JP2022522328A - Sumo活性化酵素阻害剤及びチェックポイント阻害剤の投与 - Google Patents
Sumo活性化酵素阻害剤及びチェックポイント阻害剤の投与 Download PDFInfo
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Abstract
Description
質の高い生活を維持しながら患者の寿命を延ばすために、がんの治療において薬効をもたらす療法剤の新しい組み合わせが望ましい。新しい組み合わせは、薬剤単独の各々と比較して増加した利益を提供し得る。特に、併用治療レジメンは、増殖性障害、自己免疫疾患、炎症性疾患、線維性疾患、及び腎臓疾患を含む疾患状態に罹患している患者に有用であり得、さらには、再発率を低下させるか、またはこれらの患者に時々見られる特定の抗がん剤への耐性を克服する可能性があり得る。これは、がんが現在利用可能な治療レジメンに対して耐性または抵抗性であり得る場合に特に当てはまる。
このため、併用療法を含む新たな治療レジメンが必要とされている。
本開示は、がんまたは自己免疫疾患を有する患者の併用治療を提供する。併用治療は、とりわけ、それを必要とする対象に、治療有効量の少なくとも1つのSAE阻害剤を投与することを含む。
本開示は、とりわけ、それを必要とする対象に、治療有効量の少なくとも1つのチェックポイント阻害剤(例えば、ニボルマブ、ペムブロリズマブ、アテゾリズマブ、デュルバルマブ、アベルマブ、及びイピリムマブ)を投与することを含む併用治療を提供する。いくつかの実施形態では、チェックポイント阻害剤は、抗PD-1抗体である。いくつかの実施形態では、チェックポイント阻害剤は、抗PD-L1抗体である。いくつかの実施形態では、チェックポイント阻害剤は、抗CTLA-4抗体である。
いくつかの実施形態では、本開示は、患者のがんを治療する方法であって、SAE阻害剤またはその薬学的に許容される塩と、1つ以上のチェックポイント阻害剤との組み合わせを、上記治療を必要とする患者に投与することによる方法に関する。
いくつかの実施形態では、本開示は、そのような治療を必要とする患者のがんの治療における使用のための医薬に関する。医薬は、SAE阻害剤及びチェックポイント阻害剤を含み、単一の剤形または別個の剤形である。
化合物I-263aまたはその薬学的に許容される塩は、チェックポイント阻害剤、及び任意選択で1つ以上の追加の治療薬と組み合わせて、単一の剤形で、または別個の剤形として投与され得る。いくつかの実施形態では、別個の剤形として投与する場合、チェックポイント阻害剤は、I-263aまたはその薬学的に許容される塩の投与前、それと同時、またはその投与後に投与され得る。いくつかの実施形態では、別個の剤形として投与される場合、I-263aまたはその薬学的に許容される塩の1つ以上の用量は、チェックポイント阻害剤の前に投与され得る。いくつかの実施形態では、チェックポイント阻害剤は、化合物I-263aまたはその薬学的に許容される塩の投与前に投与される。本明細書で使用されるとき、化合物I-263aまたはその薬学的に許容される塩と、チェックポイント阻害剤と、任意選択的に1つ以上の追加の治療薬との「組み合わせ」での投与は、薬剤の同時または逐次的投与だけでなく、当業者によって理解されるように、単一の治療周期中の薬剤の投与をも指す。化合物I-263aまたはその薬学的に許容される塩が、チェックポイント阻害剤、及び任意選択的での1つ以上の追加の治療薬と組み合わせて投与される場合、治療有効量の組み合わせが投与される。
本明細書に記載の方法及びキットで使用されるSAE阻害剤及びチェックポイント阻害剤は、投与に好適な医薬組成物に製剤化することができる。医薬組成物は、薬学的に許容される賦形剤を含み得る。本明細書で使用される、薬学的に許容される賦形剤としては、所望される特定の剤形に好適な、あらゆる溶媒、分散媒、または他の液体ビヒクル、分散もしくは懸濁の補助剤、希釈剤、造粒剤及び/または分散剤、界面活性剤、等張剤、増粘剤もしくは乳化剤、保存剤、結合剤、滑沢剤もしくは油、着色剤、甘味剤もしくは香味剤、安定剤、抗酸化剤、抗菌剤もしくは抗真菌剤、浸透圧調整剤、pH調整剤、緩衝剤、キレート剤、抗凍結剤、及び/または増量剤が挙げられるが、これらに限定されない。医薬組成物を製剤化するための様々な賦形剤、及び組成物を調製するための技術は、当該技術分野で既知である(その全体が参照により組み込まれる、Remington:The Science and Practice of Pharmacy,21st Ed.,A.R.Gennaro(Lippincott,Williams&Wilkins,Baltimore,MD),2006を参照されたい)。
いくつかの実施形態では、本明細書に記載のSAE阻害剤またはチェックポイント阻害剤は、キットに含めるために製造され得る。「キット」は、少なくとも1つの試薬または化学療法剤を含む任意の製品(例えば、パッケージまたは容器)である。本明細書の方法での使用のためのキットは、SAE阻害剤、例えば、式I-263aの化合物またはその薬学的に許容される塩を含み得る。いくつかの実施形態では、キットは、チェックポイント阻害剤と、任意選択の1つ以上の追加の治療薬とをさらに含んでもよい。いくつかの実施形態では、キットは、式I-263aの化合物またはその薬学的に許容される塩と、チェックポイント阻害剤と、任意選択で1つ以上の追加の治療薬とを含み得る。いくつかの実施形態では、キットは、1つ以上のSAE阻害剤またはその薬学的に許容される塩を含んでよい。いくつかの実施形態では、キットは1つ以上のチェックポイント阻害剤を含んでよい。
一般的な分析方法
別段の記載がない限り、1H NMRスペクトルは、Varian 300MHzを使用して取得した。別段の記載のない限り、HPLCは、Agilent 1100シリーズ上で取得し、UPLCは、Water Acuity Systemsにより取得した。
マウス同系腫瘍モデル
以下の同系モデルを、以下に指定されるように、研究1~8のそれぞれにおいて利用した。
以下の試験薬剤を、以下に指定されるように、研究1~8のそれぞれにおいて利用した。
腫瘍は、ノギスを使用して週に2回測定した。腫瘍体積を、以下の標準方程式を使用して計算した:V=W2×L/2(式中、腫瘍に関して、V=体積、W=幅、及びL=長さ)。研究1の場合、平均腫瘍体積が約60mm3に達したとき、研究2の場合は40mm3、研究3の場合は50mm3、研究4の場合は50mm3、研究5の場合は30mm3、研究6の場合は45mm3、研究7の場合は50mm3、研究8の場合は60mm3に達したとき、マウスを、研究1では4群(n=8/群)、研究2では4群(n=8/群)、研究3では4群(n=8/群)、研究4では6群(n=8/群)、研究5では6群(n=8/群)、研究6では6群(n=8/群)、研究7では6群(n=8/群)、及び研究8では6群(n=8/群)に無作為化し、ビヒクル(20%HPβCD)、化合物I-263a、抗mPD-1、抗mCTLA-4、または化合物I-263a+抗mPD-1もしくは抗mCTLA-4の組み合わせを様々な用量及びスケジュールで投与した。腫瘍サイズ及び体重は、研究が継続している間、週に2回測定した。マウスを、その腫瘍体積が約2500mm3を超えたとき、または個々の腫瘍がサイズについて人道的エンドポイントを超えたとき(腫瘍の長さが2cmを超えたとき)に安楽死させた。
上記の一般的な方法において記載したように行ったマウス同種腫瘍モデルを使用して、化合物I-263aと抗mPD-1または抗mCTLA-4とのインビボの組み合わせ効果を評価した。
CT26同系マウス結腸線維芽腫由来の皮下腫瘍モデルでは、マウスに接種し、0日目(接種後6日)に無作為化し、全ての群について1日目に処置を開始した。
CT26同系マウス結腸線維芽腫由来の皮下腫瘍モデルでは、マウスに接種し、0日目(接種後4日)に無作為化し、全ての群について0日目に処置を開始した。
A20同系マウスB細胞リンパ腫由来の皮下腫瘍モデルでは、マウスに接種し、0日目(接種後5日)に無作為化し、全ての群について1日目に処置を開始した。
WEHI-3同系マウス骨髄単球性白血病由来の皮下腫瘍モデルでは、マウスに接種し、0日目(接種後9日)に無作為化し、全ての群について0日目に処置を開始した。
WEHI-3同系マウス骨髄単球性白血病由来の皮下腫瘍モデルでは、マウスに接種し、0日目(接種後4日)に無作為化し、全ての群について0日目に処置を開始した。
JC同系マウス乳腺癌由来皮下腫瘍モデルでは、マウスに接種し、0日目(接種後12日)に無作為化し、全ての群について0日目に処置を開始した。
B16-F10同系マウス黒色腫由来の皮下腫瘍モデルでは、マウスに接種し、0日目(接種後8日)に無作為化し、全ての群について0日目に処置を開始した。
MC38同系マウス結腸腺癌由来の皮下腫瘍モデルでは、マウスに接種し、0日目(接種後5日)に無作為化し、全ての群について0日目に処置を開始した。
第1b/2相臨床試験は、非小細胞肺癌(NSCLC)、子宮頸癌、またはマイクロサテライト安定性結腸直腸癌(MSS-CRC)を有する成人患者におけるペンブロリズマブ静脈注入及び化合物I-263a静脈注入の投与からなる併用療法の効果を評価するために実施される。
第1b相試験の主要評価項目は、NCI CTCAEバージョン5.0に従った、全ての用量群の治療中に発生した有害事象(TEAE)及び検査室異常の頻度、重症度、及び持続時間、ならびに周期1の治療の最初の21日以内のDLTの発生が含まれるであろう。
第2相治験の主要評価項目には、固形腫瘍における奏効評価基準(RECIST)バージョン1.1に従って治験責任医師によって定義される全奏効率(ORR)(完全奏効+部分奏効)が含まれるであろう。
第1b相試験の副次評価項目には以下が含まれるであろう:RECISTバージョン1.1及び改変RECIST1.1、ならびにRECISTコンセンサスガイドライン(iRECIST)に従って治験責任医師によって定義される、ORR、疾患対照率(DCR)、奏効期間(DOR)、進行までの時間(TTP)、無増悪生存期間(PFS)、及び全生存期間(OS)。
第2相試験の副次評価項目には、NCI CTCAEバージョン5.0に従った、全ての用量群のTEAE及び検査室異常の頻度、重症度、及び持続時間、RECISTバージョン1.1及びiRECISTに従って治験責任医師によって定義されたDCR、DOR、TTP、PFS、及びOS、iRECISTに従って治験責任医師によって評価されたORR、ならびに化合物I-263aの血漿中濃度-時間データが含まれるであろう。
Claims (38)
- がん患者の治療方法であって、前記治療を必要とする患者に、
[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩と、
チェックポイント阻害剤と、を投与することを含む、前記方法。 - 前記チェックポイント阻害剤が、抗PD-1抗体である、請求項1に記載の方法。
- 前記抗PD-1抗体が、ニボルマブ、ペムブロリズマブ、ランブロリズマブ、ピディリズマブ、BMS-936559、及びAMP-224からなる群から選択される、請求項2に記載の方法。
- 前記チェックポイント阻害剤が、抗PD-L1抗体である、請求項1に記載の方法。
- 前記抗PD-L1抗体が、アテゾリズマブ、デュルバルマブ、アベルマブ、YW243.55.S70、MEDI-4736、MSB-0010718C、LY3300054、BMS-936559、MPDL3280A、及びMDX-1105からなる群から選択される、請求項4に記載の方法。
- 前記チェックポイント阻害剤が、抗CTLA-4抗体である、請求項1に記載の方法。
- 前記抗CTLA-4抗体が、イピリムマブ及びトレメリムマブからなる群から選択される、請求項6に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、経口投与される、請求項1~7のいずれか1項に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、静脈内投与される、請求項1~7のいずれか1項に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、静脈内注入によって投与される、請求項1~7のいずれか1項に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメートと、前記チェックポイント阻害剤とが、同時に投与される、請求項1~10のいずれか1項に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメートと、前記チェックポイント阻害剤とが、別個の医薬組成物で逐次的に投与される、請求項1~10のいずれか1項に記載の方法。
- 前記がんが、PD-1陽性がん、PD-L1陽性がん、またはCTLA-4陽性がんである、請求項1~12のいずれか1項に記載の方法。
- 前記がんが、黒色腫、肺癌、腎臓癌、リンパ腫、頭頸部癌、尿路上皮癌、前立腺癌、膀胱癌、乳癌、胃癌、結腸直腸癌、白血病、子宮頸癌、高頻度マイクロサテライト不安定性がん、肝細胞癌、またはメルケル細胞癌である、請求項1~12のいずれか1項に記載の方法。
- 前記黒色腫が、転移性黒色腫、切除不能な黒色腫、または皮膚黒色腫である、請求項14に記載の方法。
- 前記肺癌が、非小細胞肺癌または小細胞肺癌である、請求項14に記載の方法。
- 前記非小細胞肺癌が、転移性非小細胞肺癌、転移性扁平上皮非小細胞肺癌、または転移性非扁平上皮非小細胞肺癌である、請求項16に記載の方法。
- 前記腎癌が、腎細胞癌である、請求項14に記載の方法。
- 前記リンパ腫が、古典的ホジキンリンパ腫または縦隔原発大細胞型B細胞性リンパ腫である、請求項14に記載の方法。
- 前記頭頸部癌が、頭頸部扁平上皮細胞癌である、請求項14に記載の方法。
- 前記尿路上皮癌が、尿路上皮癌腫である、請求項14に記載の方法。
- 前記前立腺癌が、ホルモン抵抗性前立腺癌である、請求項14に記載の方法。
- 前記胃癌が、食道胃接合部腺癌である、請求項14に記載の方法。
- 前記結腸直腸癌が、マイクロサテライト安定性結腸直腸癌である、請求項14に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、2週間に1回、1週間に1回、1週間に2回、1週間に3回、または毎日投与される、請求項1~24のいずれか1項に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、1週間に2回投与される、請求項25に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、1週間に1回投与される、請求項25に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、21日の周期の1、4、8、及び11日目に投与される、請求項1~24のいずれか1項に記載の方法。
- 前記チェックポイント阻害剤が、12週間に1回、4週間に1回、3週間に1回、2週間に1回、1週間に1回、1週間に2回、1週間に3回、または毎日投与される、請求項1~24のいずれか1項に記載の方法。
- 前記チェックポイント阻害剤が、2週間に1回投与される、請求項29に記載の方法。
- 前記チェックポイント阻害剤が、3週間に1回投与される、請求項29に記載の方法。
- 前記チェックポイント阻害剤が、4週間に1回投与される、請求項29に記載の方法。
- 前記チェックポイント阻害剤が、12週間に1回投与される、請求項29に記載の方法。
- 前記チェックポイント阻害剤が、治療周期の1日目に投与される、請求項1~24のいずれか1項に記載の方法。
- 前記治療周期が14日、21日、28日、または84日である、請求項34に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩と、前記チェックポイント阻害剤とが、12週間に1回、4週間に1回、3週間に1回、2週間に1回、1週間に1回、1週間に2回、1週間に3回、毎日、または、21日の周期の1、4、8、及び11日目に投与される、請求項1~24のいずれか1項に記載の方法。
- 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、2週間に1回、1週間に1回、1週間に2回、1週間に3回、毎日、または21日の周期の1、4、8、及び11日目に投与され、
前記チェックポイント阻害剤が、12週間に1回、4週間に1回、3週間に1回、2週間に1回、1週間に1回、1週間に2回、1週間に3回、または毎日、別個に投与される、請求項1~24のいずれか1項に記載の方法。 - 前記[(1R,2S,4R)-4-{[5-({4-[(1R)-7-クロロ-1,2,3,4-テトラヒドロイソキノリン-1-イル]-5-メチル-2-チエニル}カルボニル)ピリミジン-4-イル]アミノ}-2-ヒドロキシシクロペンチル]メチルスルファメート、またはその薬学的に許容される塩が、21日の周期の1、4、8、及び11日目に投与され、
前記チェックポイント阻害剤が、21日の周期の1日目に別個に投与される、請求項1~24のいずれか1項に記載の方法。
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