the appended claims.
[0203] Unless otherwise indicated, all numbers expressing a
characteristic, item, quantity, parameter, property, term, and so
forth used in the present specification and claims are to be
understood as being modified in all instances by the term "about."
As used herein, the term "about" means that the characteristic,
item, quantity, parameter, property, or term so qualified
encompasses a range of plus or minus ten percent above and below
the value of the stated characteristic, item, quantity, parameter,
property, or term. Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the specification and
attached claims are approximations that may vary. At the very
least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, each numerical
indication should at least be construed in light of the number of
reported significant digits and by applying ordinary rounding
techniques. Notwithstanding that the numerical ranges and values
setting forth the broad scope of the invention are approximations,
the numerical ranges and values set forth in the specific examples
are reported as precisely as possible. Any numerical range or
value, however, inherently contains certain errors necessarily
resulting from the standard deviation found in their respective
testing measurements. Recitation of numerical ranges of values
herein is merely intended to serve as a shorthand method of
referring individually to each separate numerical value falling
within the range. Unless otherwise indicated herein, each
individual value of a numerical range is incorporated into the
present specification as if it were individually recited
herein.
[0204] The terms "a," "an," "the" and similar referents used in the
context of describing the present invention (especially in the
context of the following claims) are to be construed to cover both
the singular and the plural, unless otherwise indicated herein or
clearly contradicted by context. All methods described herein can
be performed in any suitable order unless otherwise indicated
herein or otherwise clearly contradicted by context. The use of any
and all examples, or exemplary language (e.g., "such as") provided
herein is intended merely to better illuminate the present
invention and does not pose a limitation on the scope of the
invention otherwise claimed. No language in the present
specification should be construed as indicating any non-claimed
element essential to the practice of the invention.
[0205] Specific embodiments disclosed herein may be further limited
in the claims using consisting of or consisting essentially of
language. When used in the claims, whether as filed or added per
amendment, the transition term "consisting of" excludes any
element, step, or ingredient not specified in the claims. The
transition term "consisting essentially of" limits the scope of a
claim to the specified materials or steps and those that do not
materially affect the basic and novel characteristic(s).
Embodiments of the present invention so claimed are inherently or
expressly described and enabled herein.
[0206] All patents, patent publications, and other publications
referenced and identified in the present specification are
individually and expressly incorporated herein by reference in
their entirety for the purpose of describing and disclosing, for
example, the compositions and methodologies described in such
publications that might be used in connection with the present
invention. These publications are provided solely for their
disclosure prior to the filing date of the present application.
Nothing in this regard should be construed as an admission that the
inventors are not entitled to antedate such disclosure by virtue of
prior invention or for any other reason. All statements as to the
date or representation as to the contents of these documents is
based on the information available to the applicants and does not
constitute any admission as to the correctness of the dates or
contents of these documents.
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