JP2021518391A - 小児患者のがんの治療方法 - Google Patents
小児患者のがんの治療方法 Download PDFInfo
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Abstract
Description
別段の定義のない限り、本明細書で用いられているすべての技術用語及び科学用語は、本開示が属する技術分野の当業者によって一般に理解される意味と同じ意味を有する。本明細書で言及されているすべての特許、出願、公開出願及びその他の刊行物は、参照により、その全体が援用される。本明細書で用いられている見出しは、整理するためのものに過ぎず、本明細書に記載されている発明を限定するものでは決してない。
また、本発明で提供するのは、本発明で提供する方法に有用である医薬組成物である。本発明で提供する方法で用いる治療剤のそれぞれ、またはそれらをいずれかに組み合わせたものは、同じ医薬組成物または異なる医薬組成物に含めることができる。
また、本発明で提供するのは、本発明で提供する第1の治療剤(例えば化合物A)及び本発明で提供する第2の治療剤(例えばALCL99化学療法レジメン)に加えて、他の経路または同じ経路を調節することが知られている1つ以上の薬剤(例えば第3の治療剤または療法剤)を使用し得るさらなる併用療法である。特定の実施形態では、このような方法は、所望の場合、相乗的な治療作用または付加的な治療作用をもたらすために、治療を必要とする対象に、化合物Aを、任意にALCL99化学療法レジメンと組み合わせて、かつさらに、抗がん剤、化学療法剤、治療用抗体及び放射線治療のような1つ以上の追加の治療剤と組み合わせて投与することを含む。
また、本発明で提供するのは、医療キットである。特定の実施形態では、本発明で提供するのは、化合物Aまたはその薬学的に許容される塩を含む医療キットである。
ブリガチニブについては、現在利用できる小児臨床PKデータはないので、アロメトリックアプローチを用いて、ブリガチニブの小児臨床PKを成人PKから推定した。この解析の重要な側面は、下に概説されている。
・ALK+NSCLCにおけるブリガチニブによる成人治験では、90mg QDの用量よりも90mg QD→180mg QDの用量で長いPFSが観察されたことから、180mg QDに伴う暴露量が、ALK+小児がんでの有効性を最大化するとは仮定できないことが示唆された。
・ALK阻害剤クリゾチニブによる小児臨床治験では、280mg/m2がMTD/RP2Dとなり、それに伴う全身暴露量は、250mg BIDでの成人臨床暴露量よりも約50%高い。
一般的戦略
ALCLまたはIMTである2歳以上の患者において、ブリガチニブについて、(a)オープンラベル第1/2相用量漸増及び拡大試験(試験1)、ならびに(b)第2相無作為化試験(試験2)という2つの臨床試験を行う。
初期試験(試験1)の第1相部分の際に段階的な血漿試料を採取して、小児集団におけるブリガチニブのPKを特徴付ける。より低年齢の小児では、血液量が限られる可能性により、間隔を大きくした採取スキームを用いる。統合母集団PKモデリングのアプローチを用いることによって、第1相試験から得られるデータと、健常な成人対象及びNSCLC患者で過去に得たPKデータを組み合わせる。アロメトリック関数を組み込んで、体格測定値(例えば、体表面積[BSA]、体重)がクリアランス及び体積パラメーターに及ぼす作用を推定する。ブリガチニブのPKが変動する原因(すなわち共変量)を探求し、小児データセットと成人データセットを組み合わせたものに基づき、成人において過去に推定された共変量の作用を改訂する。モデルの性能を、適合度のグラフによる評価、統計的基準及び視覚的な予測チェックによって評価する。そのモデルを用いて、各小児対象の暴露パラメーターを導き出し、成人の暴露指標と比較して、さらなる用量選択の指針を示す。
試験1:未分化リンパ腫キナーゼ(ALK)の遺伝子変化を有する2歳以上の悪性腫瘍患者におけるブリガチニブの第1/2相試験
主要目標
・小児患者集団において、液体製剤としてPO QDで行うブリガチニブ単剤療法のMTD/RP2Dレジメンを推定すること。
・新たに診断された高リスクALK+ALCLである小児患者において、ALCL99治療レジメンと組み合わせる液体製剤としてPO QDで投与するブリガチニブのMTD/RP2Dレジメンを推定すること。
・小児患者集団において、単剤療法として、及びALCL99と組み合わせて投与するブリガチニブの安全性及び忍容性を評価すること。
・単剤療法として、及びALCL99治療レジメンと組み合わせて投与する小児患者集団において、ブリガチニブのPKを特徴付けること。
・疾患特異的拡大コホート(IMT及び再発性/難治性ALCL)内で、ブリガチニブの抗腫瘍活性を定義すること。
・パートA−1:単剤療法におけるブリガチニブのRP2Dの決定。
・パートA−2:ALCL99と組み合わせるブリガチニブのRP2Dの決定。
・パートBコホートB−1:ORR。
・パートBコホートB−2:ORR。
・パートA−1及びA−2:MTD、DLT、安全性及び忍容性、ならびにPK。
・パートBコホートB−1及びB−2:DOR、PFS、OS、安全性及び忍容性。
・患者は、組織学的または細胞学的に確認された進行性固形腫瘍またはリンパ腫でなければならない。
・患者は、その腫瘍内に、スクリーニングの前に、認定されたアッセイ(すなわち、米国のClinical Laboratory Improvement Amendments(CLIA))によって検出された活性化ALK異常を有する必要がある。この検査から得られる報告書は、適性について、提出する必要がある。IMTまたはALCL患者では、蛍光in situハイブリダイゼーション(FISH)または次世代シーケンシング(NGS)の代わりに、ALK免疫組織化学を用いることができる。
・患者は、試験に参加する30日以内または試験中に、他の治験薬を服用してはならない。
・患者は、プロトコールに定められているような臓器機能及び系機能の要件を満たさなければならない。
・小児患者集団において早発型の肺有害反応を起こす未知の可能性、及び呼吸困難のように、患者における報告義務のある症状をモニタリングする必要性により、患者は、4歳以上でなければならない(年齢の下限は、それ以降のコホートでは、安全性及び忍容性データを精査した後、2歳まで低下することになる)。
・患者は、(1)試験への登録前のいずれかの時点での再発性/進行性疾患、(2)難治性疾患、(3)持続性疾患のうちの少なくとも1つでなければならない。
・難治性であるかまたは、すべての利用可能な標準療法に不耐である。
・患者は、この試験に参加する前のすべての過去の化学療法、免疫療法または放射線療法の急性毒性作用から完全に回復していなければならない。
・患者は、試験への参加時点または試験中に、いずれかの他の抗がん剤の投与または放射線療法を受けていてはならない。
・患者は、2歳以上、22歳未満でなければならない。
・患者は、高リスクALK+ALCLでなければならない。
・患者は、過去にいずれの全身化学療法も受けていてはならない。
・患者は、2歳以上でなければならない。
・切除不能または再発性のALK+IMTである。
・患者は、2歳以上、22歳未満でなければならない。
・再発性または難治性のALK+ALCLである。
・神経学的に不安定であるか、または漸増用量の副腎皮質ステロイドを必要とする症候性CNS転移のある患者。
・試験薬の1回目の投与の14日前以内に、強力または中程度なCYP3A阻害剤または誘導因子を服用した患者。
・以前にALK阻害剤を服用した(パートA−2及びパートBのみ)。
・パートA−1:4歳以上であり、過去に標準ケアが無効であった進行性のALK+固形腫瘍またはALCLである評価可能な患者が18人以下。18歳以下の患者が15人以上。
・パートA−2:2歳以上、22歳未満であり、新たに診断された高リスクALCLである評価可能な患者が12人以下。18歳以下の患者が9人以上。
・パートB、コホートB−1:2歳以上であり、切除不能/再発性のIMTである患者が28人。18歳以下の患者が15人以上。
・パートB、コホートB−2:2歳以上、22歳未満であり、再発性/難治性ALCLである患者が10人。18歳以下の対象が8人以上。
・ブリガチニブ単剤療法(すべての患者に対して経口液剤)。
・ブリガチニブ単剤療法:経口液剤及び錠剤(固形の経口剤形を嚥下できる患者に対する錠剤用量。錠剤用量は、パートA−1で収集したPKデータ、及び相対的バイオアベイラビリティの考察から定めることになる)
・パートA−1及びパートB:治療は、疾患の進行または許容できない毒性が認められるまで継続する。
・パートA−2:ALCL99+/−ブリガチニブを合計6サイクル投与する。2サイクルの治療後にCRまたはCRuが見られた、いずれのアームの患者にも、治験医の裁量で、移植に移行してもよい。
・PRまたは疾患の安定のいずれかが見られた患者には、試験依頼者及び治験医が同意したら、最長で1年間、疾患の進行または許容できない毒性が認められるまで、単剤としてのブリガチニブの投与を継続する。
主要目標
・これまで治療していない高リスクALCLである2歳以上の患者において、ALCL99と組み合わせたブリガチニブの有効性を評価すること。
・ALCL99と組み合わせたブリガチニブの安全性及び忍容性を評価すること。
・母集団PK解析に寄与する血漿濃度−時間データを収集すること。
・2年時点のEFS
・ORR、DOR、奏効までの時間及びOS
・患者は、2歳以上、22歳未満でなければならない。
・患者は、高リスクALK+ALCLであり、診断時にMDD+であり、かつ抗体価が1/750以下でなければならない。
・患者は、スクリーニングの前に、認定されたアッセイ(すなわち、米国のCLIA)によって検出された活性化ALK異常を有する必要がある。この試験から得られる報告書は、適性について、提出する必要がある。FISHまたはNGSの代わりに、ALK免疫組織化学を用いることができる。
・患者は、試験に参加する30日以内または試験中に、他の治験薬を服用してはならない。
・患者は、プロトコールに定められているような臓器機能及び系機能の要件を満たさなければならない。
・神経学的に不安定であるか、または漸増用量の副腎皮質ステロイドを必要とする症候性CNS転移のある患者。
・試験薬の1回目の投与の14日前以内に、強力または中程度なCYP3A阻害剤または誘導因子を服用した患者。
・以前にALK阻害剤を服用した。
・過去にALCLに対するいずれかの全身化学療法を受けた患者。
・2歳以上、22歳未満の患者約104人を1:1で無作為に分けて、ブリガチニブをALCL99と組み合わせて投与するか、またはALCL99を単独で投与する(85〜97人の患者は、18歳以下である)。
・患者は、無作為化から最長で3年間追跡する。
・ブリガチニブは、経口液剤、または経口剤形を嚥下できる患者には錠剤として提供する。試験2で用いたブリガチニブ+ALCL99治療レジメンは、試験1のパートA−2で検討された内容に従う。
Claims (36)
- 前記がんが、未分化リンパ腫キナーゼ陽性(ALK+)である、請求項1に記載の方法。
- 前記がんが、IMTまたはALCLである、請求項1または2に記載の方法。
- 前記がんが、神経芽腫である、請求項1または2に記載の方法。
- 前記がんが、IMTである、請求項1または2に記載の方法。
- 前記IMTが、切除不能または再発性のIMTである、請求項5に記載の方法。
- 前記がんが、ALCLである、請求項1または2に記載の方法。
- 前記ALCLが、再発性または難治性ALCLである、請求項7に記載の方法。
- 前記ALCLが、新たに診断されたALCLである、請求項7に記載の方法。
- 前記ALCLが、新たに診断されたALCLであって、高再発リスクALCLである、請求項9に記載の方法。
- 前記高再発リスクが、診断時に微小播種病変陽性(MDD+)であるか、または診断時の抗ALK抗体価が1/750以下であることによって特徴付けられる、請求項10に記載の方法。
- 化合物Aまたはその薬学的に許容される塩を経口投与する、請求項1〜11のいずれか1項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩を1日に1回(QD)投与する、請求項1〜12のいずれか1項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩を約30mg/m2〜約100mg/m2の用量で投与する、請求項1〜13のいずれか1項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩を約30mg/m2、約40mg/m2、約50mg/m2、約60mg/m2、約70mg/m2、約80mg/m2、約90mg/m2または約100mg/m2の用量で投与する、請求項14に記載の方法。
- 前記患者に、第2の治療剤を治療有効量投与することをさらに含む、請求項1〜15のいずれか1項に記載の方法。
- 前記第2の治療剤が、シクロホスファミド、ドキソルビシン、ビンクリスチン、副腎皮質ステロイド、イホスファミド、エトポシド、メトトレキセートもしくはシタラビン、またはこれらを組み合わせたものである、請求項16に記載の方法。
- 前記副腎皮質ステロイドが、デキサメタゾンもしくはヒドロコルチゾン、またはこれらを組み合わせたものである、請求項17に記載の方法。
- 前記第2の治療剤が、デキサメタゾンを含み、前記デキサメタゾンを約5mg/m2〜約10mg/m2の用量で投与する、請求項16〜18のいずれか1項に記載の方法。
- 前記第2の治療剤が、シクロホスファミドを含み、前記シクロホスファミドを約200mg/m2の用量で投与する、請求項16〜19のいずれか1項に記載の方法。
- 前記第2の治療剤が、イホスファミドを含み、前記イホスファミドを約800mg/m2の用量で投与する、請求項16〜20のいずれか1項に記載の方法。
- 前記第2の治療剤が、メトトレキセートを含み、前記メトトレキセートを約3g/m2の用量で投与する、請求項16〜21のいずれか1項に記載の方法。
- 前記第2の治療剤が、エトポシドを含み、前記エトポシドを約100mg/m2の用量で投与する、請求項16〜22のいずれか1項に記載の方法。
- 前記第2の治療剤が、シタラビンを含み、前記シタラビンを約150mg/m2の用量で投与するとともに、1日に2回投与する、請求項16〜23のいずれか1項に記載の方法。
- 前記第2の治療剤が、ドキソルビシンを含み、前記ドキソルビシンを約25mg/m2の用量で投与する、請求項16〜24のいずれか1項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩、及び前記第2の治療剤を21日周期で1サイクル以上投与する、請求項16〜25のいずれか1項に記載の方法。
- 化合物Aまたはその薬学的に許容される塩を前記21日周期の1〜21日目に投与する、請求項26に記載の方法。
- 前記第2の治療剤が、デキサメタゾンを含み、前記デキサメタゾンを、前記21日周期の1〜5日目に投与する、請求項26または27に記載の方法。
- 前記第2の治療剤が、シクロホスファミドを含み、前記シクロホスファミドを前記21日周期の1日目及び2日目に投与する、請求項26〜28のいずれか1項に記載の方法。
- 前記第2の治療剤が、シクロホスファミドを含み、前記シクロホスファミドを前記21日周期の1〜5日目に投与する、請求項26〜28のいずれか1項に記載の方法。
- 前記第2の治療剤が、ヒドロコルチゾン、メトトレキセート及びシタラビンを組み合わせたものを含み、前記組み合わせたものを前記21日周期の1日目に投与する、請求項26〜30のいずれか1項に記載の方法。
- 前記第2の治療剤が、イホスファミドを含み、前記イホスファミドを前記21日周期の1〜5日目に投与する、請求項26〜31のいずれか1項に記載の方法。
- 前記第2の治療剤が、メトトレキセートを含み、前記メトトレキセートを前記21日周期の1日目に投与する、請求項26〜32のいずれか1項に記載の方法。
- 前記第2の治療剤が、エトポシドを含み、前記エトポシドを前記21日周期の4日目及び5日目に投与する、請求項26〜33のいずれか1項に記載の方法。
- 前記第2の治療剤が、シタラビンを含み、前記シタラビンを前記21日周期の4日目及び5日目に投与する、請求項26〜34のいずれか1項に記載の方法。
- 前記第2の治療剤が、ドキソルビシンを含み、前記ドキソルビシンを前記21日周期の4日目及び5日目に投与する、請求項26〜35のいずれか1項に記載の方法。
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WO2016065028A1 (en) * | 2014-10-21 | 2016-04-28 | Ariad Pharmaceuticals, Inc. | Crystalline forms of 5-chloro-n4-[-2-(dimethylphosphoryl) phenyl]-n2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl) piperidin-1-yl] pyrimidine-2,4-diamine |
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LT2300013T (lt) | 2008-05-21 | 2017-12-27 | Ariad Pharmaceuticals, Inc. | Fosforo dariniai kaip kinazių inhibitoriai |
US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
US20160339023A1 (en) | 2013-12-23 | 2016-11-24 | Fang Li | Pharmaceutical Combinations |
CN109312406A (zh) * | 2016-06-01 | 2019-02-05 | 豪夫迈·罗氏有限公司 | 预测肺癌患者中对alk抑制剂疗法的响应的间变性淋巴瘤激酶中的新型突变 |
KR101888744B1 (ko) * | 2016-08-02 | 2018-10-04 | 연세대학교 산학협력단 | Alk 저해제에 내성을 획득한 eml4-alk 양성 비소세포폐암의 치료를 위한 약물 선택의 정보 제공 방법 |
EP3592338A1 (en) * | 2017-03-08 | 2020-01-15 | ARIAD Pharmaceuticals, Inc. | Pharmaceutical formulations comprising 5-chloro-n4 |
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WO2015066452A2 (en) * | 2013-11-01 | 2015-05-07 | Foundation Medicine, Inc. | Methods of treating pediatric cancers |
WO2016065028A1 (en) * | 2014-10-21 | 2016-04-28 | Ariad Pharmaceuticals, Inc. | Crystalline forms of 5-chloro-n4-[-2-(dimethylphosphoryl) phenyl]-n2-{2-methoxy-4-[4-(4-methylpiperazin-1-yl) piperidin-1-yl] pyrimidine-2,4-diamine |
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BR112020018770A2 (pt) | 2020-12-29 |
EP3768275A1 (en) | 2021-01-27 |
JP2023178473A (ja) | 2023-12-14 |
KR20200132899A (ko) | 2020-11-25 |
MX2020009769A (es) | 2020-11-09 |
US11529363B2 (en) | 2022-12-20 |
CN111989107A (zh) | 2020-11-24 |
CA3094079A1 (en) | 2019-09-26 |
US20210000845A1 (en) | 2021-01-07 |
RU2020133814A (ru) | 2022-04-19 |
AU2019238003A1 (en) | 2020-10-01 |
WO2019182936A1 (en) | 2019-09-26 |
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