JP2017508736A - びまん性大細胞型b細胞リンパ腫の予防および/または治療剤 - Google Patents
びまん性大細胞型b細胞リンパ腫の予防および/または治療剤 Download PDFInfo
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- JP2017508736A JP2017508736A JP2016551872A JP2016551872A JP2017508736A JP 2017508736 A JP2017508736 A JP 2017508736A JP 2016551872 A JP2016551872 A JP 2016551872A JP 2016551872 A JP2016551872 A JP 2016551872A JP 2017508736 A JP2017508736 A JP 2017508736A
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- cell lymphoma
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- 238000002054 transplantation Methods 0.000 description 1
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- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
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- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
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- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 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
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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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
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
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- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pathology (AREA)
- Radiology & Medical Imaging (AREA)
Abstract
Description
[1] 6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグを含有してなる、活性化B細胞様びまん性大細胞型B細胞リンパ腫の予防および/または治療剤、
[2] 活性化B細胞様びまん性大細胞型B細胞リンパ腫が、再発性または難治性の活性化B細胞様びまん性大細胞型B細胞リンパ腫である前記[1]記載の剤、
[3] CD79B野生型活性化B細胞様びまん性大細胞型B細胞リンパ腫である前記[1]または[2]記載の剤、
[4] 6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグを、1日あたり20〜600mgの用量で経口投与することを特徴とする前記[1]〜[3]のいずれかに記載の剤、
[5] 再発予防剤である前記[1]〜[4]のいずれかに記載の剤、
[6] 抗癌剤を用いた薬物療法、造血幹細胞移植法、および放射線療法からなる群から選択される1種以上の方法と組み合わせることを特徴とする、前記[1]〜[5]のいずれかに記載の剤、
[7] 抗癌剤が、アルキル化薬、代謝拮抗薬、抗癌性抗生物質、植物性アルカロイド薬、ホルモン薬、白金化合物、抗CD20抗体、プロテアソーム阻害薬、PKCベータ阻害薬、IKK阻害薬、PI3K阻害薬、Bcl−2阻害薬、mTOR阻害薬、Auroraキナーゼ阻害薬、Syk阻害薬、HDAC阻害薬、CDK阻害薬、JAK2阻害薬、MEK阻害薬、HIF−1α阻害薬、B−RAF阻害薬、PDK1阻害薬、PLK阻害薬、NAE阻害薬、PIM阻害薬、AXL阻害薬、EZH2阻害薬、HSP阻害薬、BRD4阻害薬、ALK阻害薬、ABL阻害薬、またはその他の抗癌剤である前記[6]記載の剤、
[8] 6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン 塩酸塩である前記[1]〜[7]のいずれかに記載の剤、
[9] 6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン 塩酸塩、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグの薬学的有効量を、その治療が必要なヒトに投与することからなる、活性化B細胞様びまん性大細胞型B細胞リンパ腫の予防および/または治療方法、
[10] ヒトにおける活性化B細胞様びまん性大細胞型B細胞リンパ腫の予防および/または治療に使用するための、6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン 塩酸塩、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグ、および
[11] ヒトにおける活性化B細胞様びまん性大細胞型B細胞リンパ腫の予防および/または治療用の医薬を製造するための、6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン 塩酸塩、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグの使用等に関する。
本発明において、本発明化合物とは、国際公開第2011/152351号パンフレットに記載の一般式(I)
R1は(1)ハロゲン原子、(2)C1〜4アルキル基、(3)C1〜4アルコキシ基、(4)C1〜4ハロアルキル基、または(5)C1〜4ハロアルコキシ基を表し、
ring1は(1)ハロゲン原子、(2)C1〜4アルキル基、(3)C1〜4アルコキシ基、(4)ニトリル、(5)C1〜4ハロアルキル基および(6)C1〜4ハロアルコキシ基からなる群より各々独立に選択される1〜5個の置換基で置換されていてもよい4〜7員の環状基を表し、ただし、ring1上の置換基が2個以上のとき、当該置換基はそれらが結合するring1を構成する原子と一緒になって4〜7員の環状基を形成してもよく、
ring2は1〜3個の−K−R2で置換されていてもよい4〜7員の飽和ヘテロ環を表し、
Kは(1)結合手、(2)C1〜4アルキレン、(3)−C(O)−、(4)−C(O)−CH2−、(5)−CH2−C(O)−、(6)−C(O)O−、または(7)−SO2−を表し(ただし、左側の結合手がring2と結合するものとする。)、
R2は(1)NR3R4、(2)ハロゲン原子、(3)CONR5R6、(4)CO2R7および(5)OR8からなる群より各々独立に選択される1〜5個の置換基で置換されていてもよい、(1)C1〜4アルキル、(2)C2〜4アルケニル、または(3)C2〜4アルキニル基を表し、
R3およびR4はそれぞれ独立して、(1)水素原子、または(2)OR9またはCONR10R11で置換されていてもよいC1〜4アルキル基を表し、
R3およびR4は結合する窒素原子と一緒になって、オキソ基または水酸基で置換されていてもよい4〜7員の含窒素飽和ヘテロ環を形成してもよく、
R5およびR6はそれぞれ独立して(1)水素原子、(2)C1〜4アルキル基、または(3)フェニル基を表し、
R7は(1)水素原子、または(2)C1〜4アルキル基を表し、
R8は(1)水素原子、(2)C1〜4アルキル基、(3)フェニル基、または(4)ベンゾトリアゾリル基を表し、
R9は(1)水素原子、または(2)C1〜4アルキル基を表し、
R10およびR11はそれぞれ独立して、(1)水素原子、または(2)C1〜4アルキル基を表し、
nは0〜4の整数を表し、
mは0〜2の整数を表し、
nが2以上のとき、R1は同じでも異なっていてもよい。)で示される化合物、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグ、および国際公開第2013/081016号パンフレットに記載の6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン 塩酸塩が挙げられる。
本発明において、C1〜4アルキル基とは、メチル、エチル、プロピル、イソプロピル、ブチル、sec−ブチル、tert−ブチル等の直鎖状または分岐鎖状のC1〜4アルキル基を意味する。
本発明において、C1〜4アルキレン基とは、メチレン、エチレン、プロピレン、ブチレンおよびそれらの異性体等を意味する。
本発明において、C1〜4アルコキシ基とは、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブチルオキシ、tert−ブトキシ等の直鎖状または分岐鎖状のC1〜4アルコキシ基を意味する。
本発明において、C2〜4アルキニル基とは、エチニル、1−プロピニル、2−プロピニル、1−ブチニル、2−ブチニル、3−ブチニル、1,3−ブタジイニル等の直鎖状または分岐鎖状のC2〜4アルキニル基を意味する。
本発明において、C4〜7の炭素環とは、C4〜7の単環式の脂肪族または芳香族の炭素環を意味する。脂肪族の場合は、その一部または全部が飽和されていてもよい。例えば、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロペンテン、シクロヘキセン、シクロヘプテン、シクロブタジエン、シクロペンタジエン、シクロヘキサジエン、シクロヘプタジエン、ベンゼン等が挙げられる。
本発明において、4〜7員のヘテロ環とは、4〜7員の不飽和ヘテロ環、または4〜7員の飽和ヘテロ環を意味する。
本発明において、一般式(I)で示される化合物のN−オキシド体とは、一般式(I)で示される化合物の窒素原子が、酸化されたものを表す。また、一般式(I)で示される化合物のN―オキシド体は、さらに上記のアルカリ(土類)金属塩、アンモニウム塩、有機アミン塩、酸付加物塩となっていてもよい。
本発明において、活性化B細胞様びまん性大細胞型B細胞リンパ腫には、再発性または難治性の活性化B細胞様びまん性大細胞型B細胞リンパ腫が含まれる。
抗CD20抗体の例としては、例えば、リツキシマブ、イブリツモマブ、オクレリズマブ、オファツムマブ、トシツモマブ等が挙げられる。
プロテアソーム阻害薬の例としては、例えば、ボルテゾミブ、カーフィルゾミブ、NPI−0052等が挙げられる。
PKCベータ阻害薬の例としては、例えば、エンザスタウリン、ソトラスタウリン、BHA536、LY33351等が挙げられる。
PI3K阻害薬の例としては、例えば、CAL−101、IPI−145、PI103等が挙げられる。
Bcl−2阻害薬の例としては、例えば、ナビトクラックス(ABT−263)、ABT−737、ABT−199、AT−101、オバトクラックス等が挙げられる。
mTOR阻害薬の例としては、例えば、エベロリムス、ラパマイシン(シロリムス)、テムシロリムス等が挙げられる。
Syk阻害薬の例としては、例えば、フォスタマチニブ、R406等が挙げられる。
HDAC阻害薬の例としては、例えば、スベロイルアニリドヒドロキサム酸(SAHA)、ロミデプシン、ボリノスタット、パノビノスタット、エンチノスタット、バルプロ酸、トリコスタチンA(TSA)等が挙げられる。
CDK阻害薬の例としては、例えば、ジナシクリブ、パルボシクリブ(PD−0332911)等が挙げられる。
JAK2阻害薬の例としては、例えば、フェドラチニブ、ルキソリチニブ、バリシニチニブ、タソシチニブ、SB1518、AT9283等が挙げられる。
HIF−1α阻害薬の例としては、例えば、PX−478等が挙げられる。
B−RAF阻害薬の例としては、例えば、ベムラフェニブ等が挙げられる。
PDK−1阻害薬の例としては、例えば、BX−192等が挙げられる。
PLK阻害薬の例としては、例えば、BI−6227、GSK−461364等が挙げられる。
NAE阻害薬の例としては、例えば、MLN−4924等が挙げられる。
AXL阻害薬の例としては、例えば、BGB−324、ASP2215等が挙げられる。
EZH2阻害薬の例としては、例えば、GSK−342等が挙げられる。
HSP阻害薬の例としては、例えば、NYP−AUY−922等が挙げられる。
BRD4阻害薬の例としては、例えば、CPI−203等が挙げられる。
ALK阻害薬の例としては、例えば、クリゾチニブ、アレクチニブ、セリチニブ等が挙げられる。
ABL阻害薬の例としては、例えば、イマニチブ、ニロチニブ、ダサチニブ、ボスチニブ等が挙げられる。
本発明において、他のBtk阻害剤としては、例えば、イブルチニブ(PCI−32765)、CC−292(AVL−292)、HM−71224、ACP−196、SNS−062等が挙げられる。
本発明においては、特に断わらない限り、当業者にとって明らかなように記号
本発明化合物は、国際公開第2011/152351号パンフレットに記載の方法、国際公開第2013/081016号パンフレットに記載の方法、または公知の方法、例えば、Comprehensive Organic Transformations : A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)に記載された方法等を適宜改良し、組み合わせて用いることで製造することができる。
本発明化合物の毒性は十分に低いものであり、医薬品として安全に使用することができる。
本発明化合物は、通常、全身的または局所的に、経口または非経口の形で投与される。経口剤としては、例えば、内服用液剤(例えば、エリキシル剤、シロップ剤、薬剤的に許容される水剤、懸濁剤、乳剤)、内服用固形剤(例えば、錠剤(舌下錠、口腔内崩壊錠を含む)、丸剤、カプセル剤(ハードカプセル、ソフトカプセル、ゼラチンカプセル、マイクロカプセルを含む)、散剤、顆粒剤、トローチ剤)等が挙げられる。非経口剤としては、例えば、液剤(例えば、注射剤(皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤、点滴剤等)、点眼剤(例えば、水性点眼剤(水性点眼液、水性懸濁点眼液、粘性点眼液、可溶化点眼液等)、非水性点眼剤(非水性点眼液、非水性懸濁点眼液等))等)、外用剤(例えば、軟膏(眼軟膏等))、点耳剤等が挙げられる。これらの製剤は、速放性製剤、徐放性製剤などの放出制御剤であってもよい。これらの製剤は公知の方法、例えば、日本薬局方に記載の方法等により製造することができる。
臨床試験として、本発明化合物である6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン 塩酸塩を単剤療法としてABC−DLBCL患者に投与することにより、オープンラベル多施設非無作為化試験により実施した。
既に治療を受け、より高い優先順位の治療が存在しない非ホジキンリンパ腫と診断された患者であって、かつ下記の「再発性」または「難治性」の定義に当てはまる患者のうち、以下の条件を満たす患者をエントリーした。
条件:既に2つ以上のNHLの治療に失敗したこと。
本発明化合物を、1コホート当たり、3名の患者で28日間を治療の1サイクルとして、固定用量を1日1回経口投与した。このサイクルは6サイクルまで行うものとし、最大で24サイクルまで延長することが可能なスケジュールとした。最初のコホートでは、すべての患者は、本発明化合物を20mgの固定用量で投与された。毒性がなければ、本発明化合物に関連する毒性が観察されるまで100%を超えない増分で、用量を漸増した。投与スケジュール例を以下の表に示す。
上記の条件でエントリーしたNHL患者について、患部リンパ節を一部摘出する組織生検により得られた診断サンプルを用い、常法にしたがって、免疫組織化学法または遺伝子発現プロファイリングを行って、ABC−DLBCLに罹患した患者を抽出した。
一次評価項目は、安全性、忍容性、および用量制限毒性(Dose Limiting Toxicities;DLTs)とした。これは、有害事象の発現、身体検査、臨床検査、バイタルサインおよび心電図を用いて評価した。また、有害事象の強度は、アメリカ国立癌研究所(National Cancer Institute)によるCommon Terminology Criteria for Adverse Events(CTCAE)のversion4.0を用いて判断した。
8名のABC−DLBCL患者のうち、本発明化合物の最初の投与サイクルにおいて、6名の患者でリンパ節腫脹の減少が認められた。さらに、本発明化合物を上記した投与スケジュールのコホート4(160mg)またはコホート5(320mg)で投与した結果、ORRは75%(8例中、PR6例(リンパ節減少の中央値は81.5%であった。)、病勢進行2例)であった。また、本発明化合物の投与を行った13名のABC−DLBCL患者において、高い忍容性が確認された。本発明化合物に関連した有害事象は、13例中5例で確認され、そのうち、2例の有害事象は、CTCAEによるグレード3に分類される事象(薬物反応およびリンパ球減少)であった。また、有害事象として頭蓋内出血のような出血関連イベントはまったく見られなかった。
ABC−DLBCL患者について、本発明化合物の投与前に腫瘍の生検サンプルを取得した。当該サンプルから常法により、ゲノムDNAを抽出し、ネイチャー(Nature)、第463号、88−92ページ、2010年に記載の方法に準じて、CD79Bの変異の有無を確認した。その結果、8名のABC−DLBCL患者のうち、評価可能な7名はいずれもCD79Bの野生型の遺伝子背景を有する患者であることがわかった。
比較例として、本発明化合物と同じ薬理作用を有するBtk阻害剤であるPCI−32765(一般名:イブルチニブ、以下、比較化合物とする)の治験結果を、第54回 米国血液学会(American society of hematology(ASH))、セッション:623、プログラム番号:686、”The Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutnib (PCI-32765), Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results of a Multicenter, Open-Label, Phase 2 Study”、要旨、2012年の記載から本明細書に下記の通り引用する。
再発性または難治性のDLBCL患者に、比較化合物を1日1回560mgの用量で経口投与した。Affymetrixアレイを用い、ホルマリンで固定されたパラフィンに包埋された生検組織の遺伝子発現プロファイリングを行って、DLBCLのサブタイプ(ABC、GCB、分類不可)を同定した。Sangerシークエンシングを用いて、CD79Bの変異を同定した。一次評価項目はORRとし、奏効の評価は、International Working Group Criteria for NHLを用いて行った。
70名の患者が登録され、そのうち、ABC−DLBCLの患者は29名であった。比較化合物を1用量(560mg)でABC−DLBCL患者に投与した結果、ORRは40%(25例中10例、その内訳はCRが8%(25例中2例)およびPRが32%(25例中8例)であった)であった。なお、29例中4例は、奏功の評価ができない患者であった。また、そのうちCD79Bの変異の有無を確認できた患者は24名であり、CD79Bの変異を有する患者ではそのORRは60%(5例中3例)、CD79Bの野生型を有する患者ではそのORRは37%(19例中7例)であった。
Claims (11)
- 6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグを含有してなる、活性化B細胞様びまん性大細胞型B細胞リンパ腫の予防および/または治療剤。
- 活性化B細胞様びまん性大細胞型B細胞リンパ腫が、再発性または難治性の活性化B細胞様びまん性大細胞型B細胞リンパ腫である請求項1記載の剤。
- CD79B野生型活性化B細胞様びまん性大細胞型B細胞リンパ腫である請求項1または2記載の剤。
- 6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグを、1日あたり20〜600mgの用量で経口投与することを特徴とする請求項1〜3のいずれか一項に記載の剤。
- 再発予防剤である請求項1〜4のいずれか一項に記載の剤。
- 抗癌剤を用いた薬物療法、造血幹細胞移植法、および放射線療法からなる群から選択される1種以上の方法と組み合わせることを特徴とする、請求項1〜5のいずれか一項に記載の剤。
- 抗癌剤が、アルキル化薬、代謝拮抗薬、抗癌性抗生物質、植物性アルカロイド薬、ホルモン薬、白金化合物、抗CD20抗体、プロテアソーム阻害薬、PKCベータ阻害薬、IKK阻害薬、PI3K阻害薬、Bcl−2阻害薬、mTOR阻害薬、Auroraキナーゼ阻害薬、Syk阻害薬、HDAC阻害薬、CDK阻害薬、JAK2阻害薬、MEK阻害薬、HIF−1α阻害薬、B−RAF阻害薬、PDK1阻害薬、PLK阻害薬、NEA阻害薬、PIM阻害薬、AXL阻害薬、EZH2阻害薬、HSP阻害薬、BRD4阻害薬、ALK阻害薬、ABL阻害薬、または他の抗癌剤である請求項6記載の剤。
- 6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン 塩酸塩である請求項1〜7のいずれか一項に記載の剤。
- 6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグを、治療が必要なヒトに投与することからなる、活性化B細胞様びまん性大細胞型B細胞リンパ腫の予防および/または治療方法。
- 活性化B細胞様びまん性大細胞型B細胞リンパ腫の予防および/または治療に使用するための6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグ。
- 活性化B細胞様びまん性大細胞型B細胞リンパ腫の予防および/または治療医薬を製造するための、6−アミノ−9−[(3R)−1−(2−ブチノイル)−3−ピロリジニル]−7−(4−フェノキシフェニル)−7,9−ジヒドロ−8H−プリン−8−オン、その塩、その溶媒和物、そのN−オキシド、またはそれらのプロドラッグの使用。
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WO2015146159A1 (en) | 2015-10-01 |
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US10137129B2 (en) | 2018-11-27 |
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