Copanlisib 注射用冻干制剂

1ᰕᵏ˖⌘ຎ䈤᰾Җ⭘Ǐ㦟૱਽〠ǐຎ୶૱਽〠˖ྕ㖇ᐤ®˄ALIQOPA®˅㤡᮷਽〠˖Copanlisib Hydrochloride for Injection≹䈝᤬丣˖Zhusheyong Yansuan KepanlisaiǏᡀԭǐຎॆᆖ਽〠˖2-≘ส-N-{7-⭢≗ส-8-[3-˄ੇ୹-4-ส˅щ≗ส]-2,3-Ҽ≒૚ୁᒦ[1,2-c]௩ୁ୹-5-ส}౗஦-5-⭢䞠㜪Ҽⴀ䞨ⴀॆᆖ㔃ᶴᔿ˖

ᆀᔿ˖C23H28N8O4•2HClᆀ䟿˖553.45䖵ᯉ˖ᰐ≤ᷨ€䞨ǃ⭈䵢䞷ǃ≒≗ॆ䫐DŽǏᙗ⣦ǐᒢඇ⣦⢙DŽǏ䘲ᓄ⯷ǐᵜ૱䘲⭘Ҿᰒᖰ᧕ਇ䗷㠣ቁє⿽㌫㔏ᙗ⋫⯇Ⲵ༽ਁᙗ└⌑ᙗ⏻ᐤⱔ˄ FL˅ᡀӪᛓ㘵DŽк䘠䘲ᓄ⯷DŽҾਾᵏ⺞䇱ᙗ䲿ᵪሩ➗Ѥᒺ䈅傼Ⲵ㔃᷌DŽǏ㿴Ṭǐ60 mg ˄᤹C23H28N8O4䇑 ˅Ǐ⭘⌅⭘䟿ǐ䟿

2䟿Ѫ 60 mg/ ⅑ˈ䟷⭘䰤ⅷᙗ㔉㦟ᯩṸˈԕ 28 ཙѪањ⋫⯇ઘᵏˈ൘⇿њ⋫⯇ઘᵏⲴㅜ 1ǃ8 ઼ 15⧠нਟ㙀ਇⲴ∂ᙗ৽ᓄ˄৲㿱ǏǏ⌘᜿һ亩ǐ˅DŽᵜ૱ԕ䶉㜹䗃⌘㔉㦟ˈ⇿⅑䗃⌘ᰦ䰤ᓄᤱ㔝 1 ሿᰦDŽ䟿䈳ᮤ䟿䈳ᮤᯩṸ䴰ሩᛓ㘵Ⲵオ㞩㹰㌆઼㹰঻䘋㹼䇴ՠˈྲᆈ൘ᔲᑨˈṩᦞ㺘 1䟿DŽṩᦞ㺘 1䟿ǃᔦ䘏⋫⯇ᡆ㓸→⋫⯇ˈ䘋㹼∂ᙗ㇑⨶DŽ∂ᙗˈᓄ㓸→⋫⯇DŽ㺘 1˖ 䟿䈳ᮤ઼∂ᙗ㇑⨶ a∂ᙗ ࡛b ᧘㦀Ⲵ㇑⨶ᯩṸᝏḃ˄৲㿱ǏǏ⌘᜿һ亩ǐ˅3 㓗㓗ᡆԕк ᵜ૱⋫⯇ˈⴤ㠣ᝏḃ⎸䘰DŽⲴ⯁լ㙦∿㛪ᆒᆀ㲛㛪⚾˄PJP˅ᝏḃᵜ૱⋫⯇DŽྲ᷌⺞䇔ᝏḃˈᓄ㔉Ҹ⋫⯇ˈⴤ㠣ᝏ䟿䟽ᯠᔰ࿻ᵜ૱⋫⯇ˈᒦ㚄ਸ㔉Ҹ PJP 亴䱢⭘㦟DŽ儈㹰㌆⯷˄৲㿱ǏǏ⌘᜿һ亩ǐ˅オ㞩㹰㌆•PJG/ˈᡆ䲿ᵪ䶎オ㞩㹰㌆•PJG/ᵜ૱⋫⯇ˈⴤ㠣オ㞩㹰㌆”mg/dLˈᡆ䲿ᵪ/䶎オ㞩㹰㌆”mg/dLDŽᡆ㔉㦟ਾ㹰㌆•PJG/ᵜ૱⋫⯇ˈⴤ㠣オ㞩㹰㌆”PJG/ˈᡆ䲿ᵪ/䶎オ㞩㹰㌆”PJG/䟿Ӿ 60mgቁ㠣 45 mgˈᒦ㔤ᤱ⋫⯇DŽᵜ૱⋫⯇ˈⴤ㠣オ㞩㹰㌆”PJG/ˈᡆ䲿ᵪ/䶎オ㞩㹰㌆”PJG/䟿Ӿ 45mgቁ㠣 30 mgˈᒦ㔤ᤱ⋫⯇DŽྲ᷌൘ 30 mg䟿лӽᤱ㔝ᆈ൘儈㹰㌆ˈ㓸→ᵜ૱⋫⯇DŽ儈㹰঻˄৲㿱ǏǏ⌘᜿һ亩ǐ˅㹰঻˄BP˅•PP+Jcᵜ૱⋫⯇ˈⴤ㠣䘎㔝є⅑˄㠣ቁ䰤䳄 15٬150/90mmHgDŽ㔉㦟ਾ㹰঻•PP+Jc ˄нড৺⭏ભ˅˖㔗㔝䟿㔤ᤱᵜ૱⋫⯇DŽྲ᷌䴰㘳㲁ሶᵜ૱䟿Ӿ 60 mgቁ㠣 45 mgˈᡆӾ45 mgቁ㠣 30 mgDŽྲ᷌㔉Ҹᣇ儈˄㹰঻˚150/90 mmHg㓸→ᵜ૱⋫⯇DŽ⧠ড৺⭏ભⲴ㹰঻ॷ儈 㓸→ᵜ૱⋫⯇DŽ䶎ᝏḃᙗ㛪⚾˄NIP˅˄৲㿱ǏǏ⌘᜿㓗ᵜ૱㔉㦟ˈᒦ⋫⯇ NIPDŽྲ᷌NIP ᚒ༽㠣 0 㓗ᡆ 1ԕ 45 mg䟿䟽ᯠ㔉Ҹᵜ૱DŽ3∂∂ᙗ н࡛b ᧘᧘㦀Ⲵ㇑⨶ᯩṸһһ亩ǐ˅ ྲ᷌ 2 㓗 NIP㓸→ᵜ૱⋫⯇3 㓗㓗ᡆԕк 㓸→ᵜ૱⋫⯇DŽѝ߿ቁ⯷˄৲㿱Ǐ⌘᜿һ亩ǐ˅ѝᙗ㋂㓶㜎㔍ሩ䇑ᮠ˄ANC˅˅aî3 њ㓶㜎PP3䟿DŽ㠣ቁ⇿ઘⴁ⍻а⅑ANCDŽ$1&î3 њ㓶㜎PP3ᵜ૱⋫⯇DŽ㠣ቁ⇿ઘⴁ⍻а⅑ANCˈⴤ㠣 ANC•0.5×103 њ㓶㜎/mm3䟿䟽ᯠ㔉Ҹᵜ૱DŽ⧠ $1&”î3 њ㓶㜎/mm3ቁ㠣 45 mgDŽ䟽ᓖⳞ㛔৽ᓄ˄৲㿱ǏǏ⌘᜿һ亩ǐ˅3 㓗ᵜ૱⋫⯇ˈⴤ㠣∂ᙗᚒ༽ˈᒦሶ䟿Ӿ 60 mgቁ㠣 45 mgˈᡆӾ 45 mgቁ㠣 30 mgDŽড৺⭏ભ 㓸→ᵜ૱⋫⯇DŽቁ⯷˄৲㿱ǏǏ⌘᜿һ亩ǐ˅î/ᵜ૱⋫⯇˗൘㹰ሿᶯ≤ᒣᚒ༽㠣•î9/L ਾ䟽ᯠᔰ࿻⋫⯇˖z ྲ᷌൘ 21ሶᵜ૱䟿Ӿ 60 mgቁ㠣 45 mgˈᡆӾ 45 mgቁ㠣 30 mgDŽz ྲ᷌ᵚ൘ 21㓸→ᵜ૱⋫⯇DŽԆ䟽ᓖնнড৺⭏ભⲴ∂ᙗ˄৲㿱ǏǏ⌘᜿һ亩ǐ˅3 㓗ᵜ૱⋫⯇ˈⴤ㠣∂ᙗᚒ༽ˈᒦሶ䟿Ӿ 60 mgቁ㠣 45 mgˈᡆӾ 45 mgቁ㠣 30 mgDŽa ԫօє⅑䘎㔝䗃⌘㠣ቁ䰤䳄 7 ཙDŽb˄NCI-CTCAE˅4.03 ⡸DŽc 㾱≲᭦㕙঻<150 mmHg ф㡂ᕐ঻<90 mmHgDŽ

оᕪ᭸ CYP3A䟿䈳ᮤ⭘ᕪ᭸ CYP3Aቁ㠣 45 mgຎоᕪ᭸ CYP3Aຎ᳤䵢˄AUC࣐∂ᙗ仾䲙˄৲㿱ǏǏ㦟⢙⴨ӂ֌⭘ǐ˅DŽ⢩↺Ӫ㗔ޘ䖫ᓖ㛍ᦏՔᛓ㘵˄ᙫ㛶㓒㍐ ”к䲀[ULN]≘䞨≘ส䖜〫䞦[AST]>ULNˈᡆᙫ㛶㓒㍐>1 㠣 1.5ؽULN ઼ԫ᜿ AST䟿DŽѝᓖ㛍ᦏՔ˄Child-Pugh B䟿䱽վ㠣 45 mgDŽ䟽ᓖ㛍ᦏՔ˄Child-Pugh C䟿䱽վ㠣 30 mgDŽޘຎ൘᧕ਇᡆн᧕ਇ䘿᷀Ⲵ㓸ᵛᵏ㛮⯵˄⭘ C-Gᔿՠ㇇Ⲵ CLcr<15 mL/min ˅ᛓ㘵ѝᆖቊн᰾˄৲㿱Ǐᆖǐ˅DŽ4㘱㘱ᒤӪ䟿DŽㄕቊᰐᵜ૱⭘Ҿ 18 ኱ԕлᛓ㘵ⲴѤᒺ⹄ウ䍴ᯉDŽ઼㔉㦟ᵜ૱ӵ⭘Ҿ䶉㜹䗃⌘DŽ㔉㦟DŽӵਟ⭘ᰐ㧼 0.9%≟ॆ䫐⌘ሴ⏢༽ⓦ〰䟺DŽ␧ਸᡆ⌘ሴDŽ༽ⓦ䈤᰾ᵜ૱䴰⭘ 4.4 mL ᰐ㧼 0.9% ⎃ᓖѪ 15 mg/mL Ⲵⓦ⏢DŽƔ ⭘ᑖ䪸ཤⲴ 5 mL ᰐ㧼⌘ሴಘᣭਆ 4.4 mL ᰐ㧼 0.9% ≟ॆ䫐⌘ሴ⏢DŽƔ DŽƔ 䖫䖫᩷ᱳ㦟⬦ 30ᒢ㊹ⓦ䀓DŽƔ 䶉㖞 1≄⌑кॷ㠣⏢䶒DŽƔ 䟽༽䖫઼᩷䶉㖞᫽֌DŽƔ ⴞ⍻Ựḕᴹᰐ仌㢢ਈॆ઼仇㋂⢙DŽ༽ⓦਾˈⓦ⏢ᓄѪᰐ㢢㠣␑哴㢢DŽƔ ᰐਟ㿱ᔲ⢙ਾˈᣭਆ䈕ⓦ⏢䘋а↕〰䟺DŽ䶉㜹㔉㦟Ⲵ〰䟺䈤᰾൘ 100 mL ᰐ㧼 0.9% ≟ॆ䫐⌘ሴ⏢ѝ䘋а↕〰䟺༽ⓦ⏢DŽ⭘ᰐ㧼⌘ሴಘᣭ䟿ᡰ䴰Ⲵ䘲䟿༽ⓦ⏢˖60 mg˖⭘ᰐ㧼⌘ሴಘᣭਆ 4 mL ༽ⓦ⏢DŽ45 mg˖⭘ᰐ㧼⌘ሴಘᣭਆ 3 mL ༽ⓦ⏢DŽ30 mg˖⭘ᰐ㧼⌘ሴಘᣭਆ 2 mL ༽ⓦ⏢DŽޕ100 mL ᰐ㧼 0.9% DŽᶕഎ仐␧रDŽ⭘Ⲵ༽ⓦ⏢ᡆ〰䟺ⓦ⏢DŽⲴ〰䟺ⓦ⏢Ҿ ႏaႏᆈнᗇ䎵䗷 24֯ⴤሴDŽ

Ǐн㢟৽ᓄǐԕлн㢟৽ᓄ৲㿱Ǐ⌘᜿һ亩ǐ˖Ɣ ᝏḃ5Ɣ 儈㹰㌆⯷Ɣ 儈㹰঻Ɣ 䶎ᝏḃᙗ㛪⚾Ɣ ቁ⯷Ɣ ѕ䟽Ⳟ㛔н㢟৽ᓄѤѤᒺ䈅傼㓿傼⭡ҾѤᒺ䈅傼ᱟ൘ᐞᔲᖸབྷⲴᶑԦлᔰኅⲴˈഐ↔൘Ḁ⿽㦟⢙ⲴѤᒺ䈅傼Ⲵн㢟Ⲵн㢟৽ᓄਁ⭏⦷DŽᙗ⢩ᖱᙫ㔃ᙗ⢩ᖱสҾѤᒺ⹄ウѝ 317ຎঅ㦟⋫⯇ਇ䈅㘵ⲴᮠᦞDŽຎঅ㦟⋫⯇Ⲵ䶎䴽ཷ䠁⏻ᐤⱔ˄ NHL˅˄ᜠᙗ㻝ᙗ˅઼ᇎփⱔᛓ㘵ᣕ੺Ⲵᴰѕ䟽н㢟৽ᓄѪ㛪䜘⚾⯷ǃлબ੨䚃ᝏḃቁ⯷DŽ൘Ѥᒺ⹄ウѝˈᴰᑨ㿱Ⲵн㢟৽ᓄ˄ı 20%઼㋮ቁ⯷઼ѝᙗ㋂㓶ቁ⯷DŽຎঅ㦟⋫⯇Ⲵ NHL㻝ᙗ˅઼ᇎփⱔਇ䈅㘵ᣕ੺Ⲵн㢟৽ᓄ᤹ MedDRAҾл㺘 2DŽDŽ㺘 ˖ຎঅ㦟⋫⯇ᛓ㘵ᣕ੺Ⲵ㦟⢙н㢟৽ᓄ㊫ 䶎ᑨᑨ㿱ı1/10ᑨ㿱ı1/100 㠣˘1/10нᑨ㿱ı1/1000 㠣˘1/100㹰⏢৺⏻ᐤ㌫㔏⯮⯵ ቁ⯷ǃѝᙗቁ⯷*ǃ㹰ሿቁ⯷ቁ⯷ǃਁቁ⯷*ǃఌ䞨㋂㓶㜎໎ཊ⯷

㛳㛐㌫㔏⯮⯵ 㞩⌫ǃᚦᗳǃਓ㞄哿㟌⚾˄वᤜਓ૭㌌⛲઼⒳⯑ԕ৺ਓ㞄⯬Ⰻ˅䭉ǃਓᒢǃ੎૭ഠ䳮㜠㞪⚾䓛ᙗᙗ⯮⯵৺㔉㦟䜘ս਴⿽৽ᓄл䱽˅㋈㟌⚾⯷ǃ⌘ሴ䜘ս਴⿽৽ᓄ

⯛㌫㔏⯮⯵ 䎵᭿৽ᓄ˄वᤜ䗷᭿ᙗ≤㛯઼㹰㇑ᙗ≤㛯ǃ㹰㇑㡂ᕐ઼▞㓒৽ᓄ˅

ḃ㊫⯮⯵ лબ੨䚃ᝏḃ**˄वᤜᵟ䈝ᝏḃᙗ㛪⚾**ǃ㓶

6㧼ᙗ㛪⚾ǃ㛪⚾⨳㧼ᙗ㛪⚾ǃⵏ㧼ᙗ㛪⚾ǃ⯵∂ᙗ㛪⚾ǃ㙦∿㛪ᆒᆀ㲛㛪⚾ǃ᭟≄㇑㛪ᴢ䴹⯵઼㛪䜘ᝏḃ**˅਴਴㊫Ựḕ 㜲㛚䞦ॷ儈ǃ⏰㊹䞦ॷ儈

ԓ㊫⯮⯵ 儈㹰㌆⯷* 儈㜲㹰⯷ǃ儈㜠ዋ㍐㹰⯷ǃ✖⑤

਴਴㊫⾎㓿㌫㔏⯮⯵ ᝏ㿹ᔲᑨ઼ᝏ㿹䘏䫍બબ੨㌫㔏ǃ㜨৺㓥䳄⯮⯮⯵㛪䜘⚾⯷˄वᤜ䰤䍘ᙗ㛪⯮⯵઼䶎ᝏḃᙗ㛪䜘⚾⯷˅

Ⳟ㛔৺Ⳟл㓴㓷㊫⯮⯵㝡ᙗⳞ㛔৽ᓄ˅㝡ਁ㹰㇑о⏻ᐤ㇑㊫⯮⯵ 儈㹰঻˄वᤜ㔗ਁᙗ儈㹰঻˅

*ֻ**DŽ

൘ NHL ઼ᇎփ㛯ⱔਇ䈅㘵ѝᔰኅⲴᔰ᭮ᙗ I ᵏ઼ II ᵏঅ㦟⋫⯇⹄ウѝ㿲ሏ⧠Ⲵᇎ傼ᇔỰḕ㔃᷌ᔲᑨ৲㿱㺘 3DŽ㺘 3˖NHL ઼ᇎփⱔਇ䈅㘵Ⲵ I ᵏ II⧠Ⲵᇎ傼ᇔỰḕᔲᑨ˄ı10%˅ᇎ傼ᇔỰḕᤷḷ ຎঅঅ㦟⋫⯇˄N=317*ֻᛓᛓ㘵˅ᡰᴹㅹ㓗**(%)3 㓗㓗** (%) 4 㓗㓗** (%)㹰⏢৺⏻ᐤ㌫㔏⯮⯵ቁ 84 8 0⏻ᐤ㓶㜎䇑ᮠ䱽վ 75 28 5㹰ሿᶯ䇑ᮠ䱽վ 56 6 3ѝᙗ㋂㓶㜎䇑ᮠ䱽վ 53 11 13㊫⯮⯵㹰㪑㨴㌆ॷ儈 96 38 3㹰⼧䞨ⴀ䗷ቁ 40 13 0਴㊫Ựḕ࣐ 21 2 1㜲㛚䞦ॷ儈 18 5 1* ᮠDŽ**ˈ4.03 ⡸

7Ԇ㹰⏢㌫㔏ᚦᙗ㛯ⱔѤᒺ䈅傼㓿傼ᙫ㔃ຎ 60 mg ᡆ 0.8 mg/kg䟿অ㦟⋫⯇Ⲵ 168Ԇ㹰⏢㌫㔏ᚦᙗ㛯ⱔᛓ㘵DŽѝս⋫⯇ᤱ㔝ᰦ䰤Ѫ 22ઘ˄㤳ത aઘ˅DŽᴹ 44˄26%˅ᛓ㘵ᣕ੺ѕ䟽н㢟৽ᓄDŽᴰᑨ㿱Ⲵѕ䟽н㢟৽ᓄѪᝏḃᙗ㛪⚾˄8%˅ǃ㛪䜘⚾⯷˄5%˅઼儈㹰㌆⯷˄5%˅DŽᴰᑨ㿱Ⲵн㢟৽ᓄ˄•˅ቁ⯷ǃѝᙗ㋂㓶ቁ⯷DŽн㢟৽ᓄሬ㠤 36˄21%ቁˈ27˄16%˅ᛓ㘵㓸→⋫⯇DŽቁⲴᴰᑨ㿱৏ഐѪ儈㹰㌆⯷˄ 7%ቁ⯷˄ 5%˅઼儈㹰঻˄5%˅DŽ㓸→⋫⯇Ⲵᴰᑨ㿱৏ഐᱟ㛪䜘⚾⯷˄2%˅઼儈㹰㌆⯷˄2%˅DŽ㺘 4ຎঅ㦟⋫⯇㓴ਁ⭏⦷•Ⲵн㢟৽ᓄˈ㺘 4 ᙫ㔃Ҷਟ⌞ຎ⋫⯇ѝਁ⭏⦷•Ⲵᇎ傼ᇔỰḕᔲᑨ઼ਁ⭏⦷•Ⲵ•㓗ᇎ傼ᇔỰḕᔲᑨDŽ㺘㺘 4˖ Ԇ㹰⏢㌫㔏ᚦᙗ㛯ⱔᛓ㘵ѝਁ⭏⦷•Ⲵн㢟৽ᓄн㢟৽ᓄຎ 1 ࡛3 㓗㓗 4 㓗㓗n˄˄%˅˅ n ˄˄%˅˅ n ˄˄%˅˅㊫⯮⯵儈㹰㌆⯷ 90 (54%) 56 (33%) 10 (6%)㹰⏢৺⏻ᐤ㌫㔏⯮⯵ቁ⯷ 61 (36%) 20 (12%) 26 (15%)ቁ⯷ a 53 (32%) 16 (10%) 26 (15%)ቁ⯷ 37 (22%) 12 (7%) 2 (1%)㌫㔏ᙗ⯮⯵৺㔉㦟䜘ս਴⿽৽ᓄл䱽 b 61 (36%) 6 (4%) 0㛳㛐㌫㔏⯮⯵㞩⌫ 60 (36%) 8 (5%) 0ᚦᗳ 43 (26%) 1 (<1%) 0ਓ㞄㋈㟌⚾ c 24 (14%) 3 (2%) 0અੀ 21 (13%) 0 0㹰㇑о⏻ᐤ㇑㊫⯮⯵儈㹰঻ d 59 (35%) 46 (27%) 0ᝏḃлબ੨䚃ᝏḃ e 35 (21%) 20 (12%) 3 (2%)Ⳟ㛔৺Ⳟл㓴㓷㊫⯮⯵Ⳟ⯩ f 26 (15%) 2 (1%) 1 (<1%)a ቁ⯷DŽbDŽc वᤜਓ૭㌌⛲઼⒳⯑ǃਓ㞄⯬ⰋDŽd वᤜ㔗ਁᙗ儈㹰঻DŽe वᤜᝏḃᙗ㛪⚾ǃ㓶㧼ᙗ㛪⚾ǃ㛪⚾⨳㧼ᙗ㛪⚾ǃⵏ㧼ᙗ㛪⚾ǃ⯵∂ᙗ㛪⚾ǃ㙦∿㛪ᆒᆀ㲛㛪⚾ǃ᭟≄㇑㛪ᴢ䴹⯵઼㛪䜘ᝏḃDŽf㝡ᙗⳞ㛔৽ᓄDŽ

8Ԇ㹰⏢㌫㔏ᚦᙗ㛯ⱔᛓ㘵ਁ⭏⦷ <10%Ԇ㦟⢙н㢟৽ᓄवᤜ㛪䜘⚾⯷˄9%˅ǃ㋈㟌⚾⯷˄8%˅ǃᝏ㿹ᔲᑨ઼ᝏ㿹䘏䫍˄7%˅DŽ㺘㺘 ˖ ຎ⋫⯇ѝਁ⭏⦷•Ⲵᇎ傼ᇔỰḕᔲᑨ઼ਁ⭏⦷•Ⲵ•㓗ᇎ傼ᇔỰḕᔲᑨᇎ傼ᇔ৲ᮠຎ 1 

࡛

3 㓗㓗

4 㓗㓗

n˄˄%˅˅ n ˄˄%˅˅ n ˄˄%˅˅㹰⏢ᆖᔲᑨቁ 130 (78%) 7 (4%) 0⏻ᐤ㓶㜎䇑ᮠ䱽վ 126 (78%) 43 (27%) 4 (2%)ቁ 118 (71%) 30 (18%) 3 (2%)㹰ሿᶯ䇑ᮠ䱽վ 109 (65%) 11 (7%) 3 (2%)ѝᙗ㋂㓶㜎䇑ᮠ䱽վ 104 (63%) 20 (12%) 25 (15%)㹰␵⭏ॆᔲᑨ儈㹰㌆⯷ 160 (95%) 72 (43%) 9 (5%)儈⭈⋩й䞟㹰⯷ 74 (58%) 6 (5%) 0վ⼧㹰⯷ 72 (44%) 24 (15%) 0儈ቯ䞨㹰⯷ 42 (25%) 40 (24%) 2 (1%)㹰␵㜲㛚䞦ॷ儈 34 (21%) 11 (7%) 2 (1%)* ਟ㜭ᴹᐞᔲDŽ** NCI-CTCAE v4.03

Ǐ⾱ᗼǐሩᵜ૱⍫ᙗᡀԭᡆԫօ䖵ᯉ䗷᭿㘵⾱⭘DŽǏ⌘᜿һ亩ǐᝏḃຎঅ㦟⋫⯇Ⲵ 317ᛓ㘵ѝˈᴹ 19%⧠ѕ䟽˄वᤜ㠤↫ᙗ˅ᝏḃDŽᴰᑨ㿱Ⲵѕ䟽ᝏḃѪᝏḃᙗ㛪⚾˄৲㿱ǏǏн㢟৽ᓄǐ˅DŽⴁ⍻⧠ •ຎ⋫⯇˄৲㿱Ǐ⭘⌅⭘䟿ǐ˅DŽຎঅ㦟⋫⯇Ⲵ 317ᛓ㘵ѝˈᴹ 0.6%⧠ѕ䟽㙦∿㛪ᆒᆀ㲛㛪⚾˄PJP˅ᝏḃ˄৲㿱ǏǏн㢟৽ᓄǐˈᓄ㘳㲁ሩ儈仾䲙Ӫ㗔㔉Ҹ PJPⲴ⯁լ PJP ᝏḃຎ⋫⯇DŽྲ᷌⺞䇔ᝏḃˈᓄ㔉Ҹ⋫⯇ˈⴤ㠣ᝏḃ⎸䘰DŽѻਾˈຎ⋫⯇ˈᒦ㚄ਸ㔉Ҹ PJP 亴䱢ᙗ⭘㦟˄৲㿱ǏǏ⭘⌅⭘䟿ǐ˅DŽ儈㹰㌆⯷ຎঅ㦟⋫⯇Ⲵ 317ᛓ㘵ѝˈᴹ 41%⧠ 3 㓗ᡆ 4 㓗儈㹰㌆⯷˄㹰㌆• PJG/˅˄৲㿱ǏǏн㢟৽ᓄǐ˅DŽᴹ 2.8%⧠ѕ䟽ᙗ儈㹰㌆⯷DŽབྷཊᮠᛓ㘵Ⲵ㹰㌆≤ᒣ䙊ᑨ൘䗃⌘ਾ aຎ䗃⌘ਾаཙˈӽᴹ 17.7%Ⲵᛓ㘵Ⲵ㹰㌆≤ᒣॷ儈DŽ൘ส㓯㌆ॆ㹰㓒㳻ⲭ˄HbA1c˅ <5.7%Ⲵ 155ᛓ㘵ѝˈᴹ 16˄10%˅ᛓ㘵⋫⯇㔃ᶏᰦⲴ HbA1c >6.5%DŽ9൘ CHRONOS-1ຎ⋫⯇Ⲵ 20㌆ቯ⯵ᛓ㘵ѝˈᴹ 7ᛓ㘵⧠ 4 㓗儈㹰㌆⯷ˈфᴹ 2࠶ݵࡠⴁ⍻DŽຎ䗃⌘DŽṩᦞ儈㹰㌆⯷Ⲵѕ䟽〻䟿ᡆ㓸→⋫⯇˄৲㿱ǏǏ⭘⌅⭘䟿ǐ˅DŽ儈㹰঻ຎঅ㦟⋫⯇Ⲵ 317ᛓ㘵ѝˈᴹ 26%⧠ 3 㓗儈㹰঻˄᭦㕙঻• PP+Jˈᡆ㡂ᕐ঻• PP+J˅˄৲㿱ǏǏн㢟৽ᓄǐ˅DŽ൘к䘠317ᛓ㘵ѝˈᴹ 0.9%ຎ⋫⯇ਟ㜭Պሬ㠤ᙗ儈㹰঻DŽㅜ 1 ઘᵏㅜ 1 ཙ䗃⌘ਾ 2 ሿᰦⲴ᭦㕙঻઼㡂ᕐ঻⴨ሩҾส㓯Ѫ 16.8 mmHg ઼ 7.8 mmHgDŽᒣ൷㹰঻൘䗃⌘ਾ㓖 2 ሿᰦᔰ࿻лຎ䗃⌘ਾ aˈǃਾⴁ⍻㹰঻DŽṩᦞ儈㹰঻Ⲵѕ䟽〻ᓖ઼ᤱ䟿ᡆ㓸→⋫⯇˄৲㿱ǏǏ⭘⌅⭘䟿ǐ˅DŽ䶎ᝏḃᙗ㛪⚾ຎঅ㦟⋫⯇Ⲵ 317ᛓ㘵ѝˈᴹ 5%⧠䶎ᝏḃᙗ㛪⚾˄৲㿱ǏǏн㢟৽ᓄǐ⧠ૣభǃબ੨ഠ䳮ǃ㕪≗ㅹ㛪䜘⯷⣦ˈᡆ൘ຎ⋫⯇ˈᒦሩሬ㠤к䘠⯷⣦ᡆຎሬ㠤ᰦˈຎ⋫⯇ᒦ㔉Ҹ㌫㔏ᙗ㌆Ⳟ䍘◰㍐⋫⯇DŽṩᦞ䶎ᝏḃᙗ㛪⚾Ⲵѕ䟽䟿ᡆ㓸→⋫⯇˄৲㿱ǏǏ⭘⌅⭘䟿ǐ˅DŽቁ⯷ຎঅ㦟⋫⯇Ⲵ 317ᛓ㘵ѝˈᴹ 24%⧠ 3 㓗ᡆ 4 㓗ቁ⯷DŽᴹ 1.3%ቁһԦ˄৲㿱ǏǏн㢟৽ᓄǐຎ⋫⯇ᵏ䰤ˈ㠣ቁ⇿ઘⴁ⍻а⅑㹰㓶㜎䇑ᮠDŽṩᦞѝᙗ㋂㓶䟿ᡆ㓸→⋫⯇˄৲㿱Ǐ⭘⌅⭘䟿ǐ˅DŽѕ䟽Ⳟ㛔н㢟৽ᓄຎঅ㦟⋫⯇Ⲵ 317ᴹ 2.8%઼ 0.6%⧠3 㓗઼ 4 㓗Ⳟ㛔৽ᓄ˄৲㿱ǏǏн㢟৽ᓄǐ˅DŽᴹ 0.9%Ⲵᛓ㘵ᣕ੺ѕ䟽Ⳟ㛔৽ᓄ㝡ᙗⳞ⯩ǃⱉⰂ઼Ⳟ⯩˄वᤜᯁш䟿ᡆ㓸→⋫⯇˄৲㿱ǏǏ⭘⌅⭘䟿ǐ˅DŽǏᆅྷ৺ପңᵏྷྣ⭘㦟ǐ䚯ᆅ˄৲㿱ǏǏᆅྷ৺ପңᵏྷྣ⭘㦟ǐᆅྷ˅DŽྣᙗᛓ㘵޵䟷ਆ儈᭸䚯ᆅ᧚ᯭ˄ᒤཡ䍕⦷<1%Ⲵ䚯ᆅᯩ⌅˅DŽ10⭧ᙗᛓ㘵ຎ⋫⯇ᵏ䰤઼ᵛ⅑㔉㦟ਾ䟷ਆ儈᭸䚯ᆅ᧚ᯭDŽᆅᆅྷˈᓄ䘋㹼ྺၐỰḕDŽຎՊՔᇣ㛾˄৲㿱ǏǏ㦟⨶∂⨶ǐ˅DŽ੺⸕ᵜ૱ሩᆈ൘▌൘仾䲙DŽ࣋⢙˅ᴹн㢟֌⭘˄৲㿱ǏǏ㦟⨶∂⨶ǐ˅DŽପңᵏྷྣຎ઼ /ݯຎӗ⭏ѕ䟽нຎ⋫⯇ᵏ䰤ԕ৺ᵛ⅑㔉㦟ਾ㠣ቁ 1ପңDŽㄕ⭘㦟ǐቊᵚ⺞ᇊᵜ૱൘ 18ᙗ઼ᴹ᭸ᙗDŽǏ㘱ᒤ⭘㦟ǐᒤ喴•䟿DŽຎ⋫⯇Ⲵ 168Ԇ㹰⏢㌫㔏ᚦᙗ㛯ⱔᛓ㘵ѝˈᴹ 48%Ⲵᛓ㘵ᒤ喴•኱ˈ16%Ⲵᛓ㘵ᒤ喴•኱DŽᵜ૱⋫⯇㘱ᒤᛓ㘵઼ᒤᴹѤᒺ᜿ѹⲴᐞᔲDŽ൘ᒤ喴•኱Ⲵᛓ㘵ѝˈᴹ 30%⧠ѕ䟽н㢟৽ᓄˈ21%Ⲵᛓ㘵ഐн㢟৽ᓄሬ㠤⋫⯇㓸→DŽ൘ᒤ喴<65 ኱Ⲵᛓ㘵ѝˈᴹ 23%⧠ѕ䟽н㢟৽ᓄˈ 11%Ⲵᛓ㘵ഐн㢟৽ᓄሬ㠤⋫⯇㓸→DŽǏ㦟⢙⴨ӂ֌⭘ǐຎⲴᖡ૽㺘 6ຎоᕪ᭸ CYP3Aਸᒦ⭘㦟Ⲵ▌൘᭸ᓄDŽ㺘  ຎⲴ㦟⢙⴨ӂ֌⭘ᕪ᭸ CYP3A 䈡ࡲѤᒺᖡ૽ Ɣ ຎ઼ᕪ᭸ CYP3Aਸᒦ⭘㦟ਟຎ A UC઼ Cmax л䱽˄৲㿱Ǐ㦟⨶∂⨶ǐ˅DŽ亴䱢㇑⨶ Ɣ ຎоᕪ᭸ CYP3A㚄ਸ⭘㦟11ᕪᕪ᭸ CYP3A ᣁࡲࡦѤѤᒺᖡ૽ Ɣ ຎ઼ᕪ᭸ CYP3Aਸᒦ⭘㦟ሶຎ AUC˄৲㿱ǏǏ㦟⨶∂⨶ǐ˅DŽƔ ຎ AUCਟ㜭Պሬ㠤н㢟৽ᓄ仾䲙ॷ儈亴䱢㇑⨶ Ɣ оᕪ᭸ CYP3Aਸᒦ⭘ቁ㠣 45 mg ˄৲㿱Ǐ⭘⌅⭘䟿ǐ˅DŽ

Ǐ㦟⢙䗷䟿ǐᵚ䘋㹼䈕亩⹄ウфᰐਟ䶐৲㘳᮷⥞DŽǏѤᒺ㦟⨶ǐࡦຎᱟ⼧㜲䞠㚼䞷-3 ◰䞦˄PI3Kᚦᙗ B 㓶㜎ѝ㺘䗮Ⲵ PI3K-Į઼ PI3K-įຎ䙊䗷䈡ሬ৏ਁᙗᚦᙗ Bཊ⿽䟽㾱ྲ B 㓶㜎ਇփ˄BCRਧՐሬǃCXCR12 ӻሬⲴᚦᙗB 㓶㜎䎻ॆᙗ઼⏻ᐤⱔ㓶㜎㌫ѝⲴ 1)ț%ਧՐሬDŽ㦟᭸ᆖ൘ 60 mg ˄ᡆ 0.8 mg/kg䟿лˈ㹰㌆≤ᒣॷ儈оᴤ儈Ⲵਟ⌞DŽᗳ㜿⭥⭏⨶ᆖຎнՊሬ㠤 QTcᔦ䮯>20 msec DŽа亩൘ 25ᲊᵏⱼ⯷ᛓ㘵ѝ䘋㹼Ⲵᔰ᭮ḷㆮǃу䰘 QTຎ᧘䟿 60 mg ሩ QTcⲴ QTc 䖳ส㓯Ⲵਈॆ˄'QTc˅Ѫ㕙⸝ˈѻਾ൘⋫⯇ਾ 12 㠣 24ࡠ'QTc ᔦ䮯DŽ'QTc Ⲵᡰ㠤DŽᆖ൘ a PJ䟿Ⲵ aຎⲴ㹰⍶⎃ᓖ -ᰦ䰤ᴢ㓯л䶒〟˄ AUC˅઼㹰⍶ጠ⎃ᓖ˄ Cmax䟿໎ᆖ˄ PK׍䎆ᙗˈфᵚ㿱㫴〟⧠䊑DŽ0.8 mg/kgⲴ 60 mg/kgօᒣ൷᳤䵢 Cmax Ѫ 463˄㤳ത a˗SD˖584˅ng/mLˈAUC0-25h Ѫ 1570˄㤳ത˖a˗SD˖338˅ng.hr/mLDŽᐳຎⲴӪ㹰⍶㳻ⲭ㔃ਸ⦷Ѫ 84.2%DŽⲭ㳻ⲭѪѫ㾱㔃ਸ㳻ⲭDŽփཆ⹄ウѝⲴᒣ൷㹰⏢ /㹰⍶∄Ѫ 1.7˄㤳ത˖a࠶ᐳᇩ〟Ѫ 871˄㤳ത a˗SD˖479˅LDŽ12⎸⎸䲔օᒣ൷㓸ᵛ⎸䲔ॺ㺠ᵏѪ 39.1˄㤳ത˖a˗SD˖15.0˅օᒣ൷␵䲔⦷Ѫ 17.9˄㤳ത˖a˗SD˖8.5˅L/hrDŽԓ䉒㓖 90%ຎⲴԓ䉒⭡ CYP3A ӻሬˈ⭡ CYP1A1ࡠ10%DŽM-1 ԓ䉒ӗ⢙ঐᙫ᭮ሴᙗ AUC Ⲵ 5%ˈ㘼фሩҾਇ䈅◰䞦 PI3KD઼ P,.ȕຎ⴨ᖃDŽᧂ⋴൘Ӫփѝˈ㓖 50%ˈ 50%ԕԓ䉒ӗ⢙ᖒᔿDŽঅ⅑䶉㜹㔉Ҹ 12 mg䟿Ⲵ 20%ຎਾ aཙ䟿㓖Ѫ㔉㦟䟿Ⲵ 64%ˈቯ⏢ѝⲴഎ᭦⦷㓖Ѫ 22%઼㓖ঐ㔉㦟䟿Ⲵ 30%઼ 15%DŽCYP450 ӻሬⲴ≗ॆԓ䉒ᡰӗ⭏Ⲵԓ䉒ӗ⢙ঐ㔉㦟䟿Ⲵ 41%DŽ⢩↺Ӫ㗔ᒤ喴˄aǃӪ⿽˄ⲭӪǃӊ㼄ǃ㾯⨝⢉㼄઼唁Ӫ˅ǃ੨✏⣦ᘱǃփ䟽˄ a NJ˅ǃ䖫ᓖǃѝᓖ઼䟽ᓖ㛮ᦏՔ˄ṩᦞ Cockcroft-Gault˄C-Gᔿՠ㇇ˈ CLcr•15 mL/minᆖᰐᱮ㪇Ѥᒺᖡຎ൘᧕ਇᡆн᧕ਇ䘿᷀Ⲵ㓸ᵛᵏ㛮⯵˄⭘ C-Gᔿՠ㇇Ⲵ CLcr<15mL/minᆖቊн᰾DŽ㛍ᦏՔᛓ㘵᷀ˈ䖫ᓖ㛍ᦏՔ˄ᙫ㛶㓒㍐”ؽULN фAST>ULNˈᡆᙫ㛶㓒㍐>1-1.5ؽULN ઼ԫ᜿ AST࣋ࣘᖡ૽DŽ൘а亩у䰘䇴ԧ㛍ᦏՔਇ䈅㘵᧕ਇঅ⅑ 12 mg䟿 60 mg Ⲵ 0.2˅ਟ⌞ᆖ⹄ウѝˈѝᓖ㛍ᦏՔ˄Child-Pugh B 㓗˅ਇ䈅㘵Ⲵᙫຎ Cmax ઼ AUC㠣 1.38ؽ઼ 1.71ˈ䟽ᓖ㛍ᦏՔ˄Child Pugh C㠣 1.44઼ 2.71DŽຎⲴ AUC㠣1.23઼ 3.77ຎⲴ Cmaxᒦᵚ໎ຎⲴ Cmax㠣 1.92DŽ㦟⢙⴨ӂ֌⭘⹄ウѤᒺ䈅傼CYP3A ઼ P-gpຎⲴᖡ૽䘎㔝 12 ཙ⇿ᰕ㔉Ҹ 600 mg⾿ᒣ˄а⿽ CYP3A ઼ P-㌆㳻ⲭ[P-gp]䖜䘀㳻˅ਸᒦ 60 mg ຎᒣ൷ AUC л䱽 63%ˈCmax л䱽 15%˄৲㿱ǏǏ㦟⢙⴨ӂ֌⭘ǐ˅DŽCYP3AǃP-gp ઼ BCRPຎⲴᖡ૽Ժᴢᓧୁ˄а⿽ CYP3A৺ P-gp ઼ң㞪ⱼ㙀㦟㳻ⲭ[BCRP]䖜䘀13ˈ䘎㔝 10 ཙ⇿ᰕ㔉Ҹ 200 mgԕ 60 mg ຎঅ⅑䶉㜹㔉㦟Ⲵⱼ⯷ᛓ㘵Ⲵᒣ൷ AUC ࣐53%˄1.53˅ˈն Cmax нਇᖡ૽˄1.03˅˄৲㿱ǏǏ㦟⢙⴨ӂ֌⭘ǐ˅DŽփཆ⹄ウຎⲴᖡ૽˖ຎᱟ P-gp ઼ BCRP Ⲵᓅ⢙ˈնᒦ䶎ᴹᵪ䱣⿫ᆀ䖜䘀㳻ⲭ˄OCT˅1ǃOCT2 ઼ OCT3ǃᴹᵪ䱤⿫ᆀ䖜䘀㳻ⲭ˄OAT˅1 ઼ OAT3ǃᴹᵪ䱤⿫ᆀ䖜䘀ཊ㛭˄OATP˅1B1 ઼ OATP1B3ǃཊ㦟઼∂㍐ཆᧂ㳻ⲭ 1˄MATE1˅ᡆ MATE2-KⲴᓅ⢙DŽຎሩ CYP ઼䶎 CYP 䞦Ⲵᖡ૽ሩҾ֌Ѫѫ㾱 CYP ӊර˄CYP1A2ǃ2A6ǃ2B6ǃ2C8ǃ2C9ǃ2C19ǃ2D6ǃ2E1 ઼ 3A4˅ᡆቯ㤧Ҽ⼧䞨㪑㌆䟋䞨䖜〫䞦ӊර˄ UGT˅ᡆҼ≒౗஦㝡≒䞦˄DPD˅ᓅ⢙Ⲵ㦟⢙ˈ൘ 60 mgԓ䉒ᒦᰐຎнᱟ CYP1A2ǃCYP2B6 ઼ CYP3ADŽຎሩ㦟⢙䖜䘀㳻ⲭᓅ⢙Ⲵᖡ૽൘ 60 mgຎᒦ䶎 P-gpǃBCRPޣ㳻ⲭ˄ MRP2 ˅ǃ㛶ⴀཆᧂ⌥˄ BSEP ˅ǃ OATP1B1 ǃ OATP1B3 ǃ OAT1 ǃOAT3ǃOCT1ǃOCT2 ઼ MATE1DŽຎᱟ MATE2-K˄IC50˖0.09 PM䟿䗃֌⭘ሩਸᒦ㔉ҸⲴMATE2-K ᓅ⢙㊫㦟⢙Ⲵ㹰⍶⎃ᓖᖡ૽ⲴѤᒺ᜿ѹቊн᰾DŽ䚇Ր㦟⨶ᆖᵚ䘋㹼䈕亩ᇎ傼фᰐਟ䶐৲㘳᮷⥞DŽ

ǏѤᒺ䈅傼ǐ༽ਁᙗ└⌑ᙗ⏻ᐤⱔа亩অ㟲ǃཊѝᗳǃII ᵏѤᒺ䈅傼˄NCT 01660451 ˅CHRONOS-1 䇴ԧҶᤋए 142ѝ 104ᰒᖰ᧕ਇ⋫⯇ਾ༽ਁⲴ└⌑ᙗ⏻ᐤⱔਇ䈅㘵DŽᛓ㘵ส㓯⢩ᖱᙫ㔃㿱㺘 7DŽᴰᑨ㿱Ⲵᰒᖰ㌫㔏ᙗ⋫⯇Ѫॆ⯇㚄ਸᣇ CD20⯛⯇⌅˄89%˅ǃঅ⤜ॆ⯇˄41%˅઼অ⤜ᣇ CD20⯛⯇⌅˄37%˅DŽ൘ CHRONOS-1 ѝˈᴹ 34%Ⲵᛓ㘵ᰒᖰ᧕ਇ䗷є㓯⋫⯇ᯩṸˈ36%Ⲵᛓ㘵ᰒᖰ᧕ਇ䗷й㓯⋫⯇ᯩṸDŽ㺘 7˖ ᛓ㘵ส㓯⢩ᖱ˄└⌑ᙗ⏻ᐤⱔ˅⢩ᖱ ຎ 1 ˄㤳ത˅ 6 2 ˄a˅㍒Ӫ 83%⭧ᙗ 52%ECOG փ㜭⣦ᘱ˄0 ᡆ 1˅ 96%14˄㤳ത˅ 3 ˄a˅˄㤳ത˅ 5.8 ˄a˅∄*˖ᴰਾа⿽⋫⯇ᯩṸ 62%ᴰਾа⿽ᣇ CD20⯛⯇⌅ 57%ࡲ38%ᴰਾа⿽ᣇ CD20⯛⯇⌅+Ⲵ㚄ਸ⯇⌅ 41%*䳮⋫ර˖ᰐᓄㆄˈᡆ൘ᵛ⅑⋫⯇ਾ 6⯮⯵䘋ኅDŽ

ᴹ 142ᛓ㘵᧕ਇ 60 mg ѝ 130ᛓ㘵᧕ਇ 60 mg䟿ˈ12ᛓ㘵᧕ਇ 0.8 mg/kg䟿ˈ൷Ѫ䰤ⅷᙗ㔉㦟˄㔉㦟 3㦟 1 ઘ˅ˈ൘⇿њ⋫⯇ઘᵏ˄28 ཙ˅Ⲵㅜ 1ǃ8 ઼ 15 ཙ䘋㹼ᤱ㔝 1 ሿᰦⲴ䶉㜹䗃⌘DŽᤱ㔝ᦞഭ䱵ᐕ֌㓴ᚦᙗ⏻ᐤⱔ㕃䀓ˈ䇴ՠ㛯ⱔ㕃䀓DŽ⭡⤜・ᇑḕငઈՊṩᦞᙫ㕃䀓⦷˄ ORR˅䇴ՠᴹ᭸ᙗDŽCHRONOS-1 Ⲵᴹ᭸ᙗ㔃᷌ᙫ㔃㿱㺘 8DŽ㺘㺘 ˖ ༽ਁᙗ└⌑ᙗ⏻ᐤⱔᛓ㘵Ⲵᙫ㕃䀓⦷˄ORR˅઼㕃䀓ᤱ㔝ᰦ䰤ຎ1 ORRˈn˄%˅ 61 (59%)˄95%CI˅ (49, 68)CRˈn˄%˅ 15 (14%)PRˈn˄%˅ 46 (44%)ѝս*DORˈᴸ˄㤳ത˅ 12.2 (0+, 22.6)ORR = ᙫ㕃䀓⦷˗CI = ४䰤˗CR = 㕃䀓˗PR = 㕃䀓˗DOR = 㕃䀓ᤱ㔝ᰦ䰤*Kaplan-Meier٬

㠣㕃䀓Ⲵѝսᰦ䰤Ѫ 1.7 њᴸ˄㤳ത˖aњᴸ˅DŽк䘠䘲ᓄ⯷DŽҾਾᵏ⺞䇱ᙗ䲿ᵪሩ➗Ѥᒺ䈅傼Ⲵ㔃᷌DŽǏ㦟⨶∂⨶ǐ㦟⨶֌⭘ຎᱟ⼧㜲䞠㚼䞷-3 ◰䞦˄PI3Kᚦᙗ B 㓶㜎ѝ㺘䗮Ⲵ PI3K-Į઼ PI3K-įຎ䙊䗷䈡ሬ৏ਁᙗᚦᙗ Bཊ⿽䟽㾱㓶㜎ྲ B 㓶㜎ਇփ˄BCRਧՐሬǃCXCR12 ӻሬⲴᚦᙗ B 㓶㜎䎻ॆᙗ઼⏻ᐤⱔ㓶㜎㌫ѝⲴ 1)ț%ਧՐሬDŽ∂⨶⹄ウ䚇Ր∂ᙗຎⲴ Ames 䈅傼ǃሿ啐⏻ᐤⱔ↓ੁケਈ䈅傼઼ሿ啐僘儃ᗞṨ䈅傼㔃᷌൷Ѫ䱤ᙗˈᵚ㿱䚇Ր∂ᙗDŽ15⭏⭏⇆∂ᙗ⹄ウˈն䟽༽㔉㦟∂ᙗ⹄ウѝਟ㿱䳴ᙗ઼䳼ᙗ⭏⇆㌫㔏н㢟৽ᓄDŽ䳴ᙗབྷ啐઼/䖫઼/䖫઼/ᡆቁ㋮⯷/㞪ቁ઼ /䖫˅ᯩ䶒Ⲵᖡ૽DŽ䳼ᙗབྷ啐ѝⲴн㢟৽ᓄवᤜথᐒ䖫˅ǃ䱤䚃˄অṨ㓶ቁDŽ൘བྷ啐㜊㛾-ຎ 0ǃ0.75 ᡆ 3mg/kg/ᰕDŽ3 mg/kg/䟿ਟ㿱⇽փ∂ᙗˈфᰐ⍫㛾Ԅ˗0.75 mg/kg/ ᰕਟ㿱⇽փ∂ᙗˈ㜊㛾-㛾Ԅ↫ӑ˄੨᭦⦷ॷ儈ǃ⵰ᒺਾђཡ⦷ॷ儈ˈ⇿ਚ⇽փᡰྺၐⲴ㛾䟿л䘈ਟ㿱㛾Ԅཆᖒ˄⨳ᖒཤǃ⵬⨳ᡆ⵬ネ⮨ᖒ˅ǃ䖟㓴㛒僘僬ਁ㛢н㢟ǃ㚻僘઼Ἶ僘⮨ᖒԕ৺僘⳶〫ս˅ᔲᑨⲴਁ⭏⦷ॷ儈DŽ 0.75 mg/kg/ ᰕ˄ԕփ㺘䶒〟䇑ˈ4.5 mg/m2䟿Ⲵ 12%DŽຎਾˈ㓖ᴹ 1.5%࡙ຎਾˈ㓖ᴹ 2%⋼㠣ң≱ѝ˗᭮ሴᙗⲴң≱/㹰⍶∄Ѫ 25:1DŽ㠤ⱼᙗຎⲴ㠤ⱼᙗ⹄ウDŽ

Ǐ䍞㯿ǐᇶሱˈaㄕн㜭᧕䀖ⲴൠᯩDŽǏव㻵ǐ⭘ⓤॆбสₑ㜦ຎ઼ᣇ⭏㍐⬦઼䗃⏢⬦⭘䬍ກ㓴ਸⴆव㻵DŽ1⬦/ⴂDŽǏᴹ᭸ᵏǐ36њᴸDŽǐJX20230041᮷ਧǐ16кᐲ

ǏǏкᐲ䇨ਟᤱᴹӪǐ਽〠˖Bayer HealthCare Pharmaceuticals Inc.ൠ൰˖100 Bayer Blvd, Whippany, NJ 07981 United States of AmericaǏ⭏ӗԱъǐԱъ਽〠˖Bayer AG⭏ӗൠ൰˖Mullerstrasse 178, Berlin 13353, Germany㚄㌫Ӫǐਨൠ൰˖ेӜᐲेӜ㓿⍾ᢰᵟᔰਁ४㦓Ӝь㺇7ਧ䛞᭯㕆⸱˖100176⭥䈍ਧ⸱˖010-59218282Րⵏਧ⸱˖010-59218181✝㓯⭥䈍˖400-810-0360