NZ625611B2 - Combination treatment of cancer - Google Patents
Combination treatment of cancer Download PDFInfo
- Publication number
- NZ625611B2 NZ625611B2 NZ625611A NZ62561112A NZ625611B2 NZ 625611 B2 NZ625611 B2 NZ 625611B2 NZ 625611 A NZ625611 A NZ 625611A NZ 62561112 A NZ62561112 A NZ 62561112A NZ 625611 B2 NZ625611 B2 NZ 625611B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- combination
- azd5363
- cancer
- dosed
- pharmaceutically acceptable
- Prior art date
Links
- 201000011510 cancer Diseases 0.000 title claims abstract description 67
- JDUBGYFRJFOXQC-KRWDZBQOSA-N 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide Chemical compound C1([C@H](CCO)NC(=O)C2(CCN(CC2)C=2C=3C=CNC=3N=CN=2)N)=CC=C(Cl)C=C1 JDUBGYFRJFOXQC-KRWDZBQOSA-N 0.000 claims abstract description 106
- 150000003839 salts Chemical class 0.000 claims abstract description 91
- 239000011780 sodium chloride Substances 0.000 claims abstract description 91
- WXCXUHSOUPDCQV-UHFFFAOYSA-N Enzalutamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1N1C(C)(C)C(=O)N(C=2C=C(C(C#N)=CC=2)C(F)(F)F)C1=S WXCXUHSOUPDCQV-UHFFFAOYSA-N 0.000 claims abstract description 39
- 229960004671 enzalutamide Drugs 0.000 claims abstract description 38
- 206010060862 Prostate cancer Diseases 0.000 claims abstract description 15
- 108010080146 androgen receptors Proteins 0.000 claims abstract description 11
- 230000000051 modifying Effects 0.000 claims abstract description 10
- 230000011664 signaling Effects 0.000 claims abstract description 10
- 102000001307 androgen receptors Human genes 0.000 claims abstract 2
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- 239000003814 drug Substances 0.000 claims description 23
- 239000002552 dosage form Substances 0.000 claims description 15
- GZOSMCIZMLWJML-VJLLXTKPSA-N Abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 30
- 229960000853 abiraterone Drugs 0.000 description 30
- 229960004103 abiraterone acetate Drugs 0.000 description 23
- UVIQSJCZCSLXRZ-UBUQANBQSA-N abiraterone acetate Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CC[C@@H](CC4=CC[C@H]31)OC(=O)C)C=C2C1=CC=CN=C1 UVIQSJCZCSLXRZ-UBUQANBQSA-N 0.000 description 23
- LKJPYSCBVHEWIU-KRWDZBQOSA-N bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 20
- 229960000997 bicalutamide Drugs 0.000 description 20
- JMEYDSHPKCSIJC-UHFFFAOYSA-N 1-[4-[2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]ethyl]piperazin-1-yl]ethanone Chemical compound C1CN(C(=O)C)CCN1CCOC1=CC=C(C2CCN(CC2)C=2CCC=3N(C(=NN=3)C(F)(F)F)N=2)C=C1 JMEYDSHPKCSIJC-UHFFFAOYSA-N 0.000 description 13
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- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 4
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- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
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- 125000002252 acyl group Chemical group 0.000 description 2
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- 238000002512 chemotherapy Methods 0.000 description 2
- 229940079593 drugs Drugs 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
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- 231100000486 side effect Toxicity 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003656 tris buffered saline Substances 0.000 description 2
- LAPGMTOHOQPDGI-UHFFFAOYSA-N 4-amino-2,5-difluorobenzonitrile Chemical group NC1=CC(F)=C(C#N)C=C1F LAPGMTOHOQPDGI-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
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- 206010017758 Gastric cancer Diseases 0.000 description 1
- 229960002743 Glutamine Drugs 0.000 description 1
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- 206010061256 Ischaemic stroke Diseases 0.000 description 1
- 208000007766 Kaposi Sarcoma Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
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- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 210000003491 Skin Anatomy 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000000980 acid dye Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940085282 bicalutamide 50 MG Drugs 0.000 description 1
- 201000005216 brain cancer Diseases 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
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- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylaxis Effects 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
Abstract
The disclosure relates combination comprising AZD5363 ((S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide), or a pharmaceutically acceptable salt thereof, and at least one androgen receptor signalling modulator selected from MDV-3100 (4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide) (also known as enzalutamide). The disclosure also relates to kits comprising these components and the use of these combinations for the treatment of cancer, especially prostate cancer. (4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-methylbenzamide) (also known as enzalutamide). The disclosure also relates to kits comprising these components and the use of these combinations for the treatment of cancer, especially prostate cancer.
Description
-WO-PCT
COMBINATION TREATMENT OF CANCER
Described herein is a combination comprising (S)amino-N-(1-(4-chlorophenyl)-
3-hydroxypropyl)(7H-pyrrolo[2,3-d]pyrimidinyl)piperidinecarboxamide
(“AZD5363”), or a pharmaceutically acceptable salt thereof, and at least one androgen
receptor signalling modulator selected from 4-{3-[4-cyano(trifluoromethyl)-phenyl]-
,5-dimethyloxothioxoimidazolidinyl}fluoro-N-methylbenzamide (“MDV-
3100”, also known as enzalutamide), 1-{4-[2-(4-{1-[3-(trifluoromethyl)-7,8-
dihydro[1,2,4]triazolo[4,3-b]pyrid-azinyl]piperidinyl}phenoxy)ethyl]piperazin
yl}ethanone (“AZD3514”), (3 )(pyridinyl)androsta-5,16-dienol!(“abiraterone”,
or an ester prodrug thereof:!e.g.!“abiraterone!acetate”) and N-[4-cyano(trifluoromethyl)-
phenyl][(4-fluorophenyl)-sulfonyl]hydroxymethylpropanamide (“bicalutamide”);
or a pharmaceutically acceptable salt thereof. Each of these combinations may be useful in
the treatment or prophylaxis of cancer. Also described are pharmaceutical compositions
comprising such combinations, and methods of treatment comprising the simultaneous,
sequential or separate administration of AZD5363, or a pharmaceutically acceptable salt
thereof, with at least one androgen receptor signalling modulator as described above, to
warm-blooded animal, such as a human. Also described is a kit comprising such
combinations.
Cancer affects an estimated 10 million people worldwide. This figure includes
incidence, prevalence and mortality. More than 4.4 million cancer cases are reported from
Asia, including 2.5 million cases from Eastern Asia, which has the highest rate of
incidence in the world. By comparison, Europe has 2.8 million cases, North America 1.4
million cases, and Africa 627,000 cases.
In the UK and US, for example, more than one in three people will develop cancer
at some point in their life. Cancer mortality in the U.S. is estimated to account for about
600,000 a year, about one in every four deaths, second only to heart disease in percent of
all deaths, and second to accidents as a cause of death of children 1-14 years of age. The
estimated cancer incidence in the U.S. is now about 1,380,000 new cases annually,
exclusive of about 900,000 cases of non-melanotic (basal and squamous cell) skin cancer.
Cancer is also a major cause of morbidity in the UK with nearly 260,000 new cases
(excluding non-melanoma skin cancer) registered in 1997. Cancer is a disease that affects
104216-WO-PCT
mainly older people, with 65% of cases occurring in those over 65. Since the average life
expectancy in the UK has almost doubled since the mid nineteenth century, the population
at risk of cancer has grown. Death rates from other causes of death, such as heart disease,
have fallen in recent years while deaths from cancer have remained relatively stable. The
result is that 1 in 3 people will be diagnosed with cancer during their lifetime and 1 in 4
people will die from cancer. In people under the age of 75, deaths from cancer outnumber
deaths from diseases of the circulatory system, including ischaemic heart disease and
stroke. In 2000, there were 151,200 deaths from cancer. Over one fifth (22%) of these were
from lung cancer, and a quarter (26%) from cancers of the large bowel, breast and prostate.
Worldwide, the incidence and mortality rates of certain types of cancer (stomach,
breast, prostate, skin, and so on) have wide geographical differences which are attributed to
racial, cultural, and especially environmental influences. There are over 200 different types
of cancer but the four major types, lung, breast, prostate and colorectal, account for over
half of all cases diagnosed in the UK and US.
Current options for treating cancers include surgical resection, external beam
radiation therapy and / or systemic chemotherapy. These are partially successful in some
forms of cancer, but are not successful in others. There is a clear need for new and/or
improved therapeutic treatments.
AZD5363 is disclosed amongst many other Examples in international patent
application publication WO2009/047563. In this application it is stated that the compounds
disclosed therein “may be applied as a sole therapy or may involve, in addition to a
compound of the invention, conventional surgery, radiotherapy or chemotherapy”.
WO2009/047563 then lists many potential anti-tumour agents but nowhere in WO2009/
047563 is there any mention of MDV-3100, AZD3514 or abiraterone, and nowhere is the
specific combination of AZD5363 with bicalutamide disclosed.
Surprisingly, certain combinations according to the present invention may have
particular benefit for the treatment of cancer, where a synergistic effect is observed when
using the combination, when compared against the use of either combination partner alone.
According to the present invention a combination treatment may be considered to
provide a synergistic effect if the effect is therapeutically superior, as measured by, for
example, the extent of the response, the response rate, the time to disease progression or
the survival period, to that achievable on dosing one or other of the components of the
104216-WO-PCT
combination treatment at its conventional dose. For example, the effect of the combination
treatment is synergistic if the use of the combination is superior to the effect achievable
with AZD5363 or one of the specified combination partners, when used alone. Further, the
effect of the combination treatment is synergistic if a beneficial effect is obtained in a
group of patients that does not respond (or responds poorly) to AZD5363 or one of the
specified combination partners, when used alone. In addition, the effect of the
combination treatment may be considered to provide a synergistic effect if one of the
components is dosed at its conventional dose and the other component(s) is/are dosed at a
reduced dose and the therapeutic effect, as measured by, for example, the extent of the
response, the response rate, the time to disease progression or the survival period, is
equivalent to that achievable on dosing conventional amounts of the components of the
combination treatment. In particular, synergy is deemed to be present if the conventional
dose of AZD5363 or a specified combination partner may be reduced without detriment to
one or more factors such as: extent of the response, the response rate, the time to disease
progression and survival data, in particular without detriment to the duration of the
response, but with fewer and/or less troublesome side-effects than those that occur when
conventional doses of each component are used.
Furthermore, the effect of a combination treatment may be considered to provide a
synergistic effect if one or both of the components may be dosed less frequently than the
dosing schedule used for conventional dosing of each component when used alone, while
not adversely impacting the beneficial effect otherwise achieved by the use of conventional
amounts of an agent used alone. In particular, synergy is deemed to be present if the
frequency of dosing of AZD5363 and/or a specified combination partner may be reduced
relative to what would otherwise be conventional/required when using one of the
combination partners alone, without detriment to one or more factors such as: extent of the
response, the response rate, the time to disease progression and survival data, in particular
without detriment to the duration of the response, but with fewer and/or less troublesome
side-effects than those that occur when conventional scheduling/doses of each component
are used.
Surprisingly, according to the present invention, it has been found that the
combination use of AZD5363 with certain specific androgen receptor signalling
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modulators provides a synergistic effect and may therefore provide an improved method of
treating cancer.
In a first aspect, the invention provides a combination comprising:
AZD5363, or a pharmaceutically acceptable salt thereof;
with an androgen receptor signalling modulator which is
MDV-3100, or a pharmaceutically acceptable salt thereof.
In a further aspect, the invention provides a kit comprising:
(a) AZD5363, or a pharmaceutically acceptable salt, in a first unit dosage form;
(b) MDV-3100 in a second unit dosage form;
(c) container means for containing said first and second dosage forms;
and optionally, instructions for use.
The invention is as defined in the claims. However, the description which follows
may refer to additional combinations and other subject outside the scope of the current
claims. This description is retained for technical information.
Also described herein is a combination comprising:
AZD5363, or a pharmaceutically acceptable salt thereof;
with an androgen receptor signalling modulator selected from:
MDV-3100;
AZD3514;
abiraterone, or an ester prodrug thereof; and
bicalutamide;
or a pharmaceutically acceptable salt thereof.
A pharmaceutically acceptable salt is, for example, an acid-addition salt with an
inorganic or organic acid, for example hydrochloric acid, hydrobromic acid, sulphuric acid,
phosphoric acid, trifluoroacetic acid, citric acid or maleic acid.
In any aspect, embodiment or claim herein, an ester prodrug of abiraterone may be
a compound where a C alkanoyl group is attached to the hydroxyl group of abiraterone.
In any aspect, embodiment or claim herein, an ester prodrug of abiraterone may be a
compound where a C alkanoyl group is attached to the hydroxyl group of abiraterone. In
any aspect, embodiment or claim herein, an ester prodrug of abiraterone may be a
compound where a C alkaloyl group is attached to the hydroxyl group of abiraterone (i.e.
abiraterone acetate).
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Herein,!where!the!term!“combination”!is!used!it!is!to!be!understood!that!this!may
refer to simultaneous, separate or sequential administration of the components of the
combination.
In one embodiment “combination”!refers!to!simultaneous!administration of the
components of the combination.
In one embodiment “combination”!refers!to!separate!administration of the
components of the combination.
In one embodiment “combination”!refers!to!sequential!administration of the
components of the combination.
The above-mentioned embodiments may be combined with any one or combination
of other aspect(s), claim(s) or embodiment(s) as defined herein, unless the context
otherwise requires, to provide further aspects, embodiments and claims.
Where the administration is sequential or separate, the delay in administering the
second component should not be such as to lose the benefit of the effect arising from use of
the combination. Therefore, in one embodiment such sequential or separate treatment may
involve the administration of each component of the combination within a period of 11
days.
In another embodiment this period is within 10 days.
In another embodiment this period is within 9 days.
In another embodiment this period is within 8 days.
In another embodiment this period is within 7 days.
In another embodiment this period is within 6 days.
In another embodiment this period is within 5 days.
In another embodiment this period is within 4 days.
In another embodiment this period is within 3 days.
In another embodiment this period is within 2 days.
In another embodiment this period is within 24 hours.
In another embodiment this period is within 12 hours.
In another embodiment this period is within 8 hours.
In another embodiment this period is within 6 hours.
It may be advantageous, within a given dosage cycle, to administer one specific
component (A) of the combination before the other (B) – i.e. sequential dosing. Therefore,
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when sequential dosing is used with multiple consecutive dosage cycles, it naturally
involves the dosage of A then B within a relatively short period, followed by a relatively
longer period where neither component is dosed, before A then B are dosed again.
Therefore, in one embodiment the sequential administration comprises the
sequential administration of AZD5363 prior to the administration of the other combination
partner within a dosage cycle.
Herein,!where!“the!other!combination!partner”!is!mentioned,!unless!the!context!
otherwise requires, this refers to MDV-3100; AZD3514; abiraterone, or an ester prodrug
thereof; or bicalutamide; in order to provide a range of further embodiments of the
invention.
In another embodiment the sequential administration comprises the sequential
administration of ‘the other combination partner’!(as!defined above) prior to the
administration of AZD5363 with a dosage cycle.
Dosage cycles may be separated by a number of days where none of the active
combination components are administered.
In one embodiment there is provided a combination comprising:
AZD5363, or a pharmaceutically acceptable salt thereof;
with an androgen receptor signalling modulator selected from:
MDV-3100;
AZD3514;
abiraterone, or abiraterone acetate; and
bicalutamide;
or a pharmaceutically acceptable salt thereof.
In one embodiment there is provided a combination comprising:
AZD5363, or a pharmaceutically acceptable salt thereof;
with an androgen receptor signalling modulator selected from:
MDV-3100;
AZD3514;
abiraterone acetate; and
bicalutamide;
or a pharmaceutically acceptable salt thereof.
In one embodiment there is provided a combination comprising:
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AZD5363, or a pharmaceutically acceptable salt thereof;
with an androgen receptor signalling modulator selected from:
MDV-3100;
AZD3514;
abiraterone; and
bicalutamide;
or a pharmaceutically acceptable salt thereof.
In one embodiment there is provided a combination comprising AZD5363, or a
pharmaceutically acceptable salt thereof; with MDV-3100.
In one embodiment there is provided a combination comprising AZD5363 with
MDV-3100.
In one embodiment there is provided a combination comprising AZD5363, or a
pharmaceutically acceptable salt thereof, with AZD3514, or a pharmaceutically acceptable
salt thereof.
In one embodiment there is provided a combination comprising AZD5363 with
AZD3514.
In one embodiment there is provided a combination comprising AZD5363, or a
pharmaceutically acceptable salt thereof; with abiraterone or an ester prodrug thereof; or a
pharmaceutically acceptable salt thereof.
In one embodiment there is provided a combination comprising AZD5363, or a
pharmaceutically acceptable salt thereof; with abiraterone or abiraterone acetate.
In one embodiment there is provided a combination comprising AZD5363, or a
pharmaceutically acceptable salt thereof; with abiraterone.
In one embodiment there is provided a combination comprising AZD5363, or a
pharmaceutically acceptable salt thereof; with abiraterone acetate.
In one embodiment there is provided a combination comprising AZD5363; with
abiraterone or abiraterone acetate.
In one embodiment there is provided a combination comprising AZD5363, or a
pharmaceutically acceptable salt thereof; with bicalutamide.
In one embodiment there is provided a combination comprising AZD5363; with
bicalutamide.
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In this specification any number of aspects or embodiments stated herein may be
combined in any combination with each other (unless the context otherwise requires) to
provide additional embodiments of the invention.
Where cancer is referred to, it may refer to oesophageal cancer, myeloma,
hepatocellular cancer, pancreatic cancer, cervical cancer, ewings tumour, neuroblastoma,
kaposis sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder
cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung
cancer (SCLC), gastric cancer, head and neck cancer, brain cancer, renal cancer,
lymphoma and leukaemia.
In one embodiment the cancer may be prostate cancer.
In one embodiment the cancer is hormone sensitive prostate cancer.
In one embodiment the cancer is castrate-resistant prostate cancer.
In one embodiment the cancer is non-metastatic castrate-resistant prostate cancer.
In another embodiment the cancer is in a metastatic state.
Therefore, in one embodiment the cancer is metastatic castrate-resistant prostate
cancer.
In a further embodiment of the invention, the cancer is in a non-metastatic state.
Therefore, in one embodiment the cancer is non-metastatic castrate-resistant
prostate cancer.
AZD5363 may be prepared according to the procedures described in WO2009/047563.
MDV-3100 may be prepared according the procedures described in WO2006/124118.
AZD3514 and pharmaceutically acceptable salts thereof may be prepared according to the
procedures described in WO2010/092371. Abiraterone may be prepared according to the
procedures described in WO1993/20097. Ester prodrugs of abiraterone such as abiraterone
acetate may be prepared from abiraterone using esterification conditions and reagents that
are well-known to the skilled person. Bicalutamide may be prepared according to the
procedures described in EP0100172.
According to the present invention, there is provided a combination which
comprises AZD5363, or a pharmaceutically acceptable salt thereof and MDV-3100 for use
as a medicament.
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Also described herein is a combination which comprises AZD5363, or a
pharmaceutically acceptable salt thereof; and AZD3514, or a pharmaceutically acceptable
salt thereof; for use as a medicament.
Also described herein is a combination which comprises AZD5363, or a
pharmaceutically acceptable salt thereof; and abiraterone, or a pharmaceutically acceptable
salt thereof; for use as a medicament.
Also described herein is a combination which comprises AZD5363, or a
pharmaceutically acceptable salt thereof; and abiraterone acetate, or a pharmaceutically
acceptable salt thereof; for use as a medicament.
Also described herein is a combination which comprises AZD5363, or a
pharmaceutically acceptable salt thereof; and abiraterone or abiraterone acetate; or a
pharmaceutically acceptable salt thereof; for use as a medicament.
Also described herein is a combination which comprises AZD5363, or a
pharmaceutically acceptable salt thereof; and bicalutamide; for use as a medicament.
According to a further aspect of the invention there is provided a pharmaceutical
composition which comprises AZD5363, or a pharmaceutically acceptable salt thereof; and
MDV-3100; in association with a pharmaceutically acceptable diluent or carrier.
Also described herein is a pharmaceutical composition which comprises AZD5363,
or a pharmaceutically acceptable salt thereof; and AZD3514, or a pharmaceutically
acceptable salt thereof; in association with a pharmaceutically acceptable diluent or carrier.
Also described herein is a pharmaceutical composition which comprises AZD5363,
or a pharmaceutically acceptable salt thereof; and abiraterone, or a pharmaceutically
acceptable salt thereof; in association with a pharmaceutically acceptable diluent or carrier.
Also described herein is a pharmaceutical composition which comprises AZD5363,
or a pharmaceutically acceptable salt thereof; and abiraterone acetate, or a
pharmaceutically acceptable salt thereof; in association with a pharmaceutically acceptable
diluent or carrier.
In one embodiment there is provided a pharmaceutical product comprising:
(i) a pharmaceutical composition which comprises AZD5363, or a pharmaceutically
acceptable salt thereof, in association with a pharmaceutically acceptable diluent or
carrier; and
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(ii) a pharmaceutical composition which comprises ‘the!other!combination!partner’,!or!
a pharmaceutically acceptable salt thereof, in association with a pharmaceutically
acceptable diluent or carrier.
As already specified!hereinabove,!where!“the!other!combination!partner”!is!mentioned,!
unless the context otherwise requires, this refers to one of MDV-3100; AZD3514;
abiraterone, or an ester prodrug thereof (e.g. abiraterone acetate); or bicalutamide, to
provide a range of further specific embodiments described herein.
Also described herein is a method of treating cancer, in a warm-blooded animal,
such as a human, which comprises administering to said animal an effective amount of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with an effective
amount of ‘the!other!combination!partner’!(as!defined!above),!or!a!pharmaceutically!
acceptable salt thereof.
In one aspect where the treatment of cancer is indicated, it is to be understood that
this may refer to the prevention of metastases and the treatment of metastases, i.e. cancer
spread.
Therefore the combination of the present invention might be used to treat a patient
who has no metastases to stop them occurring, or to lengthen the time period before they
occur, and to a patient who already has metastases to treat the metastases themselves.
Furthermore the treatment of cancer may refer to treatment of an established primary
tumour or tumours and developing primary tumour or tumours.
Therefore, in one aspect the treatment of cancer relates to the prevention of
metastases.
In another aspect of the invention the treatment of cancer relates to the treatment of
metastases.
In another aspect of the invention the treatment of cancer relates to treatment of an
established primary tumour or tumours or developing primary tumour or tumours.
In one embodiment the treatment of cancer relates to the treatment of primary
cancer and metastases.
Herein, the treatment of cancer may refer to the prevention of cancer per se.
According to a further aspect of the invention, there is provided a kit comprising
AZD5363, or a pharmaceutically acceptable salt thereof and ‘the!other!combination!
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partner’!(as!defined!above),!or!a!pharmaceutically!acceptable!salt!thereof; optionally with
instructions for use.
According to a further aspect of the invention, there is provided a kit comprising:
a) AZD5363, or a pharmaceutically acceptable salt, in a first unit dosage form;
b) ‘the!other!combination!partner’!(as!defined!above),!or!a!pharmaceutically!acceptable!
salt thereof, in a second unit dosage form;
c) container means for containing said first and second dosage forms; and optionally
d) instructions for use.
An example of a unit dosage from might be a tablet for oral administration.
According to a further aspect of the invention there is provided a pharmaceutical
composition which comprises AZD5363, or a pharmaceutically acceptable salt thereof; and
‘the!other!combination!partner’!(as!defined!above),!or!a!pharmaceutically!acceptable!salt!
thereof; in association with a pharmaceutically acceptable diluent or carrier, for use in the
treatment of cancer.
According to a further aspect of the invention there is provided a pharmaceutical
composition which comprises AZD5363, or a pharmaceutically acceptable salt thereof, in
association with a pharmaceutically acceptable diluent or carrier; in combination with a
pharmaceutical composition which comprises ‘the!other!combination!partner’!(as!defined!
above), or a pharmaceutically acceptable salt thereof, in association with a
pharmaceutically acceptable diluent or carrier, for use in the treatment of cancer.
The pharmaceutical compositions may be in a form suitable for oral administration,
for example as a tablet or capsule, for parenteral injection (including intravenous,
subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or
emulsion, for topical administration as an ointment or cream or for rectal administration as
a suppository. In general the above compositions may be prepared in a conventional
manner using conventional excipients.
According to a further aspect of the present invention there is provided a kit
comprising AZD5363, or a pharmaceutically acceptable salt thereof; and ‘the!other!
combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable!salt!thereof;
optionally with instructions for use; for use in the treatment of cancer.
According to a further aspect of the present invention there is provided a kit
comprising:
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a) AZD5363, or a pharmaceutically acceptable salt thereof, in a first unit dosage form;
b) ‘the!other!combination!partner’!(as!defined!above),!or!a!pharmaceutically!acceptable!salt!
thereof, in a second unit dosage form; and
c) container means for containing said first and second dosage forms; and optionally
d) instructions for use;
for use in the treatment of cancer.
According to another feature of the invention there is provided the use of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with ‘the!other!
combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable!salt!thereof, in
the manufacture of a medicament for the treatment of cancer.
It may be convenient or medically appropriate for a physician to determine the
exact dosage and scheduling for use of a combination product, such that the active
components of the combination product may necessarily not be present together within a
single dosage form at a fixed dose. Therefore a physician or pharmacist may prepare a
combination medicament comprising the active combination products in readiness for
simultaneous, separate or sequential combination use in medicine, for example to treat
cancer in a warm-blooded animal, such as human.
According to another feature of the invention there is provided the use of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with ‘the!other!
combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable salt thereof, in
the preparation of a combination medicament for use in medicine.
According to another feature of the invention there is provided the use of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with ‘the!other!
combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable!salt!thereof, in
the preparation of a combination medicament for simultaneous, separate or sequential
combination use in medicine.
According to another feature of the invention there is provided the use of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with ‘the!other!
combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable!salt!thereof, in
the preparation of a combination medicament for simultaneous, separate or sequential
combination use for the treatment of cancer.
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According to another feature of the invention there is provided the use of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with ‘the!other!
combination!partner’!(as!defined above) or a pharmaceutically acceptable salt thereof, in
the preparation of a combination medicament for simultaneous, separate or sequential
combination use for the treatment of cancer in a warm-blooded animal such as a human.
According to another feature of the invention there is provided the use of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with ‘the!other!
combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable!salt!thereof, in
the preparation of a combination medicament for separate combination use for the
treatment of cancer in a warm-blooded animal such as a human.
According to another feature of the invention there is provided the use of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with ‘the!other!
combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable!salt!thereof, in
the preparation of a combination medicament for sequential combination use for the
treatment of cancer in a warm-blooded animal such as a human.
According to another feature of the invention there is provided the use of
AZD5363, or a pharmaceutically acceptable salt thereof, in combination with ‘the!other!
combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable salt thereof, in
the preparation of a combination medicament for the treatment of cancer.
Therefore there is provided the use of AZD5363, or a pharmaceutically acceptable
salt thereof, in combination with ‘the!other!combination!partner’!(as!defined!above) or a
pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the
treatment of cancer, in a warm-blooded animal, such as a human.
According to a further aspect of the present invention there is provided a
combination comprising AZD5363, or a pharmaceutically acceptable salt thereof, and ‘the!
other!combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable!salt!
thereof, for use in the treatment of cancer.
In one embodiment there is provided AZD5363, or a pharmaceutically acceptable
salt!thereof,!and!‘the!other!combination!partner’!(as!defined!above)!or!a!pharmaceutically!
acceptable salt thereof, for use in the treatment of cancer in a warm-blooded animal such as
a human.
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In one embodiment there is provided AZD5363, or a pharmaceutically acceptable
salt!thereof,!and!‘the!other!combination!partner’!(as!defined!above)!or!a!pharmaceutically!
acceptable salt thereof, for use in the treatment of cancer in a warm-blooded animal such as
a human wherein the AZD5363, or a pharmaceutically!acceptable!salt!thereof,!and!‘the!
other!combination!partner’!(as!defined!above)!or!a!pharmaceutically!acceptable!salt!thereof!
are administered simultaneously, separately or sequentially to the warm-blooded animal.
Also described herein is a combination treatment comprising the administration
(simultaneous, separate or sequential) of an effective amount of AZD5363, or a
pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically
acceptable diluent or carrier, and an effective amount of ‘the!other!combination!partner’!(as!
defined above) or a pharmaceutically acceptable salt thereof, optionally together with a
pharmaceutically acceptable diluent or carrier, to a warm-blooded animal, such as a
human, in need of such therapeutic treatment, for the treatment of cancer.
The compositions of the invention may be obtained by conventional procedures
using conventional pharmaceutical excipients, well known in the art. Thus, compositions
intended for oral use may contain, for example, one or more colouring, sweetening,
flavouring and/or preservative agents.
A compound such as AZD5363 may normally be administered to a warm-blooded
animal at a unit dose within the range 5-5000 mg/m body area of the animal, i.e.
approximately 0.1-100 mg/kg, and this normally provides a therapeutically-effective dose.
A unit dose form such as a tablet or capsule will usually contain, for example 1-250 mg of
active ingredient. Preferably a daily dose in the range of 1-50 mg/kg is employed, for
example 4-7 mg/kg twice daily. However the daily dose will necessarily be varied
depending upon the host treated, the particular route of administration, and the severity of
the illness being treated. Accordingly the practitioner who is treating any particular patient
may determine the optimum dosage. For example, a pharmaceutical composition of the
present invention suitable for oral administration could comprise 1-200 mg/mL of
AZD5363 in 0.5% hydroxypropylmethylcellulose (HPMC). An alternative pharmaceutical
dosage form suitable for oral administration involves the use of AZD5363 alone as a
crystalline powder, within a standard capsule.
In one embodiment the AZD5363 is dosed to a patient at 150-300mg per day on the
days when it is dosed.
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In one embodiment the AZD5363 is dosed to a patient at 200-350mg per day on the
days when it is dosed.
In another embodiment the AZD5363 is dosed to a patient at 240-320mg per day on
the days when it is dosed.
In another embodiment the AZD5363 is dosed to a patient at 320-400mg per day on
the days when it is dosed.
In one embodiment the AZD5363 is dosed to a patient at 300-500mg per day on the
days when it is dosed.
In one embodiment the AZD5363 is dosed to a patient at 320-480mg per day on the
days when it is dosed.
In one embodiment the AZD5363 is dosed to a patient at 300-650mg per day on the
days when it is dosed.
In one embodiment the AZD5363 is dosed to a patient at 350-600mg per day on the
days when it is dosed.
In one embodiment the AZD5363 is dosed to a patient at 300-1100mg per day on
the days when it is dosed.
In one embodiment the AZD5363 is dosed to a patient at 400-1000mg per day on
the days when it is dosed.
In one embodiment the AZD5363 is dosed to a patient at 150-300mg per day on the
days when it is dosed, and it is dosed every day of the week. (i.e. continuous dosing).
In one embodiment the AZD5363 is dosed to a patient at 200-350mg per day on the
days when it is dosed, and it is dosed every day of the week. (i.e. continuous dosing)
In one embodiment the AZD5363 is dosed to a patient at 240-320mg per day on the
days when it is dosed, and it is dosed every day of the week. (i.e. continuous dosing).
In another embodiment the AZD5363 is dosed to a patient at 320-400mg per day on
the days when it is dosed, and it is dosed for four consecutive days and then not dosed for 3
consecutive days thereafter within a seven day dosage cycle.
In one embodiment the AZD5363 is dosed to a patient at 300-500mg per day on the
days when it is dosed, and it is dosed for four consecutive days and then not dosed for 3
consecutive days thereafter within a seven day dosage cycle.
104216-WO-PCT
In one embodiment the AZD5363 is dosed to a patient at 320-480mg per day on the
days when it is dosed, and it is dosed for four consecutive days and then not dosed for 3
consecutive days thereafter within a seven day dosage cycle.
In one embodiment the AZD5363 is dosed to a patient at 300-650mg per day on the
days when it is dosed, and it is dosed for two consecutive days and then not dosed for five
consecutive days thereafter within a seven day dosage cycle.
In one embodiment the AZD5363 is dosed to a patient at 350-600mg per day on the
days when it is dosed, and it is dosed for two consecutive days and then not dosed for five
consecutive days thereafter within a seven day dosage cycle.
In one embodiment the AZD5363 is dosed to a patient at 300-1100mg per day on
the days when it is dosed, and it is dosed for two consecutive days and then not dosed for
five consecutive days thereafter within a seven day dosage cycle.
In one embodiment the AZD5363 is dosed to a patient at 400-1000mg per day on the days
when it is dosed, and it is dosed for two consecutive days and then not dosed for five
consecutive days thereafter within a seven day dosage cycle.
The ‘other!combination!partner’!(as!defined!above) will normally be administered
(i.e. dosed) to a warm-blooded animal at a unit dose, of an amount known to the skilled
practitioner as a therapeutically effective dose. For a single dosage form, the active
ingredients may be compounded with an appropriate and convenient amount of excipients
which may vary from about 5 to about 98 percent by weight of the total composition.
Dosage unit forms will generally contain about 20 mg to about 500 mg of each active
ingredient. However the daily dose will necessarily be varied depending upon the host
treated, the particular route of administration, and the severity of the illness being treated.
Accordingly the optimum dosage may be determined by the practitioner who is treating
any particular patient.
The dosage of each of the drugs and their proportions have to be composed so that
the best possible treatment effects, as defined by national and international guidelines
(which are periodically reviewed and re-defined), will be met.
In!one!embodiment!(when!the!“other!combination!partner”!is!abiraterone!acetate)!
the abiraterone acetate is dosed orally to a patient at 750-1250mg per day on the days when
it is dosed.
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In!one!embodiment!(when!the!“other!combination!partner”!is!abiraterone!acetate)!
the abiraterone acetate is dosed orally to a patient at 450-1250mg per day on the days when
it is dosed.
In!one!embodiment!(when!the!“other!combination!partner”!is!abiraterone acetate)
the abiraterone acetate is dosed orally to a patient at 450-1250mg per day on the days when
it is dosed, and it is dosed every day of the week. (i.e. continuous dosing).
In!one!embodiment!(when!the!“other!combination!partner”!is!abiraterone acetate)
the abiraterone acetate is dosed orally to a patient at 750-1250mg per day on the days when
it is dosed, and it is dosed every day of the week. (i.e. continuous dosing).
In!another!embodiment!(when!the!“other!combination!partner”!is!abiraterone
acetate), the abiraterone acetate is dosed orally to a patient at 800-1200 mg per day on the
days when it is dosed.
In!another!embodiment!(when!the!“other!combination!partner”!is!abiraterone!
acetate), the abiraterone acetate is dosed orally to a patient at 800-1200 mg per day on the
days when it is dosed, and it is dosed every day of the week. (i.e. continuous dosing).
In!another!embodiment!(when!the!“other!combination!partner”!is!abiraterone!
acetate), the abiraterone acetate is dosed orally to a patient at 900-1100 mg per day on the
days when it is dosed.
In!another!embodiment!(when!the!“other!combination!partner”!is!abiraterone!
acetate), the abiraterone acetate is dosed orally to a patient at 900-1100 mg per day on the
days when it is dosed, and it is dosed every day of the week. (i.e. continuous dosing).
In!further!embodiments!(when!the!“other!combination!partner”!is!abiraterone!
acetate), the patient is also dosed with a therapeutically effective amount of prednisone.
Such dosing of prednisone may occur every day of the week. A therapeutically effective
amount of prednisone may be from 5-20 mg per day. (e.g. a total of 10 mg per day).
In!other!embodiments!(when!the!“other!combination!partner”!is!abiraterone
acetate), the patient is not being treated with prednisone at the same time.
In!one!embodiment!(when!the!“other!combination!partner”!is!MDV-3100), the
MDV-3100 is dosed orally to a patient at 140-180 mg per day on the days when it is dosed.
In another embodiment (when!the!“other!combination!partner”!is!MDV-3100), the
MDV-3100 is dosed orally to a patient at 150-170 mg per day on the days when it is dosed.
104216-WO-PCT
In!one!embodiment!(when!the!“other!combination!partner”!is!MDV-3100), the
MDV-3100 is dosed orally to a patient at 140-180 mg per day on the days when it is dosed
and, it is dosed every day of the week. (i.e. continuous dosing).
In another embodiment (when!the!“other!combination!partner”!is!MDV-3100), the
MDV-3100 is dosed orally to a patient at 150-170 mg per day on the days when it is dosed,
and it is dosed every day of the week. (i.e. continuous dosing).
104216-WO-PCT
List of Figures
Figure 1: Inhibition of cell growth and enhanced cell death in LNCaP cells from
combination use of AZD5363 with MDV3100.
Figure 2: Inhibition of cell growth and enhanced cell death in VCAP cells from
combination use of AZD5363 with MDV3100.
Figure 3: Enhanced anti-tumour efficacy in the LNCaP xenograft model from
combination use of AZD5363 with bicalutamide.
Figure 1 shows the mean % growth in LNCaP cells for each concentration of AZD5363,
either as a monotherapy or in combination with five different concentrations of MDV-
3100,!in!the!range!0.1"M!to!10"M!(n=3).!Positive!values!(0!to!100%)!show!anti-
proliferative effects and negative values (0 to -100%) are for cell killing. These results
demonstrate that AZD5363 can inhibit the growth of LNCaP cells and induce cell death as
a monotherapy and this effect is synergistically enhanced by treatment with MDV-3100.
Figure 2 shows the mean % growth in VCAP cells for each concentration of AZD5363,
either as a monotherapy or in combination with five concentrations of MDV-3100, in the
range!0.1"M!to!10"M!(n=3).!Positive!values!(0!to!100%)!show!anti-proliferative effects
and negative values (0 to -100%) are for cell killing. These results demonstrate that
AZD5363 can inhibit the growth of VCAP cells as a monotherapy and this effect is
synergistically enhanced by treatment with MDV-3100.
Figure 3 shows the mean tumour volume in mice, when treated with monotherapy and
combination therapy involving AZD5363 and bicalutamide. Although not explicit in the
figure,!the!“AZD5363!+!bicalutamide”!data!shown!in!the!figure!involves!the!same!dosage!
and scheduling as is shown in the figure for AZD5363 alone and for bicalutamide alone,
i.e. 100mg/kg bd 5 days on, 2 days off of AZD5363 in combination with bicalutamide
50mg/kg bd.
104216-WO-PCT
Experimental details
Combination of AZD5363 with MDV-3100
The LNCaP and VCAP prostate tumour cell lines (American Tissue Culture Collection)
were routinely cultured in RMPI supplemented with 10% FCS and 2mM L-glutamine. To
determine the effect of AZD5363 and MDV-3100, either as a monotherapy or in
combination, on cell growth, a proliferation assay was performed using the Sytox Green
endpoint to measure live cell number after 5 days. Briefly, LNCAP or VCAP cells were
seeded in 384-well plates at a density of 1500 or 2500 cells per well, respectively, and left
to adhere overnight. Cells were then dosed with increasing concentrations of AZD5363
(0.01 – 1µM), MDV-3100 (0.1-10µM) or a combination of each agent in a 6×6 matrix
format. After 5-day exposure to compound, Sytox Green nucleic acid dye (Invitrogen)
diluted in TBS-EDTA (TBS = Tris-buffered saline, EDTA = ethylenediaminetetraacetic
acid) buffer was added to cells at a final concentration of 0.13mmol/L and the number of
dead cells detected using an Acumen Explorer. Cells were then permeabilised by the
addition of saponin (0.03% final concentration, diluted in TBS-EDTA buffer), incubated
overnight and a total cell count measured. The live cell count was then determined by
subtracting the number of dead cells per well from the total number of cells. Pre-dose
measurements were made to indicate the number of live cells at the start of the experiment
(Tz) and thus an indication of whether the treatment regimen had resulted in cell death.
The data is presented as % growth using the NCI formulae as follows:
[(Ti-Tz)/(C-Tz)] × 100 for concentrations for which Ti>/=Tz
[(Ti-Tz)/Tz] × 100 for concentrations for which Ti<Tz.
Where, ‘Tz’ represents the number of live cells at time zero, ‘C’ represents the control
growth and ‘Ti’ represents the number of live cells in the presence of each drug regimen.
This formula gives a growth percentage from -100% to +100%. Negative scores are for
cell killing and positive scores are for anti-proliferation. The data are presented in Figure 1
and Figure 2. Synergism of the drug combination was evaluated using a unified approach
described by C. Harbron (Stat. Med. 2010 Jul 20; 29(16): 1746-56).
104216-WO-PCT
Combination indicies and p values for the three experiments
A combination index of <1 indicates synergism.!‘p!values’!relate!to!statistical!significance.
Cell line Experiment CI p value
1 0.38 p<0.0001
LNCaP 2 0.32 p<0.0001
3 0.51 p=0.0001
1 0.47 p=0.0003
VCAP 2 0.59 p=0.003
3 0.75 p=0.22
Combination of AZD5363 with bicalutamide
Combination of AZD5363 with bicalutamide results in greater tumour growth inhibition
than monotherapy in a xenograft model of castrate resistant prostate cancer in vivo:
LNCaP prostate cancer cells (PTEN null, androgen receptor positive) were implanted into
the flank of athymic male nude mice. Tumour growth and the concentration of Prostate
Specific Antigen (PSA) in the serum were monitored. When the serum PSA exceeded 50
ng/mL, mice were castrated. The mice were randomized into groups and treatment
commenced when the PSA concentration recovered to at least 50 ng/mL. AZD5363
monotherapy treatment (100 mg/kg bd, 5 days on, 2 days off) resulted in 56% inhibition of
tumour volume, and bicalutamide monotherapy treatment (50 mg/kg qd), resulted in 42%
inhibition of tumour volume. The combination was significantly more efficacious, and
resulted in 85% inhibition of tumour volume. This data shows that combination of
AZD5363 and the androgen antagonist bicalutamide is well tolerated and results in greater
efficacy than the equivalent monotherapy doses of each compound. The results are shown
in Figure 3.
104216-WO-PCT
Claims (11)
1. A combination comprising: AZD5363, or a pharmaceutically acceptable salt thereof; 5 with an androgen receptor signalling modulator which is MDV-3100, or a pharmaceutically acceptable salt thereof.
2. A combination as claimed in claim 1, for use as a medicament. 10
3. A combination as claimed in claim 1 or 2, for use as a medicament in the treatment of cancer.
4. A combination as claimed in claim 3 wherein the cancer is prostate cancer. 15
5. A combination as claimed in claim 3 wherein the cancer is castrate-resistant prostate cancer.
6. A kit comprising: (a) AZD5363, or a pharmaceutically acceptable salt, in a first unit dosage form; 20 (b) MDV-3100 in a second unit dosage form; (c) container means for containing said first and second dosage forms; and optionally, instructions for use.
7. A kit according to claim 6, wherein the kit is for use in the treatment of cancer.
8. A kit according to claim 6 or 7, wherein the kit is for use in the treatment of prostate cancer.
9. A kit according to claim 7, wherein the kit is for use in the treatment of castrate- 30 resistant prostate cancer.
10. A combination according to claim 1 substantially as herein described with reference to any example thereof. 104216-WO-PCT
11. A kit according to claim 6 substantially as herein described with reference to any example thereof. 104216-WO-PCT/O
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161564975P | 2011-11-30 | 2011-11-30 | |
US61/564,975 | 2011-11-30 | ||
PCT/GB2012/052969 WO2013079964A1 (en) | 2011-11-30 | 2012-11-30 | Combination treatment of cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ625611A NZ625611A (en) | 2016-10-28 |
NZ625611B2 true NZ625611B2 (en) | 2017-01-31 |
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