JP2018537538A - がんを処置する方法 - Google Patents
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- JP2018537538A JP2018537538A JP2018549427A JP2018549427A JP2018537538A JP 2018537538 A JP2018537538 A JP 2018537538A JP 2018549427 A JP2018549427 A JP 2018549427A JP 2018549427 A JP2018549427 A JP 2018549427A JP 2018537538 A JP2018537538 A JP 2018537538A
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- 239000000080 wetting agent Substances 0.000 description 1
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Abstract
Description
本発明は、がんを処置するための方法、特に、腎細胞癌などのがんにおいてVEGF−Rアンタゴニストによる処置への抵抗性を克服するための方法に関する。
本出願は、2015年12月14日に出願された米国仮特許出願番号第62/267,052号、2015年12月22日に出願された米国仮特許出願番号第62/271,087号、2016年1月22日に出願された米国仮特許出願番号第62/281,962号、および2016年12月1日に出願された米国仮特許出願番号第62/428,964号に基づく優先権の利益を主張しており、これら各々の全体は参考として本明細書中に援用される。
散発性の淡明細胞型腎細胞癌(ccRCC)を有する患者の約75%では、一般的に突然変異によるが、高メチル化によるサイレンシングにもよる、VHL遺伝子の機能的喪失がある。VHLはフォンヒッペル・リンダウ腫瘍抑制タンパク質をコードし、それは低酸素誘導因子(HIF)−αのタンパク質分解を媒介する[2]。この機能の喪失は、HIF−αレベルの増加、VEGFの発現の増加、腫瘍血管新生、および究極的にはこれらの悪性腫瘍に特徴的な血管過多をもたらす。VEGFシグナル伝達経路をブロックするチロシンキナーゼ阻害剤(TKI)、例えばスニチニブ、アキシチニブ、ソラフェニブまたはパゾパニブ、および循環するVEGFに結合し、したがってリガンドがVEGF受容体に結合することを阻止するモノクローナル抗体であるベバシズマブを含む、VEGF経路の活性化をブロックする複数の薬剤が、転帰を改善することが示されている。
CXCR4(C−X−Cケモカイン受容体4型)は、CXCL12(C−X−Cケモカインリガンド12型;SDF−1α、間質由来の因子1αとも呼ばれる)のための受容体である。CXCL12はリンパ球およびMDSC(骨髄由来のサプレッサー細胞)に強い走化活性を有し、骨髄への造血幹細胞のホーミングにおいて重要である。CXCR4は、ccRCC、卵巣がんおよびメラノーマを含む数種類のヒトがんでも発現されて、活性であり、腫瘍細胞でのCXCR4の発現の増加は有意に減少した全体的患者生存と関連付けられている[3,4,5,6]。
投薬量および製剤
(a)X4P−001または薬学的に許容されるその塩 − 組成物の約30〜40重量%;
(b)微結晶性セルロース − 組成物の約20〜25重量%;
(c)二塩基性リン酸カルシウム二水和物 − 組成物の約30〜35重量%;
(d)クロスカルメロースナトリウム − 組成物の約5〜10重量%;
(e)フマル酸ステアリルナトリウム − 組成物の約0.5〜2重量%;
(f)コロイド状二酸化ケイ素 − 組成物の約0.1〜1.0重量%;および
(g)ラウリル硫酸ナトリウム − 組成物の約0.1〜1.0重量%。
(a)X4P−001または薬学的に許容されるその塩 − 組成物の約37重量%;
(b)微結晶性セルロース − 組成物の約23重量%;
(c)二塩基性リン酸カルシウム二水和物 − 組成物の約32重量%;
(d)クロスカルメロースナトリウム − 組成物の約6重量%;
(e)フマル酸ステアリルナトリウム − 組成物の約1重量%;
(f)コロイド状二酸化ケイ素 − 組成物の約0.3重量%;および
(g)ラウリル硫酸ナトリウム − 組成物の約0.5重量%。
(a)X4P−001または薬学的に許容されるその塩 − 組成物の約8〜25重量%;
(b)微結晶性セルロース − 組成物の約65〜85重量%;
(c)クロスカルメロースナトリウム − 組成物の約2〜10重量%;
(d)フマル酸ステアリルナトリウム − 組成物の約0.1〜3重量%;および
(e)コロイド状二酸化ケイ素 − 組成物の約0.05〜0.7重量%。
(a)X4P−001または薬学的に許容されるその塩 − 組成物の約25〜45重量%;
(b)微結晶性セルロース − 組成物の約10〜35重量%;
(c)二塩基性リン酸カルシウム二水和物 − 組成物の約15〜45重量%;
(d)クロスカルメロースナトリウム − 組成物の約2〜10重量%;
(e)フマル酸ステアリルナトリウム − 組成物の約0.3〜2.5重量%;
(f)コロイド状二酸化ケイ素 − 組成物の約0.05〜1.2重量%;および
(g)ラウリル硫酸ナトリウム − 組成物の約0.2〜1.2重量%。
(a)X4P−001または薬学的に許容されるその塩 − 組成物の約35〜75重量%;
(b)微結晶性セルロース − 組成物の約5〜28重量%;
(c)二塩基性リン酸カルシウム二水和物 − 組成物の約7〜30重量%;
(d)クロスカルメロースナトリウム − 組成物の約2〜10重量%;
(e)フマル酸ステアリルナトリウム − 組成物の約0.3〜2.5重量%;
(f)コロイド状二酸化ケイ素 − 組成物の約0.05〜1.2重量%;および
(g)ラウリル硫酸ナトリウム − 組成物の約0.2〜1.2重量%。
ヒト細胞系によるマウスモデル
X4P−001およびアキシチニブの単独によるおよび組合せによる処置の、MDSCおよび他の免疫抑制細胞集団の輸送に及ぼす効果、ならびにRCC細胞によるケモカイン生成に及ぼす効果を調べた。
結果:
異種移植におけるmiRNA mir−30aおよびmir−30cの抑制ならびにHIF−2αへの効果
(実施例2)
さらなる異種移植研究
(実施例3)
サイトカインおよびケモカイン研究
(実施例4)
薬物動態研究
(実施例5)
臨床治療レジメン
投与は、毎日同じ時間±2時間にあるべきである。
1日2回投与の場合、連続した用量の間の間隔は、9時間未満でも15時間超でもあるべきでない。間隔が15時間を超える場合は投与は省略するべきであり、次の投与では通常のスケジュールを再開すべきである。
食物に関する制限。吸収は食物によって影響を受けるので、患者は以下の通りに指示される:
午前の投与については
− 真夜中から投与時間まで食物や飲料(水を除く)をとらない
− 投与から2時間の間は食物や飲料(水を除く)をとらない
第2の日用量については、適用可能な場合
− 投与前の1時間の間は食物や飲料(水を除く)をとらない
− 投与から2時間の間は食物や飲料(水を除く)をとらない。
処置への応答および疾患状態の評価
測定可能な非結節性病変 − 最大直径≧10mm。
測定可能な結節性病変 − 短軸≧15mm
測定不可能な病変 − 測定できないものを含む、より小さい病変
測定可能な疾患 − 少なくとも1つの測定可能な病変の存在。
標的病変
完全寛解(CR)
(a)全ての非結節性病変の消失、および
(b)病的なリンパ節aの不在。
部分寛解(PR)
(a)標的病変のSODにおけるベースラインからの30%以上の低下
安定疾患(SD)
(a)PRまたはPDのいずれの基準も満たさない持続的疾患
進行性疾患(PD)
a)ベースライン時または処置の間であってもよい最小合計と比較して、標的病変のSODにおける20%以上の増加;および
(b)SODにおける5mm以上の絶対増加。
対象外の病変
完全寛解(CR)
(a)全ての対象外の病変の消失、および
(b)病的なリンパ節aの不在。
非CR/非PD
1つまたは複数の対象外の病変の持続
進行性疾患(PD)
既存の対象外の病変の明確な進行。
新しい病変
薬物動態学的評価
(実施例6)
X4P−001のための製剤試験結果
序論
材料および装置
材料のリスト
微結晶性セルロース、NF、Avicel(登録商標)PH−101、ロット番号1155
二塩基性リン酸カルシウム二水和物、USP、Emcompress(登録商標)、ロット番号B10E
クロスカルメロースナトリウム、NF、Ac−Di−Sol(登録商標)、ロット番号T050N
コロイド状二酸化ケイ素、USP、Cab−O−Sil(登録商標)M−5P、ロット番号1J021
フマル酸ステアリルナトリウム、NF、PRUV(商標)、ロット番号30001902
ラウリル硫酸ナトリウム、NF、ロット番号12810
空のハードゼラチンカプセル、サイズ1の白色不透明、ロット番号582410
60ccアンバーガラスボトル、緑色のネジ式のキャップ付き
シリカゲル乾燥剤小袋、0.5g
レーヨンコイル12グラム/y
2×3 3スポット湿度指示カード、ロット番号10018
アルミ箔バッグMIL−PRF−131J
装置のリスト
2−Qt.V−ブレンダー
Bonapace In−Capカプセル充てん機
小袋シーラー
タップ密度テスター
粒径分析器(ソニックシフター)
実験および結果
パイロット試験のための製剤の選択
工程内試験
最終生成物の初期試験
安定性試験
X4P−001および粉末ブレンドの物理的特性
結論
200mgカプセル剤の開発および製剤
1.X4P−001有効成分を4クォートのVブレンダーに加える。
2.30メッシュハンドスクリーンを通してAvicel PH−101および二塩基性リン酸カルシウムをふるいにかけ、4クォートのVブレンダーに加える。4分間混合する(100回転)。
3.30メッシュハンドスクリーンを通してクロスカルメロースナトリウムおよびラウリル硫酸ナトリウムをふるいにかけ、4クォートのVブレンダーに加える。2分間混合する(50回転)。
4.30メッシュハンドスクリーンを通してコロイド状二酸化ケイ素をふるいにかけ、4クォートのVブレンダーに加える。2分間混合する(50回転)。
5.4クォートのVブレンダーから混合された材料を排出し、30メッシュスクリーンを通してふるいにかける。ふるいにかけた材料を4クォートのVブレンダーに戻し、2分間混合する(50回転)。
6.30メッシュハンドスクリーンを通してフマル酸ステアリルナトリウムをふるいにかけ、4クォートのVブレンダーに加える。3分間混合する(75回転)。
7.MF−30手動カプセル充てん機を使用して、混合された材料を325.0mg/カプセルの目標重量まで封入する。
実現可能性バッチ15/858−034を、アッセイ/関連物質、水分、溶解および含有量均一性について試験した。この試験の結果は、図9および10に示す。アッセイ試験の結果は、表示含有量の97.4%であり、全不純物0.75%、および水分値3.9w/w%であった。
参考文献
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Claims (31)
- 以下を含む組成物:
(a)X4P−001または薬学的に許容されるその塩 − 前記組成物の約30〜40重量%;
(b)微結晶性セルロース − 前記組成物の約20〜25重量%;
(c)二塩基性リン酸カルシウム二水和物 − 前記組成物の約30〜35重量%;
(d)クロスカルメロースナトリウム − 前記組成物の約5〜10重量%;
(e)フマル酸ステアリルナトリウム − 前記組成物の約0.5〜2重量%;
(f)コロイド状二酸化ケイ素 − 前記組成物の約0.1〜1.0重量%;および
(g)ラウリル硫酸ナトリウム − 前記組成物の約0.1〜1.0重量%。 - 以下を含む組成物:
(a)X4P−001または薬学的に許容されるその塩 − 前記組成物の約8〜25重量%;
(b)微結晶性セルロース − 前記組成物の約65〜85重量%;
(c)クロスカルメロースナトリウム − 前記組成物の約2〜10重量%;
(d)フマル酸ステアリルナトリウム − 前記組成物の約0.1〜3重量%;および
(e)コロイド状二酸化ケイ素 − 前記組成物の約0.05〜0.7重量%。 - 以下を含む組成物:
(a)X4P−001または薬学的に許容されるその塩 − 前記組成物の約25〜45重量%;
(b)微結晶性セルロース − 前記組成物の約10〜35重量%;
(c)二塩基性リン酸カルシウム二水和物 − 前記組成物の約15〜45重量%;
(d)クロスカルメロースナトリウム − 前記組成物の約2〜10重量%;
(e)フマル酸ステアリルナトリウム − 前記組成物の約0.3〜2.5重量%;
(f)コロイド状二酸化ケイ素 − 前記組成物の約0.05〜1.2重量%;および
(g)ラウリル硫酸ナトリウム − 前記組成物の約0.2〜1.2重量%。 - 以下を含む組成物:
(a)X4P−001または薬学的に許容されるその塩 − 前記組成物の約35〜75重量%;
(b)微結晶性セルロース − 前記組成物の約5〜28重量%;
(c)二塩基性リン酸カルシウム二水和物 − 前記組成物の約7〜30重量%;
(d)クロスカルメロースナトリウム − 前記組成物の約2〜10重量%;
(e)フマル酸ステアリルナトリウム − 前記組成物の約0.3〜2.5重量%;
(f)コロイド状二酸化ケイ素 − 前記組成物の約0.05〜1.2重量%;および
(g)ラウリル硫酸ナトリウム − 前記組成物の約0.2〜1.2重量%。 - 前記X4P−001または薬学的に許容されるその塩が、約10mg、約20mg、約25mg、約50mg、約75mg、約100mg、約150mg、約200mg、約250mg、約300mg、約400mg、約450mg、約500mg、約600mg、約700mg、約750mg、約800mg、約900mg、約1000mg、約1100mgまたは約1200mgの量で存在する、請求項1から4のいずれか一項に記載の組成物。
- 約37重量%のX4P−001または薬学的に許容されるその塩を含む、請求項1に記載の組成物。
- 約100mgのX4P−001または薬学的に許容されるその塩を含む、請求項1に記載の組成物。
- 以下を含む、請求項1に記載の組成物:
(a)X4P−001または薬学的に許容されるその塩 − 前記組成物の約37重量%;
(b)微結晶性セルロース − 前記組成物の約23重量%;
(c)二塩基性リン酸カルシウム二水和物 − 前記組成物の約32重量%;
(d)クロスカルメロースナトリウム − 前記組成物の約6重量%;
(e)フマル酸ステアリルナトリウム − 前記組成物の約1重量%;
(f)コロイド状二酸化ケイ素 − 前記組成物の約0.3重量%;および
(g)ラウリル硫酸ナトリウム − 前記組成物の約0.5重量%。 - 約15重量%のX4P−001または薬学的に許容されるその塩を含む、請求項2に記載の組成物。
- 約25mgのX4P−001または薬学的に許容されるその塩を含む、請求項2に記載の組成物。
- 以下を含む、請求項2に記載の組成物:
(a)X4P−001または薬学的に許容されるその塩 − 前記組成物の約14.7重量%;
(b)微結晶性セルロース − 前記組成物の約78.1重量%;
(c)クロスカルメロースナトリウム − 前記組成物の約6.0重量%;
(d)フマル酸ステアリルナトリウム − 前記組成物の約1.0重量%;および
(e)コロイド状二酸化ケイ素 − 前記組成物の約0.2重量%。 - 約38重量%のX4P−001または薬学的に許容されるその塩を含む、請求項3に記載の組成物。
- 約100mgのX4P−001または薬学的に許容されるその塩を含む、請求項3に記載の組成物。
- 以下を含む、請求項3に記載の組成物:
(a)X4P−001または薬学的に許容されるその塩 − 前記組成物の約37.6重量%;
(b)微結晶性セルロース − 前記組成物の約22.9重量%;
(c)二塩基性リン酸カルシウム二水和物 − 前記組成物の約31.7重量%;
(d)クロスカルメロースナトリウム − 前記組成物の約6.0重量%;
(e)フマル酸ステアリルナトリウム − 前記組成物の約1.0重量%;
(f)コロイド状二酸化ケイ素 − 前記組成物の約0.3重量%;および
(g)ラウリル硫酸ナトリウム − 前記組成物の約0.5重量%。 - 約61重量%のX4P−001または薬学的に許容されるその塩を含む、請求項4に記載の組成物。
- 約200mgのX4P−001または薬学的に許容されるその塩を含む、請求項4に記載の組成物。
- 以下を含む、請求項4に記載の組成物:
(a)X4P−001または薬学的に許容されるその塩 − 前記組成物の約61.5重量%;
(b)微結晶性セルロース − 前記組成物の約12.9重量%;
(c)二塩基性リン酸カルシウム二水和物 − 前記組成物の約17.8重量%;
(d)クロスカルメロースナトリウム − 前記組成物の約6.0重量%;
(e)フマル酸ステアリルナトリウム − 前記組成物の約1.0重量%;
(f)コロイド状二酸化ケイ素 − 前記組成物の約0.3重量%;および
(g)ラウリル硫酸ナトリウム − 前記組成物の約0.5重量%。 - 請求項1から17のいずれか一項に記載の組成物を含む単位剤形。
- カプセル剤の形である、請求項18に記載の単位剤形。
- それを必要とする患者においてがんを処置するための方法であって、前記患者に請求項1から17のいずれか一項に記載の組成物を投与することを含む方法。
- 前記がんが難治性である、請求項20に記載の方法。
- 前記患者がチロシンキナーゼ阻害剤で以前に処置されており、前記患者が血管新生逃避によって前記チロシンキナーゼ阻害剤への抵抗性を示していた、請求項20または21に記載の方法。
- 前記がんが、腎細胞癌(RCC)、固形腫瘍、膵臓、腎臓、結腸直腸、肺、乳房、甲状腺または胃新生物、神経膠芽腫、肝細胞癌または肝がん、メラノーマ、眼内メラノーマ、前立腺がん、非小細胞肺がん、腎臓腫瘍、腎臓癌(淡明細胞型および乳頭状の腎臓癌を含む)または腎臓がん、結腸直腸がん、進行した胃がん、悪性中皮腫、神経線維腫症、シュワン鞘腫、軟部組織肉腫、頭頸部扁平上皮癌、鼻咽頭癌、腺癌、神経内分泌癌、急性骨髄性白血病、骨髄異形成症候群、褐色細胞腫、パラガングリオーマ、リンパ腫、マントル細胞がん、消化管間質腫瘍または膵臓腺管癌から選択される、請求項20から22のいずれか一項に記載の方法。
- 前記がんが、進行した腎細胞癌(RCC)、淡明細胞型腎臓癌(ccRCC)または乳頭状腎臓癌である、請求項20から23のいずれか一項に記載の方法。
- 前記がんがccRCCである、請求項24に記載の方法。
- X4P−001または薬学的に許容されるその塩の1日に約100mgから約1200mgの投薬量が前記患者に投与される、請求項20から25のいずれか一項に記載の方法。
- X4P−001または薬学的に許容されるその塩の1日に約200mgから約600mgの投薬量が前記患者に投与される、請求項20から25のいずれか一項に記載の方法。
- X4P−001または薬学的に許容されるその塩の1日に約100mgから約400mgの投薬量が前記患者に投与される、請求項20から25のいずれか一項に記載の方法。
- 約25mg、約100mgまたは約200mgのX4P−001または薬学的に許容されるその塩を含む単位剤形が前記患者に投与される、請求項20から28のいずれか一項に記載の方法。
- 前記単位剤形が1日2回経口投与される、請求項29に記載の方法。
- 前記単位剤形が概ね12時間空けて投与される、請求項30に記載の方法。
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