JP2015521207A - 癌の処置用のホスホイノシチド3キナーゼ阻害化合物と化学療法剤との変異体選択性及び組み合わせ - Google Patents
癌の処置用のホスホイノシチド3キナーゼ阻害化合物と化学療法剤との変異体選択性及び組み合わせ Download PDFInfo
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Abstract
Description
米国特許法施行規則第37条1.53(b)に基づき出願した本非仮出願は、出典明示によりその全体が援用される2012年6月8日出願の米国仮出願第61/657484号及び2013年4月5日出願の米国仮出願第61/808727号について米国特許法第119条(e)に基づく利益を主張する。
GDC-0032
を有する治療上有効な量のGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される治療上有効な量の化学療法剤とを含む方法を含む。
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせを含む。
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせを含む。
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせの使用を含む。
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせの使用を含む。
a)GDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせ、並びに
b)使用説明書
を含む、過剰増殖性障害の処置用製造品を含む。
a)GDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせで、K−ras変異を有する腫瘍細胞株をインビボで処置すること、並びに
b)相乗効果又は非相乗効果を測定すること
を含み、それにより癌の処置用の相乗的な治療用組み合わせを決定する、癌の処置に組み合わせて使用する化合物の決定方法を含む。
a)GDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせを腫瘍細胞に投与すること、
b)pAktレベルの変化を測定すること、並びに
c)pAktレベルの増加を示す相乗的な治療用組み合わせを選択すること
を含む、癌の処置に組み合わせて使用する化合物の選択方法を含む。
(a)GDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせの少なくとも単回用量の投与後に患者から得られた生体試料におけるPIK3CA変異又はPTEN変異を検出すること、並びに
(b)GDC−0032又はGDC−0032と化学療法剤との組み合わせの患者への投与前に患者から得られた生体試料におけるPIK3CAの又はPTENの変異状態を比較すること
を含む、過剰増殖性障害を患う患者がGDC−0032又はGDC−0032と化学療法剤との組み合わせによる処置に反応するかどうかのモニタリング方法であって、
GDC−0032又はGDC−0032と化学療法剤との組み合わせの投与後に得られた試料におけるPIK3CAの又はPTENの変異状態の変化又はモジュレーション(変調、modulation)により、GDC−0032又はGDC−0032と化学療法剤との組み合わせによる処置に反応する患者を同定する方法を含む。
(a)GDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせの少なくとも単回用量の投与後に患者から得られた生体試料中においてPIK3CA変異又はPTEN変異を検出すること、並びに
(b)GDC−0032又はGDC−0032と化学療法剤との組み合わせの患者への投与前に患者から得られた生体試料におけるPIK3CAの又はPTENの状態を比較すること
を含む、GDC−0032又はGDC−0032と化学療法剤との組み合わせの治療効果の最適化方法であって、
GDC−0032又はGDC−0032と化学療法剤との組み合わせの投与後に得られた試料におけるPIK3CA又はPTENの変化又はモジュレーションにより、GDC−0032又はGDC−0032と化学療法剤との組み合わせによる処置が有効である可能性が増加している患者を同定する方法を含む。
(a)GDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせの少なくとも単回用量が投与されている患者から得られた生体試料におけるPIK3CA変異又はPTEN変異から選択されるバイオマーカーの発現、モジュレーション又は活性を検出すること、並びに
(b)バイオマーカーの発現、モジュレーション又は活性と参照試料におけるバイオマーカーの状態とを比較することであって、参照試料がGDC−0032又はGDC−0032と化学療法剤との組み合わせの患者への投与前に患者から得られた生体試料であること
を含む、GDC−0032又はGDC−0032と化学療法剤との組み合わせに対する反応性のモニタリング用バイオマーカーの同定方法であって、
参照試料と比較して少なくとも2分の1又は2倍のバイオ−マーカー変化のモジュレーションを、GDC−0032又はGDC−0032と化学療法剤との組み合わせに対する反応性のモニタリングに有用なバイオマーカーとして同定する方法を含む。一実施態様では、バイオマーカーはpAktである。
治療上有効な量のGDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせを患者に投与することを含む、患者の過剰増殖性障害の処置でのGDC−0032又はGDC−0032と化学療法剤との組み合わせの使用であって、
GDC−0032又はGDC−0032と化学療法剤との組み合わせの患者への投与前に患者から得られた生体試料はPIK3CAの又はPTENの変異状態に関して検査されており、PIK3CAの又はPTENの変異状態がGDC−0032又はGDC−0032と化学療法剤との組み合わせに対する患者による治療反応性を示す使用を含む。
単語「含む(comprise)」、「含んでいる(comprising)」、「含む(include)」、及び「含んでいる(including)」は本明細書及び特許請求の範囲で使用される場合、述べた特徴、整数、成分又は工程の存在を特定することを意図するが、これらは、1つ又は複数の他の特徴、整数、成分、工程又はそれらの群の存在又は追加を除外しない。
GDC−0032の調製
本発明の化合物はGDC−0032(CAS登録番号1282512−48−4)として知られ、2−(4−(2−(1−イソプロピル−3−メチル−1H−1,2,4−トリアゾール−5−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)−1H−ピラゾール−1−イル)−2−メチルプロパンアミドと命名され、立体異性体、幾何異性体、互変異性体及びそれらの薬学的に許容可能な塩を含む構造:
を有する。
ある種の化学療法剤は、インビトロ及びインビボでの細胞増殖の阻害において、GDC−0032との組み合わせで驚くべき及び予期しない特性を示している。そのような化学療法剤には、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールが含まれる。
を有する。
を有する。
を有する。
を有する。
を有する。
を有する。
を有する。
を有する。
を有する。
を有する。
(ここで、Trは、リンカー部分MCCを介してマイタンシノイド薬剤部分DM1に連結されているトラスツズマブである(米国特許5208020号;米国特許6441163号))を有する。トラスツズマブ−MCC−DM1の上記構造において、薬剤と抗体との比又は薬剤負荷がpで表され、1から約8の整数値の範囲である。薬剤負荷値pは1から8である。トラスツズマブ−MCC−DM1は、1個、2個、3個、4個、5個、6個、7個及び8個の薬剤部分が抗体であるトラスツズマブに共有結合的に付加されている、様々に負荷された及び付加された抗体−薬剤複合体の全ての混合物を含む(米国特許7097840号;米国特許出願第2005/0276812号;米国特許出願第2005/0166993号)。
を有する。
を有する。
GDC−0032の生物活性を、単剤として、並びに小分子及び大分子(タンパク質、抗体)の両方を含む様々な化学療法剤との組み合わせで測定した。単剤としての及び組み合わせでのGDC−0032のそのような生物活性をPI3K阻害剤であるGDC0941及びGDC−0980と比較した、これらは両方とも癌の処置用にGenentechにより開発されている。
GDC-0941
を有する。
GDC-0980
を有する。
単剤としてのGDC−0032の細胞傷害活性又は細胞増殖抑制活性を、細胞培養培地で増殖する哺乳動物の腫瘍細胞株を確立し、試験化合物を添加し、細胞を約6時間から約5日の期間にわたって培養すること;及び細胞生存率を測定することにより測定した(実施例3)。細胞ベースのインビトロアッセイを使用して生存率を、即ち増殖(IC50)、細胞傷害性(EC50)及びアポトーシスの誘導(カスパーゼ活性化)を測定した。
GDC−0032と例示的な化学療法剤との組み合わせの細胞傷害活性又は細胞増殖抑制活性を、細胞培養培地で増殖する哺乳動物の腫瘍細胞株を確立し、試験化合物を添加し、細胞を約6時間から約5日の期間にわたって培養すること;及び細胞生存率を測定することにより測定した(実施例3)。細胞ベースのインビトロアッセイを使用して生存率を、即ち増殖(IC50)、細胞傷害性(EC50)及びアポトーシスの誘導(カスパーゼ活性化)を測定した。
乳癌、非小細胞肺癌、卵巣癌、前立腺癌、メラノーマ及び結腸直腸癌を呈する腫瘍細胞の異種移植片を免疫無防備状態のマウスに移植し、担腫瘍動物をGDC−0032で処置することにより、GDC−0032の有効性をインビボで測定した。結果は、細胞株、腫瘍細胞におけるある種の変異の存在又は不在、GDC−0032の投薬レジメン及び他の因子に依存する。対象のマウスを薬剤又はコントロール(ビヒクル)で処置し、数週間又はそれ以上にわたってモニタリングして腫瘍倍加までの期間、死滅細胞の対数値及び腫瘍阻害を測定した(実施例4)。図13−22は、実施例4のプロトコルに従ってGDC−0032で処置した担腫瘍マウスの処置後の腫瘍体積の経時変化のプロットを示す。
癌細胞の同種移植片又は異種移植片を齧歯動物に移植し、担腫瘍動物を薬剤の組み合わせで処置することにより、GDC−0032と小分子標的剤及び大分子標的剤を含む様々な化学療法剤との組み合わせの有効性をインビボで測定した。結果は、細胞株、腫瘍細胞におけるある種の変異の存在又は不存在、GDC−0032及び化学療法剤の投与の順序、投薬レジメン及び他の因子に依存する。対象のマウスを薬剤又はコントロール(ビヒクル)で処置し、数週間又はそれ以上にわたってモニタリングして腫瘍倍加までの期間、死滅細胞の対数値及び腫瘍阻害を測定した(実施例4)。図23−36は、実施例4のプロトコルに従ってGDC−0032と様々な化学療法剤との組み合わせで処置した担腫瘍マウスの処置後の腫瘍体積の経時変化のプロットを示す。
本発明の薬学的組成物又は製剤は、GDC−0032と、化学療法剤と、1種又は複数種の薬学的の許容可能な担体、滑剤、希釈剤又は賦形剤との組み合わせを含む。
GDC−0032を、前悪性の及び非腫瘍性の又は非悪性の過剰増殖性障害と共に、固形腫瘍又は造血器腫瘍を含む過剰増殖性障害の処置用のある種の化学療法剤との組み合わせで用いることができる。ある実施態様では、GDC−0032は単一の錠剤、丸薬、カプセル剤又は溶液としての単一製剤で化学療法剤と組み合わされ、該組み合わせが同時に投与される。他の実施態様では、GDC−0032及び化学療法剤は、GDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との順次投与用の別々の錠剤、丸薬、カプセル剤又は溶液としての別々の製剤で投薬レジメン又は治療経過に従って投与される。化学療法剤は抗過剰増殖特性を有し、又は過剰増殖性障害の処置に有用である。GDC−0032と化学療法剤との組み合わせは相乗特性を有することができる。薬学的組み合わせ製剤又は投与レジメンの化学療法剤は、好ましくはGDC−0032に対する補完活性を有し、その結果、化学療法剤及びGDC−0032は互いに悪影響を与えない。治療用組み合わせのそのような化合物を、意図した目的に有効な量で投与することができる。一実施態様では、本発明の薬学的製剤は、GDC−0032及び本明細書に記載されたような化学療法剤を含む。別の実施態様では、治療用組み合わせは投薬レジメンにより投与され、ここで、治療上有効な量のGDC−0032が1日に2回から3週毎に1回(q3wk)の範囲で投与され、治療上有効な量の化学療法剤が1日に2回から3週毎に1回の範囲で別々に、交互に投与される。
本発明の治療用組み合わせを、処置する状態に適した任意の経路により投与することができる。適切な経路には、経口、非経口(皮下、筋肉内、静脈内、動脈内、吸入、皮内、くも膜下腔内、髄腔外及び注入法を含む)、経皮、直腸、経鼻、局所(頬側及び舌下を含む)、膣、腹腔内、肺内並びに鼻腔内が含まれる。局所投与には、経皮パッチ又はイオン泳動装置等の経皮投与の使用も含まれ得る。薬剤の製剤化がRemington’s Pharmaceutical Sciences,18thEd.、(1995)Mack Publishing Co.、Easton、PAで論じられている。薬剤の製剤化の他の例を、Liberman,H.A.及びLachman,L.編、Pharmaceutical Dosage Forms,Marcel Decker、Vol3、2ndEd.、New York、NY中に見出すこともできる。局所的な免疫抑制処置のために、化合物を、移植前に移植片と阻害剤とを灌流する又は接触させることを含む病巣内投与により投与することができる。当然のことながら、好ましい経路を例えばレシピエントの状態によって変更することができる。化合物が経口投与される場合、化合物を、薬学的に許容可能な担体、滑剤又は賦形剤と共に丸薬、カプセル剤、錠剤等として製剤化することができる。化合物が非経口的に投与される場合、以下に詳述するように、化合物を、薬学的に許容可能な非経口のビヒクル又は希釈剤と共に及び単位投薬注射可能な形態で製剤化することができる。
本発明の方法には:
バイオマーカーの同定に基づく診断方法;
患者がGDC−0032又はGDC−0032と化学療法剤との組み合わせに反応することができるかどうかの決定方法;
GDC−0032又はGDC−0032と化学療法剤との組み合わせのクリアランスをモニタリングすることによる、治療効果の最適化方法;
治療耐性変異の発生をモニタリングすることによる、GDC−0032又はGDC−0032と化学療法剤との組み合わせの治療レジメンの最適化方法;並びに
GDC−0032治療による又はGDC−0032と化学療法剤との組み合わせ治療による処置が最も有効である患者の同定方法、及びGDC−0032治療による又はGDC−0032と化学療法剤との組み合わせ治療による処置に対する患者の感受性及び応答性に関する患者のモニタリング方法
が含まれる。
本発明の別の実施態様では、上述した疾患及び障害の処置に有用なGDC−0032を含有する製造品又は「キット」が提供される。一実施態様では、キットはGDC−0032を含む容器を含む。キットは、容器上に又は容器と関連してラベル又はパッケージ挿入物を更に含むことができる。用語「パッケージ挿入物」は、治療用製品の市販のパッケージに慣習的に含まれる説明書を指すために使用され、そのような治療用製品の使用に関する指示、用法、投薬量、投与法、禁忌及び/又は警告についての情報が含まれる。適切な容器には、例えば瓶、バイアル、シリンジ、ブリスターパック等が含まれる。容器を、ガラス又はプラスチック等の様々な材料から形成することができる。容器は、状態を処置するのに有効なGDC−0032又はその製剤を収容することができ、無菌アクセスポートを有することができる(例えば、容器は、皮下注射針で貫通可能なストッパを有する静脈内溶液バッグ又はバイアルであることができる)。組成物中の少なくとも1種の活性な薬剤はGDC−0032である。ラベル又はパッケージ挿入物は、組成物が癌等の選択した状態の処置に使用されることを示す。一実施態様では、ラベル又はパッケージ挿入物は、異常細胞増殖から生じる障害の処置に式Iの化合物を含む組成物を使用することができることを示す。ラベル又はパッケージ挿入物はまた、他の障害の処置に組成物を使用することができることも示すことができる。あるいは又は加えて、製造品は、薬学的に許容可能な緩衝液、例えば注射用静菌水(BWFI)、リン酸緩衝食塩水、リンガー溶液及びデキストロース溶液を含む第2の容器を更に含むこともできる。第2の容器は、他の緩衝液、希釈剤、フィルタ、針及びシリンジを含む、商業的な及び使用者の観点から望ましい他の物質を更に含むことができる。
工程1: 2−(4−(2−(1−イソプロピル−3−メチル−1H−1,2,4−トリアゾール−5−イル)−5,6−ジヒドロベンゾ[f]イミダゾ[1,2−d][1,4]オキサゼピン−9−イル)−1H−ピラゾール−1−イル)−2−メチルプロパン酸エチル
結合アッセイ: 最初の偏光実験を、Analyst HT96−384(Molecular Devices Corp、サニーベール、カリフォルニア州)で実施した。偏光緩衝液(10mMのトリスpH7.5、50mMのNaCl、4mMのMgCl2、0.05%のChaps及び1mMのDTT)中20μg/mLの最終濃度で始まるp110アルファPI3Kの1:3段階希釈物(Upstate Cell Signaling Solutions、シャーロッツビル、バージニア州)を最終濃度10mMのPIP2(Echelon−Inc.、ソルトレイクシティ、ユタ州)に添加することにより、蛍光偏光親和性測定用の試料を調製した。室温での30分のインキュベーション時間後、それぞれ100nM及び5nMの最終濃度のGRP−1及びPIP3−TAMRAプローブ(Echelon−Inc.、ソルトレイクシティ、ユタ州)の添加により反応を停止させた。384ウェルのブラック低容量Proxiplates(登録商標)(PerkinElmer、ウェルズリー、マサチューセッツ州)中のローダミンフルオロフォア(λex=530nm;λem=590nm)用の標準的なカットオフフィルタによる読み取り。蛍光偏光値を、タンパク質濃度の関数としてプロットした。KaleidaGraph(登録商標)ソフトウェア(Synergy software、レディング、ペンシルベニア州)を使用してデータを4パラメータ方程式に当てはめることにより、EC50値を得た。この実験はまた、後の阻害剤との競合実験において使用する適切なタンパク質濃度も規定する。
以下のプロトコル(Mendoza等(2002) Cancer Res. 62:5485-5488)を用いる細胞増殖アッセイにより、GDC−0032及び化学治療化合物の有効性を評価した。
1.培地中に約104個の細胞を含有する100μlの細胞培養物のアリコート(細胞株及び腫瘍タイプに関して表3を参照)を、384ウェルの不透明な壁のプレートの各ウェル中に沈着させた。
2.培地を含有するが細胞を含有しないコントロールウェルを調製した。
3.化合物を実験ウェルに添加し、3−5日にわたりインキュベートした。
4.プレートを約30分にわたり室温に平衡化した。
5.各ウェル中に存在する細胞培養培地の体積と等しい体積のCellTiter−Glo(登録商標)試薬を添加した。
6.内容物を軌道振盪機上で2分にわたり混合して細胞溶解を誘発した。
7.プレートを10分にわたり室温でインキュベートし、発光シグナルを安定化させた。
8.発光を記録し、RLU=相対発光単位としてグラフで報告した。
9.Chou及びTalalayの組み合わせ法及びCalcuSyn(登録商標)ソフトウェア(Biosoft、ケンブリッジ、イギリス)による用量効果解析を使用して分析し、組み合わせ指数を得る。
マウス: 雌の重篤な複合免疫不全マウス(Fox Chase SCID(登録商標)、C.B−17/IcrHsd、Harlan)又はヌードマウス(Taconic Farms、Harlan)は8から9週齢であり、研究の0日目で15.1から21.4グラムのBW範囲を有した。動物に、水(逆浸透、1ppmCl)と18.0%粗タンパク質、5.0%粗脂肪及び5.0%粗繊維から成るNIH31改変及び照射Lab Diet(登録商標)とを適宜与えた。12時間の照明周期、21−22℃(70−72oF)及び40−60%湿度での静的マイクロアイソレーター中において、照射されたALPHA−Dri(登録商標)bed−o’cobs(登録商標)実験動物床敷上でマウスを飼育した。PRCは、拘束、飼育、手術手順、餌及び液体の調節、並びに獣医学的管理に関する実験動物の管理及び使用に関する指針の推奨を特に順守する。PRCでの動物管理及び使用プログラムは国際実験動物管理公認協会(AAALAC)の認定を受けており、実験動物の管理及び使用に関する承認された標準の順守を保障する。
腫瘍体積(mm3)=(w2×l)/2(式中、W=腫瘍の幅(mm)及びl=腫瘍の長さ(mm))を使用して算出した。腫瘍重量を、1mgが1mm3の腫瘍体積に相当すると仮定して推定することができる。
Claims (66)
- 組み合わせ製剤として又は交互に治療用組み合わせが哺乳動物に投与されることを含む過剰増殖性障害の処置方法であって、治療用組み合わせが、構造:
を有する治療上有効な量のGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される治療上有効な量の化学療法剤とを含む、方法。 - 化学療法剤が5−FUである、請求項1に記載の方法。
- 化学療法剤がドセタキセルである、請求項1に記載の方法。
- 化学療法剤がエリブリンである、請求項1に記載の方法。
- 化学療法剤がゲムシタビンである、請求項1に記載の方法。
- 化学療法剤がGDC−0973である、請求項1に記載の方法。
- 化学療法剤がGDC−0623である、請求項1に記載の方法。
- 化学療法剤がパクリタキセルである、請求項1に記載の方法。
- 化学療法剤がタモキシフェンである、請求項1に記載の方法。
- 化学療法剤がフルベストラントである、請求項1に記載の方法。
- 化学療法剤がデキサメタゾンである、請求項1に記載の方法。
- 化学療法剤がペルツズマブである、請求項1に記載の方法。
- 化学療法剤がトラスツズマブエムタンシンである、請求項1に記載の方法。
- 化学療法剤がトラスツズマブである、請求項1に記載の方法。
- 化学療法剤がレトロゾールである、請求項1に記載の方法。
- 治療用組み合わせがカルボプラチンを更に含む、請求項1に記載の方法。
- 治療用組み合わせが抗VEGF抗体を更に含む、請求項1に記載の方法。
- 抗VEGF抗体がベバシズマブである、請求項1に記載の方法。
- GDC−0032の薬学的に許容可能な塩が、塩酸と形成される塩、臭化水素酸と形成される塩、ヨウ化水素酸と形成される塩、硫酸と形成される塩、硝酸と形成される塩、リン酸と形成される塩、メタンスルホン酸と形成される塩、ベンゼンスルホン酸と形成される塩、ギ酸と形成される塩、酢酸と形成される塩、トリフルオロ酢酸と形成される塩、プロピオン酸と形成される塩、シュウ酸と形成される塩、マロン酸と形成される塩、コハク酸と形成される塩、フマル酸と形成される塩、マレイン酸と形成される塩、乳酸と形成される塩、リンゴ酸と形成される塩、酒石酸と形成される塩、クエン酸と形成される塩、エタンスルホン酸と形成される塩、アスパラギン酸と形成される塩及びグルタミン酸と形成される塩から選択される、請求項1から19の何れか一項に記載の方法。
- 治療上有効な量のGDC−0032と治療上有効な量の化学療法剤とが組み合わせ製剤として投与される、請求項1から19の何れか一項に記載の方法。
- 治療上有効な量のGDC−0032と治療上有効な量の化学療法剤とが交互に哺乳動物に投与される、請求項1から19の何れか一項に記載の方法。
- 哺乳動物が、化学療法剤を投与され、その後にGDC−0032を投与される、請求項21に記載の方法。
- 治療上有効な量のGDC−0032が1日に2回から3週毎に1回の範囲で投与され、治療上有効な量の化学療法剤が1日に2回から3週毎に1回の範囲で投与される投薬レジメンにより治療用組み合わせが投与される、請求項21に記載の方法。
- 投薬レジメンが1回又は複数回繰り返される、請求項23に記載の方法。
- 治療用組み合わせの投与により相乗効果が生じる、請求項1から19の何れか一項に記載の方法。
- 治療用組み合わせの投与により約0.7未満の組み合わせ指数値が得られる、請求項25に記載の方法。
- 過剰増殖性障害が、乳房、子宮頸部、結腸、子宮内膜、胃、神経膠腫、肺、メラノーマ、卵巣、膵臓及び前立腺から選択される癌である、請求項1から19の何れか一項に記載の方法。
- 癌が、E542K、E545K、Q546R、H1047L及びH1047Rから選択されるPIK3CA変異体を発現する、請求項27に記載の方法。
- 癌がPTEN変異体を発現する、請求項27に記載の方法。
- 癌がHER2陽性である、請求項27に記載の方法。
- 哺乳動物が乳癌患者であり、患者がHER2陰性、ER(エストロゲンレセプター)陰性及びPR(プロゲステロンレセプター)陰性である、請求項1に記載の方法。
- 乳癌のサブタイプが基底又はルミナルである、請求項31に記載の方法。
- 患者がGDC−0032及びエリブリンを投与される、請求項30に記載の方法。
- GDC−0032及び化学療法剤が単位投薬形態当たり約1mgから約1000mgの量でそれぞれ投与される、請求項1から19の何れか一項に記載の方法。
- GDC−0032及び化学療法剤が約1:50から約50:1の重量比で投与される、請求項1から19の何れか一項に記載の方法。
- GDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤とを含む薬学的製剤。
- 二酸化ケイ素、粉末化セルロース、微結晶セルロース、金属ステアレート、アルミノケイ酸ナトリウム、安息香酸ナトリウム、炭酸カルシウム、ケイ酸カルシウム、コーンスターチ、炭酸マグネシウム、アスベストフリータルク、ステアロウェットC、スターチ、スターチ1500、ラウリル硫酸マグネシウム、酸化マグネシウム及びそれらの組み合わせから選択される薬学的に許容可能な滑剤を更に含む請求項36に記載の薬学的製剤。
- GDC−0032と化学療法剤とが単位投薬形態当たり約1mgから約1000mgの量をそれぞれ占める、請求項36に記載の薬学的製剤。
- 癌の処置方法で使用するための請求項36に記載の薬学的製剤。
- 乳房、子宮頸部、結腸、子宮内膜、神経膠腫、肺、メラノーマ、卵巣、膵臓及び前立腺から選択される癌の処置用の医薬の製造における、構造:
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせの使用。 - a)請求項1から19の何れか一項に記載の治療用組み合わせ、及び
b)使用説明書
を含む、過剰増殖性障害の処置用製造品。 - 過剰増殖性障害の処置で別々に、同時に又は順次に使用するための組み合わせ製剤としての、構造:
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤と含む製品。 - a)構造:
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせで、K−ras変異を有する腫瘍細胞株をインビトロで処置すること、並びに
b)相乗効果又は非相乗効果を測定すること
を含み、それにより癌の処置用の相乗的な治療用組み合わせを決定する、癌の処置に組み合わせて使用する化合物の決定方法。 - a)構造:
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせを腫瘍細胞に投与すること、
b)pAktレベルの変化を測定すること、並びに
c)pAktレベルの増加を示す相乗的な治療用組み合わせを選択すること
を含む、癌の処置に組み合わせて使用する化合物の選択方法。 - 治療上有効な量のGDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせを患者に投与することを含む、患者の過剰増殖性障害の処置方法であって、患者から得られた生体試料は組み合わせの患者への投与前にPIK3CAの又はPTENの変異状態に関して検査されており、PIK3CAの又はPTENの変異状態が組み合わせに対する患者による治療反応性を示す、方法。
- 治療上有効な量のGDC−0032が単剤として患者に投与される、請求項45に記載の方法。
- GDC−0032と化学療法剤との治療上有効な量の組み合わせが患者に投与される、請求項45に記載の方法。
- 過剰増殖性障害がHER2発現乳癌である、請求項45に記載の方法。
- GDC−0032又はGDC−0032と化学療法剤との組み合わせの投与後に機能的PI3Kタンパク質レベルを測定することにより生体試料は検査されており、機能的PI3Kタンパク質のレベルの変化は、患者がGDC−0032又はGDC−0032と化学療法剤との組み合わせに対して耐性又は反応性であることを示す、請求項45に記載の方法。
- (a)GDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせの少なくとも単回用量の投与後に患者から得られた生体試料におけるPIK3CA変異又はPTEN変異を検出すること、並びに
(b)GDC−0032又はGDC−0032と化学療法剤との組み合わせの患者への投与前に患者から得られた生体試料におけるPIK3CAの又はPTENの変異状態を比較すること
を含む、過剰増殖性障害を患う患者がGDC−0032又はGDC−0032と化学療法剤との組み合わせによる処置に反応するかどうかのモニタリング方法であって、
GDC−0032又はGDC−0032と化学療法剤との組み合わせの投与後に得られた試料におけるPIK3CAの又はPTENの変異状態の変化又はモジュレーションにより、GDC−0032又はGDC−0032と化学療法剤との組み合わせによる処置に反応する患者を同定する、方法。 - 過剰増殖性障害がHER2発現乳癌である、請求項50に記載の方法。
- (a)GDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせの少なくとも単回用量の投与後に患者から得られた生体試料におけるPIK3CA変異又はPTEN変異を検出すること、並びに
(b)GDC−0032又はGDC−0032と化学療法剤との組み合わせの患者への投与前に患者から得られた生体試料におけるPIK3CAの又はPTENの状態を比較すること
を含む、過剰増殖性障害の処置におけるGDC−0032又はGDC−0032と化学療法剤との組み合わせの治療効果の最適化方法であって、
GDC−0032又はGDC−0032と化学療法剤との組み合わせの投与後に得られた試料におけるPIK3CAの又はPTENの変化又はモジュレーションにより、GDC−0032又はGDC−0032と化学療法剤との組み合わせによる処置が有効である可能性が増加している患者を同定する、方法。 - 過剰増殖性障害がHER2発現乳癌である、請求項50に記載の方法。
- (a)GDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせの少なくとも単回用量が投与されている患者から得られた生体試料におけるPIK3CA変異又はPTEN変異から選択されるバイオマーカーの発現、モジュレーション又は活性を検出すること、並びに
(b)バイオマーカーの発現、モジュレーション又は活性と参照試料におけるバイオマーカーの状態とを比較することであって、参照試料がGDC−0032又はGDC−0032と化学療法剤との組み合わせの患者への投与前に患者から得られた生体試料であること
を含む、過剰増殖性障害の処置におけるGDC−0032又はGDC−0032と化学療法剤との組み合わせに対する反応性のモニタリング用バイオマーカーの同定方法であって、
参照試料と比較して少なくとも2分の1又は2倍のバイオ−マーカー変化のモジュレーションを、GDC−0032又はGDC−0032と化学療法剤との組み合わせに対する反応性のモニタリングに有用なバイオマーカーとして同定する、方法。 - 過剰増殖性障害がHER2発現乳癌である、請求項54に記載の方法。
- 治療上有効な量のGDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせを患者に投与することを含む、患者の過剰増殖性障害の処置方法であって、処置がPIK3CA変異又はPTEN変異を有する患者からの試料に基づく、方法。
- バイオマーカーの変異がPIK3CAのH1047R変異又はH1047L変異である、請求項56に記載の方法。
- バイオマーカーの変異がPIK3CAのE542K変異、E545K変異又はQ546R変異である、請求項56に記載の方法。
- 過剰増殖性障害がHER2発現乳癌である、請求項56に記載の方法。
- 過剰増殖性障害がエストロゲンレセプター陽性(ER+)乳癌である、請求項56に記載の方法。
- 治療上有効な量のGDC−0032又はGDC−0032と5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との組み合わせを患者に投与することを含む、患者の過剰増殖性障害の処置でのGDC−0032又はGDC−0032と化学療法剤との組み合わせの使用であって、
患者から得られた生体試料はGDC−0032又はGDC−0032と化学療法剤との組み合わせの患者への投与前にPIK3CAの又はPTENの変異状態に関して検査されており、PIK3CAの又はPTENの変異状態がGDC−0032又はGDC−0032と化学療法剤との組み合わせに対する患者による治療反応性を示す、使用。 - 過剰増殖性障害がHER2発現乳癌である、請求項61に記載の使用。
- 過剰増殖性障害がエストロゲンレセプター陽性(ER+)乳癌である、請求項61に記載の使用。
- 乳房、子宮頸部、結腸、子宮内膜、神経膠腫、肺、メラノーマ、卵巣、膵臓及び前立腺から選択される癌の処置に使用するための、構造:
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせ。 - 乳房、子宮頸部、結腸、子宮内膜、神経膠腫、肺、メラノーマ、卵巣、膵臓及び前立腺から選択される癌の処置における、構造:
を有するGDC−0032と、5−FU、ドセタキセル、エリブリン、ゲムシタビン、GDC−0973、GDC−0623、パクリタキセル、タモキシフェン、フルベストラント、デキサメタゾン、ペルツズマブ、トラスツズマブエムタンシン、トラスツズマブ及びレトロゾールから選択される化学療法剤との治療用組み合わせの使用。 - 上記に記載の発明。
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- 2018-02-14 US US15/897,032 patent/US20180280408A1/en not_active Abandoned
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WO2011036280A1 (en) * | 2009-09-28 | 2011-03-31 | F. Hoffmann-La Roche Ag | Benzoxazepin pi3k inhibitor compounds and methods of use |
Cited By (6)
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JP2021169510A (ja) * | 2016-05-06 | 2021-10-28 | イーグル ファーマスーティカルズ、インク. | フルベストラント配合物およびその使用方法 |
JP7312523B2 (ja) | 2016-05-06 | 2023-07-21 | イーグル ファーマスーティカルズ、インク. | フルベストラント配合物およびその使用方法 |
JP2021502362A (ja) * | 2017-11-08 | 2021-01-28 | イーグル ファーマスーティカルズ、インク. | フルベストラント製剤とその使用方法 |
JP7220712B2 (ja) | 2017-11-08 | 2023-02-10 | イーグル ファーマスーティカルズ、インク. | フルベストラント製剤とその使用方法 |
JP2023504867A (ja) * | 2019-12-11 | 2023-02-07 | 上海博志研新薬物技術有限公司 | フルベストラント医薬組成物、その調製方法及び応用 |
JP7497902B2 (ja) | 2019-12-11 | 2024-06-11 | 上海雲晟研新生物科技有限公司 | フルベストラント医薬組成物、その調製方法及び応用 |
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