JP2021502415A - 癌の処置のためのアパチニブを用いる併用療法 - Google Patents
癌の処置のためのアパチニブを用いる併用療法 Download PDFInfo
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Abstract
Description
本出願は、2017年11月10日に出願された米国仮特許出願第62/584,547号の利益を主張し、該仮出願は参照により本明細書に組み込まれる。
本明細書で使用されるように、「併用療法」との用語は、単一または複数の組成物に含まれる治療上有効な薬剤(アパチニブと免疫療法剤)の組み合わせを指す。治療上有効な薬剤は、医療関係者によって規定された任意の連続的なやり方で、必要としている患者に同時に一緒に、あるいは、別々に(各々、または、その組み合わせで)投与され得る。
本明細書に記載された様々な実施形態は、チロシンキナーゼ阻害剤あるいはその薬学的に許容可能を投与する工程を含む、疾患を処置するための方法を対象としている。
リボセラニブ(化学名 N−[4−(1−シアノシクロペンチル)フェニル]−2−{[(ピリジン−4−イル)メチル]アミノ}ピリジン−3−カルボキサミド、YN968D1としても知られており、アパチニブとして中国で開発され、Aitan(登録商標)として市販されている)は、経口投与された小分子チロシンキナーゼ阻害剤である。それは、腫瘍の血管の血管新生の遮断に結びつく血管内皮増殖因子受容体(VEGFR)−2を選択的に阻害し、既存の血管の生存率を低下させ、腫瘍の成長を遅らせる。内皮細胞の増殖は直接的に標的とされ、癌細胞または間質細胞による血管新生促進成長因子の放出の阻害は間接的に標的とされる。
・リボセラニブはVEGFR−2に選択的に結合し、様々な腫瘍を抱える動物モデルにおいて効果的である。
・リボセラニブの効果的な投与量で動物において最小限の副作用がある。
・リボセラニブは、血漿アルブミンに97%以上結合する高結合性化合物である。
・リボセラニブは一般的に吸収性が悪い。
・リボセラニブの安定状態レベルはおよそ7日で達成された;28日までの試験では、それ以上の蓄積は明らかではなかった。
いくつかの実施形態において、免疫療法剤と組み合わせたチロシンキナーゼ阻害剤が本明細書に記載される。いくつかの実施形態において、免疫療法剤はPD−1あるいはPD−L1阻害剤である。
いくつかの例では、薬物投与量は患者の体表面積(BSA)の因子として決定される。いくつかの例では、BSAは、異常な脂肪量によってあまり影響を受けないため、体重よりも優れた代謝量のインジケータであり、例えば、より大きなBSAを有する患者は、おそらく、薬物を除去するためのより大きな臓器を有する。実際に、個体間の薬物クリアランスには4〜10倍の差がある場合がある。
BSA=0.007184×W0.425×H0.725
式中、Wが量(kg)であり、Hが高さ(cm)である。成人男子の平均BSAは2.060m2である。成人の女性の平均BSAは1.830m2である。いくつかの例では、ペンブロリズマブの投与量はmg/m2の単位で与えられる。いくつかの例では、ニボルマブの投与量はmg/m2の単位で与えられる。
疾患を処置するための方法が本明細書に記載され、ここで、上記方法は、2つ以上の治療の組み合わせ、特に、チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩、および免疫療法剤あるいはその薬学的に許容可能な塩を含む組み合わせを施す工程を含む。
疾患を処置するための方法が本明細書に記載され、ここで、上記方法は、2つ以上の治療の組み合わせ、特に、チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩、および免疫療法剤あるいはその薬学的に許容可能な塩を含む組み合わせを施す工程を含む。
一態様では、本開示は、本開示の化合物を含む医薬組成物に関する。すなわち、医薬組成物は、治療上有効な量のアパチニブおよび治療上有効な量の免疫療法剤ならびに薬学的に許容可能な担体であり得る。
いくつかの実施形態において、キットが提供され、上記キットは:
a)チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)免疫療法剤、あるいはその薬学的に許容可能な塩と;を含み、
ここで、上記キットは疾患を処置するためのものである。
a)リボセラニブ、あるいはその薬学的に許容可能な塩と;
b)免疫療法剤、あるいはその薬学的に許容可能な塩と;を含み、
ここで、上記キットは疾患を処置するためのものである。
a)チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)ペンブロリズマブと;を含み、
ここで、上記キットは疾患を処置するためのものである。
a)チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)ニボルマブと;を含み、
ここで、上記キットは疾患を処置するためのものである。
a)チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)免疫療法剤、あるいはその薬学的に許容可能な塩と;を含み、
ここで、上記キットは癌を処置するためのものである。
a)リボセラニブ、あるいはその薬学的に許容可能な塩と;
b)免疫療法剤、あるいはその薬学的に許容可能な塩と;を含み、
ここで、上記キットは癌を処置するためのものである。
a)チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)ペンブロリズマブと;を含み、
ここで、上記キットは癌を処置するためのものである。
a)チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)ニボルマブと;を含み、
ここで、上記キットは癌を処置するためのものである。
a)1日1回の経口投与のためのチロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)週に1回の静注投与のための免疫療法剤、あるいはその薬学的に許容可能な塩と;を含み、
ここで、上記キットは疾患を処置するためのものである。
a)チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)免疫療法剤、あるいはその薬学的に許容可能な塩と;
c)コルチコステロイドと;
d)抗ヒスタミン剤と;
e)H2受容器アンタゴニストと;を含み、
ここで、上記キットは疾患を処置するためのものである。
a)チロシンキナーゼ阻害剤、あるいはその薬学的に許容可能な塩と;
b)免疫療法剤、あるいはその薬学的に許容可能な塩と;
c)容器と;
d)哺乳動物の疾患または疾病を処置するための治療補法の使用説明書と、を含む。
ii)静注投与のためのペンブロリズマブと、を含む、癌を処置するためのキット。
ii)静注投与のためのニボルマブと、を含む、癌を処置するためのキット。
実験動物
Jackson Laboratoriesから購入した40匹の雌のC57BL/6マウスを試験に登録した。動物を安定化期間の間、収容した。動物を個々のHEPA換気ケージ(Innocage(登録商標)IVC, Innovive USA)に収容した。蛍光照明を12時間サイクルで提供した。温度および湿度はそれぞれ毎日モニタリングならびに記録され、可能な限り最大限に68〜74°F(20〜23°C)から30〜70%の湿度の間で維持した。2920X.10 18%の大豆照射げっ歯類飼料(soy irradiated rodent feed)(Harlan)およびオートクレーブ処理された酸性化水(pH 2.5−3)を自由に与えた。
接種については、LL/2細胞の生存率は98%であった。LL/2細胞を含有するCryoバイアルを解凍し、マウスへの注射のために調製した。試験日に、3つの細胞をPBSで洗浄し、計数し、および250,000の生存細胞/100μLの濃度で冷PBSにおいて再懸濁した。細胞懸濁液をPBSと混合し、動物施設への輸送中に氷上に置いた。26 7/8g(0.5mmX22mm)の針が取り付けられた、冷却された1mLのルアーロックシリンジにPBS細胞混合物を引き込むことにより、注射のための細胞を準備した。注射前に動物の毛を剃った。一度に1匹のマウスを固定し、注射部位をアルコール消毒綿で消毒した。100μLの細胞懸濁液をひ腹に皮下注射した。
図1および表3に示されるように、ビヒクルで処置された18日後のマウスと比べて、抗−muPD−1抗体の週2回のIP処置と組み合わせたアパチニブメシル酸塩(300mg/kg)の毎日の経口処置を受けた動物において、腫瘍成長阻害における統計的に非常に有意な差(p<0.0001)が見られた。一方、18、22、25日目に抗−muPD−1抗体対ビヒクルで処置された群間の腫瘍成長阻害に有意差はなかった。これらの結果は、ビヒクル群に対するDunnetの比較試験を使用した、二元配置分散分析(メインカラム効果)の分析に基づく。図2に示されるように、全投与期間に実験群の有意な体重減少はなかった。
リボセラニブ/ニボルマブ併用療法の進行中第I/II相臨床試験
全体設計:切除不能または転移性の癌を患う患者における進行中のニボルマブ処置に、リボセラニブを追加することの安全性、耐容性、および有効性を評価するための第I試験。
古典的3+3用量漸増を完了し(パート1)、試験は延長期間で現在進行中である(パート2)。我々は安全性と予備的な有効性評価を本明細書に示す。
リボセラニブ/ペンブロリズマブの併用療法の進行中の第I/II相臨床試験
全体設計:第2以降のライン設定においてペンブロリズマブへの感度を改善するための、第I/II相の非無作為化された非盲検の試験および進行性の悪性病変を有する患者に投与されたリボセラニブの有効性。
・奏効率;
・臨床的有用率による奏効率;
・無増悪生存期間;
・全生存期間;
・有害事象および重篤な有害事象
の観点から、組み合わせの有効性を決定することである。
・局所進行性あるいは転移性の尿路上皮癌(第1ラインのプラチナ製剤ベースの化学療法を受けた第2ライン以降の設定のみ);
・切除不能あるいは転移性のマイクロサテライト不安定性−フルオロピリミジン、オキサリプラチン、およびイリノテカンを用いる処置後に進行した大腸癌を含む、事前の処置中または処置後に進行し、ならびに、満足な代替的処置オプションがない、高度なあるいはミスマッチ修復機構欠損固形腫瘍;
・フルオロピリミジン含有化学療法およびプラチナ含有化学療法、ならびに適切な場合はHER2/neu標的治療を含む2回以上の全身療法以降に進行した再発性の局所進行性あるいは転移性の胃腺癌または胃食道接合部腺癌。
Claims (123)
- 癌を処置するための方法であって、
a)リボセラニブあるいはその薬学的に許容可能な塩;および、
b)ペンブロリズマブ、
を投与する工程を含む、方法。 - 癌を処置するための方法であって、
a)リボセラニブあるいはその薬学的に許容可能な塩;および、
b)ニボルマブ、
を投与する工程を含む、方法。 - リボセラニブの薬学的に許容可能な塩を投与する工程を含む、請求項1または2に記載の方法。
- リボセラニブの薬学的に許容可能な塩は、メシル酸塩である、請求項3に記載の方法。
- リボセラニブは、100mg〜1000mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは、150mg〜800mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは、200mg〜700mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは700mg未満の量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは約200mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは約300mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは約400mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは約500mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは約600mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは約685mgの量で投与される、請求項1−3のいずれか1つに記載の方法。
- リボセラニブの1日総投与量は700mg未満である、請求項1−3のいずれか1つに記載の方法。
- リボセラニブの1日総投与量は685mg未満である、請求項1−3のいずれか1つに記載の方法。
- リボセラニブは経口的に投与される、請求項1−16のいずれか1つに記載の方法。
- リボセラニブは、乾燥粉末、液体、カプセル、ペレット、あるいは錠剤として投与される、請求項1−16のいずれか1つに記載の方法。
- リボセラニブは錠剤として投与される、請求項1−16のいずれか1つに記載の方法。
- 錠剤はフィルムコーティング錠剤である、請求項19に記載の方法。
- 錠剤は約100mgの量のリボセラニブを含む、請求項19に記載の方法。
- 錠剤は約200mgの量のリボセラニブを含む、請求項19に記載の方法。
- 錠剤はさらに、α化デンプン、微結晶性セルロース、デンプングリコール酸ナトリウム、ポビドン(K−30)、コロイド状二酸化ケイ素、ステアリン酸マグネシウム、およびオパドライホワイトの1つ以上を含む、請求項19に記載の方法。
- リボセラニブは1日1回投与される、請求項1−23のいずれか1つに記載の方法。
- リボセラニブは1日2回投与される、請求項1−23のいずれか1つに記載の方法。
- ペンブロリズマブを投与する工程を含む、請求項1−23のいずれか1つに記載の方法。
- 約200mgの投与量でペンブロリズマブを投与する工程を含む、請求項1〜23のいずれか1つに記載の方法。
- ペンブロリズマブは150mg−250mgの投与量で投与される、請求項1に記載の方法。
- ペンブロリズマブは経口的にあるいは非経口的に投与される、請求項1に記載の方法。
- ペンブロリズマブは非経口的に投与される、請求項1に記載の方法。
- 非経口投与は静脈内、皮内、筋肉内、あるいは皮下の投与から選択される、請求項30に記載の方法。
- ペンブロリズマブは静脈内に投与される、請求項1に記載の方法。
- ペンブロリズマブはリボセラニブの投与後に投与される、請求項1に記載の方法。
- ペンブロリズマブはリボセラニブの投与の約1時間後に投与される、請求項1に記載の方法。
- ペンブロリズマブは1時間未満にわたって投与される、請求項1に記載の方法。
- ペンブロリズマブは約1時間にわたって投与される、請求項1に記載の方法。
- ペンブロリズマブは30−60分にわたって投与される、請求項1に記載の方法。
- ペンブロリズマブは週に1回以下投与される、請求項1に記載の方法。
- ペンブロリズマブは少なくとも週に1回投与される、請求項1に記載の方法。
- ペンブロリズマブは週に1回投与される、請求項1に記載の方法。
- ペンブロリズマブは3週間毎に投与される、請求項1に記載の方法。
- ペンブロリズマブは月に1回投与される、請求項1に記載の方法。
- ペンブロリズマブは月に2回投与される、請求項1に記載の方法。
- ペンブロリズマブは月に3回投与される、請求項1に記載の方法。
- ニボルマブを投与する工程を含む、請求項2に記載の方法。
- 約240mgの投与量でニボルマブを投与する工程を含む、請求項2に記載の方法。
- ニボルマブは200mg−300mgの投与量で投与される、請求項2に記載の方法。
- ニボルマブは、経口的にあるいは非経口的に投与される、請求項2に記載の方法。
- ニボルマブは非経口的に投与される、請求項2に記載の方法。
- 非経口投与は静脈内、皮内、筋肉内、あるいは皮下の投与から選択される、請求項49に記載の方法。
- ニボルマブは静脈内に投与される、請求項2に記載の方法。
- ニボルマブはリボセラニブの投与後に投与される、請求項2に記載の方法。
- ニボルマブはリボセラニブの投与の約1時間後に投与される、請求項2に記載の方法。
- ニボルマブは1時間未満にわたって投与される、請求項2に記載の方法。
- ニボルマブは約1時間にわたって投与される、請求項2に記載の方法。
- ニボルマブは30−60分にわたって投与される、請求項2に記載の方法。
- ニボルマブは週に1回以下投与される、請求項2に記載の方法。
- ニボルマブは少なくとも週に1回投与される、請求項2に記載の方法。
- ニボルマブは2週間毎投与される、請求項2に記載の方法。
- ニボルマブは週に1回投与される、請求項2に記載の方法。
- ニボルマブは月に1回投与される、請求項2に記載の方法。
- ニボルマブは月に2回投与される、請求項2に記載の方法。
- ニボルマブは月に3回投与される、請求項2に記載の方法。
- 癌は、肺癌、小細胞肺癌、非小細胞肺癌、細胞腫、リンパ腫、芽細胞腫、肉腫、白血病、乳癌、前立腺癌、結腸癌、扁平上皮癌、消化器癌、膵臓癌、子宮頚癌、卵巣癌、腹膜癌、肝臓癌、例えば、肝癌、膀胱癌、大腸癌、子宮内膜癌、腎癌、および、甲状腺癌から選択される、請求項1−63のいずれか1つに記載の方法。
- 癌は黒色腫または非小細胞肺癌である、請求項1に記載の方法。
- 癌は非小細胞肺癌、進行性の小細胞肺癌、転移性黒色腫、腎癌(腎細胞癌)、進行性の腎細胞癌、扁平上皮癌、肝臓癌(肝細胞癌)、膀胱癌(尿路上皮癌)、結腸癌、あるいはホジキンリンパ腫である、請求項2に記載の方法。
- 放射線照射療法を施す工程をさらに含む、請求項1−65のいずれか1つに記載の方法。
- 癌は病変を含む、請求項1−67のいずれか1つに記載の方法。
- 病変は、処置の前、および、処置の間あるいは処置の後のいずれか、あるいはその両方に測定される、請求項68に記載の方法。
- 病変はコンピュータ断層撮影または磁気共鳴画像法を使用して、放射線学的評価によって測定される、請求項69に記載の方法。
- 病変は処置の後にサイズを減少させた、請求項68に記載の方法。
- 病変は少なくとも10%サイズを減少させた、請求項68に記載の方法。
- 病変は少なくとも20%サイズを減少させた、請求項68に記載の方法。
- 病変は少なくとも50%サイズを減少させた、請求項68に記載の方法。
- 病変は少なくとも75%サイズを減少させた、請求項68に記載の方法。
- a)チロシンキナーゼ阻害剤あるいはその薬学的に許容可能な塩、および、
b)免疫療法剤あるいはその薬学的に許容可能な塩、
の組み合わせを投与する工程を含む、癌を処置するための方法。 - チロシンキナーゼ阻害剤は、血管内皮増殖因子受容体(VEGF)阻害剤である、請求項76に記載の方法。
- チロシンキナーゼ阻害剤は、選択的な血管内皮増殖因子受容体−2(VEGF2)阻害剤である、請求項77に記載の方法。
- チロシンキナーゼ阻害剤は、アファチニブ、アレクチニブ、アパチニブ、アキシチニブ、ボスチニブ、ブリガチニブ、カネルチニブ、クリゾチニブ、セリチニブ、ダサチニブ、ダヌセルチブ、ダブラフェニブ、エルロチニブ、ゲフィチニブ、イブルチニブ、イマチニブ、ラパチニブ、レンバチニブ、ネラチニブ、ニロチニブ、ニンテダニブ、オシメルチニブ、パルボシクリブ、パゾパニブ、ペガプタニブ、ポナチニブ、レバスチニブ、レゴラフェニブ、リボシクリブ、リボセラニブ、ルキソリチニブ、セマキシニブ、ソラフェニブ、スニチニブ、チボザニブ、トラメチニブ、トファシチニブ、バンデタニブ、バタラニブ、ベムラフェニブ、あるいはビスモデギブである、請求項76に記載の方法。
- チロシンキナーゼ阻害剤はリボセラニブである、請求項79に記載の方法。
- チロシンキナーゼ阻害剤はリボセラニブメシル酸塩である、請求項80に記載の方法。
- チロシンキナーゼ阻害剤は、150mg−800mgの量で投与される、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は、200mg−700mgの量で投与される、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は700mg未満の量で投与される、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は約200mgの量で投与される、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は約300mgの量で投与される、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は約400mgの量で投与される、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は約500mgの量で投与される、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は約600mgの量で投与される、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤の1日総投与量は700mg未満である、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤の1日総投与量は685mg未満である、請求項76−81のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は経口的に投与される、請求項76−91のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は錠剤として投与される、請求項76−92のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は1日1回投与される、請求項76−93のいずれか1つに記載の方法。
- チロシンキナーゼ阻害剤は1日2回投与される、請求項76−93のいずれか1つに記載の方法。
- 免疫療法剤はPD−1阻害剤である、請求項76−93のいずれか1つに記載の方法。
- PD−1阻害剤は、ニボルマブ(オプジーボ(登録商標))、ペンブロリズマブ(キイトルーダ(登録商標))、MEDI0680(AMP−514)、AMP−224、AMP−514(Amplimmune)、BGB−A317、PDR001、REGN2810、JS001、AGEN2034、およびその変異体とバイオシミラーである、請求項96に記載の方法。
- PD−1阻害剤は、ニボルマブ(オプジーボ(登録商標))、ペンブロリズマブ(キイトルーダ(登録商標))、および、その変異体とバイオシミラーから選択される、請求項97に記載の方法。
- 免疫療法剤は200mg−300mgの投与量で投与される、請求項76−98のいずれか1つに記載の方法。
- 免疫療法剤は経口的にあるいは非経口的に投与される、請求項76−99のいずれか1つに記載の方法。
- 免疫療法剤は非経口的に投与される、請求項76−99のいずれか1つに記載の方法。
- 非経口投与は静脈内、皮内、筋肉内、あるいは皮下の投与から選択される、請求項76−99のいずれか1つに記載の方法。
- 免疫療法剤は静脈内に投与される、請求項76−99のいずれか1つに記載の方法。
- 免疫療法剤はチロシンキナーゼ阻害剤の投与後に投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤はチロシンキナーゼ阻害剤の投与の約1時間後に投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は1時間未満にわたって投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は約1時間にわたって投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は30−60分にわたって投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は週に1回以下投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は少なくとも週に1回投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は2週間毎に投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は週に1回投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は月に1回投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は月に2回投与される、請求項76−103のいずれか1つに記載の方法。
- 免疫療法剤は月に3回投与される、請求項76−103のいずれか1つに記載の方法。
- a)リボセラニブあるいはその薬学的に許容可能な塩;および、
b)80mg/m2以下のペンブロリズマブ、
の組み合わせを投与する工程を含む、癌を処置するための方法。 - a)685mg以下のリボセラニブあるいはその薬学的に許容可能な塩;および、
b)ペンブロリズマブ、
の組み合わせを投与する工程を含む、癌を処置するための方法。 - a)685mg以下のリボセラニブあるいはその薬学的に許容可能な塩;および、
b)80mg/m2以下のペンブロリズマブ、
の組み合わせを投与する工程を含む、癌を処置するための方法。 - a)リボセラニブあるいはその薬学的に許容可能な塩;および、
b)ペンブロリズマブ、
の組み合わせを投与する工程を含む、癌を処置するための方法であって、
リボセラニブとペンブロリズマブは相乗的に作用する、方法。 - a)リボセラニブあるいはその薬学的に許容可能な塩;および、
b)80mg/m2以下のニボルマブ、
の組み合わせを投与する工程を含む、癌を処置するための方法。 - a)685mg以下のリボセラニブあるいはその薬学的に許容可能な塩;および、
b)ニボルマブ、
の組み合わせを投与する工程を含む、癌を処置するための方法。 - a)685mg以下のリボセラニブあるいはその薬学的に許容可能な塩;および、
b)80mg/m2以下のニボルマブ、
の組み合わせを投与する工程を含む、癌を処置するための方法。 - a)リボセラニブあるいはその薬学的に許容可能な塩;および、
b)ニボルマブ、
の組み合わせを投与する工程を含む、癌を処置するための方法であって、
リボセラニブとニボルマブは相乗的に作用する、方法。
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