JP2016519107A - Th−302抗癌療法のための予測および応答のバイオマーカー - Google Patents
Th−302抗癌療法のための予測および応答のバイオマーカー Download PDFInfo
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Abstract
Description
本発明は、癌患者が、TH-302または別の低酸素活性化プロドラッグ(HAP)系抗癌療法に好適に応答するかどうかを予測するための方法、およびかかる癌患者において癌を治療する方法を提供し、そのため生物学、化学および医学の分野に関する。
癌は、ヒトの病的状態および死亡の主要な原因の1つである。正常細胞を損傷または殺傷することなく癌細胞を殺傷することは難しいため、癌治療は困難である。癌治療の際に正常細胞を損傷または殺傷することは、患者に有害な副作用を引き起こし、癌患者に投与される抗癌薬の量を制限し得る。抗癌薬が浸透しない脈管構造から離れた領域で癌細胞を殺傷することも難しい。
式中、Z3は、
X4は、ClまたはBrである。TH-302およびTH-281として知られる該化合物は、特に有望な治療候補である。化学名(2-ブロモエチル)({[(2-ブロモエチル)アミノ][(2-ニトロ-3-メチルイミダゾール-4-イル)メトキシ]ホスホリル})アミンとして知られるTH-302は、以下に表される構造:
本発明は、TH-302または別のHAP系療法に応答する可能性が高い癌患者を同定するための方法を提供する。一般的に、これらの方法において、[18F]-HX4 PET画像化または別のPET画像化剤を使用するPET画像化を使用して、癌の低酸素状態の程度(measure)、すなわち低酸素腫瘍または他の癌性組織および癌性細胞がどれほど多く患者内にあるのかが提供される。発明の方法によると、低酸素状態が予め決定された値よりも高い場合、TH-302または別のHAP療法が開始されるか、既に開始されている場合は継続される。予め決定された値は、健常な被験体に対して行われた試験もしくは他の癌患者に対して行われた試験から確立された値から、または他の手段により選択され得るが、一般的に、患者の癌がより低酸素であるほど、患者がTH-302または別のHAP系抗癌療法に対して好ましく応答する可能性が高くなる。本発明はまた、患者における癌の低酸素状態に応じて、患者の癌を治療するための方法を提供する。
定義
以下の定義は、読者を補助するために提供される。そうではないと定義されなければ、全ての当該技術分野の用語、表記法、および他の科学用語もしくは医学用語または本明細書において使用される用語は、化学分野および医学分野の当業者に一般的に理解される意味を有することを意図する。いくつかの場合において、一般的に理解される意味を有する用語は、明確さおよび/または容易な参照のために本明細書において定義され、本明細書中にかかる定義を含むことは、当該技術分野において一般的に理解される用語の定義に対する実質的な違いを表すと解釈されるべきでない。
一般的に3種類のバイオマーカーが認識される。予後バイオマーカーは、療法とは関係なく、疾患結果に相関し、例えば一般的に良好でない予後に相関すると考えらえる「三重陰性」乳癌(ER-/PR-/HER-)を確立するために使用されるものを含む。応答バイオマーカーは、療法に対する応答の規模を測定し、RECIST応答評価に類似するものであるとみなされ得る。応答バイオマーカーとしては、例えば膵臓患者における循環CA-19.9の低下が療法の陽性応答に相関するCA-19.9、および同様に循環PSAの低下が前立腺癌患者における療法に対する陽性応答に相関するPSAが挙げられる。予測バイオマーカーは、療法について患者を分級または選択するための療法の前に使用され、例えば乳癌中のHER2プロフィールは、トラスツズマブ療法についての適合性を決定するために使用され、黒色腫中のBRAF V600Eプロフィールは、ベムラフェニブ療法についての適合性を決定するために使用される。
[18F]-HX4 PET画像化または別のPET画像化剤を使用したPET画像化を使用して、癌の低酸素状態の程度を得る工程;
得られた低酸素状態の程度と、予め決定された値を比較する工程;および
前記程度が、前記予め決定された値以上である場合に患者にTH-302または別のHAPの治療有効量を投与するか、またはかかる程度レベルが前記予め決定された値を超えない場合は、HAPの投与を含む治療以外の癌治療の治療有効量を投与する工程
を含む、患者における癌を治療するための方法を提供する。
この試験にはヒトH460非小細胞肺癌ヒト腫瘍異所異種移植片モデルを使用した。H460非小細胞肺癌異種移植片モデルは、nu/nuマウスの腹側部への1x106細胞のs.c.移植により確立した。腫瘍サイズが100mm3になった時に、1用量のTH-302(150mg/kg、i.p.)またはビヒクルを投与した。TH-302のこの投与により、58%のTGI(腫瘍成長阻害(tumor growth inhibition))、10日のTGD1000(1000mm3の腫瘍サイズまでの腫瘍成長遅延(tumor growth delay))および2%の最大体重消失が生じた。個々の動物におけるTH-302の有効性は、TGIが6.3%〜105%で異なる点で異なった。
Claims (8)
- 癌患者にTH-302を投与するべきかどうかを決定する方法であって、前記方法は、(i) [18F]-HX4 PET画像化を使用して癌の低酸素状態の程度を得る工程;および(ii) 得られた低酸素状態の程度と、予め決定された値を比較する工程を含み、前記程度が、前記予め決定された値以上である場合、TH-302を投与する決定がなされ、前記程度が、前記予め決定された値未満である場合、TH-302が投与されない、方法。
- 前記患者が、TH-302で以前に治療されていない、請求項1記載の方法。
- 前記患者が、TH-302で以前に治療されている、請求項1記載の方法。
- [18F]-HX4 PET画像化を使用して癌の低酸素状態の程度を得る工程;
得られた低酸素状態の程度と、予め決定された値を比較する工程;および
前記程度が、前記予め決定された値以上である場合、患者に治療有効量のTH-302を投与するか、かかる程度レベルが、前記予め決定された値を超えない場合、TH-302の投与を含む治療以外の治療有効量の癌治療を投与する工程
を含む、患者において癌を治療する方法。 - 前記患者が、TH-302で以前に治療されていない、請求項4記載の方法。
- 前記患者が、TH-302で以前に治療されている、請求項4記載の方法。
- [18F]-HX4およびTH-302、ならびに任意に癌患者における癌の低酸素状態を決定するための指示書および/または前記患者にTH-302を投与するための指示書を含むパーツのキット。
- 癌の低酸素状態が、[18F]-HX4 PET画像化を使用して測定され、得られた低酸素状態の程度が、予め決定された値と比較され、前記低酸素状態の程度が、前記予め決定された値以上である場合、癌の治療のためにTH-302が使用される、癌の治療のためのTH-302の使用。
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US11504075B2 (en) * | 2017-12-20 | 2022-11-22 | University Health Network | System, methods, and devices for calculating hypoxic fraction and equilibration rate of small molecular weight tracers using dynamic imaging |
KR20240051965A (ko) | 2021-08-27 | 2024-04-22 | 아센타위츠 파마슈티컬즈 리미티드 | Th-302를 이용한 parp 억제제에 내성이 있는 환자의 치료 |
KR20240047452A (ko) | 2021-08-27 | 2024-04-12 | 아센타위츠 파마슈티컬즈 리미티드 | 동결건조 제형 용액과 동결건조 제형, 및 이의 방법과 용도 |
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CARLIN, S. & HUMM, J. L.: "PET of hypoxia: current and future perspectives", J. NUCL. MED., vol. 53巻, JPN6017033378, 2012, pages pp. 1171-1174. * |
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US20160296538A1 (en) | 2016-10-13 |
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