JP2020521777A - 抗cd19抗体とベネトクラクスとの組み合わせ治療のための治療パラダイム - Google Patents
抗cd19抗体とベネトクラクスとの組み合わせ治療のための治療パラダイム Download PDFInfo
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Abstract
Description
>4G7H1.52ハイブリッドS239D/I332E
>4G7L1.155
ベネトクラクス及び他のBCL−2阻害剤の作用機序が類似しているため、非ホジキンリンパ腫、慢性リンパ球性白血病及び/又は小リンパ球性リンパ腫を有するヒトを、例証された抗CD19抗体とベネトクラクス以外のBCL−2阻害剤との組み合わせで治療した場合、本明細書に開示される投与パラダイムは、有効であると共にTLSリスクを軽減するはずであると考えられる。
を含む重鎖定常ドメインと、配列
を含む軽鎖定常ドメインとを含む。
これは、単剤として又は組み合わせ療法の一部としてBTK阻害剤で前治療された再発性/難治性(R/R)CLL又はR/R SLLの成人患者の治療のための、ベネトクラクスと組み合わされたMOR00208の多施設オープンラベル第II相試験である。欧州及び米国で合計120名の患者が登録されている。試験の主目的は、MOR00208とベネトクラクスとの組み合わせの安全性及び有効性を決定することである。
診断/試験集団
1.年齢≧18歳
2.慢性リンパ球性白血病(CLL)又は小リンパ球性リンパ腫(SLL):
a)IWCLL診断基準を満たすCLL又はSLLの診断の病歴
b)リンパ節生検により組織学的に確認されて医療記録内に文書化されたSLLの診断
c)IWCLLガイドラインにより定義された治療の適応症
3.患者は、以下の両方を有していなければならない:
a)BTK阻害剤(例えば、イブルチニブ)摂取中の再発性1若しくは難治性2の疾患又はかかる治療に不寛容
b)少なくとも1ヶ月間にわたるBTK阻害剤による単剤療法又は組み合わせ療法が患者の直近の事前抗癌療法でなければならない
1再発性疾患とは、直近のBTK阻害剤療法ですでにPR又はCRを達成した対象における進行性疾患として定義される
2難治性疾患とは、直近のBTK阻害剤療法で依然としてPRもCRも達成していない対象における進行性疾患又は直近のBTK阻害剤療法を受けた12ヶ月後の最良奏功の安定疾患として定義される
4.東部協同腫瘍学グループ(ECOG)パフォーマンスステータス0〜2
5.自家又は同種異系幹細胞移植の既往歴を有する患者は、試験登録前に活動性移植片対宿主病の証拠を何ら有することなく完全な血液学的回復を示さなければならない
6.患者は、スクリーニング時に以下の検査基準を満たさなければならない:
・以下のような適正骨髄機能:
a)絶対好中球数(ANC)≧1.0×109/L
b)臨床的に有意な出血の証拠の不在下で血小板数≧30×109/L
c)ヘモグロビン≧8.0g/dL
・以下のような適正肝及び腎機能:
d)総血清ビリルビン≦1.5×ULN又は≦3×ULN(CLLによる実証された肝障害の場合)(ジルベール病患者では、直接ビリルビンが正常である限り、3×ULNまでの血清ビリルビンが許容される)
e)ALT及びAST≦2.5×ULN又は<3×ULN(CLLによる実証された肝障害の場合)
f)標準的コッククロフト−ゴールト式を用いて計算された血清クレアチニンクリアランスは、≧50mL/minでなければならない
他の選択基準
7.出産能のある女性(FCBP、補遺Fを参照されたい)は、以下の通りでなければならない:
a)スクリーニング時の陰性血清妊娠試験及び試験治療開始前の尿妊娠試験で確認したときに妊娠していない
b)試験期間及び試験医薬の最終投与後の3ヶ月間にわたって授乳及び血液及び卵母細胞の供与を回避する(注:女性患者は、すべて上述した期間内の献血が禁止される)
c)試験期間中及び試験治療終了の3ヶ月後まで行われる妊娠試験に合意する。これは、患者が完全継続禁欲を実施している場合でも適用される
d)自身の生活習慣に合っているとしても異性間性交の継続禁断を確約するか、又は試験期間及び試験医薬の最終投与後の3ヶ月間にわたって中断することなくきわめて有効な避妊を用いることに合意し且つその遵守が可能である
e)イデラリシブ又はベネトクラクスがホルモン避妊剤の有効性に影響を及ぼすおそれがあるかは、現時点では分かっていないため、ホルモン避妊剤を用いるFCBPは、避妊の第2の形態としてバリア法を追加すべきである
8.男性は、患者がFCBPとの性交に積極的な場合、中断することなくきわめて有効な避妊法を使用すると共に、試験期間及び試験医薬の最終投与後の3ヶ月間にわたって血液又は精子の供与を回避しなければならない
このオープンラベル試験では、MOR00208とベネトクラクスとからなる治療は、疾患進行、許容できない毒性又は何れかの他の理由による中断の何れかが最初に現われるまで予定通り行われる。
MOR00208薬剤製品(DP)は、薬剤師、研究者又は正式指定者のみがアクセス可能な適切な貯蔵施設にその元のパッケージの状態で2〜8℃の冷蔵下において貯蔵しなければならない。
経口投与用として市販されているベネトクラクス錠剤は、活性成分として10若しくは100mgのベネトクラクスを含有する淡黄色フィルムコーティング錠剤として、又は活性成分として50mgのベネトクラクスを含有するベージュ色フィルムコーティング錠剤として供給される。それらは、30℃(86°F)以下で貯蔵すべきである。
Claims (15)
- 非ホジキンリンパ腫、慢性リンパ球性白血病及び/又は小リンパ球性リンパ腫に罹患している患者の治療に使用するための、抗CD19抗体とBCL−2阻害剤とを含む組み合わせにおいて、前記抗CD19抗体は、前記BCL−2阻害剤の初回投与の少なくとも7日前に投与されることを特徴とする組み合わせ。
- 請求項1に記載の組み合わせにおいて、前記抗CD19抗体は、1日目の初回投与後に週1回、2週間に1回又は月1回投与され、前記BCL−2阻害剤は、8日目に初回投与されることを特徴とする組み合わせ。
- 請求項1又は2に記載の組み合わせにおいて、前記抗CD19抗体は、1日目の初回投与後、最初の3ヵ月間にわたって週1回投与されることを特徴とする組み合わせ。
- 請求項3に記載の組み合わせにおいて、前記抗CD19抗体は、1日目の初回投与後、最初の3ヵ月間にわたって週1回及び少なくとも次の3ヶ月間にわたって2週間に1回投与されることを特徴とする組み合わせ。
- 請求項4に記載の組み合わせにおいて、前記抗CD19抗体は、1日目の初回投与後、最初の3ヵ月間にわたって週1回、次の3ヶ月間にわたって2週間に1回及びその後、月1回投与されることを特徴とする組み合わせ。
- 請求項1乃至5の何れか1項に記載の組み合わせにおいて、4日目に前記抗CD19抗体の追加の投与があることを特徴とする組み合わせ。
- 請求項1乃至6の何れか1項に記載の組み合わせにおいて、前記BCL−2阻害剤は、20mgの開始用量で8日目に初回投与され、続いて50mg、100mg、200mg及び400mgで週1回ランプアップ投与され、続いて400mgで1日1回投与されることを特徴とする組み合わせ。
- 請求項1乃至7の何れか1項に記載の組み合わせにおいて、前記抗CD19抗体及び前記BCL−2阻害剤は、個別に投与されることを特徴とする組み合わせ。
- 請求項1乃至8の何れか1項に記載の組み合わせにおいて、前記BCL−2阻害剤は、ベネトクラクスであることを特徴とする組み合わせ。
- 請求項1乃至9の何れか1項に記載の組み合わせにおいて、前記抗CD19抗体は、配列SYVMH(配列番号1)を含むHCDR1領域と、配列NPYNDG(配列番号2)を含むHCDR2領域と、配列GTYYYGTRVFDY(配列番号3)を含むHCDR3領域と、配列RSSKSLQNVNGNTYLY(配列番号4)を含むLCDR1領域と、配列RMSNLNS(配列番号5)を含むLCDR2領域と、配列MQHLEYPIT(配列番号6)を含むLCDR3領域とを含むことを特徴とする組み合わせ。
- 請求項10乃至13の何れか1項に記載の組み合わせにおいて、前記抗CD19抗体は、12mg/kgの濃度で投与されることを特徴とする組み合わせ。
- 慢性リンパ球性白血病、小リンパ球性リンパ腫又は非ホジキンリンパ腫の治療に使用するための、請求項1乃至14の何れか1項に記載の組み合わせにおいて、前記非ホジキンリンパ腫は、濾胞性リンパ腫、小リンパ球性リンパ腫、粘膜関連リンパ組織、辺縁帯、びまん性大B細胞、バーキット及びマントル細胞からなる群から選択されることを特徴とする組み合わせ。
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