JP2015500225A - 癌の併用処置 - Google Patents
癌の併用処置 Download PDFInfo
- Publication number
- JP2015500225A JP2015500225A JP2014543977A JP2014543977A JP2015500225A JP 2015500225 A JP2015500225 A JP 2015500225A JP 2014543977 A JP2014543977 A JP 2014543977A JP 2014543977 A JP2014543977 A JP 2014543977A JP 2015500225 A JP2015500225 A JP 2015500225A
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- JP
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- Prior art keywords
- combination
- pharmaceutically acceptable
- azd5363
- acceptable salt
- cancer
- Prior art date
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 75
- 201000011510 cancer Diseases 0.000 title claims abstract description 65
- 238000011282 treatment Methods 0.000 title claims abstract description 45
- 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 117
- 150000003839 salts Chemical class 0.000 claims abstract description 97
- 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 40
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- 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 claims abstract description 33
- 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 claims abstract description 28
- 229960000853 abiraterone Drugs 0.000 claims abstract description 26
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-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 claims abstract description 23
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- 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 claims abstract description 15
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- 229930182816 L-glutamine Natural products 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
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- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
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- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 125000004942 pyridazin-6-yl group Chemical group N1=NC=CC=C1* 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- A61K31/13—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
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- 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
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- 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
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- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
AZD5363または薬学的に許容しうるその塩;
と、以下から選択されるアンドロゲン受容体シグナル伝達モジュレーター:
MDV−3100;
AZD3514;
アビラテロンもしくはそのエステルプロドラッグ;および
ビカルタミド;
または薬学的に許容しうるそれらの塩。
AZD5363または薬学的に許容しうるその塩;
と、以下から選択されるアンドロゲン受容体シグナル伝達モジュレーター:
MDV−3100;
AZD3514;
アビラテロンもしくは酢酸アビラテロン;および
ビカルタミド;
または薬学的に許容しうるそれらの塩。
AZD5363または薬学的に許容しうるその塩;
と、以下から選択されるアンドロゲン受容体シグナル伝達モジュレーター:
MDV−3100;
AZD3514;
酢酸アビラテロン;および
ビカルタミド;
または薬学的に許容しうるそれらの塩。
AZD5363または薬学的に許容しうるその塩;
と、以下から選択されるアンドロゲン受容体シグナル伝達モジュレーター:
MDV−3100;
AZD3514;
アビラテロン;および
ビカルタミド;
または薬学的に許容しうるそれらの塩。
(i)AZD5363または薬学的に許容しうるその塩を、薬学的に許容しうる希釈剤または担体と共同して含む薬学的組成物;および
(ii)‘組み合わせの他のパートナー’または薬学的に許容しうるその塩を、薬学的に許容しうる希釈剤または担体と共同して含む薬学的組成物。
既に上記したように、“組み合わせの他のパートナー”について言及する場合、文脈上そうではないことが必要でない限り、これは、本発明のさまざまなさらなる具体的態様を提供するために、MDV−3100;AZD3514;アビラテロンもしくはそのエステルプロドラッグ(例えば酢酸アビラテロン);またはビカルタミドの1つをさす。
a)第1の単位剤形にあるAZD5363または薬学的に許容しうる塩;
b)第2の単位剤形にある‘組み合わせの他のパートナー’(先に定義したような)または薬学的に許容しうるその塩;
c)前記第1および第2の剤形を入れるための容器手段;ならびに所望により
d)使用説明書。
a)第1の単位剤形にあるAZD5363または薬学的に許容しうるその塩;
b)第2の単位剤形にある‘組み合わせの他のパートナー’(先に定義したような)または薬学的に許容しうるその塩;ならびに
c)前記第1および第2の剤形を入れるための容器手段;ならびに所望により
d)使用説明書。
図のリスト
図1: AZD5363とMDV3100の併用による、LNCaP細胞における細胞成長の阻害および増大した細胞死。
図2: AZD5363とMDV3100の併用による、VCAP細胞における細胞成長の阻害および増大した細胞死。
図3: AZD5363とビカルタミドの併用による、LNCaP異種移植片モデルにおける増大した抗腫瘍効果。
図1は、単剤療法としてのAZD5363または0.1μM〜10μMの異なる5濃度のMDV−3100との組み合わせでのAZD5363の各濃度に対する、LNCaP細胞における平均成長%を示す(n=3)。正の値(0〜100%)は増殖抑制効果を示し、負の値(0〜−100%)は細胞致死を示している。これらの結果は、AZD5363が単剤療法としてLNCaP細胞の成長を阻害して細胞死を引き起こすことができ、この効果がMDV−3100との処置により相乗的に高められることを示している。
図2は、単剤療法としてのAZD5363または0.1μM〜10μMの5濃度のMDV−3100との組み合わせでのAZD5363の各濃度に対する、VCAP細胞における平均成長%を示す(n=3)。正の値(0〜100%)は増殖抑制効果を示し、負の値(0〜−100%)は細胞致死を示している。これらの結果は、AZD5363が単剤療法としてVCAP細胞の成長を阻害することができ、この効果がMDV−3100との処置により相乗的に高められることを示している。
図3は、AZD5363およびビカルタミドが関与する単剤療法および併用療法で処置したときのマウスにおける平均腫瘍体積を示している。図に明示していないが、図に示した“AZD5363+ビカルタミド”のデータは、AZD5363単独およびビカルタミド単独に関し図に示したものと同じ投与量およびスケジュール、すなわち、100mg/kg、1日2回(bd)、5日間投与、2日間投与なしのAZD5363を、50mg/kg、1日2回のビカルタミドと組み合わせることを包含する。
AZD5363とMDV−3100の組み合わせ
LNCaPおよびVCAP前立腺腫瘍細胞株(American Tissue Culture Collection)を、10%FCSおよび2mM L−グルタミンを補給したRMPI中で日常的に培養した。単剤療法として、または組み合わせでのAZD5363およびMDV−3100の細胞成長に対する効果を決定するために、Sytox Green終点を用いて増殖アッセイを実施して、5日後の生細胞数を測定した。簡単に説明すると、LNCAPまたはVCAP細胞を、384ウェルプレートに1ウェルあたりそれぞれ1500または2500細胞の密度で播種し、一晩放置して付着させた。その後、6×6のマトリックスフォーマットで、細胞に、AZD5363(0.01〜1μM)、MDV−3100(0.1〜10μM)または各作用物質の組み合わせを、濃度を次第に増加させて投薬した。化合物に5日間暴露した後、TBS−EDTA(TBS=トリス緩衝食塩水、EDTA=エチレンジアミン四酢酸)緩衝液で希釈したSytox Green核酸染料(Invitrogen)を0.13mmol/Lの最終濃度で細胞に加え、Acumen Explorerを用いて死亡細胞数を検出した。その後、サポニン(最終濃度0.03%、TBS−EDTA緩衝液で希釈)の添加により細胞を透過化し、一晩インキュベートし、全細胞総数を測定した。その後、生細胞総数を、1ウェルあたりの死亡細胞数を全細胞数から差し引くことにより決定した。実験開始時の生細胞数(Tz)を示すため、したがって、処置計画が細胞死をもたらしたか否かを示すために、投薬前の測定を行った。データは、以下のNCIの式を用いて成長%として表す:
Ti>/=Tzである場合の濃度では[(Ti−Tz)/(C−Tz)]×100
Ti<Tzである場合の濃度では[(Ti−Tz)/Tz]×100
これに関し、‘Tz’はゼロ時間目の生細胞数を表し、‘C’は対照の成長を表し、‘Ti’は各投薬計画の存在下での生細胞数を表す。この式により、−100%〜+100%の成長百分率が得られる。負の評点は細胞致死に関し、正の評点は増殖抑制に関する。データを図1および図2に表す。薬剤の組み合わせの相乗効果は、C.Harbronにより記載されている統一アプローチ(Stat.Med.2010年7月20日;29(16):1746−56)を用いて評価した。
3つの実験に関する組み合わせ指数(combination index)およびp値
<1の組み合わせ指数は相乗効果を示す。‘p値’は統計的有意性に関連する。
AZD5363とビカルタミドの組み合わせは、in vivoでの去勢抵抗性前立腺癌の異種移植片モデルにおいて、単剤療法より優れた腫瘍成長阻害をもたらす:LNCaP前立腺癌細胞(PTENヌル、アンドロゲン受容体陽性)を雄の無胸腺ヌードマウスの側腹部に移植した。腫瘍成長および血清中の前立腺特異抗原(PSA)の濃度をモニタリングした。血清PSAが50ng/mLを超えたら、マウスを去勢した。マウスを無作為に群に分け、PSA濃度が少なくとも50ng/mLに回復したときに処置を開始した。AZD5363単剤療法での処置(100mg/kg 1日2回、5日間投与、2日間投与なし)は腫瘍体積の56%阻害をもたらし、ビカルタミド単剤療法での処置(50mg/kg、1日1回)は腫瘍体積の42%阻害をもたらした。組み合わせたものはさらに著しく効果的であり、腫瘍体積の85%阻害をもたらした。このデータは、AZD5363とアンドロゲンアンタゴニストであるビスカルタミドとの組み合わせが十分に耐容され、単剤療法での同等用量の各化合物より優れた効果をもたらすことを示している。結果を図3に示す。
Claims (17)
- 以下を含む組み合わせ:
AZD5363または薬学的に許容しうるその塩;
と、以下から選択されるアンドロゲン受容体シグナル伝達モジュレーター:
MDV−3100;
AZD3514;
アビラテロンもしくはそのエステルプロドラッグ;および
ビカルタミド;
または薬学的に許容しうるそれらの塩。 - AZD5363または薬学的に許容しうるその塩と、MDV−3100であるアンドロゲン受容体シグナル伝達モジュレーターとを含む、請求項1に記載の組み合わせ。
- AZD5363または薬学的に許容しうるその塩と、アビラテロンもしくは酢酸アビラテロンまたは薬学的に許容しうるその塩であるアンドロゲン受容体シグナル伝達モジュレーターとを含む、請求項1に記載の組み合わせ。
- 医薬として用いるための、請求項1〜3のいずれか一項に記載の組み合わせ。
- 癌の処置における医薬として用いるための、請求項1〜3のいずれか一項に記載の組み合わせ。
- 癌が前立腺癌である、請求項5に記載の組み合わせ。
- 癌が去勢抵抗性前立腺癌である、請求項5に記載の組み合わせ。
- 以下を含むキット:
a)第1の単位剤形にあるAZD5363または薬学的に許容しうる塩;
b)第2の単位剤形にあるMDV−3100;
c)前記第1および第2の剤形を入れるための容器手段;
ならびに、所望により使用説明書。 - 以下を含むキット:
a)第1の単位剤形にあるAZD5363または薬学的に許容しうる塩;
b)第2の単位剤形にあるアビラテロンもしくは酢酸アビラテロンまたは薬学的に許容しうるその塩;
c)前記第1および第2の剤形を入れるための容器手段;
ならびに、所望により使用説明書。 - キットが癌の処置に用いるためのものである、請求項6または7に記載のキット。
- キットが前立腺癌の処置に用いるためのものである、請求項6または7に記載のキット。
- キットが去勢抵抗性前立腺癌の処置に用いるためのものである、請求項10に記載のキット。
- 癌の処置で用いるために、
薬学的に許容しうる希釈剤または担体と一緒であってもよい有効量のAZD5363または薬学的に許容しうるその塩;
および、薬学的に許容しうる希釈剤または担体と一緒であってもよい有効量のMDV−3100を、
そのような治療的処置を必要としているヒトなどの温血動物に同時、個別または逐次的に投与することを含む、併用処置。 - 癌の処置で用いるために、
薬学的に許容しうる希釈剤または担体と一緒であってもよい有効量のAZD5363または薬学的に許容しうるその塩;
および、薬学的に許容しうる希釈剤または担体と一緒であってもよい有効量のアビラテロンもしくは酢酸アビラテロンまたは薬学的に許容しうるその塩を、
そのような治療的処置を必要としているヒトなどの温血動物に同時、個別または逐次的に投与することを含む、併用処置。 - 前立腺癌を処置するための請求項13または14に記載の併用処置。
- 癌が去勢抵抗性前立腺癌である、請求項13または14に記載の併用処置。
- 癌が転移性去勢抵抗性前立腺癌である、請求項13または14に記載の併用処置。
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