JP2020531561A - 治療レジメン - Google Patents
治療レジメン Download PDFInfo
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- JP2020531561A JP2020531561A JP2020512557A JP2020512557A JP2020531561A JP 2020531561 A JP2020531561 A JP 2020531561A JP 2020512557 A JP2020512557 A JP 2020512557A JP 2020512557 A JP2020512557 A JP 2020512557A JP 2020531561 A JP2020531561 A JP 2020531561A
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Abstract
Description
プロタイドは、ヌクレオシドのマクスドホスフェート誘導体である。これらは、抗ウイルス剤及び腫瘍学の両分野において、特に有望な治療剤であることが示されている。プロタイドは、親のヌクレオシドの有用性を制限する多くの本来の及び獲得された抵抗性機構を回避するように思われる。
(i)対象者の癌がDPD欠損又は部分的欠損であるかどうかを判定すること、及び
(ii)癌がDPD欠損又は部分的欠損であると同定された対象者に、5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]ホスフェート(NUC-3373)を投与すること
を含んでなる。
(i)癌対象者が手足症候群を有しているかどうかを判定すること、及び
(ii)手足症候群を発症した癌対象者に、薬学上有効な量の5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]ホスフェート(NUC-3373)を登用すること
を含んでなる。
本発明の第1〜第3の態様は、NUC-3373が、5−フルオロウラシル(5FU;NUC-3373が誘導される「親」化合物である)に関するよりもかなり長い期間投与された後も、血行中に保持されるとの発明者らの驚くべき知見に基づくものである。さらに実施例において説明するように、発明者らは、NUC-3373が、5FUについての半減期がわずか8〜14分であるのに対して、概ね9.4時間の血漿半減期を有するとの知見を得た。この差は、NUC-3373の治療上の有効レベルが、5FUの連続46〜48時間の投与後よりも、この投与後、かなり長い期間、維持されることを意味する。結果として、NUC-3373による有効な抗癌剤治療は、5〜10時間以下、例えば、3又は4時間、及び1又は2時間の短時間の投与期間を使用できる。これは、多くの癌の治療のための現在のケア基準である5FUによる現在の治療プロトコルとは、明らかな対照をなすものである。より短い半減期の5FUでは、治療上の活性を達成するために、薬剤が、患者に対して長期間で最適に投与されることを必要とする。46〜48時間での5FUの持続注入による治療は普通であり、5FUの短い半減期(8〜14分)を強調するものである。この注入は、しばしば、5FUの大量投与(短期注入)から始められる。持続注入とは、通常、長い期間で、液体を血管に投与することをいう。
5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]ホスフェート(NUC-3373)は、ホスフェートジアステレオ異性体の混合物であるか、実質的にジアステレオ異性的に純粋な形の(S)−エピマーとして、又は実質的にジアステレオ異性的に純粋な形の(R)−エピマーとして存在していてもよい。
癌は、膵臓癌、乳癌、卵巣癌、膀胱癌、他の尿路上皮癌、胃腸癌(消化器の癌としても知られている)、肝臓癌、肺癌、胆道癌、前立腺癌、胆管細胞癌、腎癌、神経内分泌癌、肉腫、リンパ腫、白血病、子宮頸癌、胸腺癌、原発不明癌、中皮腫、副腎癌、子宮癌、卵管癌、腹膜癌、子宮内膜癌、精巣癌、頭頚部癌、中枢神経系の癌、基底細胞癌、ボーエン病、他の皮膚癌(例えば、悪性メラノーマ、メルケル細胞腫瘍、稀な付属器腫瘍)、角結膜扁平上皮腫瘍、及び胚細胞性腫瘍からなる群から選ばれる癌である。
本発明の第1、第2及び第3の態様は、いずれも、10時間以下の期間でのNUC-337の投与を必要とする治療に関する。熟練した読者は、他に要求される場合を除き、ここに記載する本発明の医学的利用及び治療方法(このように、本発明の第7、第8、第9、第12、及び第13の態様のものを含む)は、いずれも、10時間以下の期間でのNUC-3373の投与を利用できることを認識するであろう
好ましくは、投与は注入の手段によるものであるが、ボーラス投与によって可能である(又はボーラス投与を含む)。
本発明の第4、第5、及び第6の態様は、抗癌剤療法の有効性を評価する方法を提供する。本発明の第3、第4、及び第5の態様の方法は、NUC-3373を使用する抗癌剤治療を受ける対象者において、抗癌剤療法の有効性を評価する際の特別な利用である。例えば、本発明の第3、第4、及び第5の態様の方法は、本発明の医学的利用(例えば、本発明の第1、第3、第7、第8、又は第13の態様の医学的利用)において使用されるNUC-3373による治療を受ける、又は本発明による治療方法(例えば、本発明の第2、第9、又は第12の方法)においてNUC-3373を受ける対象者について利用される。
本発明の第8〜13の態様は、いずれも、対象者がDPDにおいて欠損又は部分的に欠損である医学的利用及び治療方法に関する。
IVS14+1G>A変異(DPYD*2Aとして知られている)、エクソン6における496A>G;エクソン22における2846A>T;及びエクソン13におけるT1679G(DPYD*13)から選ばれる遺伝子変異を有する。染色体1p21.3上のDPYD遺伝子における遺伝子変異体は、不十分なDPD活性を生ずることも示されている(Diagnostic Molecular Pathology: 応用分子検査へのガイド, 2017, William B. Coleman及びGregory J. Tsongalis編)。
本発明の第14〜第17の態様は、いずれも、医学的利用及び治療方法に関するものであり、ここで、癌の患者/対象者は、手足症候群を有するか、又は5FU又はカペシタビンのような化学療法剤にて治療された際に手足症候群を発症し易いものである。手足症候群は、5FU又は5FU関連フルオロピリミジンにて治療された患者の30〜60%において発症する(Krugerら, Acta Oncologica 1-8, 2015; Chiaraら, Eur J Cancer. 33: 967-969, 1997)。手足症候群は、5FUの毒性代謝物であるdhFU及びFBALの蓄積によって生ずる。手足症候群は、潜在的に用量を制限する皮膚毒性である。手足症候群は、手足の痛み、疼き、乾燥、紅斑、スケーリング、腫脹、及び小胞形成の程度の変動とともに、手袋−靴下型分布の感覚異常によって特徴付けられる。化学療法を受けた患者における手足の霜焼け症状は、通常、H&F症候群と診断するに十分である。
本発明の第4、第5、第6、第10、及び第11の態様の方法は、「試料」、例えば、PBMCs又は癌細胞を使用することが認識されるであろう。ここで使用するように、用語「試料」は、一般的に、癌治療を必要とする又は治療中の対象者から得た又は由来の生体試料をいう。
いくつかの具体例では、一次生体試料は、生検(例えば、穿刺吸引又は組織生検)、手術、体液(例えば、血液、リンパ液、腹水、糞便)の収集からなる群から選ばれる方法によって得られる。
本明細書を通して、用語「S−エピマー」又は「S−ジアステレオ異性体」は、5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]−(S)−ホスフェートをいう。同様に、本明細書を通して、用語「R−エピマー」又は「R−ジアステレオ異性体」は、5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]−(R)−ホスフェートをいう。
治療法又は癌治療における使用のための化合物は、NUC-3373に加えて、一般的な手術又は放射線治療又は化学療法を含むことができる。このような化学療法は、1以上の他の活性剤の投与を含むことができる。
(i)抗増殖剤/抗新生物治療剤及びその組み合わせ、例えば、アルキル化剤(例えば、シクロホスファアミド、ナイトロジェンマスタード、ベンダムスチン、メルファラン、クロラムブシル、ブスルファン、テモゾロミド、及びニトロソ尿素);代謝拮抗剤(例えば、ゲムシタビン、及びフルオロピリミジン(例えば、5−フルオロウラシル及びテガフール)、ラルチトレキセド、メトトレキサート、ペメトレキセド、シトシンアラビノシド、及びヒドロキシ尿素のような葉酸代謝拮抗剤);抗生物質(例えば、アドリアマイシン、ブレオマイシン、ドキソルビシン、ダウノマイシン、エピルビシン、イダルビシン、マイトマイシン−C、ダクチノマイシン、及びミトラマイシンのようなアントラサイクリン);抗有糸分裂剤(例えば、ビンカアルカトイド(例えば、ビンクリスチン、ビンブラスチン、ビンデシン、及びビノレルビン)、及びタキソイド(例えば、タキソール及びタキソテレ)、及びポロキナーゼ阻害剤);プロテアソーム阻害剤、例えば、カーフィルゾミブ及びボルテゾミブ);インターフェロン療法;及びトポイソメラーゼ阻害剤(例えば、エピポドフィロトキシン(例えば、エトポシド及びテニポシド)、アムサクリン、トポテカン、ミトキサントロン、及びカンプトテシン);
次に、下記の実施例及び図面を参照して、本発明をさらに詳述する。
NuTide:301は、進行した固体腫瘍の患者におけるフェーズ1用量漸増治験である。全ての患者が転移拡散を有する。治験に登録する36人の患者の内、平均年齢57歳(20歳から77歳まで)及び従来の化学療法レジメンを平均3回(2回から5回までの範囲)受けている21人の患者からデータを得た。10の原発癌の種類があり、その多く(57%)は大腸癌である。
患者は、28日サイクルレジメンのday 1、8、15及び22に、30分〜2時間の静脈内注入として投与したNUC-3373を受けた。患者は、疾患の進行又は許容されない毒性が発生するまで治験を続け、治療を受けた。
NUC-3373は、ジメチルアセトアミド(DMA)及び生理食塩水の溶液(比80:20)中に250 mg/mlのNUC-3373を含有する単回用量静脈内注射剤(透明なバイアル中に収容)として存在する。製品は、可視の粒状物を含まない透明の黄色溶液である。
治験では、全ての患者を、NUC-3373のS及びR−エピマーの1:1混合物によって治療した。
これまで治療したコーホートは、投与当たり125 mg/m2、250 mg/m2、500 mg/m2、又は750mg/m2のNUC-3373を受けた。
ついで、患者の血液試料の薬物動態分析を行った。結果を図1及び2に示す。
治療サイクルのday1及び15において、血液試料を採取した。
血液試料を、下記の表1に示す12の時点で採取した。
血液試料は、採取から2時間以内に到着しなければならない。血液試料4mlを、18℃、1200gにおいて、10分間遠心分離する。殺菌したプラスチック製ピペット(PASTETTE(登録商標))を使用して、得られた結晶を取り出し、血漿〜1.0mlを、2つの凍結保存バイアル(2ml)の各々に移す。
血液試料は、採取から2時間以内に到着しなければならない。血液8mlをCPT採血管に集める(血液管を血液の採取から2時間以内に遠心分離しなければならない)。遠心分離する前に、管を優しく8〜10回転倒させることによって、血液試料を再混合する。開始時及び終了時に緩加速条件(破壊無し)となるように遠心分離機を設定する。18℃、1500gにおいて、遠心分離を20分間行う。試料を、遠心分離機から注意して取り出す。
試料は5つの層を形成する:血漿(第1);白っぽい細胞(PBMC)(第2);ポリエステルゲル(第3);稠密溶液(第4);及び残りの顆粒球及びRBC(第5)。細胞層を乱すことなく血漿の概ね半分を吸引する。パスツールピペットにてPBMC層を集め、50mlチューブに移し、冷たい(4℃)PBSを添加して、最終容積を40mlとする。2つの50mlチューブに分け(各チューブ当たり20ml)、4℃、1500gにおいて、5分間遠心分離する。細胞ペレットを乱すことなく、上澄み液をデカントし、ペレットを残りの緩衝液中に再懸濁させる。各ペレットにPBS1mlを添加して、細胞を集め、1つのペレットを、「PD PBMCs」とラベルした2mlのスクリューキャップチューブに移し、他のペレットを、「PK PBMCsペレット」とラベルした2mlのスクリューキャップチューブに移す。両チューブを、4℃、1500gにおいて、5分間遠心分離する。ピペットにて上澄み液を取り出す(p 1000μl)。上澄み液をチューブから完全に取り出して、良好な質の試料を確保するように注意する。「PD PBMCs」とラベルしたチューブに、凍結媒体溶液(4℃で提供)200μlを添加し、分析まで、−80℃で保存する。
8%メタノール(4℃)200μlを添加し、ピペットで優しく吸引及び吐出を3回行うことによって、「PK PBMCsペレット」とラベルしたチューブ内の細胞プペレットを再懸濁させる。ボルテックスミキサーによって30秒間混合する。試料を氷上に15分間放置する。4℃、1500gにおいて、5分間遠心分離する。マイクロピペットを使用して、細胞ペレットを乱すことなく、上澄み液180μlを、「PK PBMC上澄み液」とラベルした2mlのスクリューキャップチューブに移す。PBMCペレット及びPBMC上澄み液の両方を、dTMP、TS、dUMP、FBAL、及びdhFUについての分析まで、−80℃において保存する。
dTMPを検出するためにUPLC-MSを使用した、TSを検出するためにウエスタンブロットを使用した。
dhFU及びFBALを検出するためにUPLC-MS/MSを使用した。
図1は、これまで治療したコーホートに関する血漿中のNUC-3373についてのCmax及びAUCを示す。血漿中のNUC-3373の半減期は9.7時間である。これに対して、5FUは、8〜14分の血漿半減期を有する。治験した用量でのNUC-3373の投与後、毒性の副生物であるα−フルオロ−β−アラニン(FBAL)及びジヒドロフルオロウラシル(dhFU)は検出されなかった。
図2は、これまで治療したコーホートに関する細胞内FUDRモノホスフェートについてのCmax及びAUCを示す。細胞内FUDRモノホスフェートの半減期は14.9時間であるとの知見を得た。48時間の時点でも、FUDRモノホスフェートが検出された。
これに対して、5FUは、8〜14分の血漿半減期を有する。治験した用量でのNUC-3373の投与後、毒性の副生物であるα−フルオロ−β−アラニン(FBAL)及びジヒドロフルオロウラシル(dhFU)は検出されなかった。
細胞内におけるdUMPの蓄積はDNA損傷を生ずること、及びこのDNA損傷は細胞死と関連することが知られている。このように、癌細胞内でのdUMPの蓄積を促進するNUC-3373の能力は、癌細胞を死滅させることができ、このようにして、効果的に癌を治療する。
Claims (34)
- 癌治療における使用のための5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]ホスフェート(NUC-3373)、又はその薬学上許容される塩又は溶媒和物であって、前記治療が、10時間以下の期間でのNUC-3373の投与によるものであるNUC-3373、又はその薬学上許容される塩又は溶媒和物。
- 治療が、5時間以下の期間でのNUC-3373の投与によるものである請求項1に記載の使用のためのNUC-3373。
- 治療が、2時間以下の期間でのNUC-3373の投与によるものである請求項1又は2に記載の使用のためのNUC-3373。
- 治療が、1〜2時間、2〜4時間、又は1〜6時間の期間でのNUC-3373の投与によるものである請求項1に記載の使用のためのNUC-3373。
- 投与が持続注入によるものである請求項1〜4のいずれかに記載の使用のためのNUC-3373。
- 注入が静脈内注入によるものである請求項5に記載の使用のためのNUC-3373。
- 治療がボーラス投与によるNUC-3373の投与によるものであるか、ボーラス投与を含むものである請求項1〜6のいずれかに記載の使用のためのNUC-3373.
- 癌が、膵臓癌、乳癌、卵巣癌、膀胱癌、他の尿路上皮癌、胃腸癌(消化器の癌としても知られている)、肝臓癌、肺癌、胆道癌、前立腺癌、胆管細胞癌、腎癌、神経内分泌癌、肉腫、リンパ腫、白血病、子宮頸癌、胸腺癌、原発不明癌、中皮腫、副腎癌、子宮癌、卵管癌、腹膜癌、子宮内膜癌、精巣癌、頭頚部癌、中枢神経系の癌、基底細胞癌、ボーエン病、他の皮膚癌(例えば、悪性メラノーマ、メルケル細胞腫瘍、稀な付属器腫瘍)、角結膜扁平上皮腫瘍、及び胚細胞性腫瘍からなる群から選ばれるものである請求項1〜7のいずれかに記載の使用のためのNUC-3373。
- 癌が、食道癌、胃癌、腸癌、小腸癌、結腸癌、虫垂粘膜性腫瘍、胚細胞カルチノイド、肝臓癌、胆道癌、胆嚢癌、肛門癌、及び直腸癌からなる群から選ばれ消化器癌である請求項8に記載の使用のためのNUC-3373。
- 癌患者が手足症候群にも罹っている請求項1〜9のいずれかに記載の使用のためのNUC-3373.
- 患者が、先にNUC-3373以外の薬剤による治療レジメンから手足症候群を発症している請求項10に記載の使用のためのNUC-3373。
- 患者が、5FU、カペシタビン又はテガフールによって治療された際に手足症候群を発症している請求項11に記載の使用のためのNUC-3373。
- 手足症候群に罹った対象者の癌の治療における使用のための5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]ホスフェート(NUC-3373)、又はその薬学上許容される塩又は溶媒和物。
- 対象者が、5FU、カペシタビン又はテガフールのようなフルオロピリミジンによる治療後に、手足症候群を発症している請求項13に記載の使用のためのNUC-3373。
- 癌が、膵臓癌、乳癌、卵巣癌、膀胱癌、他の尿路上皮癌、胃腸癌(消化器の癌としても知られている)、肝臓癌、肺癌、胆道癌、前立腺癌、胆管細胞癌、腎癌、神経内分泌癌、肉腫、リンパ腫、白血病、子宮頸癌、胸腺癌、原発不明癌、中皮腫、副腎癌、子宮癌、卵管癌、腹膜癌、子宮内膜癌、精巣癌、頭頚部癌、中枢神経系の癌、基底細胞癌、ボーエン病、他の皮膚癌(例えば、悪性メラノーマ、メルケル細胞腫瘍、稀な付属器腫瘍)、角結膜扁平上皮腫瘍、及び胚細胞性腫瘍からなる群から選ばれるものである請求項14又は15に記載の使用のためのNUC-3373。
- 癌が、食道癌、胃癌、腸癌、小腸癌、結腸癌、虫垂粘膜性腫瘍、胚細胞カルチノイド、肝臓癌、胆道癌、胆嚢癌、肛門癌、及び直腸癌からなる群から選ばれ消化器癌である請求項14又は15に記載の使用のためのNUC-3373。
- 5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]ホスフェート(NUC-3373)、又はその薬学上許容される塩又は溶媒和物による治療に適した癌を有する対象者を選択する方法であって、該方法は、対象者が手足症候群を有するかどうかを判定し、対象者が手足症候群を有していれば、該対象者を、5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]ホスフェート(NUC-3373)による治療に適するとして選択することを含んでなる方法。
- 患者が、5FU又はカペシタビンのようなフルオロピリミジンにて治療された間に、手足症候群を発症している請求項18に記載の方法。
- ジヒドロピリミジンデヒドロゲナーゼ(DPD)欠損又は部分的欠損である対象者の癌の治療における使用のための5−フルオロ−2’−デオキシウリジン−5’−O−[1−ナフチル(ベンゾキシ−L−アラニニル)]ホスフェート(NUC-3373)、又はその薬学上許容される塩又は溶媒和物。
- 癌が、膵臓癌、乳癌、卵巣癌、膀胱癌、他の尿路上皮癌、胃腸癌(消化器の癌としても知られている)、肝臓癌、肺癌、胆道癌、前立腺癌、胆管細胞癌、腎癌、神経内分泌癌、肉腫、リンパ腫、白血病、子宮頸癌、胸腺癌、原発不明癌、中皮腫、副腎癌、子宮癌、卵管癌、腹膜癌、子宮内膜癌、精巣癌、頭頚部癌、中枢神経系の癌、基底細胞癌、ボーエン病、他の皮膚癌(例えば、悪性メラノーマ、メルケル細胞腫瘍、稀な付属器腫瘍)、角結膜扁平上皮腫瘍、及び胚細胞性腫瘍からなる群から選ばれるものである請求項19に記載の使用のためのNUC-3373。
- 癌が、食道癌、胃癌、腸癌、小腸癌、結腸癌、虫垂粘膜性腫瘍、胚細胞カルチノイド、肝臓癌、胆道癌、胆嚢癌、肛門癌、及び直腸癌からなる群から選ばれ消化器癌である請求項19又は20に記載の使用のためのNUC-3373。
- 対象者が、エクソン14欠失を伴うイントロン14におけるIVS14+1G>A変異(DPYD*2Aとして知られている)、エクソン6における496A>G;エクソン22における2846A>T;及びエクソン13におけるT1679G(DPYD*13)から選ばれる遺伝子変異を有する請求項20又は21に記載の使用のためのNUC-3373。
- 対象者が、IVS14+1G>A DPYD変異体(DPYD*2A)変異を有する請求項22に記載の使用のためのNUC-3373。
- 対象者が、以前に、5FU又はカペシタビンに対する不耐性を示しているか、又は5FU又はカペシタビンに対する不耐性の家族歴を有している請求項20〜22のいずれかに記載の使用のためのNUC-3373。
- 抗癌剤治療の有効性を判定する方法であって、該方法は、抗癌剤治療を受ける対象者からの末梢血単核球(PBMCs)又は癌細胞の試料を検査して、PBMCs又は癌細胞における細胞内デオキシチミジンモノホスフェート(dTMP)のレベルを測定することを含んでなり、ここで、PBMCs又は癌細胞における細胞内dTMPのレベルにおける減少が、抗癌剤治療が有効であることを示す方法。
- 対象者が、NUC-3373を使用する抗癌剤治療を受けている請求項25に記載の方法。
- PBMCs又は癌細胞における細胞内dTMPのレベルを、好適なコントロール値と比較する請求項25又は26に記載の方法。
- 減少が、少なくとも25%の減少である請求項25〜27のいずれかに記載の方法。
- 減少が、細胞内dTMPの実質的に完全な減少である請求項28に記載の方法。
- 抗癌剤治療の有効性を判定する方法であって、該方法は、抗癌剤治療を受ける対象者からの末梢血単核球(PBMCs)又は癌細胞の試料を検査して、PBMCs又は癌細胞における細胞内チミジル酸合成酵素(TS)のレベルを測定することを含んでなり、ここで、PBMCs又は癌細胞における細胞内TSのレベルにおける減少が、抗癌剤治療が有効であることを示す方法。
- 対象者が、NUC-3373を使用する抗癌剤治療を受けている請求項30に記載の方法。
- PBMCs又は癌細胞における細胞内TSのレベルを、好適なコントロール値と比較する請求項30又は31に記載の方法。
- 減少が、少なくとも25%の減少である請求項30〜32のいずれかに記載の方法。
- 減少が、細胞内TSの実質的に完全な減少である請求項33に記載の方法。
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JANE L. YEN-REVOLLO, CLIN CANCER RES, vol. 14, no. 1, JPN6022022929, 2008, pages 8 - 13, ISSN: 0004965402 * |
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