JP2016521266A - イブルチニブ併用療法 - Google Patents
イブルチニブ併用療法 Download PDFInfo
- Publication number
- JP2016521266A JP2016521266A JP2016507617A JP2016507617A JP2016521266A JP 2016521266 A JP2016521266 A JP 2016521266A JP 2016507617 A JP2016507617 A JP 2016507617A JP 2016507617 A JP2016507617 A JP 2016507617A JP 2016521266 A JP2016521266 A JP 2016521266A
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- Prior art keywords
- anticancer agent
- ibrutinib
- lymphoma
- inhibits
- cell
- Prior art date
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Abstract
Description
本出願は、2013年4月8日出願の米国仮特許出願第61/809,810号、表題「IBRUTINIB COMBINATION THERAPY」の利益を請求するものであり、該米国仮特許出願は、その全体を参照することにより本明細書に組み込まれる。
他に定義されない限り、本明細書で用いる全ての技術用語及び科学用語は、請求される主題が属する技術分野における当業者によって、一般に理解されるものと同じ意味を有する。前述の一般的な記述及び次の詳細な記述は、典型的且つ例示的なものだけであり、請求された任意の内容を限定するものでない、ことが理解される。本出願において、単数の使用は、特に別記しない限り複数を含んでいる。明細書と添付の請求項で使用されるように、単数形「a」、an」、及び「the」は、他にその内容が明確に指示しない限り、複数の指示標的を含むということを留意されたい。本出願において、「又は」の使用は、特に明記しない限り、「及び/又は」を意味する。更に、用語「含んでいる(including)」の使用は、「含む(include)」、「含む(includes)」、及び「含まれる(included)」といった他の形態と同じく、制限はない。
幾つかの実施形態において、本明細書に記載されるBtk阻害剤化合物は、Btkにおけるシステイン481のアミノ酸配列位置に相同するチロシンキナーゼのアミノ酸配列位置において、システイン残基を有するBtk及びキナーゼに対して選択的である。Btk阻害剤化合物は、(例えば、ミカエル反応を介して)Btkのシステイン481との共有結合を形成することができる。
本明細書には、特定の実施形態において、Btk阻害化合物と第2の抗癌剤を含む医薬の組み合わせが開示され、該組み合わせは、イブルチニブ又は第2の抗癌剤のみの投与と比較して、相乗的な治療効果を提供する。
幾つかの実施形態において、第2の抗癌剤は、Bcl−2;ヤヌスキナーゼ2(JAK2);未分化リンパ腫キナーゼ(ALK);又は、熱ショックタンパク質90(Hsp90)を阻害し、ここで、前記組み合わせは、イブルチニブ又は第2の抗癌剤のみの投与と比較して、相乗的な治療効果を提供する。幾つかの実施形態において、第2の抗癌剤はBcl−2を阻害する。幾つかの実施形態において、Bcl−2を阻害する第2の抗癌剤は、ABT−737、ABT−199、及びHA14−1から選択される。幾つかの実施形態において、第2の抗癌剤はJAK2を阻害する。幾つかの実施形態において、JAK2を阻害する第2の抗癌剤はTG−101348である。幾つかの実施形態において、第2の抗癌剤はALKを阻害する。幾つかの実施形態において、ALKを阻害する第2の抗癌剤はNVP−TAE684である。幾つかの実施形態において、第2の抗癌剤はHsp90を阻害する。幾つかの実施形態において、Hsp90を阻害する第2の抗癌剤は17−DMAGである。
幾つかの実施形態において、必要とする個体の癌を処置する方法であって、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。幾つかの実施形態において、癌は腫瘍を含む。幾つかの実施形態において、腫瘍は、肉腫、癌腫、神経線維腫(neurofibromatoma)、又はリンパ腫である。幾つかの実施形態において、リンパ腫は、拡大したリンパ節又は節外性リンパ腫である。幾つかの実施形態において、被験体は、脳、***、膀胱、骨、結腸、腎臓、肝臓、肺、卵巣、膵臓、前立腺、皮膚、或いは、近位又は末梢胆管の癌腫を患う。幾つかの実施形態において、被験体は血液癌を患う。幾つかの実施形態において、癌はリンパ腫である。幾つかの実施形態において、被験体は非ホジキンリンパ腫を患う。幾つかの実施形態において、非ホジキンリンパ腫は、慢性リンパ性白血病/小リンパ球性リンパ腫(CLL/SLL)、濾胞性リンパ腫(FL)、びまん性大細胞型B細胞リンパ腫(DLBCL)、外套細胞リンパ腫(MCL)、ワルデンストローム・マクログロブリン血症、多発性骨髄腫、辺縁帯リンパ腫、バーキットリンパ腫、非バーキットの高度のB細胞リンパ腫、又は結節外の辺縁帯B細胞リンパ腫である。幾つかの実施形態において、非ホジキンリンパ腫は、再発性又は難治性の非ホジキンリンパ腫である。幾つかの実施形態において、被験体はT細胞悪性腫瘍を患う。幾つかの実施形態において、T細胞悪性腫瘍は、非特定型末梢T細胞リンパ腫(peripheral T−cell lymphoma not otherwise specified)(PTCL−NOS)、未分化大細胞リンパ腫、血液免疫芽細胞リンパ腫、悪性皮膚T細胞リンパ腫、成人T細胞白血病/リンパ腫(ATLL)、分芽型NK細胞リンパ腫、腸疾患型T細胞リンパ腫、血液脾臓(hematosplenic)ガンマ−デルタT細胞リンパ腫、リンパ芽球性リンパ腫、鼻のNK/T細胞リンパ腫、又は処置に関連したT細胞リンパ腫である。
幾つかの実施形態において、必要とする個体の癌を処置する方法であって、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。幾つかの実施形態において、癌は、B細胞増殖性傷害である。
本明細書には、特定の実施形態において、必要とする個体の非ホジキンリンパ腫を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体のDLBCLを処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体の濾胞性リンパ腫を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体のCLL又はSLLを処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体の外套細胞リンパ腫を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体の辺縁帯B細胞リンパ腫を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体のMALTを処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体の結節周辺帯B細胞性リンパ腫を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体の脾臓周辺帯B細胞性リンパ腫を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体のバーキットリンパ腫を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体のワルデンシュトローム・マクログロブリン血症を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体の骨髄腫を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
本明細書には、特定の実施形態において、必要とする個体の白血病を処置する方法が開示され、該方法は、Btk阻害剤と第2の抗癌剤の組み合わせを投与する工程を含む。
特定の例において、付加的な治療剤と組み合わせて、Btk阻害剤と第2の抗癌剤を投与することが、適切である。特定の例において、付加的な治療剤と組み合わせて、イブルチニブと第2の抗癌剤を投与することが、適切である。付加的な治療剤は、処置されている疾病に対するそれらの特定の有用性のために選択される。一般的に、付加的な治療剤は、同じ医薬組成物において、同時に又は同じ経路を介して、及びイブルチニブ及び/又は第2の抗癌剤において投与される必要はない。1つの実施形態において、初期の投与は確立されたプロトコルに従って行われ、その後、観察された効果に基づいて、投与量、投与形態、及び投与の回数が更に変更される。
本明細書には、特定の実施形態において、(a)Btk阻害剤と第2の抗癌剤を含む医薬組成物が開示される。更に本明細書には、特定の実施形態において、(a)イブルチニブと第2の抗癌剤、及び(b)薬学的に許容可能な賦形剤を含む医薬組成物が開示される。
本明細書には、特定の実施形態において、Btk阻害剤と第2の抗癌剤を含む剤形が開示される。更に本明細書には、特定の実施形態において、イブルチニブと第2の抗癌剤を含む剤形が開示される。幾つかの実施形態において、剤形は、組み合わせた剤形である。幾つかの実施形態において、剤形は、固形経口投薬形態である。幾つかの実施形態において、剤形は、錠剤、丸剤、又はカプセルである。幾つかの実施形態において、剤形は、制御放出剤形、遅延放出剤形、拡張放出剤形、パルス放出剤形、多重微粒子剤形、又は混合した即時放出及び制御放出の製剤である。幾つかの実施形態において、剤形は制御放出コーティングを含む。幾つかの実施形態において、剤形は、イブルチニブの放出を制御する第1の制御放出コーティングと、第2の抗癌剤の放出を制御する第2の制御放出コーティングを含む。
幾つかの実施形態において、第2の抗癌剤と組み合わせて投与されるイブルチニブの量は、40mg/日までであり、及び1000mg/日を含む。幾つかの実施形態において、投与されるイブルチニブの量は約40mg/日乃至70mg/日である。幾つかの実施形態において、1日につき投与されるイブルチニブの量は、約10mg、約11mg、約12mg、約13mg、約14mg、約15mg、約16mg、約17mg、約18mg、約19mg、約20mg、約25mg、約30mg、約35mg、約40mg、約45mg、約50mg、約55mg、約60mg、約65mg、約70mg、約75mg、約80mg、約85mg、約90mg、約95mg、約100mg、約110mg、約120mg、約125mg、約130mg、約135mg、又は約140mgである。幾つかの実施形態において、投与されるイブルチニブの量は、約40mg/日である。幾つかの実施形態において、投与されるイブルチニブの量は、約50mg/日である。幾つかの実施形態において、投与されるイブルチニブの量は、約60mg/日である。幾つかの実施形態において、投与されるイブルチニブの量は、約70mg/日である。
本明細書に記載される使用の治療方法において使用するために、キット及び製品も本明細書中に記載される。このようなキットは、例えば、バイアル、チューブ、及びその他同種のもの、つまり、本明細書中に記載される方法で使用される、別個の要素の1つを含む容器の各々などの、1以上の容器を受けるために仕切られる、運搬装置、パッケージ、又は容器を含む。適切な容器は、例えば、ボトル、バイアル、シリンジ、及び試験管を含む。1つの実施形態において、容器は、ガラス又はプラスチックのような様々な材料から形成される。
BTK阻害剤イブルチニブ及び付加的な抗癌剤の組み合わせを、様々なDLBCL細胞株(TMD8 WT、TMD8イブルチニブ耐性、Ly3、Ly10、DHL2、U2932、HBL1、DHL4、DHL5、SUDHL2、DB、又はRCK8細胞)を使用して分析した。BTK阻害剤を2日間、他の制癌剤と共にインキュベートした。細胞阻害をアラマー・ブルー・アッセイによって評価した。
17のびまん性大細胞型B細胞リンパ腫(DLBCL)細胞株のハイスループット・スクリーンを、標準治療、最先端の治療(emerging therapeutics)、及び標的化した薬剤の中から選択された、99の抗癌剤と組み合わせたイブルチニブに対するそれらの反応のために実行した。プロジェクトの目的は、臨床反応に寄与する経路を同定するために、イブルチニブとの特定の相乗効果を同定し且つ定量化することであった。試験した治療の例は、第1線のDLBCL治療:RCHOP(リツキシマブ、シクロホスファミド、ドキソルビシン、ビンクリスチン、プレドニゾン)又はEPOCH(+エトポシド)、及び第2線の治療:デキサメタゾン、プレドニゾン、エトポシド、ビンクリスチン、ゲムシタビン、カルボプラチン、イホスファミド、ベンダムスチン、シクロホスファミド、リツキシマブ、レナリドミド、及びアントラサイクリンを含んでいた。
Claims (40)
- B細胞増殖性障害を処置する方法であって、該方法は:
a.イブルチニブ;及び
b.抗癌剤
を含む組み合わせの治療上有効な量を、必要とする被験体に投与する工程を含み、
ここで、前記抗癌剤は、Bcl−2;ヤヌスキナーゼ2(JAK2);未分化リンパ腫キナーゼ(ALK);又は熱ショックタンパク質90(Hsp90)を阻害するものであり、
前記組み合わせは、イブルチニブ又は抗癌剤のみの投与と比較して、相乗的な治療効果を提供する
ことを特徴とする方法 - 抗癌剤はBcl−2を阻害する、ことを特徴とする請求項1に記載の方法。
- Bcl−2を阻害する抗癌剤は、ABT−737、ABT−199、及びHA14−1から選択される、ことを特徴とする請求項2に記載の方法。
- 抗癌剤はJAK2を阻害する、ことを特徴とする請求項1に記載の方法。
- JAK2を阻害する抗癌剤はTG−101348である、ことを特徴とする請求項4に記載の方法。
- 抗癌剤はALKを阻害する、ことを特徴とする請求項1に記載の方法。
- ALKを阻害する抗癌剤はNVP−TAE684である、ことを特徴とする請求項6に記載の方法。
- 抗癌剤はHsp90を阻害する、ことを特徴とする請求項1に記載の方法。
- Hsp90を阻害する抗癌剤は17−DMAGである、ことを特徴とする請求項8に記載の方法。
- B細胞増殖性障害を処置する方法であって、該方法は:
a.イブルチニブ;及び
b.抗癌剤
を含む組み合わせの治療上有効な量を、必要とする被験体に投与する工程を含み、
ここで、前記抗癌剤は、グルココルチコイド、ビンカアルカロイド、抗代謝物質、DNA傷害剤、レナリドミド、リツキシマブ、又はPKC撹乱因子であり、
前記組み合わせは、イブルチニブ又は抗癌剤のみの投与と比較して、相乗的な治療効果を提供する
ことを特徴とする方法。 - 抗癌剤はグルココルチコイドである、ことを特徴とする請求項10に記載の方法。
- 抗癌剤はビンカアルカロイドである、ことを特徴とする請求項10に記載の方法。
- 抗癌剤は抗代謝物質である、ことを特徴とする請求項10に記載の方法。
- 抗癌剤はDNA傷害剤である、ことを特徴とする請求項10に記載の方法。
- 抗癌剤はPKC撹乱因子である、ことを特徴とする請求項10に記載の方法。
- PKC撹乱因子はエンザスタウリン及びGF109203Xから選択される、ことを特徴とする請求項15に記載の方法。
- B細胞増殖性障害を処置する方法であって、該方法は:
a.イブルチニブ;及び
b.抗癌剤
を含む組み合わせの治療上有効な量を、必要とする被験体に投与する工程を含み、
ここで、前記抗癌剤は、Lyn/Fyn、Syk、PI3K、PKCβ、及びIKKの中から選択されたB細胞受容体経路キナーゼを阻害するものであり、
前記組み合わせは、イブルチニブ又は抗癌剤のみの投与と比較して、相乗的な治療効果を提供する
ことを特徴とする方法。 - 抗癌剤は、Lyn/Fyn、Syk、PI3K、PKCβ、及びIKKの中から選択されたB細胞受容体経路キナーゼを阻害する、ことを特徴とする請求項17に記載の方法。
- 抗癌剤はLyn/Fynを阻害する、ことを特徴とする請求項18に記載の方法。
- 抗癌剤はSykを阻害する、ことを特徴とする請求項18に記載の方法。
- 抗癌剤はPCKβを阻害する、ことを特徴とする請求項18に記載の方法。
- 抗癌剤はIKKを阻害する、ことを特徴とする請求項18に記載の方法。
- 抗癌剤はPI3Kを阻害する、ことを特徴とする請求項18に記載の方法。
- PI3Kを阻害する抗癌剤は、IPI−145、BKM120、BEZ235、GDC−0941、AMG319、CAL−101、及びA66から選択される、ことを特徴とする請求項23に記載の方法。
- B細胞増殖性障害を処置する方法であって、該方法は:
a.治療上有効な量のイブルチニブ;及び
b.抗癌剤
を含む組み合わせの治療上有効な量を、必要とする被験体に投与する工程を含み、
ここで、抗癌剤は、20sプロテアソーム、IRF−4、IRAK4、EZH2、CXCR4、CXCR5、GLS、サイクリン依存性キナーゼ4/6(CDK4/6)、トポイソメラーゼII、PLK;DNAメチルトランスフェラーゼ、RAS/MAPK経路、又はFGFR1チロシンキナーゼを阻害するものであり、
前記組み合わせは、イブルチニブ又は抗癌剤のみの投与と比較して、相乗的な治療効果を提供する
ことを特徴とする方法。 - B細胞増殖性障害は、びまん性大細胞型B細胞リンパ腫(DLBCL)、慢性リンパ球性白血病(CLL)、小リンパ球性リンパ腫(SLL)、ハイリスクのCLL、又は非CLL/SLLリンパ腫、濾胞性リンパ腫、外套細胞リンパ腫、ワルデンストローム・マクログロブリン血症、多発性骨髄腫、辺縁帯リンパ腫、バーキットリンパ腫、非バーキットの高悪性度B細胞リンパ腫、又は結節外の辺縁帯B細胞リンパ腫、急性又は慢性の骨髄性(又は脊髄性)白血病、骨髄異形成症候群、或いは急性リンパ芽球性白血病である、ことを特徴とする請求項1、10、又は25の何れか1つに記載の方法。
- B細胞増殖性障害はDLBCLである、ことを特徴とする請求項26に記載の方法。
- DLBCLは「活性化B細胞(ABC)」DLBCLである、ことを特徴とする請求項27に記載の方法。
- DLBCLは「胚中心B細胞様(GCB)」DLBCLである、ことを特徴とする請求項27に記載の方法。
- イブルチニブは治療上有効な量で投与される、ことを特徴とする請求項1、10、又は25の何れか1つに記載の方法。
- 治療上有効な量のイブルチニブは、約10mgから約100mg、100mgから約200mg、又は約200から約300mg、又は約300から約500mg、又は約500から約840mgの間である、ことを特徴とする請求項30に記載の方法。
- 治療上有効な量のイブルチニブは約140mgである、ことを特徴とする請求項31に記載の方法。
- イブルチニブと抗癌剤は、組み合わせた剤形である、ことを特徴とする請求項1、10、又は25の何れか1つに記載の方法。
- イブルチニブと抗癌剤は、別個の剤形である、ことを特徴とする請求項1、10、又は25の何れか1つに記載の方法。
- イブルチニブと抗癌剤は、同時に、ほぼ同時に、又は同じ処置プロトコル内で投与される、ことを特徴とする請求項1、10、又は25の何れか1つに記載の方法。
- イブルチニブと抗癌剤は、連続して投与される、ことを特徴とする請求項1、10、又は25の何れか1つに記載の方法。
- 抗癌剤は約5mgから約1000mgの間の量で投与される、ことを特徴とする請求項1、10、又は25の何れか1つに記載の方法。
- イブルチニブ対抗癌剤の比率は、約9:1、約4:1、約7:3、約3:2、約1:1、約2:3、約3:7、約1:4、又は約1:9である、ことを特徴とする請求項1、10、又は25の何れか1つに記載の方法。
- 医薬組成物であって、該医薬組成物は:
a.治療上有効な量のイブルチニブ;及び
b.抗癌剤
を含み、
ここで、前記抗癌剤は、Bcl−2、ヤヌスキナーゼ2(JAK2)、未分化リンパ腫キナーゼ(ALK)、又は熱ショックタンパク質90(Hsp90)を阻害し;又は、前記抗癌剤は、グルココルチコイド、ビンカアルカロイド、抗代謝物質、DNA傷害剤、レナリドミド、リツキシマブ、又はPKC撹乱因子であり;又は、前記抗癌剤は、Lyn/Fyn、Syk、PI3K、PKCβ、及びIKKの中から選択されたB細胞受容体経路キナーゼを阻害し;又は、抗癌剤は、20sプロテアソーム、IRF−4、IRAK4、EZH2、CXCR4、CXCR5、GLS、サイクリン依存性キナーゼ4/6(CDK4/6)、トポイソメラーゼII、PLK;DNAメチルトランスフェラーゼ、Ras/MAPK経路、又はFGFR1チロシンキナーゼを阻害し;又は、前記抗癌剤は、AZD0503、ダサチニブ及びニロチニブ、並びにJNJ−20から選択され;
ここで、前記組み合わせは、イブルチニブ又は抗癌剤のみの投与と比較して、相乗的な治療効果を提供する
ことを特徴とする医薬組成物。 - 医薬組成物は、薬学的に許容可能な担体又はアジュバントを更に含む、ことを特徴とする請求項39に記載の医薬組成物。
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WO2021157650A1 (ja) * | 2020-02-05 | 2021-08-12 | カルナバイオサイエンス株式会社 | 抗がん剤組成物 |
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MX369503B (es) | 2019-11-11 |
CA2908375A1 (en) | 2014-10-16 |
JP6871978B2 (ja) | 2021-05-19 |
BR112015025711A8 (pt) | 2019-12-17 |
JP6575952B2 (ja) | 2019-09-18 |
AU2021200066A1 (en) | 2021-03-18 |
JP2021119150A (ja) | 2021-08-12 |
CN111317821A (zh) | 2020-06-23 |
MX2015013970A (es) | 2016-07-08 |
EP2983670A1 (en) | 2016-02-17 |
IL241710B (en) | 2018-11-29 |
AU2019203205A1 (en) | 2019-05-30 |
JP2020002146A (ja) | 2020-01-09 |
EA201591656A1 (ru) | 2016-05-31 |
KR20150141971A (ko) | 2015-12-21 |
EP2983670A4 (en) | 2017-03-08 |
US20200368235A1 (en) | 2020-11-26 |
MX2019013429A (es) | 2020-09-21 |
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