TWI818120B - 藉由免疫檢查點阻礙藥與folfirinox療法之併用的癌症治療 - Google Patents
藉由免疫檢查點阻礙藥與folfirinox療法之併用的癌症治療 Download PDFInfo
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- TWI818120B TWI818120B TW108142901A TW108142901A TWI818120B TW I818120 B TWI818120 B TW I818120B TW 108142901 A TW108142901 A TW 108142901A TW 108142901 A TW108142901 A TW 108142901A TW I818120 B TWI818120 B TW I818120B
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Abstract
本發明之課題在於提供一種針對癌症、尤其是既有療法難以治療之癌症之新穎治療法。
本發明之發明人等經過潛心研究,結果發現使免疫檢查點阻礙藥與FOLFIRINOX療法、改良FOLFIRINOX療法或其等之減量方案組合處方之治療法能夠成為有效之癌症治療法。
尤其是期待藉由本發明而提供一種針對難治性癌症之一且為既有療法難以治療之胰臟癌的新穎治療法。
Description
本發明係關於一種藉由免疫檢查點阻礙藥與FOLFIRINOX療法之併用的癌症治療法。
FOLFIRINOX療法(以下,有時簡稱為「FFX療法」)係針對無法治癒切除之胰臟癌患者進行之標準治療之一。然而,已知有高頻度地引起骨髓抑制、噁心或嘔吐等不良事件的情況,為了減輕不良事件,亦進行使其投予量減量之改良(modified)FOLFIRINOX療法(以下,有時簡稱為「mFFX療法」)。
近年來,與化學療法等先前之治療法不同,藉由作用於癌症患者自身原本所具備之免疫監視機制,強化對於癌症之免疫力,從而對其進展進行抑制以及治療的癌症免疫療法正在受到關注。尤其是針對PD-1(Programmed Cell Death-1,程式性細胞死亡受體-1)或者作為其配體之PD-L1(Programmed Cell Death Ligand-1,程式性細胞死亡配體-1)等免疫檢查點分子群之阻礙藥、所謂免疫檢查點阻礙藥(以下,有時簡稱為「免疫CP阻礙藥」)於臨床上達成一定成果。
作為癌症治療中之該等治療法之組合,併用FFX療法、抗PD-1抗體納武單抗(Nivolumab)及放射線治療之術前療法正在以無轉移之胰臟癌患者為對象於臨床進行試驗(非專利文獻1)。
先前技術文獻
非專利文獻
非專利文獻1:ClinicalTrials.gov,“Losartan and Nivolumab in Combination With FOLFIRINOX and SBRT in Localized Pancreatic Cancer”,網際網路<URL:https://clinicaltrials.gov/ct2/show/NCT03563248>
[發明所欲解決之問題]
本發明之目的在於提供一種癌症之新穎治療法。
[解決問題之技術手段]
本發明之發明人等經過潛心研究,結果發現使免疫檢查點阻礙藥與FOLFIRINOX療法或其減量方案組合處方之治療法能夠成為有效之癌症治療法,從而完成本發明。
即,本發明如下所述。
[1]一種癌症之進展抑制、復發抑制及/或治療劑,其含有免疫檢查點阻礙物質(以下,有時簡稱為「免疫CP阻礙物質」)作為有效成分,其特徵在於與FFX療法或其減量方案組合進行投予;
[2]如上述[1]記載之劑,其特徵在於以該免疫CP阻礙物質計,以1次約1~10 mg/kg(體重)或者1次約200~1200 mg間隔約2~4週進行投予;
[3]如上述[1]或[2]記載之劑,其特徵在於以該免疫CP阻礙物質計,1次投予1 mg/kg、2 mg/kg、3 mg/kg、4 mg/kg、5 mg/kg、6 mg/kg、7 mg/kg、8 mg/kg、9 mg/kg或10 mg/kg(體重);
[4]如上述[1]或[2]記載之劑,其特徵在於以該免疫CP阻礙物質計,1次投予200 mg、240 mg、250 mg、280 mg、300 mg、320 mg、350 mg、360 mg、400 mg、420 mg、450 mg、480 mg、500 mg、540 mg、560 mg、600 mg、640 mg、700 mg、720 mg、750 mg、800 mg、840 mg、900 mg、1000 mg、1080 mg、1100 mg、1120 mg或1200 mg;
[5]如上述[1]至[4]中任一項記載之劑,其特徵在於使該免疫CP阻礙物質間隔2週、3週或4週進行投予;
[6]如上述[1]至[5]中任一項記載之劑,其中免疫CP阻礙物質歷時約30分鐘至約60分鐘或者60分鐘以上進行靜脈內投予;
[7]如上述[1]至[6]中任一項記載之劑,其中該免疫CP阻礙物質係抗PD-1抗體、抗PD-L1抗體或抗CTLA-4抗體;
[8]如上述[1]至[6]中任一項記載之劑,其中該免疫CP阻礙物質係抗PD-1抗體;
[9]如上述[8]記載之劑,其中該抗PD-1抗體係納武單抗、西米單抗(Cemiplimab)、帕博利珠單抗(Pembrolizumab)、Spartalizumab、替雷利珠單抗(Tislelizumab)、AMP-514、Dostarlimab、特瑞普利單抗(Toripalimab)、卡瑞利珠單抗(Camrelizumab)、傑諾單抗(Genolimzumab)、信迪利單抗(Sintilimab)、STI-A1110、ENUM 388D4、ENUM 244C8、GLS010、MGA012、AGEN2034、CS1003、HLX10、BAT-1306、AK105、AK103、BI 754091、LZM009、CMAB819、Sym021、GB226、SSI-361、JY034、HX008、ISU106、ABBV181、BCD-100、PF-06801591、CX-188、JNJ-63723283或AB122;
[10]如上述[7]記載之劑,其中該免疫CP阻礙物質係抗PD-L1抗體,且該抗PD-L1抗體係阿特珠單抗(Atezolizumab)、阿維魯單抗(Avelumab)、度伐魯單抗(Durvalumab)、BMS-936559、STI-1014、KN035、LY3300054、HLX20、SHR-1316、CS1001、MSB2311、BGB-A333、KL-A167、CK-301、AK106、AK104、ZKAB001、FAZ053、CBT-502、JS003或CX-072;
[11]如上述[7]記載之劑,其中該免疫CP阻礙物質係抗CTLA-4抗體,且該抗CTLA-4抗體係伊匹單抗(Ipilimumab)、AGEN1884或曲美木單抗(Tremelimumab);
[12]如上述[8]記載之劑,其中該抗PD-1抗體係納武單抗;
[13]如上述[8]記載之劑,其中該抗PD-1抗體係帕博利珠單抗;
[14]如上述[8]記載之劑,其中該抗PD-1抗體係西米單抗;
[15]如上述[10]記載之劑,其中該抗PD-L1抗體係阿維魯單抗;
[16]如上述[10]記載之劑,其中該抗PD-L1抗體係阿特珠單抗;
[17]如上述[10]記載之劑,其中該抗PD-L1抗體係度伐魯單抗;
[18]如上述[11]記載之劑,其中該抗CTLA-4抗體係伊匹單抗;
[19]如上述[12]記載之劑,其特徵在於作為納武單抗,以1次3 mg/kg(體重)或者1次240 mg間隔2週,或以1次480 mg間隔4週進行投予;
[20]如上述[12]記載之劑,其特徵在於作為納武單抗,以1次480 mg間隔4週進行投予;
[21]如上述[12]記載之劑,其特徵在於作為納武單抗,以1次480 mg間隔4週,歷時約30分鐘進行靜脈內投予;
[22]如上述[13]記載之劑,其特徵在於作為帕博利珠單抗,以1次2 mg/kg(體重)或1次200 mg間隔3週進行投予;
[23]如上述[14]記載之劑,其特徵在於作為西米單抗,以1次350 mg間隔3週進行投予;
[24]如上述[15]記載之劑,其特徵在於作為阿維魯單抗,以1次10 mg/kg(體重)間隔2週進行投予;
[25]如上述[16]記載之劑,其特徵在於作為阿特珠單抗,以1次1200 mg間隔3週進行投予;
[26]如上述[17]記載之劑,其特徵在於作為度伐魯單抗,以1次10 mg/kg(體重)間隔2週進行投予;
[27]如上述[18]記載之劑,其特徵在於作為伊匹單抗,以1次3 mg/kg(體重)或1次1 mg/kg(體重)間隔3週進行4次靜脈內投予;
[28]如上述[1]至[27]中任一項記載之劑,其以與FFX療法組合進行投予為特徵,且該FFX療法中,於使奧沙利鉑(以下,簡稱為「L-OHP」)85 mg/m2
歷時2小時進行靜脈內投予後,使左亞葉酸鈣(以下,簡稱為「I-LV」)200 mg/m2
歷時2小時進行靜脈內投予,自I-LV之投予開始30分鐘後,使鹽酸愛萊諾迪肯水合物(以下,簡稱為「CPT-11」)180 mg/m2
歷時1.5小時進行靜脈內投予,進而,於I-LV之投予結束後,使5-FU 400 mg/m2
進行快速靜脈內投予,進而,使5-FU 2400 mg/m2
歷時46小時進行持續靜脈內投予,間隔2週實施該一系列之投予(以下,有時將「一系列之投予」之第2次以後之任一投予記載為「第2週期以後之任一投予」);
[29]如上述[28]記載之劑,其中於該FFX療法之第2週期以後之任一投予中,根據患者之副作用表現之程度,中止5-FU之快速靜脈內投予;
[30]如上述[28]或[29]記載之劑,其中於該FFX療法之第2週期以後之任一投予中,根據患者之副作用表現之程度,使L-OHP之投予量減量或中止投予;
[31]如上述[28]至[30]中任一項記載之劑,其中於該FFX療法之第2週期以後之任一投予中,根據患者之副作用表現之程度,使CPT-11之投予量減量或中止投予;
[32]如上述[28]至[31]中任一項記載之劑,其中於該FFX療法之第2週期以後之任一投予中,根據患者之副作用表現之程度,使供持續靜脈內投予之5-FU之投予量減量;
[33]如上述[28]記載之劑,其中於該FFX療法中,不實施5-FU之快速靜脈內投予;
[34]如上述[28]、[30]或[33]記載之劑,其中該FFX療法中之L-OHP之投予量、或者於該FFX療法之第2週期以後之任一投予中根據患者之副作用表現之程度減量之L-OHP之投予量為約65 mg/m2
、約50 mg/m2
或約85~約50 mg/m2
之間之任意投予量;
[35]如上述[28]、[31]、[33]或[34]記載之劑,其中該FFX療法中之CPT-11之投予量、或者於該FFX療法之第2週期以後之任一投予中根據患者之副作用表現之程度減量之CPT-11之投予量為約150 mg/m2
、約120 mg/m2
、約90 mg/m2
或約180~約90 mg/m2
之間之任意投予量;
[36]如上述[28]及[32]至[35]中任一項記載之劑,其中該FFX療法中供持續靜脈內投予之5-FU之投予量、或者於該FFX療法之第2週期以後之任一投予中根據患者之副作用表現之程度減量之供持續靜脈內投予之5-FU之投予量為約1800 mg/m2
、約1200 mg/m2
或約2400~約1200 mg/m2
之間之任意投予量;
[37]如上述[1]至[27]中任一項記載之劑,其以與FFX療法之減量方案組合進行投予為特徵,且該FFX療法之減量方案係如下療法:於使L-OHP 85 mg/m2
歷時2小時進行靜脈內投予後,使I-LV 200 mg/m2
歷時2小時進行靜脈內投予,自I-LV投予開始30分鐘後,使CPT-11 150 mg/m2
歷時1.5小時進行靜脈內投予,進而,於I-LV之投予結束後,使5-FU 2400 mg/m2
歷時46小時進行靜脈內投予,間隔2週實施該一系列之投予(該減量方案相當於「mFFX療法」);
[38]如上述[37]記載之劑,其中上述[37]記載之FFX療法之減量方案之第2週期以後之任一投予中,根據患者之副作用表現之程度,使L-OHP之投予量減量或中止投予;
[39]如上述[37]或[38]記載之劑,其中於上述[37]記載之FFX療法之減量方案之第2週期以後之任一投予中,根據患者之副作用表現之程度,使CPT-11之投予量減量或中止投予;
[40]如上述[37]至[39]中任一項記載之劑,其中上述[37]記載之FFX療法之減量方案之第2週期以後之任一投予中,根據患者之副作用表現之程度使供持續靜脈內投予之5-FU之投予量減量;
[41]如上述[37]或[38]記載之劑,其中上述[37]記載之FFX療法之減量方案中之L-OHP之投予量、或者於該減量方案之第2週期以後之任一投予中根據患者之副作用表現之程度減量之L-OHP之投予量為約65 mg/m2
、約50 mg/m2
或約85~約50 mg/m2
之間之任意投予量;
[42]如上述[37]、[39]或[41]記載之劑,其中上述[37]記載之FFX療法之減量方案中之CPT-11之投予量、或者於該減量方案之第2週期以後之任一投予中根據患者之副作用表現之程度減量之CPT-11之投予量為約120 mg/m2
、約90 mg/m2
或約150~約90 mg/m2
之間之任意投予量;
[43]如上述[37]及[40]至[42]中任一項記載之劑,其中於上述[37]記載之FFX療法之減量方案中供持續靜脈內投予之5-FU之投予量、或者於該減量方案之第2週期以後之任一投予中根據患者之副作用表現之程度減量之供持續靜脈內投予之5-FU之投予量為約1800 mg/m2
、約1200 mg/m2
或約2400~約1200 mg/m2
之間之任意投予量;
[44]如上述[1]至[43]中任一項記載之劑,其中當於同一天實施免疫CP阻礙物質投予與FFX療法或其減量方案之情形時,首先投予該免疫CP阻礙物質,於該免疫CP阻礙物質投予結束後經過至少約30分鐘後,開始FFX療法或其減量方案;
[45]如上述[1]至[44]中任一項記載之劑,其中首先於同一天實施免疫CP阻礙物質投予與FFX療法或其減量方案;
[46]如上述[28]至[45]中任一項記載之劑,其中根據被該FFX療法或其減量方案處方之患者之副作用表現之程度,暫時性地或者持續性地間隔3週或間隔4週實施第2週期以後之任一該一系列之投予;
[47]如上述[1]至[46]中任一項記載之劑,其中癌症係實體癌或血液癌;
[48]如上述[47]記載之劑,其中癌症係實體癌,且該實體癌係選自惡性黑色素瘤(例如,皮膚、口腔黏膜上皮或眼窩內等中之惡性黑色素瘤)、非小細胞肺癌(例如,鱗狀非小細胞肺癌及非鱗狀非小細胞肺癌)、小細胞肺癌、頭頸癌(例如,口腔癌、上咽癌、中咽癌、下咽癌、喉頭癌、鼻咽癌、唾液腺癌及舌癌)、腎細胞癌(例如,透明細胞型腎細胞癌)、乳癌、卵巢癌(例如,漿液性卵巢癌及卵巢透明細胞腺癌)、子宮癌(例如,子宮頸癌及子宮體癌)、肛門癌(例如,肛管癌)、大腸癌、直腸癌、結腸癌、肝細胞癌、食道癌、胃癌、食道胃結合部癌、胰臟癌(例如,胰管癌、胰島素瘤及胰管內乳頭狀黏液性腫瘤)、尿路上皮癌(例如,膀胱癌、上尿路癌、輸尿管癌、腎盂癌及尿道癌)、前列腺癌、輸卵管癌、原發性腹膜癌、惡性胸膜間皮瘤、膽道癌(例如,膽囊癌、膽管癌及乳頭部癌)、皮膚癌(例如,葡萄膜惡性黑色素瘤及梅克爾細胞癌)、睾丸癌(胚細胞腫瘤)、陰道癌、外陰癌、陰莖癌、小腸癌、內分泌系統癌、甲狀腺癌、甲狀旁腺癌、腎上腺癌、脊椎腫瘤、神經母細胞瘤、髓母細胞瘤、視網膜母細胞瘤、神經內分泌腫瘤、腦腫瘤(例如,神經膠質瘤(例如,神經膠母細胞瘤及神經膠質肉瘤)及腦膜瘤)及鱗狀細胞癌之1種以上之癌症;
[49]如上述[47]記載之劑,其中癌症係實體癌,且該實體癌係骨/軟組織肉瘤(例如,尤因氏肉瘤、小兒橫紋肌肉瘤、子宮平滑肌肉瘤、軟骨肉瘤、肺肉瘤、骨肉瘤及先天性纖維肉瘤)或卡波西肉瘤;
[50]如上述[47]記載之劑,其中癌症係血液癌,且該血液癌係選自多發性骨髓瘤、惡性淋巴瘤(例如,非霍奇金淋巴瘤(例如,濾泡性淋巴瘤、彌漫性大B細胞性淋巴瘤、MALT淋巴瘤、淋巴漿細胞性淋巴瘤、蕈狀肉芽腫、塞紮里氏綜合症、慢性或者急性淋巴細胞性白血病、外周性T細胞淋巴瘤、結外性NK/T細胞淋巴瘤、成人T細胞白血病、B細胞淋巴母細胞性白血病、T細胞淋巴母細胞性白血病及淋巴漿細胞性淋巴瘤)及霍奇金淋巴瘤(例如,經典霍奇金淋巴瘤及結節性淋巴細胞優勢型霍奇金淋巴瘤))、白血病(例如,急性骨髓性白血病及慢性骨髓性白血病)、中樞神經系統原發惡性淋巴瘤、骨髓化生不良綜合症及骨髓增生綜合症之1種以上之癌症;
[51]如上述[1]至[46]中任一項記載之劑,其中癌症係小兒癌症或原發不明癌症;
[52]如上述[47]記載之劑,其中癌症係實體癌,且該實體癌係胰臟癌或膽道癌;
[53]如上述[47]記載之劑,其中癌症係實體癌,且該實體癌係胰臟癌(以下,有時將「胰臟癌」記載為「胰癌」);
[54]如上述[53]記載之劑,其中胰臟癌係胰管癌、胰島素瘤或胰管內乳頭狀黏液性腫瘤;
[55]如上述[1]至[54]中任一項記載之劑,其以抗癌藥之治療效果不充分或者不夠之癌症作為對象;
[56]如上述[1]至[55]中任一項記載之劑,其以於抗癌藥之治療後發生惡化之癌症作為對象;
[57]如上述[1]至[54]中任一項記載之劑,其以無抗癌藥之治療經歷之癌症患者作為對象;
[58]如上述[1]至[57]中任一項記載之劑,其以無法根治或者切除、轉移性、復發性、難治性及/或遠處轉移性之癌症作為對象;
[59]如上述[1]至[46]中任一項記載之劑,其以無抗癌藥之治療經歷且具有遠處轉移之胰臟癌患者作為對象;
[60]如上述[55]至[57]及[59]中任一項記載之劑,其中上述[55]至[57]及[59]記載之抗癌藥係選自烷基化藥、鉑製劑、代謝拮抗劑(例如,葉酸代謝拮抗藥、吡啶代謝阻礙藥、嘌呤代謝阻礙藥)、核糖核苷酸還原酶阻礙藥、核苷酸類似物、拓樸異構酶阻礙藥、微管聚合阻礙藥、微管解聚阻礙藥、抗腫瘤性抗生素、細胞激素製劑、抗激素藥、分子靶向藥及癌症免疫治療藥之1種以上之藥劑;
[61]如上述[1]至[60]中任一項記載之劑,其以於腫瘤組織內之腫瘤細胞之中表現PD-L1之腫瘤細胞所占之比率(「Tumor Proportion Score,腫瘤比例分數」:以下,簡稱為「TPS」)為50%以上、25%以上、10%以上、5%以上或1%以上之癌症作為對象;
[62]如上述[1]至[60]中任一項記載之劑,其以TPS未達50%、未達25%、未達10%、未達5%或未達1%之癌症作為對象;
[63]如上述[1]至[60]中任一項記載之劑,其以使腫瘤組織內之各腫瘤細胞、淋巴細胞及巨噬細胞之中PD-L1陽性細胞數之合計除以該腫瘤組織中之總腫瘤細胞數並乘以100而得的數值(「Combined Positive Score,陽性聯合分數」:以下,簡稱為「CPS」)為20%以上、10%以上、5%以上或1%以上之癌症作為對象;
[64]如上述[1]至[60]中任一項記載之劑,其以CPS未達20%、未達10%、未達5%或未達1%之癌症作為對象;
[65]如上述[1]至[64]中任一項記載之劑,其以具有高頻度微隨體不穩定性(以下,簡稱為「MSI-H」)及/或錯配修復缺陷(以下,簡稱為「dMMR」)之癌症作為對象;
[66]如上述[1]至[64]中任一項記載之劑,其以不具有MSI-H及/或dMMR、或者具有低頻度微隨體不穩定性(以下,簡稱為「MSI-L」)之癌症作為對象;
[67]如上述[1]至[66]中任一項記載之劑,其以腫瘤突變負荷(以下,簡稱為「TMB」)為高頻度(每106
個鹼基之變異數為10個以上)之癌症作為對象;
[68]如上述[1]至[66]中任一項記載之劑,其以TMB為低頻度(每106
個鹼基之變異數未達10個)之癌症作為對象;
[69]如上述[1]至[68]中任一項記載之劑,其僅與FFX療法或其減量方案組合進行投予;
[70]如上述[1]至[68]中任一項記載之劑,其不進而與放射線療法併用;
[71]如上述[1]至[68]中任一項記載之劑,其不作為術前療法處方;
[72]如上述[1]至[68]中任一項記載之劑,其進而與其他抗癌藥併用;
[73]如上述[72]記載之劑,其中其他抗癌藥係選自烷基化藥、鉑製劑、代謝拮抗劑(例如,葉酸代謝拮抗藥、吡啶代謝阻礙藥、嘌呤代謝阻礙藥)、核糖核苷酸還原酶阻礙藥、核苷酸類似物、拓樸異構酶阻礙藥、微管聚合阻礙藥、微管解聚阻礙藥、抗腫瘤性抗生素、細胞激素製劑、抗激素藥、分子靶向藥及癌症免疫治療藥之1種以上之藥劑;
[74]一種含有納武單抗作為有效成分之胰臟癌之進展抑制、復發抑制及/或治療劑,其以僅與FFX療法之減量方案組合進行投予為特徵,且以該納武單抗計,以1次480 mg間隔4週,歷時30分鐘進行靜脈內投予,於該減量方案中,使L-OHP 85 mg/m2
歷時2小時進行靜脈內投予後,使I-LV 200 mg/m2
歷時2小時進行靜脈內投予,自I-LV投予開始30分鐘後,使CPT-11 150 mg/m2
歷時1.5小時進行靜脈內投予,進而,於I-LV之投予結束後,使5-FU 2400 mg/m2
歷時46小時進行靜脈內投予,間隔2週實施該一系列之投予;
[75]如上述[74]記載之劑,其中該胰臟癌係無抗癌藥之治療經歷且具有遠處轉移之胰臟癌;
[76]如上述[74]或[75]記載之劑,其中當於同一天實施該納武單抗投予與上述[74]記載之減量方案之情形時,首先投予該納武單抗,於該納武單抗投予結束後經過至少約30分鐘後,開始該減量方案;
[77]如上述[74]至[76]中任一項記載之劑,其中首先於同一天實施免疫CP阻礙物質投予與上述[74]記載之減量方案;
[1-1]一種免疫CP阻礙物質或免疫CP阻礙藥,其與FFX療法或其減量方案組合進行投予,用於癌症之進展抑制、復發抑制及/或治療;
[2-1]一種免疫CP阻礙物質之用途,其用於製造與FFX療法或其減量方案組合進行投予之癌症之進展抑制、復發抑制及/或治療劑;以及
[3-1]一種癌症之進展抑制、復發抑制及/或治療方法,其包括對患者投予FFX療法或其減量方案、及免疫CP阻礙物質或免疫CP阻礙藥。
本說明書包含作為本申請案之優先權之基礎的日本專利申請案號2018-220866號之揭示內容。
[發明之效果]
本發明提供一種尤其針對既有療法難以治療之癌症之新穎治療法。
本說明書中之「免疫檢查點阻礙藥」係指含有例如抗PD-1抗體(例如,納武單抗、西米單抗(REGN-2810)、帕博利珠單抗(MK-3475)、Spartalizumab(PDR-001)、替雷利珠單抗(BGB-A317)、AMP-514(MEDI0680)、Dostarlimab(ANB011/TSR-042)、特瑞普利單抗(JS001)、卡瑞利珠單抗(SHR-1210)、傑諾單抗(CBT-501)、信迪利單抗(IBI308)、STI-A1110、ENUM 388D4、ENUM 244C8、GLS010、MGA012、AGEN2034、CS1003、HLX10、BAT-1306、AK105、AK103、BI 754091、LZM009、CMAB819、Sym021、GB226、SSI-361、JY034、HX008、ISU106、ABBV181、BCD-100、PF-06801591、CX-188、JNJ-63723283及AB122等)、抗PD-L1抗體(例如,阿特珠單抗(RG7446/MPDL3280A)、阿維魯單抗(PF-06834635/MSB0010718C)、度伐魯單抗(MEDI4736)、BMS-936559、STI-1014、KN035、LY3300054、HLX20、SHR-1316、CS1001(WBP3155)、MSB2311、BGB-A333、KL-A167、CK-301、AK106、AK104、ZKAB001、FAZ053、CBT-502(TQB2450)、JS003及CX-072等)或抗CTLA-4抗體(例如,伊匹單抗(MDX-010)、AGEN1884及曲美木單抗等)等免疫檢查點阻礙物質作為有效成分之藥劑。
納武單抗可依據WO2006/121168中所記載之方法進行製造,帕博利珠單抗可依據WO2008/156712中所記載之方法進行製造,BMS-936559可依據WO2007/005874中所記載之方法進行製造,伊匹單抗可依據WO2001/014424中所記載之方法進行製造。
於本發明之治療法中,作為較佳之免疫CP阻礙物質,係抗PD-1抗體、抗PD-L1抗體及抗CTLA-4抗體,作為抗PD-1抗體,較佳為納武單抗、西米單抗、帕博利珠單抗、Spartalizumab、替雷利珠單抗、特瑞普利單抗、信迪利單抗及卡瑞利珠單抗,作為抗PD-L1抗體,較佳為阿特珠單抗、阿維魯單抗、度伐魯單抗及BMS-936559,作為抗CTLA-4抗體,較佳為伊匹單抗及曲美木單抗。進而,作為抗PD-1抗體,更佳為納武單抗、西米單抗及帕博利珠單抗,進而較佳為納武單抗。
本發明中之「FFX療法」係指藉由奧沙利鉑(L-OHP)、鹽酸愛萊諾迪肯水合物(CPT-11)、左亞葉酸鈣(I-LV)及氟尿嘧啶(5-FU)之4劑併用進行之癌症治療法,其係如下治療法:於使L-OHP 85 mg/m2
歷時2小時進行靜脈內投予後,使I-LV 200 mg/m2
歷時2小時進行靜脈內投予,自I-LV之投予開始30分鐘後,使CPT-11 180 mg/m2
歷時1.5小時進行靜脈內投予,進而,於I-LV之投予結束後,使5-FU 400 mg/m2
進行快速靜脈內投予,進而,使5-FU 2400 mg/m2
歷時46小時進行靜脈內投予,間隔2週實施該一系列之投予。
該FFX療法之「減量方案」係如下處方:使於該FFX療法中供投予之4劑之任一者之投予量自最初之投予開始進行減量,或者中止其投予本身,或根據因第1週期以後之任一投予而確認到之副作用表現之程度,於其後之第2週期以後之任一投予中進行減量,或者中止4劑之任一者之投予。作為其態樣,例如自最初之投予開始可不實施5-FU之快速靜脈內投予,L-OHP之投予量可為約65 mg/m2
、約50 mg/m2
或約85~約50 mg/m2
之間之任意投予量,CPT-11之投予量可為約150 mg/m2
、約120 mg/m2
、約90 mg/m2
或約180~約90 mg/m2
之間之任意投予量,供持續靜脈內投予之5-FU之投予量可為約1800 mg/m2
、約1200 mg/m2
或約2400~約1200 mg/m2
之間之任意投予量。
又,作為該減量方案之又一態樣,於該FFX療法中之第2週期以後之任一投予中,可根據患者之副作用表現之程度,中止5-FU之快速靜脈內投予,可根據患者之副作用表現之程度,使L-OHP之投予量減量至約65 mg/m2
、約50 mg/m2
或約85~約50 mg/m2
之間之任意投予量或中止L-OHP之投予,可根據患者之副作用表現之程度,使CPT-11之投予量減量至約150 mg/m2
、約120 mg/m2
、約90 mg/m2
或約180~約90 mg/m2
之間之任意投予量或中止CPT-11之投予,可使供持續靜脈內投予之5-FU之投予量根據患者之副作用表現之程度,減量至約1800 mg/m2
、約1200 mg/m2
或約2400~約1200 mg/m2
之間之任意投予量或中止該5-FU之投予。
再者,本說明書之實施例中,有時將鹽酸愛萊諾迪肯水合物簡稱為「愛萊諾迪肯」,又,同樣地有時將左亞葉酸鈣簡稱為「左亞葉酸鹽」。
又,作為該減量方案之另一態樣,亦可於使L-OHP 85 mg/m2
歷時2小時進行靜脈內投予後,使I-LV 200 mg/m2
歷時2小時進行靜脈內投予,自I-LV投予開始30分鐘後,使CPT-11 150 mg/m2
歷時1.5小時進行靜脈內投予,進而,於I-LV之投予結束後,使5-FU 2400 mg/m2
歷時46小時進行靜脈內投予,間隔2週實施該一系列之投予,尤其該減量方案作為改良FOLFIRINOX療法(mFFX療法)為人所知。
作為該mFFX療法之進一步之減量方案,例如,自最初之投予開始,L-OHP之投予量可為約65 mg/m2
、約50 mg/m2
或約85~約50 mg/m2
之間之任意投予量,CPT-11之投予量可為約120 mg/m2
、約90 mg/m2
或約150~約90 mg/m2
之間之任意投予量,供持續靜脈內投予之5-FU之投予量可為約1800 mg/m2
、約1200 mg/m2
或約2400~約1200 mg/m2
之間之任意投予量。
又,於該mFFX療法中之第2週期以後之任一投予中,可根據患者之副作用表現之程度,使L-OHP之投予量減量至約65 mg/m2
、約50 mg/m2
或約85~約50 mg/m2
之間之任意投予量或中止L-OHP之投予,可根據患者之副作用表現之程度,使CPT-11之投予量減量至約120 mg/m2
、約90 mg/m2
或約150~約90 mg/m2
之間之任意投予量或中止CPT-11之投予,可使供持續靜脈內投予之5-FU之投予量根據患者之副作用表現之程度,減量至約1800 mg/m2
、約1200 mg/m2
或約2400~約1200 mg/m2
之間之任意投予量或中止該5-FU之投予。
又,亦可使該FFX療法、該mFFX療法或其等之減量方案之一系列之投予間隔根據患者之副作用表現之程度暫時性地或者持續性地設定為間隔3週或間隔4週。
本說明書中,「放射線療法」係指照射放射線殺滅癌細胞之治療法,例如可列舉:強度調變放射線治療(IMRT)、圖像引導放射線治療(IGRT)、定位放射線治療(SRT)、軀體定位放射線治療(SBRT)、定位手術照射(SRS)、質子束治療及重粒子線治療以及密封小放射源治療等。
本發說明中,「術前療法」意指於術前先行進行藉由抗癌藥等之治療,主要以消除浸潤癌之手術後之微小轉移,預防復發為目的進行。
本說明書中之「本發明中之藥劑」或者「本發明之藥劑」中,除免疫CP阻礙藥以外,包括FFX療法、mFFX療法或其等之減量方案中所使用之含有奧沙利鉑、鹽酸愛萊諾迪肯水合物、左亞葉酸鈣及氟尿嘧啶之各有效成分之藥劑。又,本說明書中之「本發明中之治療法」或者「本發明之治療法」意指針對癌症患者之免疫CP阻礙藥與FFX療法、mFFX療法或其等之減量方案之併用療法。
本發明說明書中,「約」意指可在10%以內之範圍內低於或超過表示數值地進行變化。
[適用疾病及患者]
本發明中之藥劑或者治療法適用之癌症包括任意實體癌與血液癌,作為實體癌,例如可列舉:惡性黑色素瘤(例如,皮膚、口腔黏膜上皮或眼窩內等中之惡性黑色素瘤)、非小細胞肺癌(例如,鱗狀非小細胞肺癌及非鱗狀非小細胞肺癌)、小細胞肺癌、頭頸癌(例如,口腔癌、上咽癌、中咽癌、下咽癌、喉頭癌、鼻咽癌、唾液腺癌及舌癌)、腎細胞癌(例如,透明細胞型腎細胞癌)、乳癌、卵巢癌(例如,漿液性卵巢癌及卵巢透明細胞腺癌)、子宮癌(例如,子宮頸癌及子宮體癌)、肛門癌(例如,肛管癌)、大腸癌、直腸癌、結腸癌、肝細胞癌、食道癌、胃癌、食道胃結合部癌、胰臟癌(例如,胰管癌、胰島素瘤及胰管內乳頭狀黏液性腫瘤)、尿路上皮癌(例如,膀胱癌、上尿路癌、尿管癌、腎盂癌及尿道癌)、前列腺癌、輸卵管癌、原發性腹膜癌、惡性胸膜間皮瘤、膽道癌(例如,膽囊癌、膽管癌及乳頭部癌)、皮膚癌(例如,葡萄膜惡性黑色素瘤及梅克爾細胞癌)、睾丸癌(胚細胞腫瘤)、陰道癌、外陰癌、陰莖癌、小腸癌、內分泌系統癌、甲狀腺癌、甲狀旁腺癌、腎上腺癌、脊椎腫瘤、神經母細胞瘤、髓母細胞瘤、視網膜母細胞瘤、神經內分泌腫瘤、腦腫瘤(例如,神經膠質瘤(例如,神經膠母細胞瘤及神經膠肉瘤)及腦膜瘤)及鱗狀細胞癌等。
又,實體癌之中,作為肉瘤,可列舉:骨/軟組織肉瘤(例如,尤因氏肉瘤、小兒橫紋肌肉瘤、子宮平滑肌肉瘤、軟骨肉瘤、肺肉瘤、骨肉瘤、先天性纖維肉瘤)及卡波西肉瘤等。
又,作為血液癌,例如可列舉:多發性骨髓瘤、惡性淋巴瘤(例如,非霍奇金淋巴瘤(例如,濾泡性淋巴瘤、彌漫性大B細胞性淋巴瘤、MALT淋巴瘤、淋巴漿細胞性淋巴瘤、蕈狀肉芽腫、塞紮里氏綜合症、慢性或急性淋巴細胞性白血病、外周性T細胞淋巴瘤、結外性NK/T細胞淋巴瘤、成人T細胞白血病、B細胞淋巴母細胞性白血病、T細胞淋巴母細胞性白血病及淋巴漿細胞性淋巴瘤)及霍奇金淋巴瘤(例如,經典霍奇金淋巴瘤及結節性淋巴細胞優勢型霍奇金淋巴瘤))及白血病(例如,急性骨髓性白血病及慢性骨髓性白血病)、中樞神經系統原發惡性淋巴瘤、骨髓化生不良綜合症及骨髓增生綜合症等。
進而,本發明中之藥劑或者治療法適用之癌症亦包括小兒癌症及原發不明癌症。
作為本發明中之藥劑或者治療法適用之癌症,較適為胰臟癌及膽道癌,作為胰臟癌,較適為胰管癌、作為神經內分泌腫瘤之胰島素瘤及胰管內乳頭狀黏液性腫瘤。
本說明書中,癌症之「治療」例如包括為了(i)減少腫瘤細胞之增生、(ii)降低起因於癌症之症狀、(iii)提高癌症患者之生活質量、(iv)降低已經投予之其他抗癌藥或癌症治療輔助藥之用量、及/或(v)延長癌症患者之生存而進行的治療,癌症之「進展抑制」意指延緩癌症之進展,使與癌症相關之症狀穩定化及減退症狀之進展。又,癌症之「復發抑制」意指預防性地抑制藉由癌症治療或者切除手術使得其癌症病變完全地或者實質性地消除或者去除之患者之癌症之復發。
本發明之藥劑或者治療法有針對下述癌症患者處方之情況:即,(a)抗癌藥之治療效果不充分或者不夠之患者或者於抗癌藥治療後發生惡化之患者;(b)無法根治或者切除、轉移性、復發性、難治性及/或遠處轉移性之癌症之患者;(c)TPS為50%以上、25%以上、10%以上、5%以上或者1%以上之癌症之患者;(d)CPS為20%以上、10%以上、5%以上或者1%以上之癌症之患者;(e)具有MSI-H及/或dMMR之癌症之患者;(f)TMB為高頻度之癌症之患者。又,另一方面,本發明之藥劑或者治療法亦有更加要求針對下述癌症患者處方之情況:即,(g)無抗癌藥之治療經歷之患者;(h)TPS未達50%、未達25%、未達10%、未達5%或者未達1%之癌症之患者;(i)CPS未達20%、未達10%、未達5%或者未達1%之癌症之患者;(j)不具有MSI-H及/或dMMR、或者具有MSI-L之癌症之患者;或(k)TMB為低頻度之癌症之患者。尤其是作為要求本發明之藥劑或者治療法之處方之癌症患者,可列舉無抗癌藥之治療經歷及/或具有遠處轉移之癌症患者,尤其可列舉胰臟癌患者。此處,作為「抗癌藥」,例如可列舉:烷基化藥、鉑製劑、代謝拮抗劑(例如,葉酸代謝拮抗藥、吡啶代謝阻礙藥、嘌呤代謝阻礙藥)、核糖核苷酸還原酶阻礙藥、核苷酸類似物、拓樸異構酶阻礙藥、微管聚合阻礙藥、微管解聚阻礙藥、抗腫瘤性抗生素、細胞激素製劑、抗激素藥、分子靶向藥及癌症免疫治療藥以及分別分類於該等中之藥劑。例如,包括後述之[併用]項目中所列舉之各藥劑以及奧沙利鉑、鹽酸愛萊諾迪肯水合物、左亞葉酸鈣、氟尿嘧啶及分類於免疫CP阻礙藥中之藥劑。再者,一般而言,「抗癌藥」以與「化學療法藥」相同之含義使用。
[處方]
本發明中之免疫CP阻礙藥於與FFX療法、mFFX療法或其等之減量方案之併用中,可根據以下用法、用量進行投予。
例如,能夠以免疫CP阻礙藥之有效成分計,以1次約1~10 mg/kg(體重)或者1次約200~1200 mg間隔2~4週,歷時約30分鐘至約60分鐘或者約60分鐘以上進行靜脈內投予(例如,靜脈滴注)。此處,作為每1次投予之體重換算中之投予量,例如可列舉:1 mg/kg、2 mg/kg、3 mg/kg、4 mg/kg、5 mg/kg、6 mg/kg、7 mg/kg、8 mg/kg、9 mg/kg或10 mg/kg,另一方面,作為每1次投予之投予量,例如可列舉:200 mg、240 mg、250 mg、280 mg、300 mg、320 mg、350 mg、360 mg、400 mg、420 mg、450 mg、480 mg、500 mg、540 mg、560 mg、600 mg、640 mg、700 mg、720 mg、750 mg、800 mg、840 mg、900 mg、1000 mg、1080 mg、1100 mg、1120 mg或1200 mg。又,作為投予間隔,例如可列舉2週、3週或4週,作為1次之投予時間,例如可列舉約30分鐘、約60分鐘或約60分鐘以上。
於其有效成分係作為抗PD-1抗體之納武單抗之情形時,根據以下用法、用量進行投予。即,對於惡性黑色素瘤患者,以納武單抗計,以1次3 mg/kg(體重)間隔2週或以1次2 mg/kg(體重)間隔3週進行靜脈滴注投予,對於非小細胞肺癌、腎細胞癌、經典霍奇金淋巴瘤、頭頸癌、胃癌及惡性胸膜間皮瘤之各患者,以納武單抗計,以1次3 mg/kg(體重)間隔2週進行靜脈滴注投予。又,作為另一用法、用量,例如,對於惡性黑色素瘤、非小細胞肺癌、腎細胞癌、尿路上皮癌、MSI-H或dMMR陽性大腸癌(亦包括12歲以上之小兒患者)、胃癌、肝細胞癌、小細胞肺癌及惡性胸膜間皮瘤之各患者,以納武單抗計,以1次240 mg間隔2週、或者以1次480 mg間隔4週進行靜脈滴注投予。進而,作為另一用法、用量,例如,對於惡性黑色素瘤患者,有時於與伊匹單抗之併用中,以納武單抗計,以1次1 mg/kg(體重)間隔3週進行4次靜脈滴注,其後,以納武單抗計,以1次3 mg/kg(體重)間隔2週進行靜脈滴注,或者以納武單抗計,以1次80 mg間隔3週進行4次靜脈滴注,其後,以納武單抗計,以1次240 mg間隔2週進行靜脈滴注。又,例如,對於腎細胞癌症患者,亦有時於與伊匹單抗之併用中,以納武單抗計,以1次240 mg間隔3週進行4次靜脈滴注,其後,以納武單抗計,以1次240 mg間隔2週進行靜脈滴注。又,於同樣作為抗PD-1抗體之帕博利珠單抗之情形時,根據以下用法、用量進行投予。即,對於惡性黑色素瘤、非小細胞肺癌、經典霍奇金淋巴瘤、頭頸癌、MSI-H或者dMMR陽性實體癌或大腸癌、尿路上皮癌、子宮頸癌、原發性縱隔B細胞淋巴瘤、肝細胞癌、胃癌及梅克爾細胞癌之各患者,以帕博利珠單抗計,以1次200 mg間隔3週進行靜脈滴注投予。又,作為另一用法、用量,例如,對於2歲以上之小兒之經典霍奇金淋巴瘤、MSI-H或者dMMR陽性實體癌或大腸癌及原發性縱隔B細胞淋巴瘤之各患者,以帕博利珠單抗計,以1次2 mg/kg(體重)(1次至多200 mg)間隔3週進行靜脈滴注投予。
又,於其有效成分係作為抗PD-L1抗體之阿維魯單抗之情形時,對於梅克爾細胞癌及尿路上皮癌之各患者,以阿維魯單抗計,以1次10 mg/kg(體重)間隔2週進行靜脈滴注投予。於同樣作為PD-L1抗體之阿特珠單抗之情形時,對於非小細胞肺癌及尿路上皮癌之各患者,以阿特珠單抗計,以1次1200 mg間隔3週進行靜脈滴注投予,對於三陰性乳癌症患者,於與紫杉醇之併用中,以阿特珠單抗計,以1次840 mg間隔2週進行靜脈滴注投予。進而,於同樣作為PD-L1抗體之度伐魯單抗之情形時,對於非小細胞肺癌與尿路上皮癌之各患者,以度伐魯單抗計,以1次10 mg/kg(體重)間隔2週進行靜脈滴注投予。
又,於作為抗CTLA-4抗體之伊匹單抗之情形時,對於惡性黑色素瘤患者,於單獨或者與納武單抗之併用中,以伊匹單抗計,以1天1次3 mg/kg(體重)間隔3週進行4次靜脈滴注,對於腎細胞癌及MSI-H或dMMR陽性大腸癌之各患者,於與納武單抗之併用中,以伊匹單抗計,以1天1次1 mg/kg(體重)間隔3週進行4次進行靜脈滴注。
再者,作為該等免疫CP阻礙藥之靜脈內投予之投予形態,較佳為靜脈滴注。
另一方面,關於FFX療法,於與上述所例示之免疫CP阻礙藥之併用中,可於使L-OHP 85 mg/m2
歷時2小時進行靜脈內投予後,使I-LV 200 mg/m2
歷時2小時進行靜脈內投予,自I-LV投予開始30分鐘後,使CPT-11 180 mg/m2
歷時1.5小時進行靜脈內投予,進而,於I-LV之投予結束後,使5-FU 400 mg/m2
進行快速靜脈內投予,進而,使5-FU 2400 mg/m2
歷時46小時進行持續靜脈內投予,間隔2週處方該一系列之投予。又,可自最初之投予開始,不進行5-FU之快速靜脈內投予,進而將L-OHP、CPT-11及/或供持續靜脈內投予之5-FU之投予量設定為如上述記載所述,又,亦可於該第2週期以後之任一投予中,根據患者之副作用表現之程度,中止5-FU快速靜脈內投予,亦可根據患者之副作用表現之程度,使L-OHP、CPT-11及/或供持續靜脈內投予之5-FU之投予量如上述記載般進行減量,或中止各投予本身。
又,關於mFFX療法,於與上述所例示之免疫CP阻礙藥之併用中,亦可於使L-OHP 85 mg/m2
歷時2小時進行靜脈內投予後,使I-LV 200 mg/m2
歷時2小時進行靜脈內投予,自I-LV投予開始30分鐘後,使CPT-11 150 mg/m2
歷時1.5小時進行靜脈內投予,進而,於I-LV之投予結束後,使5-FU 2400 mg/m2
歷時46小時進行持續靜脈內投予,間隔2週實施該一系列之投予。又,可自最初之投予開始,將L-OHP、CPT-11及/或供持續靜脈內投予之5-FU之投予量設定為如上述記載所述,又,亦可於該第2週期以後之任一投予中,根據患者之副作用表現之程度,使L-OHP、CPT-11及/或供持續靜脈內投予之5-FU之投予量如上述記載般進行減量,或中止各投予本身。
該FFX療法、該mFFX療法或其等之減量方案之一系列之投予之間隔亦可根據患者之副作用表現之程度,暫時性地或者持續性地設定為間隔3週或間隔4週。
於有效成分為納武單抗之免疫CP阻礙藥與mFFX療法之併用處方中,能夠以納武單抗計,以1次3 mg/kg(體重)或者1次240 mg間隔2週、或以1次480 mg間隔4週,歷時30分鐘或60分鐘進行靜脈內投予(例如,靜脈滴注),另一方面,於mFFX療法中,於使L-OHP 85 mg/m2
歷時2小時進行靜脈內投予後,使I-LV 200 mg/m2
歷時2小時進行靜脈內投予,自I-LV投予開始30分鐘後,使CPT-11 150 mg/m2
歷時1.5小時進行靜脈內投予,進而,於I-LV之投予結束後,使5-FU 2400 mg/m2
歷時46小時進行靜脈內投予,間隔2週進行該一系列之投予。進而,作為該併用中之納武單抗之處方,較佳為以納武單抗計,以1次480 mg間隔4週,歷時30分鐘進行靜脈內投予(例如,靜脈滴注)之方法。
再者,當於同一天實施上述所例示之免疫CP阻礙藥投予與FFX療法、mFFX療法或其等之減量方案之情形時,較佳為首先投予該免疫CP阻礙藥,於該免疫CP阻礙藥之投予結束後經過至少約30分鐘後,開始FFX療法、mFFX療法或其等之減量方案。又,本發明之治療法較佳為於該併用中,首先於同一天實施免疫CP阻礙藥投予與FFX療法、mFFX療法或其等之減量方案。
[併用]
本發明中之藥劑或治療法亦可為了(1)增強癌症之進展抑制及/或治療效果、(2)減少組合使用之其他藥劑之投予量及/或(3)降低組合使用之其他藥劑之副作用,與為了治療癌症所使用之一種以上之其他藥劑(例如,抗癌藥、止吐藥)一併組合使用。本發明中,與其他藥劑一併組合進行處方之情形時之投予形態可為使其他藥劑調配至本發明中之藥劑之任一製劑中而成之調配劑之形態,又,亦可為以各別製劑之形式之投予形態。此處,其他藥劑之投予量能夠以臨床上所使用之用量為基準而適當選擇。又,其他藥劑亦可使任意2種以上以適當之比率組合投予。又,上述其他藥劑中不僅包括迄今為止發現之藥劑,亦包括今後發現之藥劑。
關於作為其他藥劑之主要一例所列舉之「其他抗癌藥」,係除奧沙利鉑、鹽酸愛萊諾迪肯水合物、左亞葉酸鈣及氟尿嘧啶以外之抗癌藥,例如可列舉:烷基化藥(例如,達卡巴仁(Dacarbazine)、尼莫司汀(Nimustine)、替莫唑胺(Temozolomide)、福莫司汀(Fotemustine)、苯達莫司汀(Bendamustine)、環磷醯胺(Cyclophosphamide)、異環磷醯胺(Ifosfamide)、雙氯乙基亞硝脲(Carmustine)、氮芥苯丁酸(Chlorambucil)及甲基苄肼(Procarbazine)等)、鉑製劑(例如,順鉑(Cisplatin)、卡鉑(Carboplatin)、奈達鉑(Nedaplatin)及奧沙利鉑(Oxaliplatin)等)、代謝拮抗劑(例如,葉酸代謝拮抗藥(例如,培美曲塞(Pemetrexed)、立可林(Leucovorin)及甲胺喋呤(Methotrexate)等)、吡啶代謝阻礙藥(例如,TS-1(註冊商標)、5-氟尿嘧啶(5-fluorouracil)、UFT、卡莫氟(Carmofur)、去氧氟尿苷(Doxifluridine)、FdUrd、阿糖胞苷(Cytarabine)及卡培他濱(Capecitabine)等)、嘌呤代謝阻礙藥(例如,氟達拉賓(Fludarabine)、克拉屈濱(Cladribine)及奈拉濱(Nelarabine)等))、核糖核苷酸還原酶阻礙藥、核苷酸類似物(例如,吉西他濱(Gemcitabine)等))、拓樸異構酶阻礙藥(例如,愛萊諾迪肯(Irinotecan)、Nogitecan及依託泊苷(Etoposide)等)、微管聚合阻礙藥(例如,長春鹼(Vinblastine)、長春新鹼(Vincristine)、長春地辛(Vindesine)、長春瑞濱(Vinorelbine)及艾立布林(Eribulin)等)、微管解聚阻礙藥(例如,多西他賽(Docetaxel)及太平洋紫杉醇(Paclitaxel))、抗腫瘤性抗生素(例如,博萊黴素(Bleomycin)、絲裂黴素(Mitomycin)C、阿黴素(Doxorubicin)、道諾黴素(Daunorubicin)、艾達黴素(Idarubicin)、依託泊苷、米托蒽醌(Mitoxantrone)、長春鹼、長春新鹼、培洛黴素(Peplomycin)、氨柔比星(Amrubicin)、阿柔比星(Aclarubicin)及表柔比星(Epirubicin)等)、細胞激素製劑(例如,IFN-α2a、IFN-α2b、聚乙二醇(PEG)-IFN-α2b、天然型IFN-β及介白素-2(Interleukin-2)等)、抗激素藥(例如,他莫昔芬(Tamoxifen)、氟維司群(Fulvestrant)、戈舍瑞林(Goserelin)、亮丙瑞林(Leuprorelin)、阿那曲唑(Anastrozole)、來曲唑(Letrozole)及依西美坦(Exemestane)等)、分子靶向藥、癌症免疫治療藥及其他抗體醫藥等。
此處,關於作為其他抗癌藥所列舉之分子靶向藥,例如可列舉:ALK阻礙劑(例如,克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、恩沙替尼(Ensartinib)、阿來替尼(Alectinib)及勞拉替尼(Lorlatinib)、BCR-ABL阻礙劑(例如,伊馬替尼(Imatinib)及達沙替尼(Dasatinib)、EGFR阻礙劑(例如,埃羅替尼(Erlotinib)、EGF816、阿法替尼(Afatinib)、甲磺酸奧希替尼(Osimertinib mesilate)、吉非替尼(Gefitinib)及諾司替尼(Rociletinib))、B-Raf阻礙劑(例如,索拉非尼(Sorafenib)、維羅非尼(Vemurafenib)、TAK-580、達拉非尼(Dabrafenib)、康奈非尼(Encorafenib)、LXH254、Emurafenib及BGB-3111)、VEGFR阻礙劑(例如,貝伐單抗(Bevacizumab)、阿帕替尼(Apatinib)、樂伐替尼(Lenvatinib)、阿帕西普(Aflibercept)及阿西替尼(Axitinib))、FGFR阻礙劑(例如,AZD4547、B-701、FGF401及INCB054828)、c-Met阻礙劑(例如,沃利替尼(Savolitinib)、美樂替尼(Merestinib)、卡馬替尼(Capmatinib)、INC280及Glesatinib)、Axl阻礙劑(例如,ONO-7475及BGB324)、Mek阻礙劑(例如,考比替尼(Cobimetinib)、比美替尼(Binimetinib)、塞魯美替尼(Selumetinib)及曲美替尼(Trametinib))、CDK阻礙劑(例如,Dinaciclib、玻瑪西尼(Abemaciclib)、帕博西尼(Palbociclib)及Trilaciclib)、Btk阻礙劑(例如,ONO-4059、依魯替尼(Ibrutinib)及阿卡替尼(Acalabrutinib))、PI3K-δ/γ阻礙劑(例如,TGR-1202、INCB050465及IPI-549)、JAK-1/2阻礙劑(例如,伊他替尼(Itacitinib)及魯索利替尼(Ruxolitinib))、ERK阻礙劑(例如,SCH 900353)、TGFbR1阻礙劑(例如,Galunisertib)、癌細胞幹細胞特性(Cancer cell stemness)激酶阻礙劑(例如,Amcasertib)、FAK阻礙劑(例如,Defactinib)、Syk/FLT3 dual阻礙劑(例如,TAK-659)、ATR阻礙劑(例如,AZD6738)、Wee1激酶阻礙劑(例如,AZD1775)、多酪胺酸激酶阻礙劑(例如,舒尼替尼(Sunitinib)、帕唑帕尼(Pazopanib)、卡博替尼(Cabozantinib)、瑞格菲尼(Regorafenib)、尼達尼布(Nintedanib)、Sitravatinib及米哚妥林(Midostaurin))、mTOR阻礙劑(例如,替西羅莫司(Temsirolimus)、依維莫司(Everolimus)、Vistusertib及愛萊諾迪肯)、HDAC阻礙劑(例如,伏立諾他(Vorinostat)、羅米地辛(Romidepsin)、恩替諾特(Entinostat)、西達本胺(Chidamide)、莫替司他(Mocetinostat)、西塔利諾司他(Citarinostat)、帕比司他(Panobinostat)及丙戊酸(Valproate))、PARP阻礙劑(例如,尼拉帕尼(Niraparib)、奧拉帕尼(Olaparib)、維利帕尼(Veliparib)、瑞卡帕布(Rucaparib)及Beigene-290)、芳香酶阻礙劑(例如,依西美坦(Exemestane)及來曲唑(Letrozole))、EZH2阻礙劑(例如,Tazemetostat)、半乳糖凝集素-3阻礙劑(例如,GR-MD-02)、STAT3阻礙劑(例如,那布卡辛(Napabucasin))、DNMT阻礙劑(例如,阿紮胞苷(Azacitidine))、SMO阻礙劑(例如,維莫德吉(Vismodegib))、Hsp90阻礙劑(例如,XL888)、γ-微管蛋白特異性阻礙劑(例如,Glaziovianin A及普那布林(Plinabulin))、HIF2α阻礙劑(例如,PT2385)、麩醯胺酶阻礙劑(例如,CB-839)、E3連接酶阻礙劑(例如,Avadomide)、Nrf2活化劑(例如,Omaveloxolone)、精胺酸酶阻礙劑(例如,CB-1158)、細胞週期阻礙劑(例如,曲貝替定(Trabectedin))、Ephrin B4阻礙劑(例如,sEphB4-HAS)、IAP拮抗劑(例如,比瑞那帕(Birinapant))、抗Her2抗體(例如,曲妥珠單抗(Trastuzumab)、曲妥珠單抗-美坦新(Trastuzumab Emtansine)、帕妥珠單抗(Pertuzumab)及Margetuximab)、抗EGFR抗體(例如,西妥昔單抗(Cetuximab)、帕尼單抗(Panitumumab)、耐昔妥珠單抗(Necitumumab)及尼妥珠單抗(Nimotuzumab))、抗VEGF抗體(例如,貝伐珠單抗(Bevacizumab))、抗VEGFR2抗體(例如,雷莫蘆單抗(Ramucirumab))、抗CD20抗體(例如,利妥昔單抗(Rituximab)、奧法木單抗(Ofatumumab)、烏妥昔單抗(Ublituximab)及阿托珠單抗(Obinutuzumab))、抗CD30抗體(例如,本妥昔單抗(Brentuximab Vedotin)、抗CD38抗體(例如,達雷木單抗(Daratumumab))、抗DR5抗體(例如,DS-8273a)、抗CA125抗體(例如,奧戈伏單抗(Oregovomab))、抗DLL4抗體(例如,登西珠單抗(Demcizumab))、抗岩藻糖基GM1抗體(例如,BMS-986012)、抗gpNMB抗體(例如,Glembatumumab vedotin)、抗間皮素(Mesothelin)抗體(例如,BMS-986148)、抗MMP9抗體(例如,安德西昔單抗(Andecaliximab))、抗GD2抗體(例如,達妥昔單抗(Dinutuximab)-β)、抗c-Met抗體(例如,ABT-399)、抗FOLR1抗體(例如,Mirvetuximab soravtansine)、抗Ang2-VEGF雙特異性抗體(例如,Vanucizumab)、抗CD30-CD16A雙特異性抗體(例如,AFM13)、抗CD79b抗體(例如,Polatuzumab Vedotin)、抗FAP抗體/IL-2融合蛋白(例如,RO6874281)、抗CEA抗體/IL-2融合蛋白(例如,Cergutuzumab Amunaleukin)、抗CEA-CD3雙特異性抗體(例如,RO6958688)、抗DLL3抗體(例如,Rovalpituzumab Tesirine)、抗CD3-CD19雙特異性抗體(例如,博納吐單抗(Blinatumomab))及抗CD20-CD3雙特異性抗體(例如,REGN1979)等。
又,關於作為其他抗癌藥所列舉之癌症免疫治療藥,係具有與本發明中之免疫CP阻礙藥之任一者不同之作用機制之癌症免疫治療藥,例如可列舉:抗PD-1抗體(例如,納武單抗、西米單抗(REGN-2810)、帕博利珠單抗(MK-3475)、Spartalizumab(PDR-001)、替雷利珠單抗(BGB-A317)、AMP-514(MEDI0680)、Dostarlimab(ANB011/TSR-042)、特瑞普利單抗(JS001)、卡瑞利珠單抗(SHR-1210)、傑諾單抗(CBT-501)、信迪利單抗(IBI308)、STI-A1110、ENUM 388D4、ENUM 244C8、GLS010、MGA012、AGEN2034、CS1003、BAT-1306、AK105、AK103、BI 754091、LZM009、CMAB819、Sym021、GB226、SSI-361、JY034、HX008、ISU106、ABBV181、BCD-100、PF-06801591、CX-188、JNJ-63723283及AB122等)、抗PD-L1抗體(例如,阿特珠單抗(RG7446/MPDL3280A)、阿維魯單抗(PF-06834635/MSB0010718C)、度伐魯單抗(MEDI4736)、BMS-936559、STI-1014、KN035、LY3300054、SHR-1316、CS1001(WBP3155)、MSB2311、BGB-A333、KL-A167、CK-301、AK106、AK104、ZKAB001、FAZ053、CBT-502(TQB2450)、JS003或CX-072等)、PD-1拮抗劑(例如,AUNP-12、BMS-M1~BMS-M10之各化合物、BMS-1、BMS-2、BMS-3、BMS-8、BMS-37、BMS-200、BMS-202、BMS-230、BMS-242、BMS-1001、BMS-1166、Incyte-1~Incyte-6之各化合物、CAMC-1~CAMC-4、RG_1及DPPΑ-1等)、PD-L1/VISTA拮抗劑(例如,CΑ-170等)、PD-L1/TIM3拮抗劑(例如,CΑ-327等)、抗PD-L2抗體、PD-L1融合蛋白、PD-L2融合蛋白(例如,AMP-224等)、抗CTLA-4抗體(例如,伊匹單抗(MDX-010)、AGEN1884及曲美木單抗等)、抗LAG-3抗體(例如,Relatlimab(BMS-986016/ONO-4482)、LAG525、REGN3767及MK-4280等)、LAG-3融合蛋白(例如,IMP321等)、抗Tim3抗體(例如,MBG453及TSR-022等)、抗KIR抗體(例如,Lirilumab(BMS-986015/ONO-4483)、IPH2101、LY3321367及MK-4280等)、抗BTLA抗體、抗TIGIT抗體(例如,Tiragolumab(MTIG-7192A/RG-6058/RO-7092284)及BMS-986207(ONO-4686))、抗VISTA抗體(例如,JNJ-61610588等)、抗CD137抗體(例如,Urelumab(ONO-4481/BMS-663513)及Utomilumab(PF-05082566)等)、抗CSF-1R抗體或者CSF-1R阻礙劑(例如,Cabiralizumab(FPA008/BMS-986227/ONO-4687)、Emactuzumab (RG7155/RO5509554)、LY3022855、MCS-110、IMC-CS4、AMG820、培西達替尼(Pexidartinib)、BLZ945及ARRY-382等)、抗OX40抗體(例如,MEDI6469、PF-04518600、MEDI0562、MEDI6383、Efizonerimod、GSK3174998、BMS-986178及MOXR0916等)、抗HVEM抗體、抗CD27抗體(例如,Varlilumab(CDX-1127)等)、抗GITR抗體(例如,MK-4166、INCAGN01876、GWN323及TRX-518等)、抗CD28抗體、抗CCR4抗體(例如,莫加珠單抗(Mogamulizumab)等)、抗B7-H3抗體(例如,Enoblituzumab等)、抗ICOS促效劑抗體(例如,JTX-2011及GSK3359609等)、抗CD4抗體(例如,MTRX-1011A、TRX-1、伊巴利珠單抗(Ibalizumab)、huB-F5、紮木單抗(Zanolimumab)、4162W94、克立昔單抗(Clenoliximab)、凱利昔單抗(Keliximab)、AD-519、PRO-542、西利珠單抗(Cedelizumab)、TNX-355、達西珠單抗(Dacetuzumab)、曲加珠單抗(Tregalizumab)、普立昔單抗(Priliximab)、MDX-CD4、CAMPATH-9及IT1208等)、抗DEC-205抗體/NY-ESO-1融合蛋白(例如,CDX-1401等)、抗SLAMF7抗體(例如,埃羅妥珠單抗(Elotuzumab)等)、抗CD73抗體(例如,Oleclumab及BMS-986179等)、抗CD122抗體(例如,NKTR-214等)、抗CD40促效劑抗體(例如,ABBV-428、APX005M及RO7009789等)、IDO阻礙劑(例如,艾卡哚司他(Epacadostat)、Indoximod及BMS-986205等)、TLR促效劑(例如,Motolimod、CMP-001、G100、IMO-2125、SD-101及MEDI9197等)、腺苷A2A受體拮抗劑(例如,Preladenant、AZD4635、PBF 509及CPI-444等)、抗NKG2A抗體(例如,Monalizumab等)、抗CSF-1抗體(例如,PD0360324等)、免疫增強劑(例如,PV-10等)、IL-15超級促效劑(例如,ALT-803等)、可溶性LAG3(例如,IMP321等)、CD47拮抗劑(例如,ALX148等)及IL-12拮抗劑(例如,M9241等)等。
進而,作為其他抗體醫藥,例如可列舉:抗IL-1β抗體(例如,卡那奴單抗(Canakinumab)等)及抗CCR2抗體(例如,Plozalizumab等)等。
作為其他藥劑之主要一例,可列舉止吐藥,作為止吐藥,例如可列舉腎上腺皮質類固醇(例如,地塞米松(Dexamethasone)及甲潑尼龍(Methylprednisolone))、5-HT3
受體拮抗劑(例如,阿紮司瓊(Azasetron)、吲地司瓊(Indisetron)、昂丹司瓊(Ondansetron)、格拉司瓊(Granisetron)、拉莫司瓊(Ramosetron)及帕洛諾司瓊(Palonosetron))、NK1受體拮抗劑(例如,阿瑞吡坦(Aprepitant)及福沙吡坦(Fosaprepitant))、多巴胺D2
受體拮抗劑(例如,多潘立酮(Domperidone)及甲氧氯普胺(Metoclopramide))、苯二氮呯系抗焦慮藥(例如,阿普唑侖(Alprazolam)及勞拉西泮(Lorazepam))、啡噻𠯤系抗精神病藥(例如,丙氯拉𠯤(Prochlorperazine)及氯丙𠯤(Chlorpromazine))、苯丁酮系抗精神病藥(例如,氟哌啶醇(Haloperidol))、苯并異㗁唑系抗精神病藥(例如,利司培酮(Risperidone))、多受體作用抗精神病藥(例如,奧氮平(Olanzapine))以及丙胺系抗組胺藥(例如,氯苯那敏(Chlorpheniramine))等。
[製劑]
於本發明中之免疫CP阻礙藥作為注射劑或用於點滴之輸液製劑化並使用之情形時,該注射劑或輸液可為水溶液、懸浮液或乳濁液之任一形態,又,亦可以藉由於使用時加入溶劑而溶解、懸浮或乳濁並使用之方式,與藥學上可容許之載體一併製劑化成固體劑。作為注射劑或用於點滴之輸液所使用之溶劑,例如可使用:注射用蒸餾水、生理鹽水、葡萄糖溶液及等張液(例如,氯化鈉、氯化鉀、甘油、甘露醇、山梨醇、硼酸、硼砂、丙二醇等溶液)等。
此處,作為藥學上可容許之載體,例如可列舉:穩定劑、增溶劑、懸浮劑、乳化劑、鎮痛劑、緩衝劑、保存劑、防腐劑、pH值調整劑及抗氧化劑等。作為穩定劑,例如可使用:各種胺基酸、白蛋白、球蛋白、明膠、甘露醇、葡萄糖、葡聚糖、乙二醇、丙二醇、聚乙二醇、抗壞血酸、亞硫酸氫鈉、硫代硫酸鈉、乙二胺四乙酸鈉、檸檬酸鈉、二丁基羥基甲苯等。作為增溶劑,例如可使用:醇(例如,乙醇等)、聚醇(例如,丙二醇、聚乙二醇等)、非離子性界面活性劑(例如,聚山梨醇酯20(註冊商標)、聚山梨醇酯80(註冊商標)、HCO-50等)等。作為懸浮劑,例如可使用:單硬脂酸甘油酯、單硬脂酸鋁、甲基纖維素、羧甲基纖維素、羥甲基纖維素、月桂基硫酸鈉等。作為乳化劑,例如可使用:阿拉伯膠、海藻酸鈉、黃耆膠等。作為鎮痛劑,例如可使用:苯甲醇、氯丁醇、山梨醇等。作為緩衝劑,例如可使用:磷酸緩衝液、乙酸緩衝液、硼酸緩衝液、碳酸緩衝液、檸檬酸緩衝液、三羥甲基胺基甲烷緩衝液、麩胺酸緩衝液、ε-胺基己酸緩衝液等。作為保存劑,例如可使用:對羥苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯、對羥基苯甲酸丁酯、氯丁醇、苯甲醇、氯化苄烷銨、脫氫乙酸鈉、乙二胺四乙酸鈉、硼酸、硼砂等。作為防腐劑,例如可使用:氯化苄烷銨、對羥苯甲酸、氯丁醇等。作為pH值調整劑,例如可使用:鹽酸、氫氧化鈉、磷酸、乙酸等。作為抗氧化劑,例如可使用:(1)抗壞血酸、半胱胺酸鹽酸鹽、重硫酸鈉、偏重亞硫酸鈉、亞硫酸鈉等之類之水溶性抗氧化劑;(2)抗壞血酸棕櫚酸酯、丁基化羥基甲氧苯、丁基化羥基甲苯、卵磷脂、沒食子酸丙酯、α-生育酚等之類之油溶性抗氧化劑及(3)檸檬酸、乙二胺四乙酸、山梨醇、酒石酸、磷酸等之類之金屬螯合劑等。
例如,於其有效成分為納武單抗之免疫CP阻礙藥之情形時,作為其製劑中之添加物,例如可列舉:D-甘露醇、檸檬酸鈉水合物、氯化鈉、二伸乙基三胺五乙酸、聚山梨醇酯80及pH值調節劑。又,於其有效成分為帕博利珠單抗之免疫CP阻礙藥之情形時,作為其製劑中之添加物,例如可列舉:L-組胺酸、L-組胺酸鹽酸鹽水合物、精製白糖及聚山梨醇酯80,於其有效成分為阿維魯單抗之免疫CP阻礙藥之情形時,作為其製劑中之添加物,例如可列舉:D-甘露醇、聚山梨醇酯20、冰乙酸及氫氧化鈉。
於其有效成分為阿特珠單抗之免疫CP阻礙藥之情形時,作為其製劑中之添加物,例如可列舉:L-組胺酸、冰乙酸、精製白糖及聚山梨醇酯20,於其有效成分為度伐魯單抗之免疫CP阻礙藥之情形時,作為其製劑中之添加物,例如可列舉:L-組胺酸、L-組胺酸鹽酸鹽水合物、海藻糖水合物及聚山梨醇酯80,於其有效成分為伊匹單抗之免疫CP阻礙藥之情形時,作為其製劑中之添加物,例如可列舉:胺丁三醇鹽酸鹽、氯化鈉、D-甘露醇、二伸乙基三胺五乙酸、聚山梨醇酯80及其他pH值調節劑。
注射劑或用於點滴之輸液可藉由於其最終步驟中進行殺菌,或者藉由無菌操作法,例如利用過濾器等進行過濾並殺菌,繼而填充於無菌之容器而進行製造。又,注射劑或用於點滴之輸液亦可使藉由真空乾燥及冷凍乾燥而成之無菌粉末(亦可包括藥學上可容許之載體之粉末)於使用時溶解於適當之溶劑而使用。
本說明書中,明確引用之所有專利文獻與非專利文獻或者參考文獻之內容均可作為本說明書之一部分引用至本文。
藉由以下實施例,進而詳細地對本發明進行說明,但本發明之範圍不受其限定。本領域技術人員能夠基於本發明之記載進行各種各樣之變更、修飾,該等變更、修飾亦包含於本發明。
實施例
實施例1:以胰癌患者為對象,對併用納武單抗與mFFX療法時之有效性與安全性進行評價之多設施共同非盲檢試驗
本臨床試驗之目的在於研究針對無化學療法經歷且具有遠處轉移之胰癌患者併用納武單抗與mFFX療法時之有效性及安全性。根據該臨床試驗,可對納武單抗與mFFX療法之併用效果進行評價。
[對象患者]
無化學療法經歷且具有遠處轉移之胰癌患者
[患者選擇基準]
登錄時選擇滿足考慮到關於納武單抗與FFX療法或者mFFX療法迄今為止所實施之各種臨床試驗中之患者選擇基準而決定之所有特定之患者選擇基準的患者。再者,於自登錄起至初次投予納武單抗之前,明確不滿足該基準之情形時,不開始投予納武單抗,而中止臨床試驗。
[患者排除基準]
登錄時將認為符合以下患者排除基準之任一者之患者排除:與納武單抗及FFX療法或者mFFX療法有關之各種臨床試驗中之患者排除基準;或者考慮到關於納武單抗與FFX療法公佈之各種正確使用指南或者正確使用資訊中之患者選擇時之注意事項而決定之特定之患者排除基準。再者,於自登錄起至初次投予納武單抗之前,與該基準之任一者抵觸之情形時,不開始投予納武單抗,而中止臨床試驗。
[用法、用量及投予期間]
<納武單抗>
使納武單抗480 mg間隔4週,歷時30分鐘進行靜脈內投予,繼續投予納武單抗直至符合關於納武單抗之特定之投予中止基準為止。不容許納武單抗之用量之變更。再者,於在同一天投予納武單抗與mFFX療法之情形時,首先投予納武單抗,於納武單抗之投予結束後經過至少30分鐘後,開始mFFX療法之投予。
<mFFX療法>
使奧沙利鉑85 mg/m2
歷時2小時進行靜脈內投予後,使左亞葉酸鹽200 mg/m2
歷時2小時進行靜脈內投予。自開始投予左亞葉酸鹽30分鐘後,使愛萊諾迪肯150 mg/m2
歷時1.5小時進行靜脈內投予。又,於左亞葉酸鹽之投予結束後,使氟尿嘧啶2400 mg/m2
歷時46小時進行靜脈內投予。將其作為1週期,每2週地反覆進行。
再者,本臨床試驗之mFFX療法中所使用之治療藥(奧沙利鉑、左亞葉酸鹽、愛萊諾迪肯及氟尿嘧啶)使用市售品。
[臨床試驗排程]
本試驗包括篩選期、治療期及後觀察期。將臨床試驗排程之概要示於圖1。
篩選期(治療開始前第-7~-1天)中,臨床試驗責任醫師或臨床試驗助理醫師使滿足上述選擇基準且不與上述排除基準抵觸而判斷作為本臨床試驗之對象合格的患者入選。
治療期中,對於已登錄之受驗者,依據關於納武單抗之上述「用法、用量及投予期間」及關於mFFX療法之上述「用法、用量及投予期間」,開始併用投予,並依據關於納武單抗之以下投予基準以及關於mFFX法之以下投予基準、減量基準及減量時之投予量,繼續進行投予。
投予臨床試驗藥之所有受驗者之中,對於符合關於納武單抗之以下投予中止基準及關於mFFX療法之以下投予中止基準之任一者之受驗者,實施治療期結束時(中止時)之評價,並移行至後觀察期。後觀察期中,實施治療期結束28天後之評價與追蹤調查。
<納武單抗之投予基準>
受驗者於每次投予開始時,必須符合考慮到關於納武單抗迄今為止所實施之臨床試驗中之投予基準而決定之所有特定之投予基準。於不符合該基準之任一者之情形時,延期進行預定之納武單抗之投予。但即便於不符合該基準之任一者之情形時,只要未確認到判斷為因病情進展所導致之臨床症狀之惡化,期待藉由繼續投予所帶來之臨床性之益處,並考慮到受驗者之底線及併用藥之影響判斷能夠安全地繼續進行納武單抗之投予,則能夠繼續投予納武單抗。於該情形時,於繼續投予納武單抗之前,在確認受驗者之繼續治療之意願之基礎上,於診療記錄中留下記錄,並聯繫臨床試驗委託人(只有於判斷需要儘早進行納武單抗之投予之情形時,容許對於臨床試驗委託人進行事後報告)。
<納武單抗之投予中止基準>
治療期中,對於符合考慮到關於納武單抗迄今為止所實施之臨床試驗中之投予中止基準而決定之特定之投予中止基準之任一者的受驗者,中止納武單抗之投予。
<mFFX療法之投予基準>
受驗者於該療法之第1週期中,必須符合考慮到關於FFX療法或者mFFX療法迄今為止所實施之各臨床試驗中之投予基準而決定之所有特定之投予基準。
又,受驗者於該療法之第2週期以後,同樣地必須符合考慮到關於FFX療法或者mFFX療法迄今為止所實施之各臨床試驗中之投予基準而決定之所有特定之投予基準。直至恢復至投予預定日之臨床檢查值滿足該基準之條件之狀態為止,延期進行投予,於確認不符合各藥劑之禁忌之基礎上進行投予。
<mFFX療法之減量基準及減量時之投予量>
依據2013年12月20日藥食審查發1220第7號、厚生勞動省醫藥食品局審查管理課長通知「關於使用適合無法治癒切除之胰癌之併用化學療法(FOLFIRINOX法)時之注意事項」中所記載之「減量基準」與「減量時之投予量」實施。
<mFFX療法之投予中止基準>
治療期中,對於符合考慮到關於FFX療法或者mFFX療法迄今為止所實施之各臨床試驗中之投予中止基準而決定之特定之投予中止基準之任一者的受驗者,中止mFFX療法之投予。
[有效性之評價項目]
藉由利用胸部、腹部及骨盆之CT/核磁共振圖像(MRI)拍攝之圖像診斷而進行,依據RECIST指南1.1版,測量目標病變之腫瘤直徑,判定抗腫瘤效果。於以下所示之時點,進行圖像診斷(腫瘤直徑之測量與抗腫瘤效果之判定)。
<篩選期>
治療開始前第-7~-1天
<治療期>
週期2以後之週期(自初次納武單抗投予日開始每8週(±7日))及治療期結束時(或中止時)
<後期觀察期>
治療期結束28天後及追蹤調查期間
<主評價項目>
起效率
<次要評價項目>
(1)起效率、(2)總生存期間、(3)無惡化生存期間、(4)起效期間、(5)起效前之期間、(6)最良綜合效果、(7)病情控制率、(8)目標病變之腫瘤直徑和之變化率、及(9)目標病變之腫瘤直徑和之最大變化率
[安全性之評價項目]
關於以下項目,由臨床試驗責任醫師等在規定時期實施測定、檢查及調查。
(1)不良事件、(2)一般臨床檢查(血液學檢查、血液生化學檢查、尿定性檢查、免疫學性檢查、激素檢查)、及(3)生命徵象(收縮期血壓/擴張期血壓、脈搏數、體溫)
[有效性評價結果]
於第1例之受驗者登錄後經過6個月之時點,獲得臨床試驗實施計劃書中所規定之每8週之圖像診斷進行完2次(臨床試驗藥投予開始16週後)之7例之有效性評價(中間判定)。起效率為42.9%(CR:0例、PR:3例)。
[產業上之可利用性]
本發明之治療法尤其作為針對既有療法難以治療之癌症之新穎治療法有用。
本說明書所引用之所有刊物、專利及專利申請直接藉由引用編入至本說明書中。
圖1表示以胰癌患者作為對象,對併用納武單抗與mFFX療法時之有效性及安全性進行評價之多設施共同非盲檢試驗之臨床試驗排程之概要。
Claims (18)
- 一種納武單抗之用途,其係用於製造胰臟癌之進展抑制、復發抑制及/或治療劑,其特徵在於與FOLFIRINOX療法或其減量方案組合進行投予,(1)該劑係以納武單抗計,以1次3mg/kg(體重)或者以1次240mg間隔2週、以1次360mg間隔3週、或以1次480mg間隔4週進行投予(其中,該劑不作為術前療法處方);(2-1)該FOLFIRINOX療法係如下療法:使奧沙利鉑85mg/m2歷時2小時進行靜脈內投予後,使左亞葉酸鈣200mg/m2歷時2小時進行靜脈內投予,自該左亞葉酸鈣之投予開始30分鐘後,使鹽酸愛萊諾迪肯水合物180mg/m2歷時1.5小時進行靜脈內投予,進而,於該左亞葉酸鈣之投予結束後,使氟尿嘧啶400mg/m2進行快速靜脈內投予,進而,使氟尿嘧啶2400mg/m2歷時46小時進行持續靜脈內投予,間隔2週實施該一系列之投予;(2-2)該FOLFIRINOX療法之減量方案係如下療法:使奧沙利鉑85mg/m2歷時2小時進行靜脈內投予後,使左亞葉酸鈣200mg/m2歷時2小時進行靜脈內投予,自該左亞葉酸鈣投予開始30分鐘後,使鹽酸愛萊諾迪肯水合物150mg/m2歷時1.5小時進行靜脈內投予,進而,於該左亞葉酸鈣之投予結束後,使氟尿嘧啶2400mg/m2歷時46小時進行持續靜脈內投予,間隔2週實施該一系列之投予。
- 如請求項1之用途,其中該劑係以納武單抗計,以1次480mg間隔4週 進行投予。
- 如請求項2之用途,其中該劑係以納武單抗計,以1次480mg間隔4週,歷時約30分鐘進行靜脈內投予。
- 如請求項1之用途,其中於該FOLFIRINOX療法之第2週期以後之任一投予中,根據患者之副作用表現之程度,實施以下(1)~(4)之任一項以上,(1)中止氟尿嘧啶之快速靜脈內投予;(2)使奧沙利鉑之投予量減量或中止投予;(3)使鹽酸愛萊諾迪肯水合物之投予量減量或中止投予;(4)使供持續靜脈內投予之氟尿嘧啶之投予量減量。
- 如請求項1之用途,其中於該FOLFIRINOX療法之減量方案中,不實施氟尿嘧啶之快速靜脈內投予。
- 如請求項1之用途,其中(1)該FOLFIRINOX療法中之奧沙利鉑之投予量、或者於該療法之第2週期以後之任一投予中根據患者之副作用表現之程度減量之奧沙利鉑之投予量為約65mg/m2、約50mg/m2或約85~約50mg/m2之間之任意投予量;(2)該FOLFIRINOX療法中之鹽酸愛萊諾迪肯水合物之投予量、或者於該療法之第2週期以後之任一投予中根據患者之副作用表現之程度減量 之鹽酸愛萊諾迪肯水合物之投予量為約150mg/m2、約120mg/m2、約90mg/m2或約180~約90mg/m2之間之任意投予量;(3)該FOLFIRINOX療法中供持續靜脈內投予之氟尿嘧啶之投予量、或者於該療法之第2週期以後之任一投予中根據患者之副作用表現之程度減量之供持續靜脈內投予之氟尿嘧啶之投予量為約1800mg/m2、約1200mg/m2或約2400~約1200mg/m2之間之任意投予量。
- 如請求項1之用途,其中於該FOLFIRINOX療法之第2週期以後之任一投予中,根據患者之副作用表現之程度,實施以下(1)~(3)之任一項以上,(1)使奧沙利鉑之投予量減量或中止投予;(2)使鹽酸愛萊諾迪肯水合物之投予量減量或中止投予;(3)使供持續靜脈內投予之氟尿嘧啶之投予量減量。
- 如請求項1之用途,其中(1)該FOLFIRINOX療法之減量方案中之奧沙利鉑之投予量、或者於該減量方案之第2週期以後之任一投予中根據患者之副作用表現之程度減量之奧沙利鉑之投予量為約65mg/m2、約50mg/m2或約85~約50mg/m2之間之任意投予量;(2)該FOLFIRINOX療法之減量方案中之鹽酸愛萊諾迪肯水合物之投予量、或者於該減量方案之第2週期以後之任一投予中根據患者之副作用表現之程度減量之鹽酸愛萊諾迪肯水合物之投予量為約120mg/m2、約90mg/m2或約150~約90mg/m2之間之任意投予量; (3)該FOLFIRINOX療法之減量方案中供持續靜脈內投予之氟尿嘧啶之投予量、或者於該減量方案之第2週期以後之任一投予中根據患者之副作用表現之程度減量之供持續靜脈內投予之氟尿嘧啶之投予量為約1800mg/m2、約1200mg/m2或約2400~約1200mg/m2之間之任意投予量。
- 如請求項1之用途,其中當於同一天實施納武單抗之投予與該FOLFIRINOX療法或其減量方案之情形時,首先投予納武單抗,於納武單抗之投予結束後經過至少約30分鐘後,開始FOLFIRINOX療法或其減量方案。
- 如請求項1之用途,其中胰臟癌係胰管癌、胰島素瘤或胰管內乳頭狀黏液性腫瘤。
- 如請求項1之用途,其以無抗癌藥之治療經歷之胰臟癌患者作為對象。
- 如請求項1之用途,其以具有遠處轉移之胰臟癌患者作為對象。
- 如請求項1之用途,其以無抗癌藥之治療經歷且具有遠處轉移之胰臟癌患者作為對象。
- 一種納武單抗之用途,其係用於製造無抗癌藥之治療經歷且具有遠處轉移之胰臟癌之進展抑制、復發抑制及/或治療劑,其特徵在於與 FOLFIRINOX療法之減量方案組合進行投予,(1)該劑係以納武單抗計,以1次480mg間隔4週,歷時30分鐘進行靜脈內投予(其中,該劑不作為術前療法處方);(2)該FOLFIRINOX療法之減量方案係如下療法:使奧沙利鉑85mg/m2歷時2小時進行靜脈內投予後,使左亞葉酸鈣200mg/m2歷時2小時進行靜脈內投予,自該左亞葉酸鈣投予開始30分鐘後,使鹽酸愛萊諾迪肯水合物150mg/m2歷時1.5小時進行靜脈內投予,進而,於該左亞葉酸鈣之投予結束後,使氟尿嘧啶2400mg/m2歷時46小時進行持續靜脈內投予,間隔2週實施該一系列之投予。
- 如請求項1之用途,其僅與FOLFIRINOX療法或其減量方案組合進行投予。
- 一種納武單抗之用途,其係用於製造無抗癌藥之治療經歷且具有遠處轉移之胰臟癌之進展抑制、復發抑制及/或治療劑,其特徵在於僅與FOLFIRINOX療法之減量方案組合進行投予,且(1)該劑係以該納武單抗計,以1次480mg間隔4週,歷時30分鐘進行靜脈內投予,(2)該減量方案係於使奧沙利鉑85mg/m2歷時2小時進行靜脈內投予後,使左亞葉酸鈣200mg/m2歷時2小時進行靜脈內投予,自該左亞葉酸鈣投予開始30分鐘後,使鹽酸愛萊諾迪肯水合物150mg/m2歷時1.5小時進行靜脈內投予,進而,於該左亞葉酸鈣之投予結束後,使氟尿嘧啶2400mg/m2歷時46小時進行持續靜脈內投予,間隔2週實施該一系列之投 予的療法。
- 如請求項16之用途,其中當於同一天實施該納武單抗投予與該減量方案之情形時,首先投予該納武單抗,於該納武單抗之投予結束後經過至少約30分鐘後,開始該減量方案。
- 如請求項1或14之用途,其進而不與放射線療法併用。
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網路文獻 二プロ株式会社, FOLFIRINOX 療法(治癒切除不能な膵癌)適正使用情報, 2015年4月 * |
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