NZ711757B2 - Drug combinations comprising derivatives of decitabine - Google Patents
Drug combinations comprising derivatives of decitabine Download PDFInfo
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- NZ711757B2 NZ711757B2 NZ711757A NZ71175714A NZ711757B2 NZ 711757 B2 NZ711757 B2 NZ 711757B2 NZ 711757 A NZ711757 A NZ 711757A NZ 71175714 A NZ71175714 A NZ 71175714A NZ 711757 B2 NZ711757 B2 NZ 711757B2
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- KMQQRWRHVOPBQI-JERNAADCSA-N CC(OCC(O[C@H](C1)[n]2c(N=C(N)NC3=O)c3nc2)=C1OP(O)(OC[C@H](C(C1)OC(C)=O)O[C@H]1N(C=NC(N)=N1)C1=O)=O)=O Chemical compound CC(OCC(O[C@H](C1)[n]2c(N=C(N)NC3=O)c3nc2)=C1OP(O)(OC[C@H](C(C1)OC(C)=O)O[C@H]1N(C=NC(N)=N1)C1=O)=O)=O KMQQRWRHVOPBQI-JERNAADCSA-N 0.000 description 1
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- UHSFNJNLQIXTBR-STLZSZFDSA-N NC(NC1=O)=Nc2c1nc[n]2C(C1)O[C@H](COP(OC(CCO)(C2)CO[C@H]2N(C=NC(N)=N2)C2=O)(S)=O)C1O Chemical compound NC(NC1=O)=Nc2c1nc[n]2C(C1)O[C@H](COP(OC(CCO)(C2)CO[C@H]2N(C=NC(N)=N2)C2=O)(S)=O)C1O UHSFNJNLQIXTBR-STLZSZFDSA-N 0.000 description 1
- YOLQYVHWNYYAAO-ZSZFIPSZSA-N NC(NC1=O)=Nc2c1nc[n]2[C@@H](C1)OC(COCc2ccccc2)=C1OP(O)(OC[C@H](C(C1)OCc2ccccc2)O[C@H]1N(C=NC(N)=N1)C1=O)=O Chemical compound NC(NC1=O)=Nc2c1nc[n]2[C@@H](C1)OC(COCc2ccccc2)=C1OP(O)(OC[C@H](C(C1)OCc2ccccc2)O[C@H]1N(C=NC(N)=N1)C1=O)=O YOLQYVHWNYYAAO-ZSZFIPSZSA-N 0.000 description 1
- NYYKAKOUVDNRQK-OLNPOFRYSA-N NC(NC1=O)=Nc2c1nc[n]2[C@@H](C1)O[C@H](COP(O)(OC(C2)[C@@H](COCc3ccccc3)O[C@H]2N(C=NC(N)=N2)C2=O)=O)C1OCc1ccccc1 Chemical compound NC(NC1=O)=Nc2c1nc[n]2[C@@H](C1)O[C@H](COP(O)(OC(C2)[C@@H](COCc3ccccc3)O[C@H]2N(C=NC(N)=N2)C2=O)=O)C1OCc1ccccc1 NYYKAKOUVDNRQK-OLNPOFRYSA-N 0.000 description 1
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Abstract
The invention provides combinations of derivatives of decitabine and other active agents, including T-cell activating agents, cancer vaccines, and adjuvants. Some derivatives of decitabine exhibit superior chemical stability and shelf life, with similar physiological activity. Methods of treating one or more myelodysplasia syndromes, cancers, haematological disorders, or diseases associated with abnormal haemoglobin synthesis using the combinations are described. e or more myelodysplasia syndromes, cancers, haematological disorders, or diseases associated with abnormal haemoglobin synthesis using the combinations are described.
Description
DRUG COMBINATIONS COMPRISING DERIVATIVES OF DECITABINE
CROSS REFERENCE
This application claims the benefit of U.S. Provisional Patent Application No.
61/887,165, filed on October 4, 2013, and U.S. Provisional Patent Application No.
61/771,525, filed on March 1, 2013, each of which is incorporated herein by reference in
its entirety
BACKGROUND
Epigenetic modification of the genome, and in particular DNA methylation, plays
a major role in human malignancies by influencing crucial cellular pathways in cancer
initiation and progression (including cell cycle control, apoptosis, invasive and metastatic
potential and angiogenesis). DNA methylation is mediated by the enzyme DNA
methyltransferase, and results in the addition of a methyl group to a cytosine when the
cytosine occurs in the context of a CpG dinucleotide.
DNA methylation of promoter-associated CpG islands results in silencing of the
corresponding gene - in general, promoter-associated CpG islands are unmethylated in
nonmalignant cells. Aberrant DNA hypermethylation in tumour cells is therefore a
functional equivalent to inactivation of tumour suppressor genes by mutation, and so
promotes tumour escape from host immune recognition via the down-regulation of
various components of the tumour recognition complex in neoplastic cells (including
HLA class I antigens, CTA antigens and accessory/co-stimulatory molecules). This
results in a reduction in clinical efficacy of immunotherapeutic approaches for cancer
treatment.
DNA hypomethylating agents (DHAs) induce global and gene-specific DNA
hypomethylation. This promotes re-expression of tumour-associated antigens and thereby
boosts immune recognition. Examples include 5-azacytidine, 5-aza-2’-deoxycytidine
(decitabine) and Zebularine: 5-azacytidine and 5-aza-2’-deoxycytidine are currently
approved by the US Food and Drug Administration for the treatment of patients with
myelodysplastic syndromes, and decitabine is currently being developed as a
pharmaceutical for the treatment of chronic myelogenous leukemia (CML),
myelodysplastic syndrome (MDS), non-small cell lung cancer (NSCLC), sickle-cell
anaemia and acute myelogenous leukemia (AML).
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification
are herein incorporated by reference to the same extent as if each individual publication,
patent, or patent application was specifically and individually indicated to be incorporated
by reference.
SUMMARY OF THE INVENTION
In one aspect, the invention provides a combination comprising:
a) a compound of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I)
wherein L is of Formula (II):
OR R
(II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R
together with the oxygen atom to which R is bound forms an ether, an ester, a carbonate,
4 4 4
or a carbamate; R is H, or R together with the oxygen atom to which R is bound forms
an ether, an ester, a carbonate, or a carbamate; and X together with the oxygen atoms to
which X is bound forms a phosphodiester, a phosphorothioate diester, a boranophosphate
diester, or a methylphosphonate diester; and
b) a T-cell activating agent;
wherein the compound of Formula I or pharmaceutically-acceptable salt thereof is for
administration before administration of the T-cell activating agent.
[0006a] In another aspect, the invention provides a kit comprising:
(a) a first vessel containing the compound of Formula I or pharmaceutically-
acceptable salt thereof as defined in any one of claims 1-8;
(b) a second vessel containing a substantially anhydrous solvent as defined in any
one of claims 9-15; and
(c) a T-cell activating agent;
wherein the compound of Formula I or pharmaceutically-acceptable salt thereof is
for administration before administration of the T-cell activating agent.
[0006b] In another aspect, the invention provides a process for producing a
pharmaceutical composition comprising a compound of Formula I or a pharmaceutically-
acceptable salt thereof as defined in any one of claims 1-8 in the form of a substantially
anhydrous powder, the process comprising dissolving said compound of Formula I or salt
thereof in DMSO to produce a solution in DMSO, lyophilizing said solution to provide
said compound of Formula I or pharmaceutically-acceptable salt thereof as a substantially
anhydrous powder, wherein the substantially anhydrous powder is for administration
before administration of the T-cell activating agent.
[0006c] In another aspect, the invention provides a substantially anhydrous powder
consisting essentially of a compound of Formula I or salt thereof as defined in any one of
claims 1-8 and DMSO, the DMSO being present in an amount of ≤200 % w/w, in
combination with T-cell activating agent wherein the substantially anhydrous powder is
for administration before administration of the T-cell activating agent.
[0006d] In another aspect, the invention provides a pharmaceutical composition obtained
by the process of the invention.
[0006e] In another aspect, the invention relates to use of the combination, kit, process,
powder or composition of the invention in the manufacture of a medicament for use in
immunotherapy or for treating a disease selected from:
(a) a myelodysplastic syndrome (MDS);
(b) a cancer;
(c) a leukemia; and
(d) a disease associated with abnormal haemoglobin synthesis, wherein the disease
associated with abnormal haemoglobin synthesis is selected from sickle cell anaemia and
ß-thalassemia.
[0006f] In some embodiments, described is a combination comprising a compound of
Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I)
wherein L is a phosphorous-containing linker wherein the number of phosphorus atoms in
L is 1;
and one or more ancillary therapeutic component(s) selected from:
(a) a T-cell activating agent;
(b) a cancer vaccine; and
(c) an adjuvant.
Alternatively, described is a combination comprising a compound of Formula I or
a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I)
wherein L is a phosphorous-containing linker wherein the number of phosphorus atoms in
L is 1;
and one or more ancillary therapeutic component(s) selected from:
(a) a T-cell activating agent;
(b) a cancer vaccine;
(c) an IDO inhibitor; and
(d) an adjuvant.
In some embodiments, in the compound of Formula I, L is of Formula (II):
OR R (II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R
together with the oxygen atom to which R is bound forms an ether, an ester, a carbonate,
4 4 4
or a carbamate; R is H, or R together with the oxygen atom to which R is bound forms
an ether, an ester, a carbonate, or a carbamate; and X together with the oxygen atoms to
which X is bound forms a phosphodiester, a phosphorothioate diester, a boranophosphate
diester, or a methylphosphonate diester. In some embodiments, R and R are
independently H, OH, OMe, OEt, OCH CH OMe, OBn, or F, and X together with the
oxygen atoms to which X is bound form a phosphodiester. In some embodiments, R and
R are H.
In some embodiments, the compound of Formula I is any one of I-(1-44). In some
embodiments, the compound of Formula I is:
NH O
O P OH O P OH
N NH
I-1: OH or I-2: OH .
In some embodiments, the compound of formula I is of the formula:
O P OH
N NH
OH I-1
or a pharmaceutically-acceptable salt thereof. In some embodiments, the salt is a sodium
salt.
The compound or salt thereof can be in the form of a formulation, for example
being dissolved in a substantially anhydrous solvent comprising about 45% to about 85%
propylene glycol; about 5% to about 45% glycerin; and 0% to about 30% ethanol. In
such embodiments, said solvent can comprise about 65% to about 70% propylene glycol;
about 25% to about 30% glycerin, and 0% to about 10% ethanol, for example: (a) 65% to
70% propylene glycol and 25% to 30% glycerin, any balance being ethanol; (b) about
65% propylene glycol; about 25% glycerin; and about 10% ethanol; (c) 65% propylene
glycol; 25% glycerin; and 10% ethanol; (d) about 70% propylene glycol and about 30%
glycerin, ethanol being absent; (e) 45% to 85% propylene glycol; 5% to 45% glycerin;
and 0% to 30% ethanol; (f) 65% to 70% propylene glycol; 25% to 30% glycerin, and 0%
to 10% ethanol. The formulation can further comprise DMSO, optionally at a
DMSO:compound ratio of 2:1; 1:1; 0.5:1; 0.3:1 or 0.2-0.3:1. The combination can be
suitable for administration by subcutaneous injection.
When present as part of a formulation, the compound can be present at a
concentration of about 80 mg/mL to about 110 mg/mL, optionally about 100 mg/mL.
In some embodiments, tdescribed is a kit comprising:
(a) a first vessel containing the compound or salt thereof as described herein;
(b) a second vessel containing a substantially anhydrous solvent as described
herein; and
(c) one or more ancillary therapeutic component(s) as described herein.
The compound can be present in the kit in the form of a substantially anhydrous
powder, for example being lyophilized. In some embodiments, the first vessel can
contain about 80 mg to about 110 mg of said compound, for example about 100 mg of
said compound, and can further comprise instructions for administration by subcutaneous
injection.
In some embodiments, described is a process for preparing a pharmaceutical
composition, the process comprising dissolving a compound or salt thereof as defined
above in a substantially anhydrous solvent as also defined above, and then combining the
dissolved compound with one or more ancillary therapeutic component(s) as also defined
above. In some embodiments, the process further comprises the preliminary steps of:
(a) dissolving said compound in DMSO to produce a solution of said
compound in DMSO; and
(b) lyophilizing said solution of step (a) to provide said compound as a
substantially anhydrous powder.
In some embodiments, described is a process for producing a pharmaceutical
composition comprising a compound or salt thereof as defined above in the form of a
substantially anhydrous powder, the process comprising dissolving said compound in
DMSO to produce a solution in DMSO, lyophilizing said solution to provide said
compound as a substantially anhydrous powder and then combining the powder with one
or more ancillary therapeutic component(s). In some embodiments, said substantially
anhydrous powder comprises residual DMSO, for example: (a) present in an amount of
≤2000, or about 0.1 to about 2000 mg/g of said compound; or (b) present in an amount of
≤1000, or about 0.1 to about 1000 mg/g; ≤600, or about 0.1 to about 600mg/g; ≤500, or
about 0.1 to about 500 mg/g; ≤400, or about 0.1 to about 400 mg/g; ≤300, or about 0.1 to
about 300 mg/g; or about 200 – about 300mg/g of said compound; or (c) present in an
amount of 200-300 mg/g of said compound.
In some embodiments, described is a substantially anhydrous powder consisting
essentially of a compound or salt thereof as defined above and DMSO, the DMSO being
present in an amount of ≤200, or about 0.1% to about 200% w/w, in combination with
one or more ancillary therapeutic component(s) as defined above. In such embodiments,
the DMSO is present in an amount of ≤100%, or about 0.1% to about 100%, ≤60%, or
about 0.1% to about 60%, ≤50%, or about 0.1% to about 50%, ≤40%, or about 0.1% to
about 40%, or ≤30%, or about 0.1% to about 30% w/w DMSO/compound, for example in
an amount of about 20 – about 30% w/w DMSO/compound.
Also provided is a pharmaceutical composition obtainable by, or obtained by, the
processes as described herein.
In some embodiments, the ancillary therapeutic component comprises a T-cell
activating agent.
In some embodiments, the ancillary therapeutic component comprises a cancer
vaccine.
In some embodiments, the ancillary therapeutic component comprises an adjuvant.
In some embodiments, the ancillary therapeutic component comprises a T-cell
activating agent and a cancer vaccine.
In some embodiments, the ancillary therapeutic component comprises a T-cell
activating agent, for example being selected from agonists or antibodies for: ICOS, GITR,
MHC, CD80, CD86, Galectin 9 and LAG-3.
In other embodiments, the T-cell activating agent is an antibody, for example
being selected from: (a) a CD137 agonist; (b) a CD40 agonist; (c) an OX40 agonist; (d) a
PD-1 mAb; (e) a PD-L1 mAb; (f) a PD-L2 mAb; (g) a CTLA-4 mAb; and (h)
combinations of (a)-(g).
In some embodiments, the ancillary therapeutic component is Tremelimumab or
Ipilimumab.
In some embodiments, the ancillary therapeutic component comprises a CTA
cancer vaccine, for example being based on a CTA antigen selected from: NY-ESO-1,
LAGE-1, MAGE-A1, -A2, -A3, -A4, -A6, -A10, -A12, CT7, CT10, GAGE1-6, GAGE 1-
2, BAGE, SSX1-5, SSX 2, HAGE, PRAME, RAGE-1, XAGE-1, MUC2, MUC5B,
B7.1/2, CD28, B7-H1, HLA, CD40L and HMW-MAA, for example based on MAGE-A3
(for example recMAGE-A3), NY-ESO-1 and PRAME.
In some embodiments, the ancillary therapeutic component comprises an IDO
inhibitor, for example selected from INCB24360, 1 methyl tryptophan and NLG919.
In some embodiments, described is a method of immunotherapy or for treating a
disease selected from:
(a) a myelodysplastic syndrome (MDS);
(b) a cancer;
(c) a haematological disorder; or
(d) a disease associated with abnormal haemoglobin synthesis,
the method comprising administering combination, kit, process, powder or composition as
described herein to a subject in need or want thereof. In some embodiments, the
compound or salt thereof as defined above can be administered before,
contemporaneously with, or after administration of the one or more ancillary therapeutic
component(s). In some embodiments, the compound of Formula I or salt thereof is
administered first (as a priming therapy), followed by administration of the ancillary
therapeutic component(s).
The MDS can be selected from low-, intermediate- and high-risk MDS and
myloproliferative neoplasms.
The haematological disorder can be leukemia, for example, selected from: acute
myeloid leukemia (AML), acute promyelocyte leukemia, acute lymphoblastic leukemia,
and chronic myelogenous leukemia. In some embodiments, the AML can be selected
from elderly AML, first relapse AML and second relapse AML.
The cancer can be selected from breast cancer, skin cancer, bone cancer, prostate
cancer, liver cancer, lung cancer, non-small cell lung cancer, squamous non-small cell
lung adenocarcinoma, brain cancer, cancer of the larynx, gall bladder, pancreas, rectum,
parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, and
kidney cancer, basal cell carcinoma, squamous cell carcinoma of both ulcerating and
papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell
sarcoma, myeloma, giant cell tumour, small-cell lung tumour, gallstones, islet cell
tumour, primary brain tumour, acute and chronic lymphocytic and granulocytic tumours,
hairy-cell tumour, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma,
mucosal neuronms, intestinal ganglioneuromas, hyperplastic corneal nerve tumour,
marfanoid habitus tumour, Wilm's tumour, seminoma, ovarian tumour, platinum resistant
ovarian cancer, leiomyomater tumour, cervical dysplasia and in situ carcinoma,
neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin
lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma,
malignant hypercalcemia, renal cell tumour, polycythemia vera, adenocarcinoma,
glioblastoma multiforma, leukemias, lymphomas, melanoma, epidermoid carcinomas,
hepatocellular carcinoma and solid tumours.
In some embodiments, the cancer is selected from pancreatic cancer, ovarian
cancer, melanoma and lung cancer.
In some embodiments, the disease associated with abnormal haemoglobin
synthesis is selected from sickle cell anaemia and ß-thalassemia.
In some embodiments, described is the combination, kit, process, powder or
composition as defined in the claims appended hereto or as described herein for use in
therapy or prophylaxis, for example for use in immunotherapy or for treating a disease as
defined in claims appended hereto and described above or herein.
In some embodiments, described is the use of the combination, kit, process,
powder or composition as defined in the claims appended hereto or as described herein
for the manufacture of a medicament for use in immunotherapy or in a method of treating
a disease in claims appended hereto and described above or herein.
The combination, kit, process, powder or composition of the invention can be
administered to a subject according to a dosage regimen of: (a) once, twice, three times,
four times, five times, six times or seven times a week; or (b) every day for 5, 6, 7, 8, 9 or
days; or (c) every day for up to 10 days; or (d) every day for between 5 and 10 days; or
(e) every day for 5 days, immediately followed by two dose-free days and then every day
for the next 5 days. Administration can be subcutaneous.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE 1 illustrates the mean plasma concentrations of the compound I-1 in
male and female cynomolgus monkeys given weekly subcutaneous doses of compound I-
1 in a pahrmacokinetic study.
FIGURE 2 illustrates the mean plasma concentrations of decitabine in male and
female cynomolgus monkeys given weekly subcutaneous doses of decitabine in a
pharmacokinetic study.
FIGURE 3 illustrates the decrease in LINE1 methylation levels observed in blood
samples drawn from cynomolgus monkeys on various days (D) after pretest.
FIGURE 4 illustrates the change in total related substances of the sodium salt of a
compound of Formula I-1 in various DMSO and DMSO/water compositions.
FIGURE 5 illustrates the anti-tumor effect of SGI-110 in combination with anti-
mouse CTLA-4.
FIGURE 6 illustrates the anti-tumor effect of two cycles of sequential
administration of SGI-110 followed by anti-mouse CTLA-4 mAb 9H10.
DETAILED DESCRIPTION OF THE INVENTION
The combinations of the present invention activate the expression of, or strongly
up-regulate constitutive levels of expression of, components of the tumour recognition
complex in neoplastic cells of diverse histotypes. They can therefore be used as
immunomodulatory agents to increase immunogenicity and immune recognition of
neoplastic cells. This, in turn, should allow for better therapeutic outcomes in terms of
tumor control and regression, prolong disease-free progression, and improve overall
survival.
Second generation DHAs derived from decitabine, including the DNA
hypomethylating agent of compound I-1 (a dinucleotide of 5-aza-2’-deoxycytidine and
deoxyguanosine), are described in WO2007/041071 (which is hereby incorporated by
reference in its entirety).
Compounds of Formula I for use in the combinations of the invention
In some embodiments, described are combinations comprising a compound of
Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in
L is 1.
L is a group suitable for linking the 5-azacytosine group with the guanine group.
In some embodiments, L comprises a carbohydrate. In some embodiments, L comprises
more than one carbohydrate. In some embodiments, L comprises two carbohydrates.
When L comprises more than one carbohydrate, the carbohydrates can be the same or
different. A carbohydrate can be a monosaccharide in the closed ring form, such as a
pyranose or furanose form. A carbohydrate can be substituted at any position or
deoxygenated at any position that would be oxygenated in a naturally-occurring form of
the carbohydrate. In some embodiments, the carbohydrate is ribose. In some
embodiments, the carbohydrate is 2-deoxyribose. The ribose or 2-deoxyribose can be
substituted at any position.
The phosphate atom of L can be present in any naturally-occurring or synthetic
functional group containing a phosphorus atom. Non-limiting examples of such
functional groups include phosphodiesters, phosphorothioate diesters, boranophosphate
diesters, and methylphosphonate diesters.
In some embodiments, L comprises Formula II. In some embodiments, L is
Formula II.
OR R (II),
wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an
acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R
together with the oxygen atom to which R is bound forms an ether, an ester, a carbonate,
4 4 4
or a carbamate; R is H, or R together with the oxygen atom to which R is bound forms
an ether, an ester, a carbonate, or a carbamate; and X together with the oxygen atoms to
which X is bound forms a phosphodiester, a phosphorothioate diester, a boranophosphate
diester, or a methylphosphonate diester.
The 5-azacytosine group can be linked to either end of L, and the guanine group
can be linked to the other end of L as long as the compound contains one 5-azacytosine
group and one guanine group. Constitutional isomers can thus be prepared by exchanging
the connectivity of the 5-azacytosine group and the guanine group.
1 2 1 2
R and R can be the same or different. In some embodiments, R and R are
independently H, OH, OMe, OEt, OPh, OCH CH OMe, OCH CH OEt,
2 2 2 2
OCH CH OBn,OBn, OAc, OBz, OCOOMe, OCOOEt, OCOOBn, OCONH , OCONMe ,
2 2 2 2
OCONEt , OCONBn , OCONHMe, OCONHEt, OCONHBn, F, Cl, Br, or I. In some
embodiments, R and R are independently H, OH, OMe, OEt, OCH2CH2OMe, OBn, or
F. In some embodiments, R and R are independently H or OH. In some embodiments,
1 2 1 2
R and R are H. In some embodiments, R and R are OH.
R and R can be the same or different.
3 3 3
In some embodiments, R is H, or R together with the oxygen atom to which R is
bound forms OH, OMe, OEt, OPh, OCH CH OMe, OCH CH OEt, OCH CH OBn,OBn,
2 2 2 2 2 2
OAc, OBz, OCOOMe, OCOOEt, OCOOBn, OCONH , OCONMe , OCONEt ,
2 2 2
OCONBn , OCONHMe, OCONHEt, or OCONHBn. In some embodiments, R is H, or
R together with the oxygen atom to which R is bound forms OH, OMe, OEt,
OCH CH OMe, or OBn. In some embodiments, R is H.
4 4 4
In some embodiments, R is H, or R together with the oxygen atom to which R is
bound forms OH, OMe, OEt, OPh, OCH CH OMe, OCH CH OEt, OCH CH OBn,OBn,
2 2 2 2 2 2
OAc, OBz, OCOOMe, OCOOEt, OCOOBn, OCONH , OCONMe , OCONEt ,
2 2 2
OCONBn , OCONHMe, OCONHEt, or OCONHBn. In some embodiments, R is H, or
R together with the oxygen atom to which R is bound forms OH, OMe, OEt,
OCH CH OMe, or OBn. In some embodiments, R is H.
In some embodiments, X is P(O)OH, P(O)SH, P( →O)BH , or P(O)Me. In some
embodiments, X is P(O)OH. In some embodiments, X together with the oxygen atoms to
which X is bound forms a phosphodiester.
Non-limiting examples of alkyl include straight, branched, and cyclic alkyl
groups. Non-limiting examples of straight alkyl groups include methyl, ethyl, propyl,
butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
Branched alkyl groups include any straight alkyl group substituted with any
number of alkyl groups. Non-limiting examples of branched alkyl groups include
isopropyl, isobutyl, sec-butyl, and t-butyl.
Non-limiting examples of cyclic alkyl groups include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptlyl, and cyclooctyl groups. Cyclic alkyl groups also
include fused-, bridged-, and spiro-bicycles and higher fused-, bridged-, and spiro-
systems. A cyclic alkyl group can be substituted with any number of straight or branched
alkyl groups.
A halo-alkyl group can be any alkyl group substituted with any number of
halogen atoms, for example, fluorine, chlorine, bromine, and iodine atoms.
An alkoxy group can be, for example, an oxygen atom substituted with any alkyl
group. An ether or an ether group comprises an alkoxy group. Non-limiting examples of
alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and isobutoxy.
An alkoxyalkoxy group can be, for example, an alkoxy group substituted at any
position with any alkoxy group. Non-limiting examples of alkoxyalkoxy groups include
methoxyethoxy, ethyoxyethoxy, ethoxyethoxyethoxy, groups derived from any order of
glyme, and groups derived from polyethylene glycol.
An aryl group can be heterocyclic or non-heterocyclic. An aryl group can be
monocyclic or polycyclic. An aryl group can be substituted with any number of
hydrocarbyl groups, alkyl groups, and halogen atoms. Non-limiting examples of aryl
groups include phenyl, toluyl, naphthyl, pyrrolyl, pyridyl, imidazolyl, thiophenyl, and
furyl.
An aryloxy group can be, for example, an oxygen atom substituted with any aryl
group, such as phenoxy.
An aralkyl group can be, for example, any alkyl group substituted with any aryl
group, such as benzyl.
An arylalkoxy group can be, for example, an oxygen atom substituted with any
aralkyl group, such as benzyloxy.
A heterocycle can be any ring containing a ring atom that is not carbon. A
heterocycle can be substituted with any number of alkyl groups and halogen atoms. Non-
limiting examples of heterocycles include pyrrole, pyrrolidine, pyridine, piperidine,
succinamide, maleimide, morpholine, imidazole, thiophene, furan, tetrahydrofuran,
pyran, and tetrahydropyran.
An acyl group can be, for example, a carbonyl group substituted with hydrocarbyl,
alkyl, hydrocarbyloxy, alkoxy, aryl, aryloxy, aralkyl, arylalkoxy, or a heterocycle. Non-
limiting examples of acyl include acetyl, benzoyl, benzyloxycarbonyl, phenoxycarbonyl,
methoxycarbonyl, and ethoxycarbonyl.
An acyloxy group can be an oxygen atom substituted with an acyl group. An ester
or an ester group comprises an acyloxy group.
A carbonate group can be an oxygen atom substituted with
hydrocarbyloxycarbonyl, alkoxycarbonyl, aryloxycarbonyl, or arylalkoxycarbonyl.
A carbamate group can be an oxygen atom substituted with a carbamoyl group,
wherein the nitrogen atom of the carbamoyl group is unsubstituted, monosubstituted, or
disubstituted with one or more of hydrocarbyl, alkyl, aryl, heterocyclyl, or aralkyl. When
the nitrogen atom is disubstituted, the two substituents together with the nitrogen atom
can form a heterocycle.
Any functional group of a compound described herein can be optionally capped
with a capping group. For examples of capping groups, see GREENE’S PROTECTIVE
GROUPS IN ORGANIC SYNTHESIS, 4th Ed. (Wiley 2006) (1980) and PROTECTING GROUPS,
3d Ed. (Thieme 2005) (1994), each of which is incorporated by reference in its entirety.
Non-limiting examples of suitable capping groups for a hydroxyl group include
alkyl, haloalkyl, aryl, aralkyl, carbonate, carbamate, and acyl groups.
Non-limiting examples of suitable capping groups for nitrogen-functionalities
include alkyl, aryl, aralkyl, an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl
group, and an aminocarbonyl group. A capping group together with the nitrogen atom to
which the capping group is bound can form, for example, an amide, a carbamate, a
urethane, a heterocycle, or an amine. Two capping groups bound to the same nitrogen
atom can form together with the nitrogen atom a heterocycle.
Also described are pharmaceutically-acceptable salts of any compound described
herein. Pharmaceutically-acceptable salts include, for example, acid-addition salts and
base-addition salts. The acid that is added to a compound to form an acid-addition salt
can be an organic acid or an inorganic acid. A base that is added to a compound to form a
base-addition salt can be an organic base or an inorganic base. In some embodiments, a
pharmaceutically-acceptable salt is a metal salt. In some embodiments, a
pharmaceutically-acceptable salt is an ammonium salt.
Acid addition salts can arise from the addition of an acid to a compound described
herein. In some embodiments, the acid is organic. In some embodiments, the acid is
inorganic. Non-limiting examples of suitable acids include hydrochloric acid,
hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a
phosphoric acid, nicotinic acid, isonicotinic acid, lactic acid, salicylic acid, 4-
aminosalicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic
acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid,
propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, oxalic acid, maleic
acid, hydroxymaleic acid, methylmaleic acid, glycolic acid, malic acid, cinnamic acid,
mandelic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid,
phenylacetic acid, N-cyclohexylsulfamic acid, methanesulfonic acid, ethanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-
disulfonic acid, 4-methylbenzenesulfonic acid, naphthalenesulfonic acid, naphthalene-
1,5-disulfonic acid, 2-phosphoglyceric acid, 3-phosphoglyceric acid, glucose
phosphoric acid, and an amino acid.
Non-limiting examples of suitable acid addition salts include a hydrochloride salt,
a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite
salt, a phosphate salt, a hydrogen phosphate salt, a dihydrogen phosphate salt, a carbonate
salt, a bicarbonate salt, a nicotinate salt, an isonicotinate salt, a lactate salt, a salicylate
salt, a 4-aminosalicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a
gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a
glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a
fumarate salt, a succinate salt, a citrate salt, an oxalate salt, a maleate salt, a
hydroxymaleate salt, a methylmaleate salt, a glycolate salt, a malate salt, a cinnamate salt,
a mandelate salt, a 2-phenoxybenzoate salt, a 2-acetoxybenzoate salt, an embonate salt, a
phenylacetate salt, an N-cyclohexylsulfamate salt, a methanesulfonate salt, an
ethanesulfonate salt, a benzenesulfonate salt, a p-toluenesulfonate salt, a 2-
hydroxyethanesulfonate salt, an ethane-1,2-disulfonate salt, a 4-methylbenzenesulfonate
salt, a naphthalenesulfonate salt, a naphthalene-1,5-disulfonate salt, a 2-
phosphoglycerate salt, a 3-phosphoglycerate salt, a glucosephosphate salt, and an
amino acid salt.
Metal salts can arise from the addition of an inorganic base to a compound
described herein. The inorganic base consists of a metal cation paired with a basic
counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate. The
metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
Non-limiting examples of suitable metals include lithium, sodium, potassium, caesium,
cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminium,
copper, cadmium, and zinc.
Non-limiting examples of suitable metal salts include a lithium salt, a sodium salt,
a potassium salt, a caesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron
salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, a aluminium salt, a
copper salt, a cadmium salt, and a zinc salt.
Ammonium salts can arise from the addition of ammonia or an organic amine to a
compound described herein. Non-limiting examples of suitable organic amines include
triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine,
morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine,
dibenzyl amine, piperazine, pyridine, pyrrazole, pipyrrazole, imidazole, pyrazine,
pipyrazine, ethylenediamine, N,N'-dibenzylethylene diamine, procaine, chloroprocaine,
choline, dicyclohexyl amine, and N-methylglucamine.
Non-limiting examples of suitable ammonium salts include is a triethyl amine salt,
a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine
salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-
methylpiperidine salt, an N-ethylpiperidine salt, a dibenzyl amine salt, a piperazine salt, a
pyridine salt, a pyrrazole salt, a pipyrrazole salt, an imidazole salt, a pyrazine salt, a
pipyrazine salt, an ethylene diamine salt, an N,N'-dibenzylethylene diamine salt, a
procaine salt, a chloroprocaine salt, a choline salt, a dicyclohexyl amine salt, and a N-
methylglucamine salt.
Non-limiting examples of compounds of Formula I include:
O P OH
N NH
I-1: OH ; I-2:
N NH
O P OH
O P SH
I-3: OH ; I-
N NH
O P SH
4: ;
O P BH
N NH
I-5: OH ; I-
N NH
O P BH
6: ;
O P Me
N NH
I-7: OH ; I-8:
N NH
O P Me
O P OH
N NH
I-9: OMe ;
N NH
O P OH
I-10: ;
O P OH
I-11: OEt ; I-
N NH
O P OH
12: ;
O P OH
N NH
I-13: OAc ;
N NH
O P OH
I-14: ;
N NH
BnO BnO
O P OH O P OH
N NH
I-15: OBn ; I-16: OBn ;
O P OH
I-17: OBz ; I-
N NH
O P OH
18: ;
EtOOCO
O P OH
I-19: OCOOEt ;
N NH
EtOOCO
O P OH
I-20: OCOOEt ;
(Me) NOCO
O P OH
N NH
OCON(Me)
I-21: 2 ;
N NH
(Me) NOCO
O P OH
OCON(Me)
I-22: ;
N NH
O OH O OH
O P OH O P OH
N NH
OH OH OH
I-23: ; I-24: OH ;
N NH
HO HO
O O OMe
OMe N N
O P OH O P OH
N NH
I-25: OMe ; I-26: OH OMe ;
N O N
N NH
O OEt O OEt
O P OH O P OH
OH OH
I-27: OEt ; I-28: OEt ;
N O N
N NH
HO HO
O OQ
O OQ
O P OH O P OH
OH OQ OH
OQ = OCH CH OMe OQ = OCH CH OMe
2 2 2 2
I-29: ; I-30: ;
N NH
O OBn O OBn
O P OH
O P OH
OH OH
I-31: OBn ; I-32: OBn ;
N NH
HO HO
O OAc O OAc
O P OH O P OH
N NH
I-33: OH OAc ; I-34: OAc ;
N O N
N NH
O O OBz
OBz N
O P OH O P OH
N N O
OH OBz OH OBz
I-35: ; I-36: ;
N NH
O OQ O OQ
O P OH
O P OH
OH OQ
OH OQ
OQ = OCOOEt OQ = OCOOEt
I-37: ; I-38: ;
N O N
N NH
HO HO
N O OQ
O OQ N
O P OH O P OH
OH OQ
OQ = OCON(Me) OQ = OCON(Me)
I-39: 2 ; I-40: 2 ;
N O N
N NH
HO HO
O O F
O P OH O P OH
OH OH F
I-41: F ; I-42: ;
N O N
N NH
O Cl O Cl
O P OH O P OH
OH OH
I-43: Cl ; I-44: Cl ;
and pharmaceutically-acceptable salts of any of the foregoing. In some embodiments, a
salt is a sodium salt of any of the foregoing.
The compounds described herein can be synthesized by methods known in the art,
for example, solution phase or solid phase synthesis. For descriptions of the synthesis of
compounds useful in the invention, and for a description of the mechanism of action of
compounds useful in the invention, see WO2007/041071, which is incorporated by
reference herein in its entirety.
Formulations for use in the combinations of the invention.
The compounds for use in the combinations of the invention can be provided in
any suitable form and can be formulated in accordance with known techniques (see, for
example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA,
USA). Examples of suitable formulations are described in WO2007/041071 at pages 13-
23, which teaching is hereby incorporated by reference.
An efficacious therapy can provide advantageous effects such as additivity,
synergism, reduced side effects, reduced toxicity, increased time to disease progression,
increased time of survival, sensitisation or desensitisation of one agent to another, or
improved response rate. Advantageously, an efficacious effect can allow for lower doses
of each or either component to be administered to a patient, thereby decreasing the
toxicity of chemotherapy, whilst producing and/or maintaining the same therapeutic
effect.
A response rate can describe the percentage of patients achieving a response
status. Thus, for example, a 50% response rate means that half of the patients treated
achieve response status. A response status can relate to a type of malignancy, for
example, whether solid or haematological. In the former case it is usually defined by the
RECIST criteria (Response Evaluation Criteria In Solid Tumors), while in the latter other
response criteria are used (mainly those of the IWG (International Working Group)).
A synergistic effect can be a therapeutic effect produced by the combination
which is larger than the sum of the therapeutic effects of the components of the
combination when presented individually.
An additive effect can be a therapeutic effect produced by the combination which
is larger than the therapeutic effect of any of the components of the combination when
presented individually.
Non-limiting examples of pharmaceutical compositions include any composition
suitable for administration to a patient, being, for example, in a form, concentration
and/or level of purity suitable for administration to a human or animal subject. In some
embodiments, pharmaceutical compositions are sterile and/or non-pyrogenic. A non-
pyrogenic pharmaceutical composition does not elicit undesirable inflammatory responses
when administered to a patient.
Non-limiting examples of a pharmaceutical kit include an array of one or more
unit doses of a pharmaceutical composition together with a dosing device (e.g. measuring
device) and/or a delivery device (e.g. inhaler or syringe), optionally all contained within
common outer packaging. In pharmaceutical kits comprising a combination of two or
more compounds/agents, the individual compounds/agents can be unitary or non-unitary
formulations. In some embodiments, the unit dose(s) can be contained within a blister
pack. In some embodiments, the pharmaceutical kit further comprises instructions for
use.
A pharmaceutical pack can be an array of one or more unit doses of a
pharmaceutical composition, optionally contained within common outer packaging. In
pharmaceutical packs comprising a combination of two or more compounds/agents, the
individual compounds/agents can be unitary or non-unitary formulations. The unit
dose(s) can be contained within a blister pack. In some embodiments, the pharmaceutical
pack further comprises instructions for use.
A patient pack can be a package, prescribed to a patient, which contains
pharmaceutical compositions for the whole course of treatment. Patient packs can contain
one or more blister pack(s). Patient packs have an advantage over traditional
prescriptions, where a pharmacist divides a patient’s supply of a pharmaceutical from a
bulk supply, in that the patient always has access to the package insert contained in the
patient pack, normally missing in patient prescriptions. The inclusion of a package insert
has been shown to improve patient compliance with the physician’s instructions.
Non-limiting examples of non-physically associated combined compounds/agents
include:
• material (e.g. a non-unitary formulation) comprising at least one of the two or
more compounds/agents together with instructions for the extemporaneous
association of the at least one compound/agent to form a physical association of
the two or more compounds/agents;
• material (e.g. a non-unitary formulation) comprising at least one of the two or
more compounds/agents together with instructions for combination therapy with
the two or more compounds/agents;
• material comprising at least one of the two or more compounds/agents together
with instructions for administration to a patient population in which the other(s) of
the two or more compounds/agents have been (or are being) administered;
• material comprising at least one of the two or more compounds/agents in an
amount or in a form which is specifically adapted for use in combination with the
other(s) of the two or more compounds/agents.
Non-limiting examples of combination therapies include therapies which comprise
the use of a combination of two or more compounds/agents (as defined above). The
compounds can be administered as part of the same overall treatment regimen. As such,
the posology of each of the two or more compounds/agents can differ: each can be
administered at the same time or at different times. In some embodiments, the
compounds/agents of the combination can be administered sequentially (e.g. before or
after) or simultaneously, either in the same pharmaceutical formulation (i.e. together), or
in different pharmaceutical formulations (i.e. separately). Simultaneously in the same
formulation is as a unitary formulation whereas simultaneously in different
pharmaceutical formulations is non-unitary. In some embodiments, the compound of
Formula I or salt thereof is administered first (as a priming therapy), followed by
administration of the ancillary therapeutic component(s). The posologies of each of the
two or more compounds/agents in a combination therapy can also differ with respect to
the route of administration.
In some embodiments, the combinations of the invention produce a therapeutically
efficacious effect relative to the therapeutic effect of the individual compounds/agents
when administered separately.
An ancillary therapeutic component can be a compound/agent which yields an
efficacious combination when combined with a compound of the formula (I). The
ancillary component can contribute to the efficacy of the combination (for example, by
producing a synergistic or additive effect or improving the response rate).
The antitumour efficacy of the combinations can be evaluated by reference to
effects on DNA methylation and/or modulation of tumour immunological profile. Global
or gene-specific DNA methylation can be monitored by analysis of sodium bisulfite-
treated DNA using pyrosequencing, quantitative methylation-specific PCR or RT-PCR
and real-time quantitative RT-PCR analyses. Tumour immunological profile can be
characterized by immunohistochemistry (IHC) for the presence and relative frequency of
activated T cells. The immunomodulatory activity of the combinations can also be
evaluated by RT-PCR and real time quantitative RT-PCR analyses of the induction or
modulation of Cancer Testis Antigens (CTA) such as NY-ESO-1 or MAGE family of
antigens. The efficacy of the combination treatment can be also determined by the
immune response to the anti-tumour activity of the combinations. For example,
modulation of an anti-tumour T cell response can be evaluated by Mixed Lymphocyte
Tumour Cell (MLTC) assays. Further details of such analytical techniques are provided
in e.g. Coral et al. (2012) Immunomodulatory activity of SGI-110, a 5-aza-2 ′-
deoxycytidine-containing demethylating dinucleotide Cancer Immunol. Immunother. DOI
.1007/s002621365-7.
Non-limiting examples of antibodies include: i) whole antibodies (including
polyclonal antibodies and monoclonal antibodies (mAbs)); ii) antibody fragments,
including F(ab), F(ab'), F(ab')2, Fv, Fc3 and single chain antibodies (and combinations
thereof), which can be produced by recombinant DNA techniques or by enzymatic or
chemical cleavage of intact antibodies; iii) bispecifc or bifunctional antibodies, which are
synthetic hybrid antibodies having two different heavy/light chain pairs and two different
binding sites; iv) chimaeric antibodies (antibodies having a human constant antibody
immunoglobulin domain coupled to one or more non-human variable antibody
immunoglobulin domain, or fragments thereof); v) minibodies (see WO 94/09817), single
chain Fv-Fc fusions and human antibodies produced by transgenic animals; and vi)
multimeric antibodies and higher-order complexes of proteins (e.g. heterodimeric
antibodies). Bispecific antibodies can be produced by a variety of methods including
fusion of hybridomas or linking of Fab' fragments. In some embodiments, chimaeric
antibodies are humanized antibodies.
Non-limiting examples of immunotherapy include an intervention (e.g. the
administration of the combination of the invention to a subject) which cures, ameliorates
or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s),
and which is mediated, at least in part, by components of the host immune system.
Immunotherapy can be achieved by immunomodulation, can be the stimulation and/or
suppression one or more components or activities of the immune system.
The formulations described herein provide the compounds described herein in a
form with high solubility, low injection volumes, and good chemical stability and shelf-
life. These properties provide formulations that retain a high percentage of the initial
efficacy and deliver a therapeutically-effective amount of the compound even after
storage at or below room temperature for extended times.
In some embodiments, described are combinations comprising a formulation
comprising: a) a compound of Formula I or a pharmaceutically-acceptable salt thereof:
(5-azacytosine group)-L-(guanine group) (I),
wherein L is a phosphorus-containing linker wherein the number of phosphorus atoms in
L is 1; and b) a solvent comprising: about 45% to about 85% propylene glycol; about 5%
to about 45% glycerin; and 0% to about 30% ethanol; and c) optionally, a
pharmaceutically-acceptable excipient.
Suitable formulations can be solutions or suspensions of a compound in a
solvent or a mixture of solvents. Non-limiting examples of suitable solvents include
propylene glycol, glycerin, ethanol, and any combination of the foregoing. The
formulations can be prepared as non-aqueous formulations. The formulations can be
anhydrous or substantially anhydrous.
A mixture of solvents can contain a percentage of propylene glycol on
either a mass or a volume basis. In some embodiments, the percentage of propylene
glycol can be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least
about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about
50%. In some embodiments, the percentage of propylene glycol can be at most 90%, at
most 80%, at most 70%, at most 60%, at most about 90%, at most about 80%, at most
about 70%, or at most about 60%. In some embodiments, the percentage of propylene
glycol can be 30% to 90%, 45% to 85%, 55% to 75%, 60% to 70%, about 30% to about
90%, about 45% to about 85%, about 55% to about 75%, or about 60% to about 70%. In
some embodiments, the percentage of propylene glycol can be 30%, 35%, 40%, 45%,
50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, about 30%, about 35%, about 40%,
about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about
80%, about 85%, or about 90%.
A mixture of solvents can contain a percentage of glycerin on either a mass
or a volume basis. In some embodiments, the percentage of glycerin can be at least 5%,
at least 10%, at least 15%, at least 25%, at least 30%, at least about 5%, at least about
%, at least about 15%, at least about 25%, or at least about 30%. In some
embodiments, the percentage of glycerin can be at most 70%, at most 60%, at most 50%,
at most 40%, at most 30%, at most about 70%, at most about 60%, at most about 50%, at
most about 40%, or at most about 30%. In some embodiments, the percentage of glycerin
can be 0% to 50%, 5% to 45%, 15% to 35%, 20% to 30%, 0% to about 50%, about 5% to
about 45%, about 15% to about 35%, or about 20% to about 30%. In some embodiments,
the percentage of glycerin can be 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,
50%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%,
about 40%, about 45%, or about 50%.
A mixture of solvents can contain a percentage of ethanol on either a mass
or a volume basis. In some embodiments, the percentage of ethanol can be at least 1%, at
least 3%, at least 5%, at least 10%, at least 15%, at least about 1%, at least about 3%, at
least about 5%, at least about 10%, or at least about 15%. In some embodiments, the
percentage of ethanol can be at most 30%, at most 25%, at most 20%, at most 15%, at
most 10%, at most about 30%, at most about 25%, at most about 20%, at most about 15%,
or at most about 10%. In some embodiments, the percentage of ethanol can be 0% to
%, 0% to 25%, 0% to 20%, 5% to 15%, 0% to about 30%, 0% to about 25%, 0% to
about 20%, or about 5% to about 15%. In some embodiments, the percentage of ethanol
can be 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,
about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,
about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%.
In some embodiments, a solvent or a mixture of solvents comprises 45% to
85% propylene glycol, 5% to 45% glycerin, and 0% to 30% ethanol. In some
embodiments, a solvent or a mixture of solvents comprises about 45% to about 85%
propylene glycol, about 5% to about 45% glycerin, and 0% to about 30% ethanol. In
some embodiments, a solvent or a mixture of solvents consists essentially of 45% to 85%
propylene glycol, 5% to 45% glycerin, and 0% to 30% ethanol. In some embodiments, a
solvent or a mixture of solvents consists essentially of about 45% to about 85% propylene
glycol, about 5% to about 45% glycerin, and 0% to about 30% ethanol. In some
embodiments, a solvent or a mixture of solvents is 45% to 85% propylene glycol, 5% to
45% glycerin, and 0% to 30% ethanol. In some embodiments, a solvent or a mixture of
solvents is about 45% to about 85% propylene glycol, about 5% to about 45% glycerin,
and 0% to about 30% ethanol.
In some embodiments, a solvent or a mixture of solvents comprises 55% to
75% propylene glycol, 15% to 35% glycerin, and 0% to 20% ethanol. In some
embodiments, a solvent or a mixture of solvents comprises about 55% to about 75%
propylene glycol, about 15% to about 35% glycerin, and 0% to about 20% ethanol. In
some embodiments, a solvent or a mixture of solvents consists essentially of 55% to 75%
propylene glycol, 15% to 35% glycerin, and 0% to 20% ethanol. In some embodiments, a
solvent or a mixture of solvents consists essentially of about 55% to about 75% propylene
glycol, about 15% to about 35% glycerin, and 0% to about 20% ethanol. In some
embodiments, a solvent or a mixture of solvents is 55% to 75% propylene glycol, 15% to
% glycerin, and 0% to 20% ethanol. In some embodiments, a solvent or a mixture of
solvents is about 55% to about 75% propylene glycol, about 15% to about 35% glycerin,
and 0% to about 20% ethanol.
In some embodiments, a solvent or a mixture of solvents comprises 60% to
70% propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol. In some
embodiments, a solvent or a mixture of solvents comprises about 60% to about 70%
propylene glycol; about 20% to about 30% glycerin; and about 5% to about 15% ethanol.
In some embodiments, a solvent or a mixture of solvents consists essentially of 60% to
70% propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol. In some
embodiments, a solvent or a mixture of solvents consists essentially of about 60% to
about 70% propylene glycol; about 20% to about 30% glycerin; and about 5% to about
% ethanol. In some embodiments, a solvent or a mixture of solvents is 60% to 70%
propylene glycol; 20% to 30% glycerin; and 5% to 15% ethanol. In some embodiments, a
solvent or a mixture of solvents is about 60% to about 70% propylene glycol; about 20%
to about 30% glycerin; and about 5% to about 15% ethanol.
In some embodiments, a solvent or a mixture of solvents comprises 65%
propylene glycol; 25% glycerin; and 10% ethanol. In some embodiments, a solvent or a
mixture of solvents comprises about 65% propylene glycol; about 25% glycerin; and
about 10% ethanol. In some embodiments, a solvent or a mixture of solvents consists
essentially of 65% propylene glycol; 25% glycerin; and 10% ethanol. In some
embodiments, a solvent or a mixture of solvents consists essentially of about 65%
propylene glycol; about 25% glycerin; and about 10% ethanol. In some embodiments, a
solvent or a mixture of solvents is 65% propylene glycol; 25% glycerin; and 10% ethanol.
In some embodiments, a solvent or a mixture of solvents is about 65% propylene glycol;
about 25% glycerin; and about 10% ethanol.
Formulations for use in the combinations of the invention can be prepared,
stored, transported, and handled in anhydrous or substantially-anhydrous form. A solvent
can be dried prior to preparing a formulation, and a compound can be dried, for example,
by lyophilization. A drying agent, or dessicant, can be used during preparation, storage,
transportation, or handling to regulate water content. Non-limiting examples of drying
agents include silica gel, calcium sulfate, calcium chloride, calcium phosphate, sodium
chloride, sodium bicarbonate, sodium sulfate, sodium phosphate, montmorillonite,
molecular sieves (beads or powdered), alumina, titania, zirconia, and sodium
pyrophosphate. A drying agent can contact a formulation directly, be inserted into the
formulation in the form of a packet with a permeable membrane, or be stored with the
formulation in a sealed environment, such as a dessicator, such that the drying agent and
the formulation are simultaneously exposed to the same controlled atmosphere. A drying
agent can be removed from a formulation, for example, by filtration or cannulation.
Additionally, a formulation can be stored in a sealed container within a controlled
atmosphere consisting essentially of, or enriched in, nitrogen or argon.
Anhydrous or substantially-anhydrous conditions benefit the shelf-life of a
formulation disclosed herein at both ambient and reduced temperatures. This benefit
reduces the costs associated with the storage, transportation, and spoilage of a
formulation, increases the convenience of storage and handling, and avoids the need to
administer cold formulations, thereby improving subject tolerance and compliance to a
regimen of a formulation as described herein.
The formulations can further include a pharmaceutically-acceptable
excipient. Non-limiting examples of excipients include mannitol, sorbitol, lactose,
dextrose, and cyclodextrins. Excipients can be added to modulate the density, rheology,
uniformity, and viscosity of the formulation.
The formulations can include acidic or basic excipients to modulate the
acidity or basicity of the formulation. Non limiting examples of acids suitable to increase
the acidity of a formulation include hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfuric acid, phosphoric acid, nitric acid, ascorbic acid, citric acid, tartaric acid, lactic
acid, oxalic acid, formic acid, benzenesulphonic acid, benzoic acid, maleic acid, glutamic
acid, succinic acid, aspartic acid, diatrizoic acid, and acetic acid. Non limiting examples
of bases suitable to increase the basicity of a formulation include lithium hydroxide,
sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium
phosphate, potassium phosphate, sodium acetate, sodium benzoate, tetrabutylammonium
acetate, tetrabutylammonium benzoate, and trialkyl amines. Polyfunctional excipients,
such as ethylene diamine tetraacetic acid (EDTA), or a salt thereof, can also be used to
modulate acidity or basicity.
The compound of Formula I as hereinbefore defined can be present in a
formulation in any amount. In some embodiments, the compound is present in a
concentration of 1 mg/mL to 130 mg/mL, 10 mg/mL to 130 mg/mL, 40 mg/mL to 120
mg/mL, 80 mg/mL to 110 mg/mL, about 1 mg/mL to about 130 mg/mL, about 10 mg/mL
to about 130 mg/mL, about 40 mg/mL to about 120 mg/mL, or about 80 mg/mL to about
110 mg/mL. In some embodiments, the compound is present in a concentration of 10
mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL,
90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL,
160 mg/mL, 170 mg/mL, 180 mg/mL, 190 mg/mL, 200 mg/mL, about 10 mg/mL, about
mg/mL, about 30 mg/mL, about 40 mg/mL, about 50 mg/mL, about 60 mg/mL, about
70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 110 mg/mL,
about 120 mg/mL, about 130 mg/mL, about 140 mg/mL, about 150 mg/mL, about 160
mg/mL, about 170 mg/mL, about 180 mg/mL, about 190 mg/mL, or about 200 mg/mL.
In some embodiments, the compound is present in a concentration of 100 mg/mL. In
some embodiments, the compound is present in a concentration of about 100 mg/mL.
The formulation can be prepared by contacting a compound described
herein with a solvent or a mixture of solvents. Alternatively, the compound can be
contacted with a single solvent, and other solvents can be added subsequently, as a
mixture, or sequentially. When the final formulation is a solution, complete solvation can
be achieved at whatever step of the process is practical for manufacturing. Optional
excipients can be added to the formulation at whatever step is practical for manufacturing.
Preparation of the formulation can be optionally promoted by agitation,
heating, or extension of the dissolution period. Non-limiting examples of agitation
include shaking, sonication, mixing, stirring, vortex, and combinations thereof.
In some embodiments, the formulation is optionally sterilized. Non-
limiting examples of sterilization techniques include filtration, chemical disinfection,
irradiation, and heating.
Dimethyl sulfoxide (DMSO)
The use of DMSO as a solvent in the preparation of the formulations for
use in the combinations of the invention permit reduction in bulk solution and fill
volumes (both bulk and fill volumes can be reduced to 1/5 of those used with aqueous
systems) and relieves time and temperature restrictions on scale-up. Moreover, the use of
substantially anhydrous DMSO greatly increases stability: increasing water concentration
is correlated with a decrease in stability (as shown in Figure 4, which shows the % change
in total related substances of the sodium salt of a compound of Formula I-1 when stored
in DMSO or DMSO/water (water for injection, “WFI”) at 25°C/60% RH for 24 hours).
Any source of DMSO can be used according to the invention. In some
embodiments, the DMSO source is suitable for healthcare and drug delivery applications,
for example conforming to USP or Ph. Eur monographs, and be manufactured under
cGMP and API guidelines. Grades such as anhydrous or Pharma Solvent can be used
according to the invention.
The DMSO for use according to the invention can have impurities in very
low levels, for example <0.2% water by KF, <0.01% non-volatile residue and <0.1% of
related compounds.
In some embodiments, DMSO can incliude isosteres thereof, including in
particular DMSO isosteres in which one or more atom(s) is(are) replaced by a cognate
isotope, for example hydrogen by deuterium.
Dosing and Administration
Suitable doses of formulations as described herein can be administered to a
subject by methods known in the art, and exemplary dosing and administration
parameters are described in WO2007/041071, which teaching is hereby incorporated by
reference in its entirety.
Thus, non-limiting examples of methods of administration include
subcutaneous injection, intravenous injection, and infusion. In some embodiments, a
subject is in need or want of the formulation. In some embodiments, the administration is
subcutaneous administration.
A therapeutically effective amount of a compound as described herein can
be expressed as mg of the compound per kg of subject body mass. In some embodiments,
a therapeutically effective amount is 1-1,000 mg/kg, 1-500 mg/kg, 1-250 mg/kg, 1-100
mg/kg, 1-50 mg/kg, 1-25 mg/kg, or 1-10 mg/kg. In some embodiments, a therapeutically-
effective amount is 5 mg/kg, 10 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 150
mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700
mg/kg, 800 mg/kg, 900 mg/kg, 1,000 mg/kg, about 5 mg/kg, about 10 mg/kg, about 25
mg/kg, about 50 mg/kg, about 75 mg/kg, about 100 mg/kg, about 150 mg/kg, about 200
mg/kg, about 250 mg/kg, about 300 mg/kg, about 400 mg/kg, about 500 mg/kg, about 600
mg/kg, about 700 mg/kg, about 800 mg/kg, about 900 mg/kg, or about 1,000 mg/kg.
A therapeutically effective amount of a compound as described herein can
also be expressed as mg of the compound per square metre of subject body area. In some
embodiments, the combinations of the invention can be administered subcutaneously in a
range of doses, for example 1 to 1500 mg (0.6 to 938 mg/m2), or 2 to 800 mg (1.25 to
500mg/m2), or 5 to 500 mg (3.1 to 312 mg/m2), or 2 to 200 mg (1.25 to 125 mg/m2) or
to 1000 mg (6.25 to 625 mg/m2), particular examples of doses including 10 mg (6.25
mg/m2), 20 mg (12.5 mg/m2), 50 mg (31.3 mg/m2), 80 mg (50 mg/m2), 100 mg (62.5
mg/m2), 200 mg (125 mg/m2), 300 mg (187.5 mg/m2), 400 mg (250 mg/m2), 500 mg
(312.5 mg/m2), 600 mg (375 mg/m2), 700 mg (437.5 mg/m2), 800 mg (500 mg/m2), 900
mg (562.5mg/m2) and 1000 mg (625 mg/m2).
The combination can be administered once or more than once each day.
The combination is typically administered continuously (i.e. taken every day without a
break for the duration of the treatment regimen).
In some embodiments, a therapeutically effective amount can be
administered 1-35 times per week, 1-14 times per week, or 1-7 times per week. In some
embodiments, a therapeutically-effective amount can be administered 1-10 times per day,
1-5 times per day, 1 time, 2 times, or 3 times per day.
In some embodiments, the materials as described herein can be
administered according to a dosage regimen of: (a) once, twice, three times, four times,
five times, six times or seven times a week; or (b) every day for 5, 6, 7, 8, 9 or 10 days; or
(c) every day for up to 10 days; or (d) every day for between 5 and 10 days; or (e) every
day for 5 days, immediately followed by two dose-free days and then every day for the
next 5 days. In some embodiments, administration is subcutaneous.
Therapeutic Uses
The combinations of the present invention can be used to treat a wide
variety of diseases.
Indications that can be treated include those involving undesirable or
uncontrolled cell proliferation. Such indications include benign tumours, various types of
cancers such as primary tumours and tumour metastasis, restenosis (e.g. coronary, carotid,
and cerebral lesions), haematological disorders, abnormal stimulation of endothelial cells
(atherosclerosis), insults to body tissue due to surgery, abnormal wound healing,
abnormal angiogenesis, diseases that produce fibrosis of tissue, repetitive motion
disorders, disorders of tissues that are not highly vascularized, and proliferative responses
associated with organ transplants.
Generally, cells in a benign tumour retain their differentiated features and
do not divide in a completely uncontrolled manner. A benign tumour is usually localized
and nonmetastatic. Specific types benign tumours that can be treated using the present
invention include hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal
nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct
cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular
regenerative hyperplasia, trachomas and pyogenic granulomas.
In a malignant tumour cells become undifferentiated, do not respond to the
body's growth control signals, and multiply in an uncontrolled manner. The malignant
tumour is invasive and capable of spreading to distant sites (metastasizing). Malignant
tumours are generally divided into two categories: primary and secondary. Primary
tumours arise directly from the tissue in which they are found. A secondary tumour, or
metastasis, is a tumour which is originated elsewhere in the body but has now spread to a
distant organ. The common routes for metastasis are direct growth into adjacent
structures, spread through the vascular or lymphatic systems, and tracking along tissue
planes and body spaces (peritoneal fluid, cerebrospinal fluid, etc.).
Specific types of cancers or malignant tumours, either primary or
secondary, that can be treated using this invention include breast cancer, skin cancer, bone
cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gall
bladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck,
colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma of both
ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma,
veticulum cell sarcoma, myeloma, giant cell tumour, small-cell lung tumour, gallstones,
islet cell tumour, primary brain tumour, acute and chronic lymphocytic and granulocytic
tumours, hairy-cell tumour, adenoma, hyperplasia, medullary carcinoma,
pheochromocytoma, mucosal neuronms, intestinal ganglioneuromas, hyperplastic corneal
nerve tumour, marfanoid habitus tumour, Wϊlm's tumour, seminoma, ovarian tumour,
leiomyomater, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma,
soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fimgoide,
rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant
hypercalcemia, renal cell tumour, polycythemia vera, adenocarcinoma, glioblastoma
multiforma, leukemias, lymphomas, malignant melanomas, epidermoid carcinomas, and
other carcinomas and sarcomas.
Haematologic disorders include abnormal growth of blood cells which can
lead to dysplastic changes in blood cells and haematologic malignancies such as various
leukemias. Examples of haematologic disorders include but are not limited to acute
myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic
myelogenous leukemia, the myelodysplastic syndromes, and sickle cell anaemia.
Treatment of abnormal cell proliferation due to insults to body tissue
during surgery can be possible for a variety of surgical procedures, including joint
surgery, bowel surgery, and cheloid scarring. Diseases that produce fibrotic tissue include
emphysema. Repetitive motion disorders that can be treated using the present invention
include carpal tunnel syndrome. An example of cell proliferative disorders that can be
treated using the invention is a bone tumour.
The proliferative responses associated with organ transplantation that can
be treated using this invention include those proliferative responses contributing to
potential organ rejections or associated complications. Specifically, these proliferative
responses can occur during transplantation of the heart, lung, liver, kidney, and other
body organs or organ systems.
Abnormal angiogenesis that can be treated using this invention include, for
example, those abnormal angiogenesis accompanying rheumatoid arthritis, ischaemic-
reperfusion related brain oedema and injury, cortical ischemia, ovarian hyperplasia and
hypervascularity, (polycystic ovary syndrome), endometriosis, psoriasis, diabetic
retinopathy, and other ocular angiogenic diseases such as retinopathy of prematurity
(retrolental fibroplastic), muscular degeneration, corneal graft rejection, neuroscular
glaucoma and Oster Webber syndrome.
Diseases associated with abnormal angiogenesis require or induce vascular
growth. For example, corneal angiogenesis involves three phases: a pre-vascular latent
period, active neovascularization, and vascular maturation and regression.
In some embodiments, the formulations as described herein and
compositions of the present invention can be used for treating diseases associated with
undesired or abnormal angiogenesis. The method comprises administering to a patient
suffering from undesired or abnormal angiogenesis the pharmaceutical formulations as
described herein alone, or in combination with anti-neoplastic agent whose activity as an
anti-neoplastic agent in vivo is adversely affected by high levels of DNA methylation. The
particular dosage of these agents required to inhibit angiogenesis and/or angiogenic
diseases can depend on the severity of the condition, the route of administration, and
related factors that can be decided by the attending physician. Generally, accepted and
effective daily doses are the amount sufficient to effectively inhibit angiogenesis and/or
angiogenic diseases.
In some embodiments, the pharmaceutical formulations as described
herein can be used to treat a variety of diseases associated with undesirable angiogenesis
such as retinal/choroidal neovascularization and corneal neovascularization. Examples of
retinal/choroidal neovascularization include, but are not limited to, Bests diseases,
myopia, optic pits, Stargarts diseases, Paget’s disease, vein occlusion, artery occlusion,
sickle cell anaemia, sarcoid, syphilis, pseudoxanthoma elasticum carotid obstructive
diseases, chronic uveitis/vitritis, mycobacterial infections, Lyme's disease, systemic lupus
erythematosis, retinopathy of prematurity, Eales disease, diabetic retinopathy, macular
degeneration, Bechets diseases, infections causing a retinitis or chroiditis, presumed
ocular histoplasmosis, pars planitis, chronic retinal detachment, hyperviscosity
syndromes, toxoplasmosis, trauma and post- laser complications, diseases associated with
rubesis (neovascularization of the angle) and diseases caused by the abnormal
proliferation of fϊbrovascular or fibrous tissue including all forms of proliferative
vitreoretinopathy.
Non-limiting examples of corneal neuvascularization include, but are not
limited to, epidemic keratoconjunctivitis, Vitamin A deficiency, contact lens overwear,
atopic keratitis, superior limbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea,
phylectenulosis, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection,
Mooren ulcer, Terrien's marginal degeneration, marginal keratolysis, polyarteritis,
Wegener sarcoidosis, Scleritis, periphigoid radial keratotomy, neo vascular glaucoma and
retrolental fibroplasia, syphilis, Mycobacteria infections, lipid degeneration, chemical
burns, bacterial ulcers, fungal ulcers, Herpes simplex infections, Herpes zoster infections,
protozoan infections and Kaposi sarcoma.
In some embodiments, the pharmaceutical formulations as described
herein can be used for treating chronic inflammatory diseases associated with abnormal
angiogenesis. The method comprises administering to a patient suffering from a chronic
inflammatory disease associated with abnormal angiogenesis the pharmaceutical
formulations as described herein alone, or in combination with an anti-neoplastic agent
whose activity as an anti-neoplastic agent in vivo is adversely affected by high levels of
DNA methylation. The chronic inflammation depends on continuous formation of
capillary sprouts to maintain an influx of inflammatory cells. The influx and presence of
the inflammatory cells produce granulomas and thus, maintains the chronic inflammatory
state. Inhibition of angiogenesis using the pharmaceutical formulations as described
herein can prevent the formation of the granulosmas, thereby alleviating the disease.
Examples of chronic inflammatory disease include, but are not limited to, inflammatory
bowel diseases such as Crohn's disease and ulcerative colitis, psoriasis, sarcoidois, and
rheumatoid arthritis.
Inflammatory bowel diseases such as Crohn's disease and ulcerative colitis
are characterized by chronic inflammation and angiogenesis at various sites in the
gastrointestinal tract. For example, Crohn's disease occurs as a chronic transmural
inflammatory disease that most commonly affects the distal ileum and colon but can also
occur in any part of the gastrointestinal tract from the mouth to the anus and perianal area.
Patients with Crohn's disease generally have chronic diarrhoea associated with abdominal
pain, fever, anorexia, weight loss and abdominal swelling. Ulcerative colitis is also a
chronic, nonspecific, inflammatory and ulcerative disease arising in the colonic mucosa
and is characterized by the presence of bloody diarrhoea. These inflammatory bowel
diseases are generally caused by chronic granulomatous inflammation throughout the
gastrointestinal tract, involving new capillary sprouts surrounded by a cylinder of
inflammatory cells. Inhibition of angiogenesis by the pharmaceutical formulations as
described herein should inhibit the formation of the sprouts and prevent the formation of
granulomas. The inflammatory bowel diseases also exhibit extra intestinal manifectations,
such as skin lesions. Such lesions are characterized by inflammation and angiogenesis and
can occur at many sites other the gastrointestinal tract. Inhibition of angiogenesis by the
pharmaceutical formulations as described hereinshould reduce the influx of inflammatory
cells and prevent the lesion formation.
Sarcoidois, another chronic inflammatory disease, is characterized as a
multi-system granulomatous disorder. The granulomas of this disease can form anywhere
in the body and, thus, the symptoms depend on the site of the granulomas and whether the
disease is active. The granulomas are created by the angiogenic capillary sprouts
providing a constant supply of inflammatory cells. By using the pharmaceutical
formulations as described herein to inhibit angiogenesis, such granulomas formation can
be inhibited. Psoriasis, also a chronic and recurrent inflammatory disease, is characterized
by papules and plaques of various sizes. Treatment using the pharmaceutical formulations
as described herein should prevent the formation of new blood vessels necessary to
maintain the characteristic lesions and provide the patient relief from the symptoms.
Rheumatoid arthritis (RA) is also a chronic inflammatory disease
characterized by non-specific inflammation of the peripheral joints. It is believed that the
blood vessels in the synovial lining of the joints undergo angiogenesis. In addition to
forming new vascular networks, the endothelial cells release factors and reactive oxygen
species that lead to pannus growth and cartilage destruction. The factors involved in
angiogenesis can actively contribute to, and help maintain, the chronically inflamed state
of rheumatoid arthritis. Treatment using the pharmaceutical formulations as described
herein alone or in conjunction with other anti-RA agents can prevent the formation of new
blood vessels necessary to maintain the chronic inflammation and provide the RA patient
relief from the symptoms.
In some embodiments, the pharmaceutical formulations as described
herein can be used for treating diseases associated with abnormal haemoglobin synthesis.
The method comprises administering the pharmaceutical formulations as described herein
to a patient suffering from disease associated with abnormal haemoglobin synthesis.
Decitabine containing formulations stimulate foetal haemoglobin synthesis because the
mechanism of incorporation into DNA is associated with DNA hypomethylation.
Examples of diseases associated with abnormal haemoglobin synthesis include, but are
not limited to, sickle cell anaemia and beta-thalassemia.
In some embodiments, the pharmaceutical formulations as described
herein can be used to control intracellular gene expression. The method comprises
administering the pharmaceutical formulations as described herein to a patient suffering
from disease associated with abnormal levels of gene expression. DNA methylation is
associated with the control of gene expression. Specifically, methylation in or near
promoters inhibit transcription while demethylation restores expression. Examples of the
possible applications of the described mechanisms include, but are not limited to,
therapeutically modulated growth inhibition, induction of apoptosis, and cell
differentiation.
Gene activation facilitated by the pharmaceutical formulations as described
herein can induce differentiation of cells for therapeutic purposes. Cellular differentiation
is induced through the mechanism of hypomethylation. Examples of morphological and
functional differentiation include, but are not limited to differentiation towards formation
of muscle cells, myotubes, cells of erythroid and lymphoid lineages.
Myelodysplastic syndromes (MDS) are heterogeneous clonal
haematopoietic stem cell disorders associated with the presence of dysplastic changes in
one or more of the haematopoietic lineages, including dysplastic changes in the myeloid,
erythroid, and megakaryocytic series. These changes result in cytopenias in one or more
of the three lineages. Subjects afflicted with MDS typically develop complications related
to anaemia, neutropenia (infections), or thrombocytopenia (bleeding). Generally, from
about 10% to about 70% of subjects with MDS develop acute leukemia. Representative
myelodysplastic syndromes include acute myeloid leukemia, acute promyelocytic
leukemia, acute lymphoblastic leukemia, and chronic myelogenous leukemia.
Acute myeloid leukemia (AML) is the most common type of acute
leukemia in adults. Several inherited genetic disorders and immunodeficiency states are
associated with an increased risk of AML. These include disorders with defects in DNA
stability leading to random chromosomal breakage, such as Bloom's syndrome, Fanconi's
anaemia, Li-Fraumeni kindreds, ataxia-telangiectasia, and X-linked agammaglobulinemia.
Acute promyelocytic leukemia (APML) represents a distinct subgroup of
AML. This subtype is characterized by promyelocytic blasts containing the 15; 17
chromosomal translocation. This translocation leads to the generation of a fusion
transcript comprising a retinoic acid receptor sequence and a promyelocytic leukemia
sequence.
Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with
distinct clinical features displayed by various subtypes. Reoccurring cytogenetic
abnormalities have been demonstrated in ALL. The most common associated cytogenetic
abnormality is the 9; 22 translocation leading to development of the Philadelphia
chromosome.
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative
disorder of a pluripotent stem cell, generally caused by ionizing radiation. CML is
characterized by a specific chromosomal abnormality involving the translocation of
chromosomes 9 and 22, creating the Philadelphia chromosome.
Compounds described herein and formulations thereof can be used to
provide therapy for a MDS. In some embodiments, a compound or formulation thereof
can provide therapy for more than one MDS in a single administration.
In some embodiments, described is a method for treating a
myelodysplastic syndrome (MDS). In some embodiments, described is a method for
treating one or more myelodysplastic syndromes, leukemia, or solid tumours. In some
embodiments, described is a method for treating acute myeloid leukemia (AML). In
some embodiments, described is a method for treating acute promyelocytic leukemia
(APML) in a subject. In some embodiments, described is a method for treating acute
lymphoblastic leukemia (ALL). In some embodiments, described is a method for treating
chronic myelogenous leukemia (CML).
In some embodiments, the myelodysplastic syndrome is acute myeloid
leukemia (AML), acute promyelocytic leukemia (APL), acute lymphoblastic leukemia
(ALL), or chronic myelogenous leukemia (CML).
In some embodiments, the administration is subcutaneous.
Treatment of any condition described above, such as tumor growth, a
myelodysplastic syndrome, or an angiogenesis-related condition, can be accomplished
with a level of efficacy. A level of efficacy can be 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 62.9%, about 65%, about 70%, about 75%, about 80%, about
84.4%, about 85%, about 90%, about 95%, about 97%, about 98%, about 99%, or about
100%. A level of efficacy can be at least 5%, at least 10%, at least 15%, at least 20%, at
least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least
55%, at least 60%, at least 62.9%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 84.4%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, or at least
99%.
Combination Therapy
The compounds, compositions and formulations as described herein are
used in combination with one or more ancillary therapeutic components selected from the
following classes:
1. T-cell activating agents, including immunomodulating antibodies;
2. Cancer vaccines;
3. Indoleamine 2,3-dioxygenase (IDO) inhibitors;
4. Adjuvants; and
. Combinations of two or more of the foregoing classes, including in particular
combinations of T-cell activating agents and cancer vaccines.
Alternatively, the compounds, compositions and formulations as described
herein are used in combination with one or more ancillary therapeutic components
selected from the following classes:
1. T-cell activating agents, including immunomodulating antibodies;
2. Cancer vaccines;
3. Adjuvants; and
4. Combinations of two or more of the foregoing classes, including in particular
combinations of T-cell activating agents and cancer vaccines.
In some embodiments, an ancilliary agent can be an ionic form, salt,
solvate, isomer, tautomer, N-oxide, ester, prodrug, isotope or protected form of an
ancilliary agent (for example, the salts or tautomers or isomers or N-oxides or solvates
thereof).
1. T-cell activating agents, including immunomodulating antibodies
Suitable ancillary therapeutic components for use in the combinations of
the invention include T-cell activating agents.
Such agents include, for example, those which promote T-cell activation
and render T effector cells resistant to T regulatory cells (Tregs), including agents which
block CTLA-4.
Anti-CTLA-4 mAb therapy represents an anti-tumour strategy implicated
in augmentation of the cell-mediated immune system by blocking inhibitory pathways of
T-cell activation (O’Day SJ, et al. Cancer 2007; 110:2614–2627). Blockade of CTLA-4
signalling has been shown to induce tumour rejection in animal models, when used alone
or combined with other immunotherapeutic strategies (Leach DR, et al. Science
1996;271:1734-1736; Weber J, Semin Oncol 2010;37:430-439). Anti-CTLA-4 mAb are
proving effective in inducing long lasting clinical responses and improved survival in
metastatic cutaneous melanoma patients (Hodi FS, et al. N Engl J Med 2010;363:711-23;
Di Giacomo A, et al. Cancer Immunol Immunother 2011;60:467-77).
In embodiments in which the ancillary therapeutic component comprises
an agent which blocks CTLA-4 signalling (e.g. an anti-CTLA-4 mAb as described
below), the compound of Formula I or salt thereof is preferably administered first (as a
priming therapy), followed by administration of the agent which blocks CTLA-4 (e.g.
anti-CTLA mAb).
Non-limiting examples of a suitable anti-CTLA-4 mAbs include
Tremelimumab (CP675,206) (Pfizer), an IgG2 isotype monoclonal antibody and
Ipilimumab (MDX-010) (BMS/Medarex), an IgG1 isotype monoclonal antibody.
Tremelimumab is described in e.g. WO00/037504 (the teachings of which
are hereby incorporated by reference) and; and in WO2006/048749 (the teachings of
which are hereby also incorporated by reference).
Ipilimumab is described in e.g. WO01/014424 (the teachings of which are
hereby incorporated by reference); and in WO2012/033953 (the teachings of which are
hereby also incorporated by reference).
Another class of T-cell activating agents suitable for use as ancillary
therapeutic components are agents which eliminate or suppress peripheral tolerance
and/or reduce the numbers of Tregs at the tumour site. Examples of such agents include
agents which block programmed death receptor-1 (PD-1), programmed death receptor-1
ligand (PD-L1) and programmed death receptor-2 ligand (PD-L2), including antibodies
against PD-1, PD-L1 and PD-L2.
Programmed death 1 (PD-1) protein, a T-cell co-inhibitory receptor, and its
ligands, PD-L1 and PD-L2, play a crucial role in the ability of tumour cells to evade the
host’s immune system. Blockade of interactions between PD-1 and PD-L1/2 mediates
antitumour activity in preclinical models (Iwai Y et al., Proc Natl Acad Sci USA (2002)
99: 12293-12297). Studies identified clinical activity of both anti-PD-1 and anti-PD-L1
mAb in patients with advanced cancers, including non–small-cell lung cancer, melanoma,
and renal-cell cancer (Brahmer JR, et al. N Engl J Med. 2012 Jun 2; Topalian SL, et al. N
Engl J Med. 2012 Jun 2).
Non-limiting examples of suitable anti-PD-1 and anti-PD-L1 mAbs
include BMS-936558 (Nivolumab, ONO 4538), a fully-human monoclonal IgG4 antibody
against PD-1 and BMS-936559 (a fully-human, PD-L1-specific, IgG4 (S228P)
monoclonal antibody that inhibits the binding of PD-L1 to PD-1 and CD80) described in
WO2007/005874. These mAbs can be adminsitered according to the recommendations of
the manufacturers, and suitable dosages for Nivolumab are described in WO2006/121168,
which is hereby specifically incorporated by reference.
Other anti-PD-1 agents include MK-3475 (Lambrolizumab), a humanized
anti-PD-1 IgG4 monoclonal antibody. Suitable dosages for Lambrolizumab include 10
mg/kg once every 2 weeks.
Other anti-PDL-1 agents include MED14736 (a human IgG1 monoclonal
antibody against PDL-1), and MPDL3280A (is a human IgG monoclonal antibody whose
Fc-domain has been specifically engineered to prevent antibody-dependent cell-mediated
cytotoxicity). These mAbs can be adminsitered according to the recommendations of the
manufacturers.
Other classes of T-cell activating agents suitable for use as ancillary
therapeutic components include agonists for CD137, CD40 and OX40. Examples of such
agents include monoclonal antibodies which act as agonists of CD137, CD40 or OX40.
CD137 is also known as the 4-1BB receptor (4-1BBR), a glycoprotein
which is a member of the tumor necrosis factor receptor superfamily 1−4 and binds to a
high-affinity ligand (4-1BBL) expressed on several antigen-presenting cells such as
macrophages and activated B cells. A suitable agonist for CD137 is PF-05082566, a fully
human IgG2 mAb that binds to the extracellular domain of human CD137 with high
affinity and specificity (see Fisher et al. (2012) Cancer Immunology, Immunotherapy,
Volume 61, Issue 10, pp 1721-1733).
Other classes of T-cell activating agents suitable for use as ancillary
therapeutic components include agonists for ICOS, GITR, MHC, CD80, CD86, Galectin
9 and LAG-3. Examples of such agents include monoclonal antibodies which act as
agonists of ICOS, GITR, MHC, CD80, CD86, Galectin 9 and LAG-3.
Combinations of two or more T-cell activating agents (for example,
combinations of CTLAblocking antibodies and/or antibodies against PD-1 and PD-L1
and/or PD-L2) can also be used as ancillary therapeutic components for use according to
the invention.
2. Cancer vaccines
Cancer vaccines which stimulate the adaptive immune response find
application as ancillary therapeutic components for use in the combinations of the
invention.
Cancer vaccines present tumour associated antigen(s) (TAA) to the
immune system of a host to prompt that host to mount a therapeutic adaptive cellular
and/or humoral immune response, for example via T-cell activation and/or dendritic cell
(DC) activation. Cancer vaccines can be based on whole tumour cells, tumour cell
extracts or fractions. Also suitable for use according to the invention are subunit cancer
vaccines, conjugate cancer vaccines and DNA vaccines.
Any suitable antigen or combination of TAAs can be used in the vaccines
as described herein, including, for example, nucleic acid(s) (DNA or RNA) which encode
one or more TAA(s); protein(s) or peptide(s); glycoprotein(s); polysaccharide(s) and other
carbohydrate(s)); fusion protein(s); lipid(s); glycolipid(s); peptide mimic(s) of
polysaccharides; carbohydrate(s) and a protein(s) in admixture; carbohydrate-protein
conjugate(s); cells or extracts thereof or tumour cells or extracts thereof.
Subunit vaccines are based on synthetic or isolated antigens created using
(bio)chemical and/or recombinant techniques (e.g. recombinant peptides, protein and/or
carbohydrate synthesis or purification). Conjugate vaccines involve the linkage (usually
by chemical crosslinking) of relatively non-immunogenic (usually carbohydrate-based)
antigens to more strongly immunogenic carrier proteins. DNA/RNA vaccines deliver the
antigen(s) in the form of encoding nucleic acid and so rely on endogenous expression of
the coding sequence after administration. Such vaccines normally require an appropriate
vector (e.g. plasmid, viral or lipid vesicle) to deliver the coding nucleic acid to the
appropriate compartment of the host.
Suitable cancer vaccines for use in combination with the compositions,
formulations and compounds as described herein can be classified according to the nature
of the TAA, and include cancer testis antigen (CTA) vaccines.
Cancer/testis antigens (CTAs) are highly immunogenic with no or highly
restricted expression in normal tissues (testis and placenta). Examples include vaccines
based on: NY-ESO-1, LAGE-1, MAGE-A1, -A2, -A3, -A4, -A6, -A10, -A12, CT7,
CT10, GAGE1-6, GAGE 1-2, BAGE, SSX1-5, SSX 2, HAGE, PRAME, RAGE-1,
XAGE-1, MUC2, MUC5B, B7.1/2, CD28, B7-H1, HLA, CD40L and HMW-MAA. In
some embodiments, the CTA vaccines includes those based on MAGE-A1, MAGE-A3
(for example recMAGE-A3), NY-ESO-1 and PRAME. The foregoing CTA’s can be used
alone or in combination, for example a mixture of two or more of MAGE-A1, MAGE-A3
(for example recMAGE-A3), NY-ESO-1 and/or PRAME can be used.
MAGE-A1 is described in e.g. WO2002/094859 (the teachings of which
are hereby incorporated by reference). It can be used unadjuvanted or adjuvanted.
MAGE-A3 (and in particular recMAGE-A3), or Astuprotimut-R) is
described in e.g. WO1999/040188 (the teachings of which are hereby incorporated by
reference). It can be used unadjuvanted or adjuvanted, for example in the form of
Astuprotimut-R. It can be used at a dose of about 1 to about 1000 μg of protein. In some
embodiments, ther dose is about 30 - about 300 μg.
NY-ESO-1 is described in e.g. WO2005/032475 (the teachings of which
are hereby incorporated by reference). It can be used unadjuvanted or adjuvanted, and
may be used with other chemotherapeutic agents (including, for example, doxorubicin).
PRAME (a.k.a. preferential antigen of melanoma, MAPE, DAGE and
OIP4) is described in e.g. WO2006/071983 (the teachings of which are hereby
incorporated by reference). It can be used unadjuvanted or adjuvanted.
The various CTA antigens described above can be used in the context of
various cell-based vaccines, for example dendritic cell-based vaccines. For example, in
one dendritic cell-based treatment paradigm, the cells are loaded (pulsed, primed or
spiked) with a particular antigen or antigens (e.g. MAGE-A1, MAGE-A3 (for example
recMAGE-A3), NY-ESO-1 or PRAME) and then administered to promote an immune
response. This approach can be used in conjunction with various adjuvants, including for
example TLR agonists (e.g. imiquimod).
In an illustrative example of a cell-based treatment paradigm, the patient
receives 3 monthly cycles of the compound of Formula I (or salt thereof) for 5 days, with
each cycle followed by 2 weekly vaccines comprising autologous dendritic cells pulsed
with overlapping peptides derived from full-length MAGE-A1, MAGE-A3, and NY-
ESO-1 (JPT Peptide Technologies, Berlin, Germany). Imiquimod is administered at the
vaccine site before and after vaccination, to promote immune cell infiltration at the
vaccination site.
Another suitable class of cancer vaccines are those based on differentiation
antigens, including MART-1, tyrosinase and Gp100.
In some embodiments, cancer vaccines are used in combination with one
or more adjuvants as further ancillary therapeutic components for use in the combinations
of the invention, as described below.
3. IDO inhibitors
Suitable ancillary therapeutic components for use with the combinations of
the invention include inhibitors of indoleamine 2,3-dioxygenase (IDO).
IDO is an important immune regulator, having a key role in tumour
immunosurveillance. Immune escape is a fundamental trait of cancer in which the Th1-
type cytokine interferon- γ (IFN-γ) seems to play a key role. Among other tumoricidal
biochemical pathways, IFN-γ induces IDO in a variety of cells including macrophages,
dendritic cells (DCs) and tumor cells. IDO works by preventing T cell activation and
blocking immune responses to cancer cells. While the pathways responsible for
tryptophan depletion are unknown, hypermethylation could be one of the causative
mechanisms that result in failure to mount an immune response.
IDO inhibitors may therefore increase the efficacy of anticancer
immunotherapy, and may be used in the combinations of the invention to prevent IDO-
mediated immunologic tolerance/immune escape (see e.g. Sucher et al. (2010) IDO-
Mediated Tryptophan Degradation in the pathogenesis of Malignant Tumor Disease.
International Journal of Tryptophan Research: 3, 113–120).
Any suitable IDO inhibitor may be used according to the invention. Also
suitable are inhibitors of IDO isoenzymes, including for example tryptophan (2,3)-
dioxygenase (TDO) and/or IDO2. Thus, the IDO inhibitor for use with the combinations
of the invention may inhibit, directly or indirectly, IDO and/or TDO and/or IDO2.
Suitable IDO inhibitors include those based on natural products, such as
the cabbage extract brassinin, the marine hydroid extract annulin B and the marine sponge
extract exiguamine A, including synthetic derivatives thereof.
Other suitable IDO inhibitors include molecular analogues of its substrate,
tryptophan. Such inhibitors include the tryptophan mimetic 1-methyl tryptophan (1-MT).
1-MT occurs as two stereoisomers: the L isomer significantly inhibits IDO1, while the D
isomer is more specific for IDO2. The D isomer (DMT, indoximod) is currently being
evaluated in a phase II, double-blind, randomized, placebo-controlled trial.
Other suitable IDO inhibitors include INCB24360, a hydroxyamidine
small-molecule inhibitor. Unlike 1-MT-based inhibitors, hydroxyamidine inhibitors also
inhibit tryptophan (2,3)-dioxygenase (TDO), an enzyme with identical activity to IDO.
Yet another suitable IDO inhibitor is NLG919.
Agents which do not inhibit the IDO enzyme directly, but rather block the
downstream effects of IDO activation, are also suitable for use with the combinations of
the invention. Such IDO pathway inhibitors are intended to be encompassed by the term
"IDO inhibitors" as used herein.
4. Adjuvants
Suitable ancillary therapeutic components for use with the combinations of
the invention include adjuvants.
An adjuvant is any compound or composition that increases the strength
and/or duration of an immune response to a foreign antigen relative to that elicited by the
antigen alone. Key functional characteristics of an adjuvant therefore include its ability to
enhance an appropriate immune response to the target antigen, long-term safety in
widespread application, and flexibility in use with different antigen/disease applications.
An adjuvant can be, for example, an agent that does not constitute a specific antigen, but
boosts the strength and/or longevity of the immune response (including for example the
innate immune response) to a co-administered antigen.
Where an adjuvant is used as an ancillary therapeutic component, the
compound and adjuvant can be co-administered, i.e. simultaneously or sequentially.
When the adjuvants are administered simultaneously they can be administered in the same
or separate formulations, and in the latter case at the same or separate sites, but can be
administered at the same time. The adjuvants can be administered sequentially, when the
administration of the at least two adjuvants is temporally separated. The separation in
time between the administration of the two adjuvants can be a matter of minutes or it can
be longer. The separation in time can be less than 14 days, less than 7 days, or less than 1
day. The separation in time can also be, for example, with one adjuvant at prime and one
at boost, or one at prime and the combination at boost, or the combination of one at prime
and one at boost.
Non-limiting examples of suitable adjuvants/adjuvant classes include
Pathogen-Recognition Receptors (PRRs) ligands. The include ligands/agonists for RIG-1
receptors, NOD-protein ligands, Toll-like receptor (TLR) ligands and C-type lectin
ligands. Suitable PRR ligands bind to one or more of TLR1, TLR2, TLR3, TLR4, TLR5,
TLR6, TLR7, TLR8, TLR9, TLR10 and TLR11, i.e. TLR ligands. In some embodiments,
a ligand is a TLR9 or TLR4 ligand. In some embodiments, a ligand is an adjuvants that
comprises TLR ligands for two or more different TLRs, including for example adjuvants
which comprise double or triple TLR ligands, for example TLR2 and/or TLR6 and/or
TLR3 and/or TLR9. In some embodiments, a triple TLR ligand comprises a ligand of
TLR2, TLR3, and TLR9. In some embodiments, the adjuvant comprises a combination
of: (i) a TLR 7/8 agonist with a TLR 9 agonist; (ii) a TLR 7/8 agonist with a TLR 4
agonist; or (iii) a TLR 9 agonist with a TLR 3 agonist.
TLR-based adjuvants are reviewed in Steinhagen et al. (2011) TLR-Based
Immune Adjuvants Vaccine 29(17): 3341–3355, the teachings of which are hereby
incorporated by reference.
The combinations of the invention can also be used adjunctively with other
chemotherapeutic and/or non-chemotherapeutic treatments such as radiotherapy, surgery
and stem cell transplantation. For example, the combinations of the invention can be used
following surgery and/or radiotherapy of a primary tumour to prevent or delay
relapse/metastasis. In the case of adjunctive use with stem cell transplants, the
combinations can be used as a “bridge to transplant”, where the combinations of the
invention are used to achieve a response rate sufficient (for example, curative) for stem
cell transplantation. The combinations can also be used at a lower, maintenance dose
after stem cell transplantation to reduce/prevent recurrence.
EXAMPLES
EXAMPLE 1: Molecular, phenotypic, and functional in vivo effects of SGI-110
combined with immunostimulatory mAb in a murine cancer model
A syngeneic model of murine cancer is utilized to evaluate, at preclinical
level, the molecular, phenotypic, and functional in vivo effects of the sodium salt of a
compound of Formula I-1 (SGI-110), administered alone or combined with anti-murine
immunostimulatory mAb.
The study analyses: (a) the therapeutic effectiveness of combined
administration of SGI-110 and immunostimulatory mAb in murine cancer; and (b) the
involvement of host immune response in the potential anti-tumour effects of the most
effective therapeutic administration of SGI-110 and immunostimulatory mAb.
In vitro immunomodulatory activity SGI-110 in murine cancer
Preliminary in vitro experiments will be carried out to study the
immunomodulatory effects of SGI-110 on the murine mammary carcinoma cells, TS/A,
selected for their immunophenotype, growth rate and tumour take in mice. Cells are in
vitro treated according to a standard schedule and RT-PCR and Real-Time quantitative
RT-PCR analyses investigate the efficacy of treatment to induce and/or up-regulate
murine CTA (including P1A, Mage-a family) in cancer cells.
Therapeutic efficacy of SGI-110 in combination with immunostimulatory mAb in mouse
cancer
Immunostimulatory mAb treatment is given either concomitantly or
subsequently to SGI-110 schedules according to the dosage regimen described below.
BALB/c mice (6 per group) are grafted into the flank region with TS/A cells and treated
with SGI-110, administered alone or in combination with the anti-murine CTLA-4 or
anti-murine PD-1 mAbs. The effectiveness and tolerability of treatments are evaluated by
tumour volume and body weight measurements, respectively.
• Day -6: Murine TS/A cells are inoculated subcutaneously into the flank region of
all mice.
• Day 0: After a latency period of 7 days, mice bearing clearly palpable and visible
tumour grafts (diameter ≥ 0.2 cm) are separated in different groups of treatment (6
animals per group).
Treatment schedule: subcutaneous (SQ) administration over 5 days
(“SQ5”)
Group 1: Vehicle qdx5 SQ at days 1-5
Group 2: SGI-110, 3mg/kg qdx5 SQ at days 1-5
Group 3: anti-murine CTLA-4 at days 2, 5, 8
Group 4: anti-murine CTLA-4 at days 8, 11, 14
Group 5: SGI-110, 3mg/kg qdx5 SQ (at days 1-5) + anti-murine CTLA-4 (at days 2,
, 8) (concomitant schedule)
Group 6: SGI-110, 3mg/kg qdx5 SQ (at days 1-5) + anti-murine CTLA-4 (at days 8,
11, 14) (subsequent schedule)
Group 7: anti-murine PD-1 at days 2, 5, 8
Group 8: anti-murine PD-1 at days 8, 11, 14
Group 9: SGI-110, 3mg/kg qdx5 SQ (at days 1-5) + anti-murine PD-1 (at days 2, 5,
8) (concomitant schedule)
Group 10: SGI-110, 3mg/kg qdx5 SQ (at days 1-5) + anti-murine PD-1 (at days 8, 11,
14) (subsequent schedule)
Treatment schedule: i.p. weekly
Group 11: Vehicle (3 i.p. injections every 3 hours) at days 1 and 8
Group 12: SGI-110, 36.6 mg/kg day (3 i.p. injections every 3 hours) at days 1 and 8
Group 13: anti-murine CTLA-4 at days 3, 6, 9
Group 14: SGI-110, 36.6 mg/kg day (3 i.p. injections every 3 hours) at days 1 and 8 +
anti-murine CTLA-4 (at days 3, 6, 9)
Therapeutic efficacy of the SQ5 schedule
Based on the results generated by in vivo administration of SGI-110
according to the SQ5 schedule (see above), a single dose of “SQ weekly” schedule of
SGI-110 administration is tested in combination with the immunostimulatory mAb. MAb
treatment is given either concomitantly or subsequently to SGI-110 schedules. To this
end, BALB/c mice (6 per group) are grafted into the flank region with TS/A cells and
treated with SGI-110, administered alone or in combination with the anti-murine CTLA-4
or anti-murine PD-1 mAbs. The effectiveness and tolerability of treatments is evaluated
by tumour volume and body weight measurements, respectively.
Treatment schedule: SQ weekly.
Group 1: Vehicle weekly SQ at days 1, 8, 15
Group 2: SGI-110, 24.4 mg/kg weekly SQ at days 1, 8, 15
Group 3: anti-murine CTLA-4 at days 3, 6, 9
Group 4: anti-murine CTLA-4 at days 17, 20, 23
Group 5: SGI-110, 24.4 mg/kg weekly SQ (at days 1, 8, 15) + anti-murine CTLA-4
(at days 3, 6, 9) (concomitant schedule)
Group 6: SGI-110, 24.4 mg/kg weekly SQ (at days 1, 8, 15) + anti-murine CTLA-4
(at days 17, 20, 23) (subsequent schedule)
Group 7: anti-murine PD-1 at days 3, 6, 9
Group 8: anti-murine PD-1 at days 17, 20, 23
Group 9: SGI-110, 24.4 mg/kg weekly SQ (at days 1, 8, 15) + anti-murine PD-1 (at
days 3, 6, 9) (concomitant schedule)
Group 10: SGI-110, 24.4 mg/kg weekly SQ (at days 1, 8, 15) + anti-murine PD-1 (at
days 17, 20, 23) (subsequent schedule)
Treatment schedule: i.p. weekly.
Group 11: Vehicle (3 i.p. injections every 3 hours) at days 1 and 8
Group 12: SGI-110, 36.6 mg/kg day (3 i.p. injections every 3 hours) at days 1 and 8
Group 13: SGI-110, 36.6 mg/kg day (3 i.p. injections every 3 hours) at days 1 and 8 +
anti-murine CTLA-4 (at days 3, 6, 9)
Molecular, phenotypic and functional correlates of SGI-110 combined with
immunostimulatory mAb
The modifications induced in vivo by the most effective therapeutic
regimen utilizing SGI-110, combined with the immunostimulatory mAb is investigated on
both tumours and host’s immune compartments. To this end, based on the results
generated in Step 2, BALB/c mice (6 per group) are grafted into the flank region with
TS/A cells and treated with the most effective therapeutic regimen of SGI-110,
administered in combination with one immunostimulatory mAb.
DNA hypomethylation, as well as modulation of immune profile of murine
tumour tissues, excised from control and treated mice, is evaluated by molecular assays
(including quantitative methylation-specific PCR, RT-PCR and real-time quantitative RT-
PCR analyses). Immune infiltrates of neoplastic tissues is characterized for presence and
relative frequency of activated T cells by immunohistochemistry (IHC). Furthermore,
normal tissues from control and treated mice are surgically removed and adequately
conserved for following experimental analyses (see below).
In vivo immunomodulatory effects of combined administration of SGI-110and
immunostimulatory mAb, in benign tissues
The association of the in vivo immunomodulatory activity with systemic
autoimmunity phenomena (including the induction and/or modulation of immune-related
genes in normal tissues) is investigated.
The presence and levels of expression of murine CTA (i.e. P1A, Mage-a
family) are evaluated by RT-PCR and real time quantitative RT-PCR analyses in at least 4
benign samples (including the heart, lung, liver, intestine, kidney, muscle and skin).
Furthermore, immune infiltrates of normal tissues are characterized for presence and
relative frequency of activated T cells by IHC.
Contribution of immune response to the anti-tumour activity of the investigated
combination therapies
The involvement of the host immune response in the potential anti-tumour
effects of the selected combined regimen is investigated. Both immunocompetent (i.e.
BALB/c) and immunodeficient (i.e. T cell-deficient athymic nude mice and T-cell-, B-
cell- and natural killer cell-deficient SCID/Beige) mouse strains (6 mice per group) are
grafted into the flank region with TS/A cells and treated with the chosen therapeutic
regimen. The effectiveness of treatment is evaluated by tumour volume assessment,
which comparative analysis allows to determine the contribution of T, B and NK cell
immunity to the presumed anti-tumour activity of combined chemo-immunotherapies.
Modulation of anti-tumour T cell response can be evaluated through
MLTC, cell proliferation, IFN-g release and/or cytotoxicity assays.
EXAMPLE 2: Inhibition of DNA Methylation by Compounds as described herein
The demethylating activity of the compounds was tested in a cell-based
green fluorescent protein (GFP) assay. In the assay, a decrease in methylation resulting
from exposure to a methylation inhibitor leads to GFP expression, and is readily scored.
The CMV-EE210 cell line containing the epigenetically silenced GFP
transgene was used to assay for reactivation of GFP expression by flow cytometry. CMV-
EE210 was made by transfecting NIH 3T3 cells with the pTR-UF/UF1/UF2 plasmid,
which contained pBS(+) (Stratagene, Inc.) with a cytomegalovirus (CMV) promoter
driving a humanized GFP gene adapted for expression in mammalian cells. After
transfection, high-level GFP expressing cells were initially selected by FACS analysis and
sorting using a MoFlo cytometer (Cytomation, Inc.).
Decitabine, a potent inhibitor of mammalian DNMT1, was used as a
positive control. To screen for reactivation of CMV-EE210, decitabine (1 μM) or a test
compound (30-50 μM) was added to complete medium (phenol red free DMEM (Gibco,
Life Technologies) supplemented with 10% foetal bovine serum (Hyclone)). Cells were
then seeded to 30% confluence (~5000 cell/well) in a 96-well plate containing the test
compounds, and grown for three days in at 37 °C. in 5% CO .
The plates were examined under a fluorescent microscope using a 450-490
excitation filter (I3 filter cube, Leica, Deerfield Ill.). Wells were scored g1 positive, g2
positive, or g3 if GFP was expressed in 10%, 30%, >75% of viable cells, respectively.
Table 1 provides the results of the test for decitabine and the test
compounds as DNA methylation inhibitors. GFP is the concentration of an inhibitor at
which the Green Fluorescent Protein (GFP) expression level is reduced from g3 to g1/2.
Table 1 demonstrates that the tested compounds were inhibited DNA methylation
effectively at low concentrations, resulting in reactivation of GFP gene transcription.
TABLE1.
GFP Expression GFP
Compound
Level (nM)
Decitabine g3 500
g3 400
O P OH
I-1: OH
g3 700
O P OH
I-2: OH
EXAMPLE 3: Stability of a Representative Compound in Solvent Formulations.
The stability of a compound useful in the invention in various formulations
under various storage conditions was investigated. Stability was determined by HPLC at
the designated time intervals. The results are summarized in Table 2 for formulations
comprising a sodium salt of compound I-1 (i.e. SGI-110):
O P OH
N NH
OH .
TABLE 2.
Percent
Storage % decomposition
Formulation Time Point compound
Conditions per hour
detected
0 95.8%
water, pH 7.0 2-8 °C
hours 95.1% 0.14
0 95.8%
Room
water, pH 7.0
temperature
hours 90.4% 1.1
°C / 60% 0 93.7%
DMSO / water
relative
(1:1, w/w)
hours 90.1%
humidity 0.72
°C / 60% 0 96.6%
DMSO / water
relative
(3:1, w/w)
24 hours 94.2%
humidity 0.10
Propylene 0 96.8%
glycol /
Room
Glycerin
temperature
24 hours 96.3%
(70:30, v/v) 0.021
0 95.8%
Propylene
2-8 °C
Glycol /
3 months 95.1% 0.00032
Glycerin /
Ethanol
°C / 60% 0 95.8%
(65:25:10,
relative
3 months 67.6%
w/w/w)
humidity 0.013
Solution of SGI-110 in water at pH 7, the pH at which compounds of this
class are most stable, led to rapid decomposition in a few hours, even at lower
temperatures making it unsuitable for manufacturing process. Use of DMSO / water (1:1)
gave slightly better results at higher temperatures. A slight improvement was noted in
using 3:1 DMSO / water formulation. The said compound is stable in anhydrous DMSO,
therefore a solvent of choice for manufacturing process.
In regard to selection of pharmaceutically acceptable solvents for final
formulation ready for administration, the anhydrous propylene glycol / glycerin system
provided better stability. The final formulation was prepared by substituting small
amounts of propylene glycol and glycerin with ethanol, to provide propylene glycol /
glycerin / ethanol (65:25:10). This formulation was the only one of several tested that
provided a great improvement in the solubility and stability of the compound at both
higher and lower temperatures.
Based on the experiments conducted in water, a 10-fold improvement in
stability could have been expected upon changing from room temperature to colder (2-8
°C) storage conditions. However, in the propylene glycol / glycerin / ethanol (65:25:10)
system, changing from warmer to colder storage conditions provided a 40-fold
improvement in stability. The combined effects of cooling plus the addition of ethanol to
the propylene glycol / glycerin system provided a 66-fold improvement in stability. Such
great improvements in the stability of SGI-110 during storage could not have been
expected.
The propylene glycol / glycerin / ethanol (65:25:10) system provided SGI-
110 as a solution, which was smooth, free-flowing, and suitable for passage through a 23-
gague needle without complications or clogging. The maximum solubility of the
compound in this medium was determined to be about 130-150 mg/mL, which compares
favourably to the aqueous solubility of 20 mg/mL. The good chemical stability taken
together with the excellent solubility identified the glycol / glycerin / ethanol (65:25:10)
system as a formulation for use in animal experiments.
EXAMPLE 4: Animal Studies with the Formulation of EXAMPLE 3
The glycol / glycerin / ethanol (65:25:10) formulation of EXAMPLE 3,
containing 100 mg/mL free base equivalent of the sodium salt of compound I-1 was
administered to live animals. An analogous decitabine formulation was used for
comparison (50 mg lyophilized decitabine powder vial reconstituted to 10 mg/mL with
water for injection and administered as infusions by diluting in infusion bags).
Administration of a single dose of the formulations to monkeys (10 mg/kg)
produced higher physiological concentrations of compound I-1 (C 1,130 ng/mL; AUC
of 1,469 ng•hr/mL) than of decitabine (C 160 ng/mL; AUC of 340 ng•hr/mL).
In a repeat dose study, monkeys were dosed 3x weekly subcutaneously (3
mg/kg). At day 15, the systemic exposure to compound I-1 (C 181 ng/mL; AUC of
592 ng•hr/mL) was greater than that of decitabine (C 28 ng/mL; AUC of 99 ng•hr/mL).
The pharmacokinetic parameters of the compounds did not vary significantly over the 22-
day observation period, and minimal accumulation was detected. (FIGURES 1 and 2.)
Pharmacodynamic properties (not shown) were monitored and were acceptable. Blood
samples were drawn periodically to assay LINE-1 DNA methylation.
Decreases in LINE-1 DNA methylation, the indicator of biological
activity, were observed, and the decrease continued until termination of the study on day
22. The observed LINE-1 methylation was significantly different (ρ < 0.05) from the
methylation level observed prior to initial dosing. (FIGURE 3.)
The formulation was well-tolerated in the species tested. Three regimens
were evaluated: a) once daily subcutaneous dose in rats and rabbits for 5 days; b) once
weekly subcutaneous dose in rabbits and cynomolgus monkeys for 28 days as tolerated;
and c) twice weekly subcutaneous dose in rats for 28 days as tolerated. Rabbits tolerated
the 5-day regimen well, up to a dose of 1.5 mg/kg/day, which is equivalent to 18
mg/kg/day in humans, and the weekly regimen up to a dose of 1.5 mg/kg/week for 3
weeks.
Cynomolgus monkeys tolerated the weekly regimen well, up to a dose of
3.0 mg/kg/week for 3 weeks, which is equivalent to 36 mg/kg/week. Rats tolerated much
higher doses: 30 mg/kg/day over 5 days; and 20 mg/kg twice weekly for 4 weeks.
The main toxicity in all experiments was myelosuppression. However, the
subcutaneous formulation tested exhibited less myelosuppression and faster recovery.
EXAMPLE 5: Preparation of a kit for use according to the invention
First vessel: Compound of formula I-1 for Injection, 100 mg
The sodium salt of the compound of the formula:
O P OH
N NH
(also referred to herein as “SGI-110”) was prepared as described in US 7700567 (the
content of which is hereby incorporated by reference - see in particular column 41, final
two paragraphs) by coupling 1s (where R = carbamate protective group) with
phosphoramidite building block 1d:
A protected 2’-deoxyguanosine-linked CPG solid support 1s (where R =
tert-butyl phenoxyacetyl) is coupled with 2-2.5 equivalents of phenoxyacetyl decitabine
phosphoramidite (1d, where R = phenoxyacetyl) in the presence of 60% of 0.3 M
benzylthiotetrazole activator (in acetonitrile) for 10 minutes. The CPG solid support
containing protected DpG dinucleotide is treated with 20 mL of 50 mM K CO in
methanol for 1 hour and 20 minutes. The coupled product is oxidized, protective group
removed, washed, filtered, and purified by the ÄKTA Explorer 100 HPLC with a Gemini
C18 preparative column (Phenomenex), 250x21.2 mm, 10μm with guard column
(Phenomenex), 50x21.2mm, 10μm, with 50 mM triethylammonium acetate (pH 7) in
MilliQ water (Mobile Phase A) and 80% acetonitrile in MilliQ water (Mobile Phase B),
with 2% to 20/25% Mobile Phase B in column volumes.
The ESI-MS (-ve) of DpG dinucleotide 2b:
where X = triethylammonium (calculated exact mass for the neutral compound
C H N O P is 557.14), exhibited m/z 556.1 [M-H] and 1113.1 for [2M-H] (see mass
18 24 9 10
spectrum in Figure 31 of US 7700567).
The sodium salt of the compound of formula I-1 (i.e. DpG dinucleotide 2b,
where X = sodium; SGI-110) is obtained by re-dissolving the triethylammonium salt in 4
ml water, 0.2 ml 2M NaClO solution. When 36 mL acetone is added, the dinucleotide
precipitates. The solution is kept at -20°C for several hours and centrifugated at 4000 rpm
for 20 minutes. The supernatant is discarded and the solid is washed with 30 mL acetone
followed by an additional centrifugation at 4000 rpm for 20 minutes. The precipitate is
dissolved in water and freeze dried, which exhibited m/z 556.0 [M-H] (see mass
spectrum in Figure 36 of US 7700567).
Compounding and filling of bulk formulation
Based on the assay value of SGI-110 lot, needed quantities of SGI-110 and
DMSO are calculated and weighed appropriately for the intended batch scale.
2. SGI-110 is dissolved in DMSO utilizing an overhead mixer in an
appropriately sized stainless steel (SS) vessel.
3. Upon complete solubilization of the drug in DMSO, samples of the bulk
solution are tested using a UV or HPLC in-process method to determine that the amount
of SGI-110 is within 95-105% of the target concentration.
4. Bulk solution is filtered through a series of two pre-sterilized 0.2 micron
sterilizing filters that are DMSO compatible, and collected into a 2L SS surge vessel.
Filtration rate is continuously adjusted by visual monitoring of quantity
available for filling in the surge vessel.
One gram of the filtered bulk solution is filled into each of the 5 cc
depyrogenated, clear glass vials and the operation is continued with until all of the filtered
bulk solution is filled.
Each vial is automatically and partially stoppered on the fill line with a
fluoropolymer coated, chlorobutyl rubber lyo stopper that is pre-sterilized.
Product vials are transferred to lyophilizer under aseptic transfer
conditions for initiation of lyophilization cycle.
Lyophilization and capping of vials
Vials are lyophilized using the cycle parameters as below.
Freezing Primary/Secondary Drying Final Set
point
(stoppering
conditions)
Temperature -40°C -5°C 10°C 30°C 60°C 25°C
Ramp time (min) 133 117 50 67 100 -
Time (min.) 360 1440 1440 1440 1440 hold
Vacuum (mTorr) - 100 100 50 50 50 mT
(note:100 before back
mT for fill
evacuation
-50°C)
2. Upon completion of the lyo cycle, lyophilizer is back filled with
nitrogen, and the vials are completely and automatically stoppered.
3. Vials are aseptically transferred to an isolator where each of the vials is
automatically capped with a blue aluminum flip-off cap.
4. Vials are visually inspected before proceeding with sampling for release
testing, and the labeling and packaging operation. Vials are kept at 2-8°C until ready.
Labeling and Packaging
Each vial is labeled per approved content, and packaged individually into
heat-sealed aluminum foil pouch with a desiccant under vacuum. The foil pouch is
labeled outside with the same label as was used for the product vial. Labeled and
packaged vials are stored at 2-8°C until further distribution.
Residual DMSO
Four batches of the same scale of 3000 vials/batch were prepared using the
same process as described above. DMSO was consistently removed to the following
residual levels to yield a solid white powder, demonstrating that lyophilization of SGI-
110 out of DMSO as described above yields a safe and chemically stable SGI-110
powder:
# DMSO in
mg/vial
Batch 1 25
Batch 2 28
Batch 3 27
Batch 4 29
Second vessel: SGI-110 Diluent for Reconstitution, 3 mL
Compounding and filling of bulk formulation
Calculated quantities (see table below) of propylene glycol, ethanol, and
glycerin in the aforementioned order are added into an appropriately sized stainless steel
vessel equipped with an overhead mixer.
% of each Grade Function
ingredient
Propylene glycol 65 NF, PhEur Solvent
Glycerin 25 NF, PhEur solvent
Alcohol/Ethanol 10 USP, PhEur Thinning agent
2. Intermittent mixing during addition of components is followed by at
least 30 minutes of mixing to yield a well-mixed solution.
3. Bulk solution is filtered through a series of two pre-sterilized 0.2 micron
compatible sterilizing filters, and collected into a 2L SS surge vessel.
4. Filtration rate is adjusted by visual monitoring of quantity available for
filling in the surge vessel.
At least 3.15 g, equivalent to 3.0 mL, of the filtered bulk solution is filled
into each of the 5 cc depyrogenated, clear glass vials followed by automatic stoppering
using fluoropolymer coated chlorobutyl rubber closures.
Stoppered vials are capped with sterilized white aluminum flip-off caps.
Vials are visually inspected prior to sampling for the release testing and
labeling operation and are stored at 2-30°C until ready.
Labeling and Packaging
Each diluent vial is labeled per approved content. Labeled vials are stored
at 2-30°C until further distribution.
EXAMPLE 6: Anti-tumour activity of SGI-110 in combination with anti-CTLA-4
antibody
The anti-tumor effect of SGI-110 in combination with anti-mouse CTLA-4
was evaluated in murine breast cancer model.
Materials and Methods
TS/A is a murine mammary carcinoma originated from a moderately
differentiated, weakly immunogenic mammary adenocarcinoma spontaneously arising in
a 20-mo-old female BALB/c mouse.
The anti-mouse CTLA-4 was the CTLA-4 mAb 9H10, obtained from
BioXCell (West Lebanon, NH, USA), dosed at 100μg/mouse in 200μl (ip).
Balb/c mice (6/group) were injected SQ in the flank region with murine
mammary carcinoma cells TS/A (2×10 ).
Mice bearing palpable tumor grafts (diameter ≥ 0.2 cm) were injected
subcutaneously with 3mg/kg of reconstituted SGI-110 QDx5 (daily for five days) at days
1-5, alone or in combination with 100µg/hamster anti-murine CTLA-4 monoclonal
antibodies (mAb), either concurrently (at days 2, 5 and 8) or subsequently (at days 8, 11
and 14).
Control mice were injected with diluent for reconstitution. The
effectiveness and tolerability of treatments was evaluated by tumor volume and body
weight measurements, respectively.
Results and conclusions
The results are shown in Figure 5. The best antitumour effect was achieved
in mice treated with SGI-110 followed by anti-CTLA-4 mAb. In this case, a tumour mass
significantly (p<0.05) smaller than that of control mice was observed, indicating, at day
26, a tumor growth inhibition of 84.4%. Moreover, a significant, but lower, reduction in
tumor mass occurred in SGItreated mice as compared to control mice, with a tumor
growth inhibition of 62.9% at days 26. No difference in tumor growth inhibition was
observed in mice treated with SGI-110 combined with anti-CTLA-4 mAb given
concomitantly as compared to mice treated with SGI-110 alone. No loss in body weight
was observed (data not shown) in all mice investigated, demonstrating a good tolerability
of all therapeutic regimens tested.
Thus, epigenetic priming with SGI-110 followed by CTLA-4 blockade
provides improved antitumour activity.
EXAMPLE 7: Anti-tumour activity of two cycles of sequential SGI-110 and anti-
CTLA-4
The anti-tumor effect of two cycles of sequential administration of SGI-
110 followed by anti-mouse CTLA-4 mAb 9H10 was also evaluated in TS/A murine
model.
Materials and Methods
Balb/c mice (6/group) were injected SQ in the flank region with murine
mammary carcinoma cells TS/A (2×10 ).
Mice bearing palpable tumor grafts (diameter ≥ 0.2 cm) were treated with
two cycles of 3mg/kg of reconstituted SGI-110 QDx5 (injected subcutaneously daily for
five days) at days 1-5 and 21-25, alone or in combination with two subsequent cycles of
100µg/hamster anti-murine CTLA-4 monoclonal antibodies (mAb), at days 8, 11, 14, 28,
31 and 34.
Control mice were injected with diluent for reconstitution. The
effectiveness and tolerability of treatments was evaluated by tumor volume and body
weight measurements, respectively.
Results and conclusions
The results are shown in Figure 6: two cycles of sequential administration
of SGI-110 and anti-CTLA4 antibody is efficacious and enhances the antitumour effect of
the antibody. Body weight measurements (not shown) showed that the treatment was
well-tolerated.
Claims (53)
1. A combination comprising: a) a compound of Formula I or a pharmaceutically-acceptable salt thereof: (5-azacytosine group)-L-(guanine group) (I) wherein L is of Formula (II): OR R (II), wherein, R and R are independently H, OH, an alkoxy group, an alkoxyalkoxy group, an acyloxy group, a carbonate group, a carbamate group, or a halogen; R is H, or R together with the oxygen atom to which R is bound forms an ether, an ester, a carbonate, 4 4 4 or a carbamate; R is H, or R together with the oxygen atom to which R is bound forms an ether, an ester, a carbonate, or a carbamate; and X together with the oxygen atoms to which X is bound forms a phosphodiester, a phosphorothioate diester, a boranophosphate diester, or a methylphosphonate diester; and b) a T-cell activating agent; wherein the compound of Formula I or pharmaceutically-acceptable salt thereof is for administration before administration of the T-cell activating agent.
2. The combination of claim 1, wherein R and R are independently H, OH, OMe, OEt, OCH CH OMe, OBn, or F.
3. The combination of any one of the preceding claims wherein X together with the oxygen atoms to which X is bound forms a phosphodiester.
4. The combination of any one of the preceding claims wherein R and R are H.
5. The combination of any one of the preceding claims, wherein the compound of Formula I is any one of I-(1-44).
6. The combination of any one of the preceding claims, wherein the compound of Formula I is: NN N N NH O P OH O P OH I-1: OH or I-2: OH .
7. The combination of any one of the preceding claims wherein the compound of formula I is of the formula: O P OH N NH or a pharmaceutically-acceptable salt thereof.
8. The combination of claim 7 wherein said salt is a sodium salt.
9. The combination of any one of the preceding claims wherein the compound of Formula I or pharmaceutically-acceptable salt thereof is in the form of a formulation, being dissolved in a substantially anhydrous solvent comprising about 45% to about 85% propylene glycol; about 5% to about 45% glycerin; and 0% to about 30% ethanol.
10. The combination of claim 9 wherein said solvent comprises about 65% to about 70% propylene glycol; about 25% to about 30% glycerin, and 0% to about 10% ethanol.
11. The combination of claim 10 wherein said solvent comprises 65% to 70% propylene glycol and 25% to 30% glycerin, any balance being ethanol.
12. The combination of claim 9 wherein said solvent comprises about 65% propylene glycol; about 25% glycerin; and about 10% ethanol.
13. The combination of claim 12 wherein said solvent is 65% propylene glycol; 25% glycerin; and 10% ethanol.
14. The combination of claim 10 wherein said solvent comprises about 70% propylene glycol and about 30% glycerin, ethanol being absent.
15. The combination of claim 9 wherein said solvent comprises: (a) 45% to 85% propylene glycol; 5% to 45% glycerin; and 0% to 30% ethanol; or (b) 65% to 70% propylene glycol; 25% to 30% glycerin, and 0% to 10% ethanol.
16. The combination of any one of claims 9-15 wherein the compound of Formula I or pharmaceutically-acceptable salt thereof is present in the formulation at a concentration of about 80 mg/mL to about 110 mg/mL, optionally about 100 mg/mL.
17. The combination of any one of claims 9-16 wherein the formulation further comprises DMSO, optionally at a DMSO:compound ratio of 2:1; 1:1; 0.5:1; 0.3:1 or 0.2- 0.3:1.
18. The combination of any one of claims 9-17 wherein the formulation is suitable for administration by subcutaneous injection.
19. A kit comprising: (a) a first vessel containing the compound of Formula I or pharmaceutically- acceptable salt thereof as defined in any one of claims 1-8; (b) a second vessel containing a substantially anhydrous solvent as defined in any one of claims 9-15; and (c) a T-cell activating agent; wherein the compound of Formula I or pharmaceutically-acceptable salt thereof is for administration before administration of the T-cell activating agent.
20. The kit of claim 19 wherein the compound of Formula I or pharmaceutically- acceptable salt thereof is in the form of a substantially anhydrous powder.
21. The kit of claim 20 wherein the compound of Formula I or pharmaceutically- acceptable salt thereof is lyophilized.
22. The kit of any one of claims 19-21 wherein the first vessel contains about 80 mg to about 110 mg of said compound of Formula I or pharmaceutically-acceptable salt thereof.
23. The kit of any one of claims 19-22 wherein the first vessel contains about 100 mg of said compound of Formula I or pharmaceutically-acceptable salt thereof.
24. The kit of any one of claims 19-23 further comprising instructions for administration by subcutaneous injection.
25. A process for producing a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically-acceptable salt thereof as defined in any one of claims 1- 8 in the form of a substantially anhydrous powder, the process comprising dissolving said compound of Formula I or salt thereof in DMSO to produce a solution in DMSO, lyophilizing said solution to provide said compound of Formula I or pharmaceutically- acceptable salt thereof as a substantially anhydrous powder, wherein the substantially anhydrous powder is for administration before administration of the T-cell activating agent.
26. The process of claim 25 wherein said substantially anhydrous powder comprises residual DMSO.
27. The process of claim 26 wherein said residual DMSO is present in an amount of about 0.1 to about 2000 mg/g of said compound of Formula I or salt thereof.
28. The process of claim 27 wherein said residual DMSO is present in an amount of about 0.1 to about 1000 mg/g; about 0.1 to about 600 mg/g; about 0.1 to about 500 mg/g; about 0.1 to about 400 mg/g; about 0.1 to about 300 mg/g or about 200 – about 300mg/g of said compound of Formula I or salt thereof.
29. The process of claim 28 wherein said residual DMSO is present in an amount of 200- 300 mg/g of said compound of Formula I or salt thereof.
30. A substantially anhydrous powder consisting essentially of a compound of Formula I or salt thereof as defined in any one of claims 1-8 and DMSO, the DMSO being present in an amount of ≤200 % w/w, in combination with T-cell activating agent wherein the substantially anhydrous powder is for administration before administration of the T-cell activating agent.
31. The powder of claim 30 wherein the DMSO is present in an amount of about 0.1% to about 100%, about 0.1% to about 60%, about 0.1% to about 50%, about 0.1% to about 40% or about 0.1% to about 30% w/w DMSO/compound of Formula I or salt thereof.
32. The powder of claim 31 wherein the DMSO is present in an amount of 20-30% w/w DMSO/compound of Formula I or salt thereof.
33. A pharmaceutical composition obtained by the process of claim 25 or 26.
34. The combination, kit, process, powder or composition of any one of the preceding claims wherein the T-cell activating agent is selected from agonists or antibodies for: ICOS, GITR, MHC, CD80, CD86, Galectin 9 and LAG-3.
35. The combination, kit, process, powder or composition of any one of the preceding claims, wherein the T-cell activating agent is selected from (a) a CD137 agonist; (b) a CD40 agonist; (c) an OX40 agonist; (d) a PD-1 mAb; (e) a PD-L1 mAb; (f) a PD-L2 mAb; (g) a CTLA-4 mAb; and (h) combinations of (a)-(g).
36. The combination, kit, process, powder or composition of any one of the preceding claims, wherein the T-cell activating agent is selected from (a) Tremelimumab; (b) Ipilimumab; (c) Nivolumab; (d) Lambrolizumab; (e) BMS-936559; (f) MEDI4736; (g) MPDL3280A; and (h) PF-05082566.
37. Use of the combination, kit, process, powder or composition of any one of claims 1- 36 in the manufacture of a medicament for use in immunotherapy or for treating a disease selected from: (a) a myelodysplastic syndrome (MDS); (b) a cancer; (c) a leukemia; and (d) a disease associated with abnormal haemoglobin synthesis, wherein the disease associated with abnormal haemoglobin synthesis is selected from sickle cell anaemia and ß-thalassemia.
38. The use of claim 37 wherein the T-cell activating agent comprises a CTLA-4 mAb.
39. The use of claim 37 or 38 wherein the leukemia is selected from: acute myeloid leukemia (AML), acute promyelocyte leukemia, acute lymphoblastic leukemia, and chronic myelogenous leukemia.
40. The use of claim 39 wherein the AML is selected from elderly AML, first relapse AML and second relapse AML.
41. The use of any one of claims 37-40 wherein the cancer is selected from breast cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, non-small cell lung cancer, squamous non-small cell lung adenocarcinoma, brain cancer, cancer of the larynx, gall bladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach and bronchi, kidney cancer, basal cell carcinoma, squamous cell carcinoma of both ulcerating and papillary type, metastatic skin carcinoma, osteo sarcoma, Ewing's sarcoma, veticulum cell sarcoma, myeloma, giant cell tumour, small- cell lung tumour, gallstones, islet cell tumour, primary brain tumour, acute and chronic lymphocytic and granulocytic tumours, hairy-cell tumour, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuronms, intestinal ganglioneuromas, hyperplastic corneal nerve tumour, marfanoid habitus tumour, Wilm's tumour, seminoma, ovarian tumour, platinum resistant ovarian cancer, leiomyomater tumour, cervical dysplasia and in situ carcinoma, neuroblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic sarcoma, malignant hypercalcemia, renal cell tumour, polycythemia vera, adenocarcinoma, glioblastoma multiforma, lymphomas, melanoma, epidermoid carcinomas, hepatocellular carcinoma and solid tumours.
42. The use of claim 37 or 38 wherein the MDS is selected from low-, intermediate- and high-risk MDS and myeloproliferative neoplasms.
43. The use of any one of claims 37-42 wherein said formulation, kit or composition is to be administered to a subject according to a dosage regimen of: (a) once, twice, three times, four times, five times, six times or seven times a week; or (b) every day for 5, 6, 7, 8, 9 or 10 days; or (c) every day for up to 10 days; or (d) every day for between 5 and 10 days; or (e) every day for 5 days, immediately followed by two dose-free days and then every day for the next 5 days; (f) every day for 5 days, immediately followed by two dose-free days, whereby the T-cell activating agent is then to be administered.
44. The use of claim 43, wherein said formulation, kit or composition is to be administered to a subject according to a dosage regimen of every day for 5 days, immediately followed by two dose-free days, whereby the T-cell activating agent is then to be administered, wherein the T-cell activating agent is a CTLA-4 mAb.
45. The use of claim 43 or 44 wherein the administration of the T-cell activating agent is to immediately follow said dose-free days.
46. The use of any one of claims 37-45 wherein the administration is to be subcutaneous administration.
47. The use, combination, kit, process, powder, composition or use of any one of the preceding claims wherein the T-cell activating agent is Ipilimumab.
48. A combination according to any one of claims 1 to 18, substantially as herein described with reference to any example thereof.
49. A kit according to any one of claims 19 to 24, substantially as herein described with reference to any example thereof.
50. A process according to any one of claims 25 to 29, substantially as herein described with reference to any example thereof.
51. A substantially anhydrous powder according to any one of claims 30 to 32, substantially as herein described with reference to any example thereof.
52. A pharmaceutical compositon according to claim 33, substantially as herein described with reference to any example thereof.
53. A use according to any one of claims 37 to 47, substantially as herein described with reference to any example thereof. 1000.0 n Males, first weekly dose —^— Females, first weekly dose ^ 100.0 Males, third weekly dose —A— Fem ales, third weekly dose I 10.0 - o 1.0 - V. 0.1 T . 0 6 12 18 24 30 36 42 48 Time (hr) 100,0 Males, first weekly dose —5—Females, first weekly dose Males, third weekly dose o> 10.0 - —A— Femaies, third v/eekiy dose 1.0 ^ u —'A 12 18 24 30 36 42 48 Time(hr) Female Monkey 102 Male Monkey 101 10Q-I 100-1 ^ p < 0.05 * p < 0.05 1 90- M 90- 2 85- & <5 <y % change of total related substance with respect to TO I- O' >- o 'j - 3 C' a o a c SR fi SR tilft ; *? ^ ^ § S K o „ ^ o a o ? § s s - S ' S S o I ^ ^ ^ ti ti *ri ! - % : ’■' ■ i> 3.50 3.00 2.50 CTRL 2.00 CTLA-4 con 1.50 CTLA-4 subs -#-SGI+CTLA-4con 1.00 SGI+CTLA-4Subs 0.50 0.00 1 2 3 4 5 6 8 9 11 13 14 16 20 23 27 29 34 37 days t tttt SGI-110 t t t CTLA-4 concurrent t t t CTLA-4 subsequent 3,00 Veh icle qdx5x2 S Q at days 1-5, 21-25 « 2,50 SGI-110 3mg/l(gqd)(5)i2Saat daysl-5, 21-25 anti-murine CTLAt4x2 at days 3, 11. 14; 2S. 31. 34 £ 2,00 S GI-110 3mg/kg qdx5x2 SQ (at days 1-5; 21-25;. + antlmurine CTLA-4)i2 (at days 3, 11.14; 23, 31. 34) > 1,50 |5 i.oo 0,50 0,00 0 1 2 3 A 5 6 7 8 9 ID 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 3S 39 40 41 42 43 SGlllO S GI-110 Anti-CTLA-4 Anti-CTlAr4
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NZ750690A NZ750690B2 (en) | 2013-03-01 | 2014-02-27 | Drug combinations comprising derivatives of decitabine |
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US201361771525P | 2013-03-01 | 2013-03-01 | |
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US201361887165P | 2013-10-04 | 2013-10-04 | |
US61/887,165 | 2013-10-04 | ||
PCT/US2014/019137 WO2014134355A1 (en) | 2013-03-01 | 2014-02-27 | Drug combinations |
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