JP2017524127A - 癌に罹患していることが疑われる患者のアフリベルセプトを用いた処置の結果を予測するための方法 - Google Patents
癌に罹患していることが疑われる患者のアフリベルセプトを用いた処置の結果を予測するための方法 Download PDFInfo
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Abstract
Description
17: 1063-1072)。循環内皮細胞(CEC)及び血漿サイトカイン及び血管新生因子(CAF)をベースライン及び処置の間中測定した。
b) 患者の生物学的サンプル中のインターロイキン−8(IL−8)のレベルを決定する工程を含み、
ここで、インターロイキン−8(IL−8)レベルの増加は、その後の投与におけるアフリベルセプト、又はziv−アフリベルセプトの量を減少する必要性を示す。
(a) アフリベルセプト、又はziv−アフリベルセプトを用いた処置の開始前に、患者からの生物学的サンプル中のインターロイキン−8(IL−8)レベルを決定する工程;
(b) 処置と並行して、患者からの生物学的サンプル中のインターロイキン−8(IL−8)レベルを決定する工程、
(c) 工程(b)において決定されたインターロイキン−8(IL−8)レベルを、工程(a)において決定されたレベルと比較する工程
を含み、
それにより、工程(a)のサンプルにおけるレベルと比較した工程(b)のサンプルにおけるより高いインターロイキン−8(IL−8)レベルは、該患者が詳しくモニタリングされるべきであることを示す。
a) インターロイキン−8(IL−8)レベルを測定するための手段;及び
b) 場合により、癌に罹患していることが疑われる患者が、アフリベルセプト治療又はziv−アフリベルセプト治療の候補であるかどうかを予測する際の該キットの使用のための指示を伝えるラベル
を含む。
a) 包装材料;
b) インターロイキン−8(IL−8)レベルを測定するための手段;及び
c) 癌に罹患していることが疑われる患者が、アフリベルセプト治療又はziv−アフリベルセプト治療の候補であるかどうかを予測する際の前記キットの使用のための指示を伝えるラベル
を含む製品にさらに関する。
- 100mgアフリベルセプト又はziv-アフリベルセプト/4.0mL(名目の濃度)での体裁
- 200mgアフリベルセプト又はziv-アフリベルセプト/8.0mL(名目の濃度)での第二の体裁。
a) (a)のポリペプチドの成熟アイソフォームに対応するポリペプチド(すなわち、シグナルペプチドの切断後に得られる);及び/又は
b) (a)若しくは(b)のポリペプチドの対立遺伝子変異体;及び/又は
c) (a)、(b)若しくは(c)のポリペプチドのスプライシング変異体;及び/又は
d) (a)、(b)、(c)若しくは(d)のポリペプチドの構成的活性変異体
e) (a)、(b)、(c)、(d)若しくは(e)のポリペプチドのタンパク質分解プロセスにより得られるアイソフォームを指す。
実施例: AFFIRM研究におけるPFSに対するインターロイキン8の効果
研究ECF10668 (AFFIRM)
EFC10668は:
i) 第一選択処置として2週ごとに静脈内投与される改変FOLFOX6(オキサリプラチン、5-フルオロウラシル(5-FU)及びフォリン酸の組み合わせ)(アームA);又は
ii) 第一選択処置として2週ごとに静脈内投与される改変FOLFOX6と組み合わせた4mg/kgでのアフリベルセプト;又は
で処置された転移性結腸直腸癌(MCRC)を有する患者における有害な効果を比較する無作為化多国籍研究として設計された。
割り当てられたアームによって、患者にアフリベルセプト、その直後にオキサリプラチン、5-フルオロウラシル(5-FU)及びフォリン酸 (改変FOLFOX6レジメン)又は改変FOLFOX6単独のいずれかを静脈内投与した。
アフリベルセプトアームに無作為に選ばれた患者に4mg/kg静脈内(IV)を2週ごとに投与した。
・ オキサリプラチン(Eloxatin(R))
・ フォリン酸 (ロイコボリンとしても知られる)
・ 5-フルオロウラシル
オキサリプラチン、5-フルオロウラシル、及びフォリン酸の処方:
・ 使用した製品は病院/診療所の薬局で入手可能なものであった
・ 投与経路: IV
・ 用量: オキサリプラチン、フォリン酸、及び5-フルオロウラシルを、以下のように、mFOLFOX6レジメンに従って投与した:
・ 1日目に2時間IV注入としてオキサリプラチン 85mg/m2
・ 1日目に2時間IV注入としてフォリン酸 350mg/m2
・ 1日目にIVボーラスとして5-フルオロウラシル400mg/m2、次いで1日目に開始した46時間持続IV注入として2400mg/m2。
個々の患者についての処置を、進行まで、又は許容できない毒性が発生するまで若しくは患者の脱退の同意まで施した。
以下の表1は、バイオマーカー評価可能集団と評価不能集団との間のベースラインでの人口統計学及び患者の特徴を比較する。
ベースラインでの疾患特徴は2つの集団で同様であった(以下の表2及び3を参照のこと)。
A. 曝露の程度
以下の表4は、バイオマーカー評価可能集団の患者を、バイオマーカー評価不能集団の患者よりもわずかに長く処置に曝露されたことを示す(サイクル数の中央値: 9又は10に対して12)。
27のサイトカイン、増殖因子又は可溶性受容体の血漿濃度を、酵素結合免疫吸着測定法(ELISA)により2つのFluorokine(R) MAPキット(ヒト血管形成パネルA及びヒト好感度サイトカインパネル; R&D Systems)を使用して決定した。競合実験を行い、VEGF-A、VEGF-D及び胎盤増殖因子(PlGF)を検出しながらアフリベルセプトの干渉を調べた。アンジオポエチン-2 (ANGPT2)、SDF1-α、HGF、VEGF-C、可溶性VEGF受容体3(sFLT4、sVEGFR3)及びsVEGFR2を単一ELISA(R&D Systems)により評価した。血漿マーカーをベースライン、最初の研究処置注入の30日後及び60日後、並びに最後のアフリベルセプト注入の30日後に分析した。
評価可能なバイオマーカーを用いた患者と評価可能なバイオマーカーを用いていない患者との間の差異を、カテゴリー変数について両側フィッシャー直接確率法、及び連続型変数についてはANOVAを使用して評価した。体細胞変異の不在又は存在を0又は1として、及び存在するマイナー対立遺伝子の数によってSNP遺伝子型を0、1又は2としてコードすることにより、バイオマーカーを定量的変数として分析した。PFSに対するベースラインバイオマーカーの線形効果を、以下の共変数を用いてCox比例ハザードモデルを使用して評価した: 米国東海岸癌臨床試験グループ(ECOG)一般状態(0-1対2)、肝臓のみ転移(有/無)、及び遠隔転移器官の数(1対>1)、処置効果、バイオマーカー効果及びバイオマーカー−処置相互作用効果。後者の2つの効果の有意性を、2自由度Wald検定により一緒に調べた。拡張統計法を補助的方法で記載する。
AFFIRM試験のITT集団における236人の患者のうち、227人(96%)が応答について評価可能であった。これらのうち、130人(57%)は少なくとも1つの生物学的サンプルを提供し、そのうち60人(46%)及び70人(54%)はそれぞれmFOLFOX6アーム及びmFOLFOX6+アフリベルセプトアームに参加した。ベースライン又は有効性及び安全性エンドポイントでの患者のバイオメトリクス、民族性、及び疾患特徴に関して、生物学的サンプルを提供した患者と提供しなかった患者との間で偽発見率(FDR)調整P値0.05で大きな差異はなかった(表1)。少なくとも1つの生物学的サンプルを提供した者のうち、51人(39%)は3つのバイオマーカータイプのそれぞれについてサンプルを提供し、88人(68%)及び97人(74%)の患者はそれぞれのバイオマーカータイプのうち2つ又は1つについてサンプルを提供した。サブ解析(sub-analyses)のために小さすぎる患者群を避けるために、各バイオマーカータイプを別々に分析した。
27のマーカーの血漿レベルを、表5に示されるように、異なる時点(すなわち、ベースライン[87人の患者];処置開始の30日後及び60日後[82人及び73人の患者];並びに最後の処置の30日後[56人の患者])で測定した。
我々は、ベースラインでの高いIL8レベルがより短い生存期間と相関しており、そして処置の間に増加するレベルのIL8を有する患者はより進行する可能性が高いということを確認した。
Claims (25)
- 癌に罹患していることが疑われる患者の、アフリベルセプト又はziv−アフリベルセプトを用いた処置の結果を予測するためのバイオマーカーとしてのインターロイキン−8(IL−8)の使用。
- 癌に罹患していることが疑われる患者が、該癌のアフリベルセプト治療又はziv−アフリベルセプト治療の候補であるかどうかを決定する方法であって、患者の生物学的サンプルを少なくとも1つのアッセイにかけて、ベースラインでIL−8レベルを測定する工程を含み、ここで生物学的サンプルのIL−8レベルがIL−8の発現の参照レベルと比較して低い場合、該患者は癌の治療の候補として同定される、上記方法。
- 癌に罹患していることが疑われる患者が、該癌のアフリベルセプト治療又はziv−アフリベルセプト治療の候補であるかどうかを決定する方法であって、患者の生物学的サンプルを少なくとも1つのアッセイにかけて、ベースラインでIL−8レベルを測定する工程を含み、ここで生物学的サンプルのIL−8レベルがIL−8の発現の参照レベルと比較して高い場合、該患者は癌の治療の候補ではないと同定される、上記方法。
- 癌を有する患者をアフリベルセプト又はziv−アフリベルセプトを用いて処置するための方法であって、治療有効量のアフリベルセプト、又はziv−アフリベルセプトを患者に投与することを含み、ここで患者の生物学的サンプル中のIL−8レベルはIL−8の発現の参照レベルよりも低い、上記方法。
- IL−8の発現の参照レベルに対する相対物が約10と約30pg/mlとの間である、請求項2〜4のいずれか1項に記載の方法。
- IL−8の発現の参照レベルに対する相対物が約19pg/mlである、請求項2〜5のいずれか1項に記載の方法。
- 癌の処置についての治療有効性を最適化する方法であって:
・ アフリベルセプト、又はziv−アフリベルセプトを、癌に罹患していることが疑われる患者に投与する工程;及び
・ 患者の生物学的サンプル中のインターロイキン−8(IL−8)のレベルを決定する工程を含み、
ここで、インターロイキン−8(IL−8)レベルの増加は、その後の投与におけるアフリベルセプト、又はziv−アフリベルセプトの量を減少する必要性を示す、上記方法。 - 癌に罹患していることが疑われる患者の処置におけるアフリベルセプト、又はziv−アフリベルセプトの安全な使用を可能にするためにリスクを管理する方法であって、該方法は、以下の工程:
(a) アフリベルセプト、又はziv−アフリベルセプトを用いた処置の開始前に、患者からの生物学的サンプル中のインターロイキン−8(IL−8)レベルを決定する工程;
(b) 処置と並行して、患者からの生物学的サンプル中のインターロイキン−8(IL−8)レベルを決定する工程、
(c) 工程(b)において決定されたインターロイキン−8(IL−8)レベルを、工程(a)において決定されたレベルと比較する工程
を含み、
それにより、工程(a)のサンプルにおけるレベルと比較した工程(b)のサンプルにおけるより高いインターロイキン−8(IL−8)レベルは、該患者が詳しくモニタリングされるべきであることを示す、上記方法。 - 生物学的サンプルは、血液、血清及び血漿からなる群より選択される、請求項2〜8のいずれか1項に記載の方法。
- 癌が、結腸癌、結腸直腸癌又は直腸癌である、請求項2〜8のいずれか1項に記載の方法。
- 結腸直腸癌が転移性結腸直腸癌である、請求項10に記載の方法。
- 決定されるインターロイキン−8(IL−8)レベルが循環レベルである、請求項2〜8のいずれか1項に記載の方法。
- 前記患者に、治療有効量のアフリベルセプト、又はziv−アフリベルセプト、オキサリプラチン、5−フルオロウラシル(5−FU)及びフォリン酸を投与することを含む、請求項4〜6のいずれか1項に記載の方法。
- 前記患者に、治療有効量のアフリベルセプト、又はziv−アフリベルセプト、フォリン酸、5−フルオロウラシル(5−FU)及びイリノセタンを投与することを含む、請求項4〜6のいずれか1項に記載の方法。
- 前記患者は、以前にオキサリプラチン又はベバシズマブに基づく治療で処置されていたことがある、請求項4〜6のいずれか1項に記載の方法。
- 前記患者は、化学療法、放射線療法、又は外科手術が不成功であった、請求項4〜6のいずれか1項に記載の方法。
- 約200mg/m2と約600mg/m2との間に含まれる投薬量でのフォリン酸、約2000mg/m2と約4000mg/m2との間に含まれる投薬量での5−フルオロウラシル(5−FU)、約100mg/m2と約300mg/m2との間に含まれる投薬量でのイリノセタン、及び約1mg/kgと約10mg/kgとの間に含まれる投薬量でのアフリベルセプトが患者に投与される、請求項4〜6のいずれか1項に記載の方法。
- 約400mg/m2の投薬量でのフォリン酸、約2800mg/m2の投薬量での5−フルオロウラシル(5−FU)、約180mg/m2の投薬量でのイリノセタン、及び約4mg/kgの投薬量でのアフリベルセプトが患者に投与される、請求項4〜6及び17のいずれか1項に記載の方法。
- フォリン酸が約400mg/m2の投薬量で静脈内投与され、5−フルオロウラシル(5−FU)が約2800mg/m2の投薬量で静脈内投与され、イリノセタンが約180mg/m2の投薬量で静脈内投与され、かつアフリベルセプトが約4mg/kgの投薬量で静脈内投与され、そしてここで組み合わせは2週間毎に投与される、請求項4〜6、17及び18のいずれか1項に記載の方法。
- フォリン酸、5−フルオロウラシル(5−FU)、イリノセタン及びアフリベルセプトが、9週と18週との間に含まれる期間の間2週間毎に静脈内投与される、請求項4〜6及び17〜19のいずれか1項に記載の方法。
- フォリン酸が アフリベルセプト投与の直後に静脈内投与される、請求項4〜6及び17〜20のいずれか1項に記載の方法。
- フォリン酸が、アフリベルセプト投与の直後に約2時間の期間にわたって静脈内投与される、請求項4〜6及び17〜21のいずれか1項に記載の方法。
- 癌に罹患していることが疑われる患者を処置するための、アフリベルセプト、又はziv−アフリベルセプトであって、ここで患者の生物学的サンプル中のIL−8レベルは、IL−8の発現の参照レベルより低い、上記アフリベルセプト、又はziv−アフリベルセプト。
- 癌に罹患していることが疑われる患者が、アフリベルセプト治療又はziv−アフリベルセプト治療の候補であるかどうかを予測するためのキットであって、該キットは:
a) インターロイキン−8(IL−8)レベルを測定するための手段;及び
b) 場合により、癌に罹患していることが疑われる患者が、アフリベルセプト治療又はziv−アフリベルセプト治療の候補であるかどうかを予測する際の該キットの使用のための指示を伝えるラベル
を含む、上記キット。 - a) 包装材料;
b) インターロイキン−8(IL−8)レベルを測定するための手段;及び
c) 癌に罹患していることが疑われる患者が、アフリベルセプト治療又はziv−アフリベルセプト治療の候補であるかどうかを予測する際の前記キットの使用のための指示を伝えるラベル
を含む製品。
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