JP2019510005A - 急性骨髄性白血病の治療方法 - Google Patents
急性骨髄性白血病の治療方法 Download PDFInfo
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Abstract
Description
(i)全末梢白血球の10%未満であり;
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い;および/または
(iii)前記CXCR4アンタゴニストでの処置の1日以上後、少なくとも2倍高い、とき、
前記被験者は、前記CXCR4と化学療法剤との併用治療のために選択される。
(a)AMLを有する被験者の末梢血および骨髄における芽細胞の密度を測定する工程と、
(b)該被験者にCXCR4アンタゴニストを投与する工程と、
(c)末梢血中の前記芽細胞密度が
(i)全末梢白血球の10%未満であり;
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い;および/または
(iii)工程(b)の1日以上後、少なくとも2倍高い;
場合、治療有効量の前記CXCR4アンタゴニストおよび治療有効量の化学療法剤を前記被験者に投与する工程とを含み、
それにより、AML治療に対する前記被験者の応答を最大限にしている。
(a)末梢血中の全白血球の10%未満である芽細胞の密度を有するAMLと被験者を特定(分類)する工程と;
(b)治療有効量のCXCR4−アンタゴニストおよび治療有効量の化学療法剤を前記被験者に投与し、それによりAMLを治療する工程とを含む。
(a)骨髄中の芽細胞の密度よりも少なくとも5倍低い末梢血中の芽細胞の密度を有するAMLと被験者を特定する工程と;
(b)治療有効量のCXCR4−アンタゴニストおよび治療有効量の化学療法剤を前記被験者に投与し、それによりAMLを治療する工程とを含む。
(a)被験者へのCXCR4アンタゴニストの投与の少なくとも1日後に、末梢血中の芽細胞の密度の少なくとも2倍の増加を示すAMLと被験者を特定する工程と;
(b)段階(a)で同定された前記被験者に、治療有効量の前記CXCR4−アンタゴニストおよび治療有効量の化学療法薬を投与し、それにより前記AMLを治療する工程と、を含む。
(i)全末梢白血球の10%未満であり;
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い;および/または
(iii)前記CXCR4アンタゴニストでの処置の1日以上後、少なくとも2倍高い。
(i)全末梢白血球の10%未満であり;
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い;および/または
(iii)前記CXCR4アンタゴニストでの処置の1日以上後、少なくとも2倍高い、とき、
前記被験者は、前記CXCR4と化学療法剤との併用治療のために選択される。
(a)AMLを有する被験者の末梢血および骨髄における芽細胞の密度を測定する工程と、
(b)該被験者にCXCR4アンタゴニストを投与する工程と、
(c)末梢血中の前記芽細胞密度が、
(i)全末梢白血球の10%未満であり;
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い;および/または
(iii)工程(b)の1日以上後に少なくとも2倍高い場合、治療有効量の前記CXCR4アンタゴニストおよび治療有効量の化学療法剤を前記被験者に投与する工程とを含み、
それにより、AML治療に対する前記被験者の応答性を最大化している。
(a)末梢血中の全白血球の10%未満である芽細胞の密度を有するAMLと被験者を特定する工程と、
(b)治療有効量のCXCR4−アンタゴニストおよび治療有効量の化学療法剤を前記被験者に投与し、それによりAMLを治療する工程とを含む。
(a)骨髄中の芽細胞の密度よりも少なくとも5倍低い末梢血中の芽細胞の密度を有するAMLと被験者を特定する工程と;
(b)治療有効量のCXCR4−アンタゴニストおよび治療有効量の化学療法剤を前記被験者に投与し、それによってAMLを治療する工程とを含む。
(a)被験者へのCXCR4アンタゴニストの投与の少なくとも1日後に、末梢血中の芽細胞の密度の少なくとも2倍の増加を示すAMLと被験者を特定する工程と、
(b)段階(a)で同定された前記被験者に、治療有効量の前記CXCR4−アンタゴニストおよび治療有効量の化学療法薬を投与し、それにより前記AMLを治療する工程と、を含む。
(i)全末梢白血球の10%未満であり;
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い;および/または
(iii)前記CXCR4アンタゴニストでの処置の1日以上後、少なくとも2倍高い。
1 2 3 4 5 6 7 8 9 10 11 12 13 14
A1−A2−A3−Cys−Tyr−A4−A5−A6−A7−A8−A9−A10−Cys−A11 (I)
A2は、A1が存在する場合、アルギニンまたはグルタミン酸残基を表す。またはA2は、A1が存在しない場合、アルギニンまたはグルタミン酸残基またはこれらのアミノ酸のN-α-置換誘導体を表す。
A3は、芳香族アミノ酸残基を表す。
A4、A5およびA9は、それぞれ独立に、アルギニン、リシン、オルニチン、シトルリン、アラニンまたはグルタミン酸残基を表す。
A6は、プロリン、グリシン、オルニチン、リシン、アラニン、シトルリン、アルギニンまたはグルタミン酸残基を表す。
A7は、プロリン、グリシン、オルニチン、リジン、アラニン、シトルリンまたはアルギニン残基を表す。
A8は、チロシン、フェニルアラニン、アラニン、ナフチルアラニン、シトルリンまたはグルタミン酸残基を表す。
A10は、シトルリン、グルタミン酸、アルギニンまたはリジン残基を表す。
A11は、アルギニン、グルタミン酸、リジンまたはシトルリン残基を表し、C末端カルボキシルは誘導体化されていてもよい。
4位または13位のシステイン残基は、ジスルフィド結合を形成することができる。そして、アミノ酸は、L体またはD体のいずれであってもよい。
Kwon Y-U、Kodadek T. ペプトイドおよびペプチドの相対細胞透過性の定量的評価。J Am Chem Soc, 2007; 129:1508を参照。
Miller S, Simon R, Ng S, Zuckermann R, Kerr J, Moos W. 同族L−アミノ酸、D−アミノ酸、N−置換グリシンペプチドおよびペプトイドオリゴマーのタンパク質分解感受性の比較。Drug Dev Res. 1995; 35:20-32を参照。
Yoshikawa Y, Kobayashi K, Oishi S, Fujii N, Furuya T. 環状ペンタペプチドCXCR4アンタゴニストの分子モデリング研究:CXCR4−FC131相互作用の新しい知見。Bioorg Med Chem Lett. 2012; 22:2146-50を参照。
Jaahnichen S, Blanchetot C, Maussang D, Gonzalez-Pajuelo M, Chow KY, Bosch L, De Vrieze S, Serruys B, Ulrichts H, Vandevelde W. CXCR4ナノ体(VHHベースの単一可変ドメイン)は、走化性およびHIV−1複製を強力に阻害し、幹細胞を強く結集させる。Proc Natl Acad Sci USA. 2010; 107:20565-70を参照。
(i)全末梢白血球の10%未満または5%未満または3%未満、
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い、少なくとも4倍低い、少なくとも3倍低い、または少なくとも2倍低い、および/または
(iii)前記CXCR4アンタゴニスト(化学療法剤なし)での治療の1日以上(例えば、1〜4、2〜4、2〜3日)後、少なくとも2倍高い、少なくとも3倍高い、少なくとも4倍高い、または少なくとも5倍高い
(i)全末梢白血球の10%未満または5%未満または3%未満、および
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い、少なくとも4倍低い、少なくとも3倍低い、または少なくとも2倍低い
(i)全末梢白血球の10%未満または5%未満または3%未満、および
(ii)前記CXCR4アンタゴニスト(化学療法剤なし)での治療の1日以上(例えば、1〜4、2〜4、2〜3日)後、少なくとも2倍高い、少なくとも3倍高い、少なくとも4倍高い、または少なくとも5倍高い
(i)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い、少なくとも4倍低い、少なくとも3倍低い、または少なくとも2倍低い、および
(ii)前記CXCR4アンタゴニスト(化学療法剤なし)での治療の1日以上(例えば、1〜4、2〜4、2〜3日)の後、少なくとも2倍高い、少なくとも3倍高い、少なくとも4倍高い、または少なくとも5倍高い
一実施形態では、化学療法剤は、キザチニブ(AC220)である。
薬物
凍結乾燥された4F−ベンゾイル−TN14003(BL−8040)は、MSD/N.V.(Organon, Kloosterstraat 6, 5349 AB, Oss, Netherlands)によって、cGMPに従って製造された。
シタラビン(シトシンアラビノシド;ARA−C)は、Hadassah cytotoxica pharmacy(イスラエル)から購入された。
オープンラベル単一アームフェーズ1/2試験で、再発性または難治性疾患を有するAMLと診断された患者は、1〜2日目で単独療法として、1日1回の皮下(SC)用量のBL−8040を投与され、続いて3〜7日目で、同じ用量のBL−8040プラスAra−C(60歳以上の患者では1.5g/m2;60歳より下の患者では3g/m2)を投与された。BL−8040(0.5〜2.0mg/kg)の6用量レベルは、増殖フェーズのために選択された1.5mg/kgで、用量漸増フェーズで試験された。モビリゼーションの程度などの広範な薬力学(PD)パラメータは、研究中に評価された。治療に対する臨床的応答性は、30日目のBM生検によって決定された。治療に対する臨床的応答性は、30日目のBM生検によって決定された。
骨髄芽細胞数は、Lee et al.(Int. Jnl. Lab. Hem. 30:349-364, 2008)によって記載されているような手順を本質的に使用して実行された。
ANL治療に対する臨床的応答性は、AMLの国際ワーキンググループの基準に従って決定された(Cheson et al., J. Clin. Oncol. 21: 4642-4649, 2003;Dohner et al., Blood 115: 453-474, 2010;およびde Greef et al., British Journal of Hematology 128: 184-91, 2005)。これらを下記の表4にまとめた。
完全寛解(CR)、または、不完全な回復を伴う完全寛解(CRiまたはCRp)を達成した治療患者は、応答性があると考えられた。少なくとも1mg/kgのBL−8040を投与されている全ての患者の中で、ベースラインBM芽細胞密度において、応答性患者と、非応答性患者との間に本質的に差はなかった(それぞれ、37.8%および40.8%:図1)。測定は、シタラビンを有する配列番号1の併用治療の前に行われた。
Claims (14)
- 急性骨髄性白血病(AML)を有する被験者の治療計画を選択する方法であって、
前記方法は、前記被験者の末梢血および所望により骨髄における芽細胞の密度を測定する工程を含み、
前記被験者は、CXCR4アンタゴニストで処置されており、
前記末梢血中の前記芽細胞密度が次の(i)、(ii)および/または(iii)の時、
(i)全末梢白血球の10%未満
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い
(iii)前記CXCR4アンタゴニストでの処置の1日以上後、少なくとも2倍高い
前記被験者は、前記CXCR4と化学療法剤との併用治療のために選択されることを特徴とする治療計画を選択する方法。 - 急性骨髄性白血病(AML)の治療に対する応答性を最大化する方法であって、前記方法は、
(a)前記AMLを有する被験者の末梢血および骨髄における芽細胞の密度を測定する工程と、
(b)前記被験者にCXCR4アンタゴニストを投与する工程と、
(c)前記末梢血中の前記芽細胞密度が以下の(i)、(ii)および/または(iii)場合、前記CXCR4アンタゴニストの治療有効量と、化学療法剤の治療有効量とを前記被験者に投与する工程と、を含み、
(i)全末梢白血球の10%未満
(ii)前記骨髄中の前記芽細胞密度よりも少なくとも5倍低い
(iii)前記工程(b)の1日以上後、少なくとも2倍高い
前記AMLの治療に対する前記被験者の応答性を最大化することを特徴とする方法。 - AMLを治療する方法であって、前記方法は、
(a)末梢血中の全白血球の10%未満である芽細胞の密度を有するAMLと被験者を特定する工程と、
(b)治療有効量のCXCR4−アンタゴニストと、治療有効量の化学療法剤とを前記被験者に投与し、それにより前記AMLを治療する工程と、を含むことを特徴とするAMLを治療する方法。 - AMLを治療する方法であって、前記方法は、
(a)骨髄中の芽細胞の密度よりも少なくとも5倍低い末梢血中の芽細胞の密度を有するAMLと被験者を特定する工程と、
(b)治療有効量のCXCR4−アンタゴニストと、治療有効量の化学療法剤とを前記被験者に投与し、それにより前記AMLを治療する工程と、を含むことを特徴とするAMLを治療する方法。 - AMLを治療する方法であって、前記方法は、
(a)被験者へのCXCR4アンタゴニストの投与の少なくとも1日後に、末梢血中の芽細胞の密度の少なくとも2倍の増加を示す前記AMLと前記被験者を特定する工程と、
(b)治療有効量の前記CXCR4−アンタゴニストと、治療有効量の化学療法薬とを前記工程(a)で特定された前記被験者に投与し、それにより前記AMLを治療する工程と、を含むことを特徴とするAMLを治療する方法。 - 被験者のAMLの治療におけるCXCR4アンタゴニストおよび化学療法剤であって、
前記被験者は、選択され、前記CXCR4アンタゴニストで治療され、次の(i)、(ii)および/または(iii)である末梢血中の芽細胞密度を示すことを特徴とするCXCR4アンタゴニストおよび化学療法剤。
(i)全末梢白血球の10%未満
(ii)骨髄中の前記芽細胞密度よりも少なくとも5倍低い
(iii)前記CXCR4アンタゴニストでの処置の1日以上後、少なくとも2倍高い - 前記CXCR4アンタゴニストは、CXCR4−アンタゴニストペプチドである請求項1ないし6のいずれか1項に記載の方法またはCXCR4アンタゴニストおよび化学療法剤。
- 前記CXCR4−アンタゴニストペプチドは、配列番号1に記載のものである請求項7に記載の方法またはCXCR4アンタゴニストおよび化学療法剤。
- 前記末梢血中の前記芽細胞の密度は、5%未満である請求項1ないし8のいずれか1項に記載の方法またはCXCR4アンタゴニストおよび化学療法剤。
- 前記CXCR4−アンタゴニストペプチドは、体重1kg当たり0.1〜5mgの1日用量で前記被験者に投与される請求項8または9に記載の方法またはCXCR4アンタゴニストおよび化学療法剤。
- 前記CXCR4アンタゴニスト−ペプチドは、皮下投与される請求項7ないし10のいずれか1項に記載の方法またはCXCR4アンタゴニストおよび化学療法剤。
- 前記CXCR4−アンタゴニストは、前記化学療法剤の投与の少なくとも1日前に、単独療法として前記被験者に投与される請求項1ないし11のいずれか1項に記載の方法またはCXCR4アンタゴニストおよび化学療法剤。
- 前記CXCR4−アンタゴニストは、前記化学療法剤の投与の少なくとも1時間前に、前記被験者に投与される請求項1ないし12のいずれか1項に記載の方法またはCXCR4アンタゴニストおよび化学療法剤。
- 前記化学療法剤は、シタラビン(ARA−C)を含む請求項1ないし13のいずれか1項に記載の方法またはCXCR4アンタゴニストおよび化学療法剤。
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