JPWO2017030146A1 - 胆道癌治療剤 - Google Patents
胆道癌治療剤 Download PDFInfo
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- JPWO2017030146A1 JPWO2017030146A1 JP2017535551A JP2017535551A JPWO2017030146A1 JP WO2017030146 A1 JPWO2017030146 A1 JP WO2017030146A1 JP 2017535551 A JP2017535551 A JP 2017535551A JP 2017535551 A JP2017535551 A JP 2017535551A JP WO2017030146 A1 JPWO2017030146 A1 JP WO2017030146A1
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- cancer
- biliary tract
- pharmaceutical composition
- tract cancer
- therapeutic agent
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
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Abstract
Description
[1] 化合物Aまたはその薬理学的に許容される塩を含有する胆道癌治療剤。
[2] 化合物Aまたはその薬理学的に許容される塩を含有する胆道癌治療用医薬組成物。
[3] 化合物Aまたはその薬理学的に許容される塩を、それを必要とする患者に投与することを含む、胆道癌を治療する方法。
[4] さらに少なくとも1種の抗腫瘍剤を当該患者に投与することを含む、上記方法。
[5] 胆道癌治療のための化合物Aまたはその薬理学的に許容される塩。
[6] 胆道癌治療のための化合物Aまたはその薬理学的に許容される塩を含有する医薬組成物。
[7] 化合物Aまたはその薬理学的に許容される塩の胆道癌治療のための使用。
[8] 胆道癌治療剤または胆道癌治療用医薬組成物を製造するための化合物Aまたはその薬理学的に許容される塩の使用。
[9] さらに賦形剤を含有する、上記治療剤または医薬組成物。
[10] 上記化合物Aまたはその薬理学的に許容される塩が、化合物Aのメタンスルホン酸塩である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[11] 胆道癌が肝内胆管癌、肝外胆管癌、胆嚢管癌、胆嚢癌または十二指腸乳頭部癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[12] 胆道癌が肝内胆管癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[13] 胆道癌が肝外胆管癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[14] 胆道癌が胆嚢管癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[15] 胆道癌が胆嚢癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[16] 胆道癌が十二指腸乳頭部癌である、上記治療剤、医薬組成物、治療方法、使用または化合物。
[17] 化合物Aまたはその薬理学的に許容される塩が、1日あたり1〜100mgの投与量で経口投与されることを特徴とする、上記治療剤、医薬組成物、治療方法、使用または化合物。
各群6例のヌードマウス(CAnN.Cg−Foxn1nu/CrlCrlj、雌、日本チャールズリバー株式会社)を使用して、化合物Aを投与した場合の抗腫瘍効果を評価した。ヒト由来の肝外胆管癌細胞株TFK−1(理研バイオリソースセンター)を、RPMI1640培地(和光純薬工業株式会社、10%FBS含有)に、2×108個/mLの濃度となるように懸濁し、十分に混和した。その混和液をさらに等量のマトリゲル基底膜マトリクス(コーニング社)と混合して1×108個/mLの細胞混和液を調製し、各マウスの右脇腹皮下部に、0.1mLずつ移植した。移植から7日後に、腫瘍の長径および短径を電子デジタルノギス(ABSデジマチックキャリパ、株式会社ミツトヨ)で測定した。各群の腫瘍体積の平均値がほぼ等しくなるように、マウスを群分けした。なお、腫瘍の体積を、以下の式に従って算出した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
各群5例のヌードマウス(CAnN.Cg−Foxn1nu/CrlCrlj、雌、日本チャールズリバー株式会社)を使用して、化合物Aを投与した場合の抗腫瘍効果を評価した。ヒト由来の胆管癌細胞株OZ(JCRB細胞バンク)を、Williams’E(シグマアルドリッチ社、2mmol/L L−グルタミン,10%FBS含有)に、2×108個/mLの濃度となるように懸濁し、十分に混和した。その混和液をさらに等量のマトリゲル基底膜マトリクス(コーニング社)と混合して1×108個/mLの細胞混和液を調製し、各マウスの右脇腹皮下部に、0.1mLずつ移植した。移植から13日後に、腫瘍の長径および短径を電子デジタルノギス(ABSデジマチックキャリパ、株式会社ミツトヨ)で測定した。各群の腫瘍体積の平均値がほぼ等しくなるように、マウスを群分けした。なお、腫瘍の体積を、以下の式に従って算出した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
各群6例のヌードマウス(CAnN.Cg−Foxn1nu/CrlCrlj、雌、日本チャールズリバー株式会社)を使用して、化合物Aを投与した場合の抗腫瘍効果を評価した。ヒト由来のヒト十二指腸乳頭部癌細胞株SNU−869(Creative Bioarray社)を、RPMI1640培地(和光純薬工業株式会社、25mM HEPES、10%FBS含有)に、2×108個/mLの濃度となるように懸濁し、十分に混和した。その混和液をさらに等量のマトリゲル基底膜マトリクス(コーニング社)と混合して1×108個/mLの細胞混和液を調製し、各マウスの右脇腹皮下部に、0.1mLずつ移植した。移植から7日後に、腫瘍の長径および短径を電子デジタルノギス(ABSデジマチックキャリパ、株式会社ミツトヨ)で測定した。各群の腫瘍体積の平均値がほぼ等しくなるように、マウスを群分けした。なお、腫瘍の体積を、以下の式に従って算出した。
腫瘍体積(mm3)=長径(mm)×短径(mm)×短径(mm)/2
本治験は、切除不能の胆道癌に対しゲムシタビンを含む2剤併用化学療法(ゲムシタビンおよびシスプラチン、またはゲムシタビンおよび他の白金製剤もしくはフッ化ピリミジン製剤の2剤併用化学療法)の前治療歴1レジメンを有する患者を対象とした多施設共同、単群、非盲検の臨床試験であった。
(1)組織学的または細胞学的に腺癌と診断された胆道癌(肝内胆管癌、肝外胆管癌、胆嚢癌、Vater膨大部癌)患者
(2)切除不能(例:局所進行または転移を有する)の胆道癌を有する患者
(3)切除不能の胆道癌に対してゲムシタビンを含む2剤併用化学療法(例:ゲムシタビンおよびシスプラチン)の前治療を1レジメン受けており、それ以外の胆道癌に対する化学療法を受けていない患者
ここで、術後補助化学療法を受けた患者は、当該療法が完了しており、完了後6ヵ月間再発が認められない場合には適格とする。
(4)以下の基準を満たす測定可能な病変を有する患者
Response Evaluation Criteria in Solid Tumors 1.1(RECIST1.1)に基づき、CTまたはMRIを用いて、非リンパ節の場合は長径が1.0cm以上またはリンパ節の場合は短径が1.5cm以上の継続的に測定可能な病変を少なくとも1つ有する。
放射線外照射療法(EBRT)またはラジオ波(RF)焼灼などの局所療法を受けた病変を標的病変とする場合は、RECIST1.1に基づく病勢の進行が認められていること。
(5)Eastern Cooperative Oncology Group(ECOG)Performance Statusが0〜1の患者
(6)本治験薬投与開始後、3ヵ月以上の生存が見込まれる患者
(7)同意取得時の年齢が20歳以上の男性または女性
(8)脱毛、不妊および選択基準の範囲内の有害事象を除く、化学療法または放射線療法に関連した全ての毒性がCommon Terminology Criteria for Adverse Events(CACAE v4.03)でGrade0〜1まで回復している患者
(9)降圧剤使用の有無にかかわらず血圧(BP)が十分にコントロールされている(定義:収縮期血圧150mmHg以下および拡張期血圧90mmHg以下、かつ、本治験薬投与開始前の1週間以内に降圧剤の変更がない)患者
(10)主要臓器機能および抗凝固能が十分保たれている患者
1)好中球数(ANC)≧1500/mm3(≧1.5×103/μL)
2)血小板数≧100,000/mm3(≧100×109/L)
3)ヘモグロビン≧9.0g/dL
4)総ビリルビン≦2.0 mg/dL(非抱合型高ビリルビン血症またはGilbert症候群の場合を除く)
5)ALP、AST およびALT≦3.0×ULN(施設基準値上限)(肝転移を有する場合は≦5.0×ULN)
6)クレアチニン・クリアランス≧40 mL/min(Cockcroft−Gault法)
7)プロトロンビン時間国際標準比(PT−INR)≦1.5
(11)自由意志により本治験参加に文書で同意した患者
(12)治験実施計画書を遵守する意思があり、かつ、遵守することができる患者
(1)本治験薬投与開始前の21日以内に抗がん治療(BSCを除く)を受けた患者
(2)本治験薬投与開始前の21日以内に大手術(麻酔または呼吸補助を要する手術)を受けた患者、または本治験中に手術が計画されている患者(胆道ドレナージを除く)
(3)中等度、高度またはドレナージを要する腹水を有する患者
(4)尿試験紙で2+以上の蛋白尿を有する患者(定量評価でGrade1以下の場合は適格とする)
(5)消化管の吸収不良、または治験責任医師もしくは治験分担医師により本治験薬の吸収に影響を与える可能性があると判断されるその他の身体状態を示す患者
(6)本治験薬投与開始前の6ヵ月以内に、New York Heart Association分類でクラス2以上のうっ血性心不全、不安定狭心症、心筋梗塞または臨床的意義のある心血管障害に関連した重篤な不整脈を有する患者
(7)QT/QTc間隔延長(QTcF>480ms)を有する患者
(8)HIV抗体検査で陽性と判明している患者
(9)全身療法を要する活動性の感染症を有する患者
(10)出血性もしくは血栓性疾患を有する、またはINRモニタリングを要するワーファリンもしくは同種の薬剤などの抗凝固薬(低分子量へパリンの使用は可)を慢性使用している患者
(11)本治験薬投与開始前の21日以内に消化管出血または活動性喀血(小さじ1/2以上の鮮血)が認められた患者
(12)本治験薬投与開始前の24ヵ月以内に活動性の悪性腫瘍を有する患者(胆道癌、完全に処置された非浸潤性メラノーマ、皮膚の基底細胞癌または扁平上皮癌、非浸潤性子宮頚部癌および早期胃癌/大腸癌は除く)
(13)髄膜癌腫症と診断された患者
(14)脳または硬膜下転移を有する患者。ただし、本治験薬投与開始の28日以上前に、局所の治療が既に完了しており、当該転移の治療として副腎皮質ホルモンの投与を中止している患者は除く。本治験薬投与開始の28日以上前に脳転移の徴候(例えば放射線検査上)または症状が安定していなければならない。
(15)本治験薬または賦形剤の成分に忍容性がないと判明している患者
(16)本治験薬投与開始前の24ヵ月以内に薬物もしくはアルコールの依存または乱用の既往がある患者
(17)医学的またはその他の理由により、治験責任医師または治験分担医師が本治験の参加対象として不適格と判断した患者
(18)女性の場合には、スクリーニング時またはベースライン時に、授乳中または妊娠している患者(ヒト絨毛性ゴナドトロピン[hCGまたはβ−hCG]検査で陽性が確認された患者)。スクリーニング時の検査が本治験薬投与開始より3日以上前に行われた場合には、当該検査で陰性であったとしても、再度検査をする必要がある。
(19)生殖能力のある男性および妊娠する可能性のある女性の場合、本人およびそのパートナーが治験期間を通じて医学的に適切な避妊方法を用いることに同意しない患者
上記避妊方法においては、コンドーム、避妊用スポンジ、避妊用フォーム、避妊用ゼリー、避妊用ペッサリーもしくは避妊リングを使用、または本治験薬投与開始の28日以上前から経口(経皮または経膣も可能)の避妊薬を使用すること。
本臨床試験の中間解析を行った。中間解析対象の患者総数は17人であり、そのうち肝外胆管癌患者は3人、肝内胆管癌患者4人、胆嚢癌患者は9人、十二指腸乳頭部癌患者は1人であった。
中間解析の結果、部分奏効(PR)は1人(5.9%)、安定(SD;6週以上)は13人(76.5%)であった。また、SD13人のうち8人において、腫瘍縮小傾向が確認された。
Claims (15)
- 4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキサミドまたはその薬理学的に許容される塩を含有する胆道癌治療剤。
- 4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキサミドまたはその薬理学的に許容される塩を含有する胆道癌治療用医薬組成物。
- 薬理学的に許容される塩が、メタンスルホン酸塩である請求項1に記載の治療剤または請求項2に記載の医薬組成物。
- さらに賦形剤を含有する請求項1〜3のいずれか1項に記載の治療剤または医薬組成物。
- 胆道癌が肝内胆管癌、肝外胆管癌、胆嚢管癌、胆嚢癌または十二指腸乳頭部癌である、請求項1〜4のいずれか1項に記載の治療剤または医薬組成物。
- 胆道癌が肝内胆管癌である、請求項5に記載の治療剤または医薬組成物。
- 胆道癌が肝外胆管癌である、請求項5に記載の治療剤または医薬組成物。
- 胆道癌が胆嚢管癌である、請求項5に記載の治療剤または医薬組成物。
- 胆道癌が胆嚢癌である、請求項5に記載の治療剤または医薬組成物。
- 胆道癌が十二指腸乳頭部癌である、請求項5に記載の治療剤または医薬組成物。
- 4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキサミドまたはその薬理学的に許容される塩が、1日あたり1〜100mgの投与量で経口投与されることを特徴とする、請求項1〜10のいずれか1項に記載の治療剤または医薬組成物。
- 4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキサミドまたはその薬理学的に許容される塩を、それを必要とする患者に投与することを含む、胆道癌を治療する方法。
- さらに少なくとも1種の抗腫瘍剤を当該患者に投与することを含む、請求項12の方法。
- 胆道癌治療のための4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキサミドまたはその薬理学的に許容される塩を含有する医薬組成物。
- 胆道癌治療用医薬組成物を製造するための4−[3−クロロ−4−(シクロプロピルアミノカルボニル)アミノフェノキシ]−7−メトキシ−6−キノリンカルボキサミドまたはその薬理学的に許容される塩の使用。
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2016
- 2016-08-17 SG SG11201800865WA patent/SG11201800865WA/en unknown
- 2016-08-17 KR KR1020187003198A patent/KR20180037953A/ko not_active Application Discontinuation
- 2016-08-17 EP EP16837135.9A patent/EP3338778A4/en not_active Withdrawn
- 2016-08-17 US US15/748,980 patent/US20190000829A1/en not_active Abandoned
- 2016-08-17 AU AU2016308390A patent/AU2016308390A1/en not_active Abandoned
- 2016-08-17 JP JP2017535551A patent/JPWO2017030146A1/ja active Pending
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- 2016-08-17 WO PCT/JP2016/074017 patent/WO2017030146A1/ja active Application Filing
- 2016-08-17 SG SG10201913215YA patent/SG10201913215YA/en unknown
- 2016-08-17 CA CA2994224A patent/CA2994224A1/en not_active Abandoned
- 2016-08-17 RU RU2018103737A patent/RU2728932C2/ru active
- 2016-08-17 BR BR112018002239-0A patent/BR112018002239A2/ja not_active Application Discontinuation
- 2016-08-17 CN CN201680044979.XA patent/CN107921039A/zh active Pending
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Also Published As
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US20190000829A1 (en) | 2019-01-03 |
WO2017030146A1 (ja) | 2017-02-23 |
EP3338778A4 (en) | 2019-04-17 |
IL257292A (en) | 2018-03-29 |
BR112018002239A2 (ja) | 2018-09-18 |
RU2728932C2 (ru) | 2020-08-03 |
MX2018001439A (es) | 2018-05-28 |
EP3338778A1 (en) | 2018-06-27 |
SG10201913215YA (en) | 2020-02-27 |
KR20180037953A (ko) | 2018-04-13 |
AU2016308390A1 (en) | 2018-02-22 |
CA2994224A1 (en) | 2017-02-23 |
SG11201800865WA (en) | 2018-02-27 |
RU2018103737A (ru) | 2019-09-19 |
RU2018103737A3 (ja) | 2019-10-11 |
CN107921039A (zh) | 2018-04-17 |
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