TW202135792A - 治療癌症之方法 - Google Patents
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Abstract
本發明係關於用β-GPA治療癌症之方法。本發明亦提供包括β-GPA及額外抗癌療法之組合之治療癌症之方法。
Description
β-胍基丙酸(β-GPA),亦稱為胍基丙酸,β-胍基丙酸或N-(胺基亞胺基甲基)-β-丙胺酸係肌酸類似物。針對動物(大鼠、猴、倉鼠)之研究顯示酸性胍衍生物(諸如β-GPA)可在非胰島素依賴型糖尿病之動物模型中改善高血糖。因此,其有時在糖尿病病患中用作膳食補充劑以調節血糖含量。
最近已發現β-GPA有效抑制轉移,尤其胃腸道癌中之肝轉移,例如,參見國際專利公開案WO2014/071067。因此,需開發針對癌症之治療有效且同時減少不良事件之β-GPA之給藥方案。
本發明係關於藉由每天兩次投與約1,500 mg至約4,000 mg之β-GPA來治療癌症之方法。發明人已發現此給藥方案意外導致高於全身循環之β-GPA之預期含量。
因此,在一項態樣中,本發明係關於一種治療有需要個體之癌症(例如,胃腸道癌(諸如結腸癌或胃癌)、胰癌、肝癌、乳癌、前列腺癌、肺癌、食道胃交界之腺癌,及黑色素瘤)之方法。此方法包括每天兩次向該個體投與約1,500 mg至約4,000 mg (例如,約1,500 mg至約2,000 mg、約1,750 mg至約2,250 mg、約2,000 mg至約2,500 mg、約2,250 mg至約2,750 mg、約2,400 mg至約2,800 mg、約2,700 mg至約3,000 mg、約2,750 mg至約3,250 mg、約3,100 mg至約3,400 mg、約3,200 mg至約3,600 mg)之β-GPA或其醫藥上可接受之鹽。在前述方法之任何一者之一些實施例中,該方法包括每天兩次向該個體投與約2,400 mg至約3,600 mg之β-GPA或其醫藥上可接受之鹽。在前述方法之任何一者之一些實施例中,該方法包括每天兩次向該個體投與約2,400 mg之β-GPA或其醫藥上可接受之鹽。在前述方法之任何一者之一些實施例中,該方法包括每天兩次向該個體投與約3,600 mg之β-GPA或其醫藥上可接受之鹽。
在前述方法之任何一者之一些實施例中,該方法進一步包括投與一或多種其他抗癌療法(例如,放射療法、手術及/或一或多種治療劑)。在前述方法之任何一者之一些實施例中,該等一或多種其他抗癌療法包括醛葉酸、氟尿嘧啶、伊立替康(irinotecan)及/或奧沙利鉑(oxaliplatin)。在前述方法之任何一者之一些實施例中,該等一或多種其他抗癌療法包括FOLFIRI,即,醛葉酸、氟尿嘧啶及伊立替康。在前述方法之任何一者之一些實施例中,該方法包括在各28天週期之第1天及第15天,靜脈內投與約180 mg/m2
之伊立替康,歷時90分鐘,同時靜脈內投與約400 mg/m2
或2 x 250 mg/m2
醛葉酸,歷時120分鐘,接著靜脈內推注可選約400至500 mg/m2
(例如,約400 mg/m2
)之氟尿嘧啶,接著靜脈內輸注約2400至3000 mg/m2
(例如,約2400 mg/m2
)之氟尿嘧啶,歷時46小時,例如,約每十四天重複一次。在前述方法之任何一者之一些實施例中,該等一或多種治療劑係環肌酸、RNAi藥劑、核酸、載體、5-氟尿嘧啶、奧沙利鉑、伊立替康、卡培他濱(capecitabine)、吉西他濱(gemcitabine)、西妥昔單抗(cetuximab)、紫杉醇(taxol)、阿瓦斯汀(avastin)、醛葉酸(甲醯四氫葉酸)、雷戈非尼(regorafenib)、阿柏西普(zaltrap)、拓撲異構酶I抑制劑、依替尼替康聚乙二醇(etirinotecan pegol)、伊凡替尼(tivantinib)、索諾西布(sonolisib)、索拉非尼(sorafenib)、利尼法尼(linifanib)、激酶抑制劑、替拉替尼(telatinib)、BMS-908662 (即,N-[6-[2-(5-氯-2-甲基苯基)-1-羥基-3-側氧基異吲哚-1-基]-1H-苯并咪唑-2-基]胺甲酸甲酯)、羅巴單抗(robatumumab)及/或IGF1-R抑制劑。
在前述方法之任何一者之一些實施例中,該方法進一步包括手術(例如,在投與β-GPA或其醫藥上可接受之鹽之前或之後)。
在前述方法之任何一者之一些實施例中,該癌症係轉移癌(例如,轉移性胃腸道癌(諸如轉移性結腸癌或轉移性胃癌)、轉移性胰癌、轉移性肝癌、轉移性乳癌、轉移性前列腺癌、轉移性肺癌、轉移性食道胃交界之腺癌或轉移性黑色素瘤)。
在前述方法之任何一者之一些實施例中,該癌症係胃腸道癌(例如,結腸直腸癌、胃癌或食道胃交界之腺癌)。
在前述方法之任何一者之一些實施例中,該癌症表現CKB。在前述方法之任何一者之一些實施例中,該個體經鑒定為患有轉移癌或處於患有轉移癌之風險下(例如,基於CKB之表現含量高於預定參考值)。
在前述方法之任何一者之一些實施例中,該癌症對一或多種治療劑具有抗性。在前述方法之任何一者之一些實施例中,該癌症在使用一或多種抗癌療法之治療時或之後進展。
在前述方法之任何一者之一些實施例中,該β-GPA或其醫藥上可接受之鹽係β-GPA之琥珀酸鹽(例如,β-GPA之2:1琥珀酸鹽)。
定義
如本文使用,術語「約」表示在該術語「約」後之值之±10%之範圍內之值。
如本文使用,術語「投與」係指向個體或系統投與組合物(例如,化合物或包括如本文描述之化合物之製劑)。向動物個體(例如,向人類)投與可藉由任何適當之途徑。例如,在一些實施例中,投與可為支氣管(包括藉由支氣管滴注)、頰、腸內、皮間、動脈內、皮內、胃內、髓內、肌內、鼻內、腹膜內、鞘內、靜脈內、腦室內、黏膜、鼻、經口、直腸、皮下、舌下、局部、氣管(包括藉由氣管內滴注)、經皮、陰道及玻璃體。
術語「癌症」係指由惡性腫瘤細胞增殖引起之任何癌症,諸如腫瘤、贅瘤、癌、肉瘤、白血病及淋巴瘤。
如本文使用,「確定為抗藥性」之癌症係指基於對化學治療劑無反應性或減小之反應性為抗藥性之癌症,或基於預後分析(例如,基因表現分析)預測為抗藥性之癌症。
「抗藥性」癌症意謂對一或多種化學治療劑(例如,本文描述之任何藥劑)無反應或顯示減小之反應之癌症。
如本文使用,術語「對先前療法沒有反應」或「先前療法難治」係指即使使用該療法治療仍進展之癌症。
如本文使用,「轉移性腫瘤」係指其中形成該腫瘤之癌細胞具有高潛力或已開始經由淋巴系統或經由血原性擴散於個體內自一個位置轉移或擴散至另一位置或其他位置,例如,於該個體內產生繼發性腫瘤之腫瘤或癌症。此轉移性行為可指示惡性腫瘤。在一些情況下,轉移性行為可與腫瘤細胞之細胞遷移及/或入侵行為增加相關聯。
可定義為轉移性之癌症之實例包括(但不限於)非小細胞肺癌(例如,非鱗狀非小細胞肺癌)、乳癌、卵巢癌、結腸直腸癌、膽道癌、膀胱癌、腦癌(包括神經膠質母細胞瘤及神經管胚細胞瘤)、子宮頸癌、絨毛膜癌、子宮內膜癌、食道癌、胃癌、血液贅瘤、多種性骨髓瘤、白血病、上皮內贅瘤、肝癌、淋巴瘤、神經胚細胞瘤、口腔癌、胰癌、前列腺癌、肉瘤、皮膚癌(包括黑色素瘤)、基底細胞癌、鱗狀細胞癌、睾丸癌、基質瘤、生殖細胞腫瘤、甲狀腺癌及腎癌。
如本文使用,術語「醫藥組合物」係指活性化合物與一或多種醫藥上可接受之載劑調配在一起。在一些實施例中,活性化合物係以適用於在治療方案中投與之單位劑量量存在,當向相關群體投與時,其顯示達成預定治療效應之統計顯著概率。在一些實施例中,醫藥組合物可經特別調配用於以固體或液體形式投與,包括彼等適用於下列者:經口投與,例如,浸液(水性或非水性溶液或懸浮液)、錠劑(例如,彼等針對頰、舌下及全身吸收者)、施用至舌頭之大丸劑、粉末、顆粒、糊劑;非經腸投與,例如,藉由皮下、肌內、靜脈內或硬膜外注射,呈(例如)無菌溶液或懸浮液或持續釋放調配物;局部施用,例如,呈施用至皮膚、肺或口腔之霜劑、軟膏劑或控制釋放貼劑或噴霧;陰道內或直腸內,例如,呈子宮托、霜劑或泡沫;舌下;經眼;經皮;或經鼻、肺或至其他黏膜表面。
如本文使用,「醫藥上可接受之賦形劑」係指在個體中具有無毒及非發炎之性質之任何非活性成分(例如,可懸浮或溶解活性化合物之媒劑)。典型之賦形劑包括(例如):抗黏附劑、抗氧化劑、黏合劑、包衣、壓縮助劑、崩解劑、染料(顏料)、軟化劑、乳化劑、填料(稀釋劑)、成膜劑或包衣、調味劑、香精、助流劑(流動增強劑)、潤滑劑、防腐劑、印刷油墨、吸附劑、懸浮劑或分散劑、甜味劑或水合水。一般技術者熟習適合作為賦形劑之各種藥劑及材料。
如本文使用,術語「醫藥上可接受之鹽」係指於合理之醫學判斷之範圍內,適用於與人類及動物之組織接觸而無過度之毒性、刺激、過敏反應及類似者且與合理之利益/風險比相稱之本文描述之化合物的彼等鹽。此項技術中熟知醫藥上可接受之鹽。例如,醫藥上可接受之鹽係描述於:Berge等人,J. Pharmaceutical Sciences 66:1-19, 1977以及Pharmaceutical Salts: Properties, Selection, and Use, (P.H. Stahl及C.G. Wermuth編), Wiley-VCH, 2008中。該等鹽可在本文描述之化合物之最終分離及純化期間原位製備或藉由使游離鹼基與合適之有機酸反應分開製備。
本發明之化合物可具有可電離基團以便於可製備為醫藥上可接受之鹽。此等鹽可為涉及無機酸或有機酸之酸加成鹽,或在本發明之化合物之酸性形式之情況下,該等鹽可自無機鹼或有機鹼製備。通常,將該等化合物製備成或用作醫藥上可接受之鹽,其等製備成醫藥上可接受之酸或鹼之加成產物。此項技術中熟知合適之醫藥上可接受之酸及鹼。
如本文使用,術語「個體」係指人類或非人類動物(例如,哺乳動物,諸如非人類靈長類動物、馬、奶牛或狗)。
術語「治療(treatment)」(亦稱為「治療(treat)」或「治療(treating)」)在其最廣泛之意義上係指部分或完全減輕、改善、緩解、抑制、延遲特定疾病、疾患及/或病症之一或多種症狀、特徵及/或病因之發作、降低其等之嚴重程度及/或降低其等之發病率之物質(例如,本文提供之組合物)之任何投與。在一些實施例中,此治療可向不顯示相關疾病、疾患及/或病症之徵象之個體及/或顯示該疾病、疾患及/或病症之僅早期徵象之個體投與。或者或另外,在一些實施例中,治療可向顯示相關疾病、疾患及/或病症之一或多種已確立徵象之個體投與。在一些實施例中,治療可為已診斷為罹患相關疾病、疾患及/或病症之個體之治療。在一些實施例中,治療可為已知具有與罹患相關疾病、疾患及/或病症之風險增加在統計上相關之一或多種易感性因素之個體之治療。
除非另有定義,否則本文使用之所有技術及科學術語具有與本發明所屬領域之一般技術者通常瞭解之含義相同之含義。本文描述之方法及材料用於本發明中;亦可使用此項技術中已知的其他合適之方法及材料。材料、方法及實例係僅說明性的而非意欲限制。本文提及之所有公開案、專利申請案、專利、序列、資料庫條目及其他參考文獻係以全文引用之方式併入本文中。在衝突之情況下,將以本說明書(包括定義)為準。
本發明之一或多個實施例之細節闡述於下文實施方式中。本發明之其他特徵、目標及優點將自實施方式及申請專利範圍顯而易見。
本發明係關於藉由每天兩次投與約2,000 mg至約4,000 mg之β-GPA來治療癌症之方法。發明人已發現此給藥方案意外導致高於循環之β-GPA之預期含量。
β-GPA係兩性離子且高度可溶於水(> 50 mg/mL)中,但在有機溶劑中具有低溶解度。β-GPA具有鹼性胍基,且因此可與二酸形成1:1 (β-GPA:酸)及2:1 (β-GPA:酸)鹽。如本文使用,β-GPA與二酸之「2:1鹽」 (例如,2:1琥珀酸鹽)係指包括兩個β-GPA分子及一個二酸分子之鹽,例如,「2:1琥珀酸鹽」包括兩個β-GPA分子及一個琥珀酸分子。
治療方法
最近已發現β-GPA有效抑制轉移。作用機制已假定為抑制肌酸運輸及/或肌酸激酶。磷酸肌酸系統藉由充當ATP產生之能量儲存庫以忍受肝缺氧來增強肝中瀰漫性癌細胞之存活而促進轉移。抑制肌酸運輸至癌細胞內限制可用於產生ATP之磷酸肌酸之量。抑制肌酸激酶抑制通過磷酸肌酸轉化為肌酸產生ATP。
可用本發明之方法治療之典型之血管化腫瘤包括實性瘤,尤其癌,其等需血管組分用於提供氧及營養素。例示性實性瘤包括(但不限於)肺癌、乳癌、骨癌、卵巢癌、胃癌、胰癌、喉癌、食管癌、睪丸癌、肝癌、腮腺癌、膽道癌、結腸癌、直腸癌、子宮頸癌、子宮癌、子宮內膜癌、腎癌、膀胱癌、前列腺癌、甲狀腺癌、鱗狀細胞癌、腺癌、小細胞癌、黑色素瘤、神經膠質瘤、神經膠質母細胞瘤、神經胚細胞瘤、卡波西氏肉瘤(Kaposi's sarcoma)及肉瘤。
治療癌症可導致腫瘤之尺寸或體積減小。例如,治療後,腫瘤尺寸相對於其治療前之尺寸,減小5%或更大(例如,10%、20%、30%、40%、50%、60%、70%、80%、90%或更大)。腫瘤之尺寸可藉由任何可重複之量測方式量測。例如,腫瘤之尺寸可量測為該腫瘤之直徑。
治療癌症可進一步導致腫瘤之數量減少。例如,治療後,腫瘤數量相對於治療前之數量減少5%或更大(例如,10%、20%、30%、40%、50%、60%、70%、80%、90%或更大)。腫瘤之數量可藉由任何可重複之量測方式量測,例如,腫瘤之數量可藉由計數肉眼可見或在規定放大率(例如,2x、3x、4x、5x、10x或50x)下可見之腫瘤量測。
治療癌症可導致遠離原發腫瘤位點之其他組織或器官中之轉移性結節之數量減少。例如,治療後,轉移性結節之數量相對於治療前之數量減少5%或更大(例如,10%、20%、30%、40%、50%、60%、70%、80%、90%或更大)。轉移性結節之數量可藉由任何可重複之量測方式量測。例如,轉移性結節之數量可藉由計數肉眼可見或在規定放大率(例如,2x、10x或50x)下可見之轉移性結節量測。
治療癌症可導致相較於未經治療之個體之群體,根據本發明治療之個體之群體之平均存活時間增加。例如,該平均存活時間增加超過30天(超過60天、90天或120天)。群體之平均存活時間之增加可藉由任何可重複之方式量測。群體之平均存活時間之增加可(例如)藉由針對群體計算使用本發明之化合物之治療開始後之存活之平均長度量測。群體之平均存活時間之增加亦可(例如)藉由針對群體計算完成第一輪使用本發明之醫藥上可接受之鹽之治療後之存活之平均長度量測。
治療癌症亦可導致相較於未經治療之群體,經治療之個體之群體之死亡率下降。例如,該死亡率下降超過2% (例如,超過5%、10%或25%)。經治療之個體之群體之死亡率之下降可藉由任何可重複之方式量測,例如,藉由針對群體計算使用本發明之醫藥上可接受之鹽之治療開始後之每單位時間內疾病相關之死亡之平均數量。群體之死亡率之降低亦可(例如)藉由針對群體計算完成第一輪使用本發明之方法之治療後之每單位時間內疾病相關之死亡之平均數量量測。
組合物
於本發明之範圍內係含有合適之賦形劑及上文描述之醫藥上可接受之鹽中之一或多者之組合物。該組合物可為含有醫藥上可接受之賦形劑之醫藥組合物、含有飲食上可接受之合適之賦形劑之飲食組合物或含有化妝品上可接受之賦形劑之化妝品組合物。
術語「醫藥組合物」係指活性劑與賦形劑(惰性或活性)之組合,使得該組合物尤其適用於活體內或離體診斷或治療用途。「醫藥上可接受之賦形劑」在向個體投與後或一經向個體投與,不引起非所需之生理效應。該醫藥組合物中之賦形劑亦在其可與活性成分相容且可穩定其之意義上必須係「可接受的」。一或多種增溶劑可用作醫藥賦形劑用於遞送活性化合物。醫藥上可接受之賦形劑之實例包括(但不限於)生物相容性媒劑、佐劑、添加劑及稀釋劑以達成可用作劑型之組合物。
如上文描述,本發明之醫藥組合物另外包括醫藥上可接受之賦形劑,如本文使用,其包括任何及所有溶劑、稀釋劑或其他液體媒劑、分散助劑或懸浮助劑、表面活性劑、等滲劑、增稠劑或乳化劑、防腐劑、固體黏合劑及潤滑劑,以適合所需之特定劑型。Remington’s Pharmaceutical Sciences,第十六版,E. W. Martin (Mack出版公司,Easton, Pa., 1980)揭示用於調配醫藥組合物之各種賦形劑及用於製備其之已知技術。除任何習知賦形劑介質與本發明之化合物不相容外,諸如藉由產生任何非所需之生物效應或另外以有害之方式與醫藥組合物之任何其他組分相互作用,其用途經審慎考慮係於本發明之範圍內。
呈上文描述之形式中之任何一者之上文描述組合物可用於治療癌症,或本文描述之任何其他疾病或病症。有效量係指賦予經治療之個體治療效應所需之活性化合物/藥劑之量。如由熟習此項技術者知曉,有效劑量將取決於治療之疾病之類型、投與途徑、賦形劑使用及與其他治療性治療共同使用之可能性而變化。
本發明之醫藥組合物可非經腸、經口、經鼻、經直腸、局部或經頰投與。如本文使用之術語「非經腸」係指皮下、皮內、靜脈內、肌內、關節內、動脈內、滑膜內、胸骨內、鞘內、病灶內或顱內注射,及任何合適之輸注技術。
無菌可注射組合物可為於無毒非經腸可接受之稀釋劑或溶劑中之溶液或懸浮液。另外,非揮發性油習知用作溶劑或懸浮介質(例如,合成單甘油酯或雙甘油酯)。出於調配之目的,亦可使用其他常用之表面活性劑,諸如(但不限於) Tween或Span或其他類似乳化劑或生物有效性增強劑,其等通常用於製造醫藥上可接受之固體、液體或其他劑型。
用於經口投與之組合物可為任何經口可接受之劑型,包括膠囊、錠劑、乳液及水性懸浮液、分散液及溶液。當經口投與水性懸浮液或乳液時,可將活性成分懸浮或溶解於與乳化劑或懸浮劑組合之油相中。視需要,可添加某些甜味劑、調味劑或著色劑。
組合療法
在一些實施例中,醫藥組合物可進一步包括具有抗增殖活性之額外化合物。亦將知曉本發明之化合物及醫藥組合物可經調配並用於組合療法中,即,該等化合物及醫藥組合物可與一或多種其他所需治療劑或醫學程序同時、之前或之後調配或投與。用於組合方案中之療法(治療劑或程序)之特定組合將考慮所需治療劑及/或程序之相容性及待達成之所需治療效應。亦將知曉採用之療法可針對相同疾患達成所需效應,或其等可達成不同效應(例如,任何副作用之控制)。
實例
實例1:β-GPA藥物動力學。
方法:在600 mg BID、1,200 mg BID、2,400 mg BID或3,600 mg BID之方案中,對個體投與RGX-202 (β-GPA之高度可壓縮鹽形式),且在投與後24小時內自該等個體抽取血漿樣本並使用下文描述之方案測試β-GPA之含量。
藉由蛋白質沈澱提取程序自50.0 μL人類血漿提取分析物β-GPA及內標準(IS) ([13C415N3]-β-GPA)。該提取程序起始於將50.0 μL內標準工作溶液添加至所有孔,除雙空白外,該等雙空白接受50.0 μL水。接著,將該盤上蓋並渦旋。然後將500 μL乙腈/甲醇(50/50,v/v)添加至所有孔。接著,將該盤上蓋,渦旋並離心。使用Tomtec Quadra 4,將200 μL上清液轉移至新盤內。然後將300 μL乙腈/甲醇(50/50,v/v)添加至所有孔。然後將該盤密封並渦旋。提取物係在逆相條件下在Luna HPLC管柱50 × 2.0 mm,3 μm管柱上使用具有於水及乙腈中之10 mM乙酸銨梯度系統層析。化合物係藉由串聯質譜法以陽離子模式在配備Turbo Ionspray®界面之MDS Sciex API 4000上偵測及定量。
結果:如下表1中顯示(由劑量標準化累積比),投與2,400 mg BID或3,600 mg BID之β-GPA導致個體中高於預期AUC及Cmax
含量。
表1:
劑量 | 平均AUC0-24 (ng-hr/mL) | 劑量標準化平均AUC0-24 (ng-hr/mL) | AUC劑量累積比 | 平均Cmax (ng/mL) | 劑量標準化平均Cmax (ng/mL) | Cmax 劑量累積比 |
600 mg BID | 15,700 | 13.1 | 1.0 | 1,400 | 1.2 | 1.0 |
1,200 mg BID | 45,200 | 18.8 | 1.4 | 4,790 | 2.0 | 1.7 |
2,400 mg BID | 164,800 | 34.3 | 2.7 | 26,800 | 5.6 | 4.8 |
3,600 mg BID | 241,097 | 33.5 | 2.6 | 47,660 | 6.6 | 5.7 |
實例2:用於治療GI腫瘤之β-GPA。
方法:對患有晚期胃腸道腫瘤(例如,局部晚期且無法切除或轉移性)之個體投與多個劑量之經口投與之RGX-202作為單一療法或與伊立替康、醛葉酸及氟尿嘧啶之組合。在研究之單一療法臂中,在各28天週期之第1至28天,經口投與RGX-202每天兩次或三次。劑量方案係依賴於其中登記病患之定群。在研究之組合臂中,RGX-202係以與針對與FOLFIRI組合之單一療法臂描述之方法相同之方法投與。FOLFIRI係藉由在各28天週期之第1天及第15天,靜脈內投與伊立替康(180 mg/m2
),歷時90分鐘,同時靜脈內投與醛葉酸(400 mg/m2
),歷時2小時,接著靜脈內推注氟尿嘧啶(5-FU) (400 mg/m2
)及然後靜脈內輸注5-FU (2400 mg/m2
),歷時46小時投與。
在劑量遞增期間,評估藥物在個體中之藥物動力學(使用如實例1中描述之方法)、藥效學、安全性及效用。
結果:個體不顯示劑量限制性毒性。觀察目標單一療法(RGX-202)及組合療法(RGX-202 + FOLFIRI)活性。在接受組合療法之7個個體中,在治療40週後(例如,RGX-202之劑量≥1,800 mg BID),6個個體顯示穩定疾病(如由RECIST 1.1指導方針描述)。在接受單一療法之10個個體中,一個個體顯示部分反應(在3,600 mg BID之劑量下在40週後),及三個個體顯示穩定疾病(在1,200 mg BID、2,400 mg BID及3,600 mg BID之劑量下)。
其他實施例
儘管本發明已結合其特定實施例描述,但應瞭解其可經進一步修飾且本申請案意欲涵蓋一般遵循本發明之原理之本發明之任何變更、用途或適應性,且包括在本發明所屬領域內之已知或習知實務中且可在闡述前應用於本文之基本特徵之本發明之此等偏離。本申請案主張2019年12月11日申請之美國臨時序列第62/946,581號之權益,其係以全文引用之方式併入本文中。
Claims (21)
- 一種治療有需要個體之癌症之方法,該方法包括每天兩次向該個體投與約1,500 mg至約4,000 mg之β-胍基丙酸(β-GPA)或其醫藥上可接受之鹽。
- 如請求項1之方法,其中該方法包括每天兩次向該個體投與約2,400 mg至約3,600 mg之β-GPA或其醫藥上可接受之鹽。
- 如請求項1或2之方法,其中該方法包括每天兩次向該個體投與約2,400 mg之β-GPA或其醫藥上可接受之鹽。
- 如請求項1或2之方法,其中該方法包括每天兩次向該個體投與約3,600 mg之β-GPA或其醫藥上可接受之鹽。
- 如請求項1至4中任一項之方法,其中該方法進一步包括投與一或多種其他抗癌療法。
- 如請求項5之方法,其中該等一或多種抗癌療法包含放射療法、手術及/或一或多種治療劑。
- 如請求項5或6之方法,其中該等一或多種其他抗癌療法包含醛葉酸、氟尿嘧啶、伊立替康(irinotecan)及/或奧沙利鉑(oxaliplatin)。
- 如請求項5至7中任一項之方法,其中該等一或多種其他抗癌療法包含醛葉酸、氟尿嘧啶及伊立替康。
- 如請求項8之方法,其中方法包括靜脈內投與約180 mg/m2 之伊立替康,歷時90分鐘,同時靜脈內投與約400 mg/m2 醛葉酸,歷時120分鐘,接著靜脈內輸注約2400 mg/m2 之氟尿嘧啶,歷時46小時。
- 如請求項9之方法,其中該投與係約每十四天重複一次。
- 如請求項5至10中任一項之方法,其中該方法進一步包括手術。
- 如請求項11之方法,其中該手術係在投與β-GPA或其醫藥上可接受之鹽之前。
- 如請求項1至12中任一項之方法,其中該癌症係轉移癌。
- 如請求項1至13中任一項之方法,其中該癌症係胃腸道癌。
- 如請求項14之方法,其中該胃腸道癌係結腸直腸癌、胃癌或食道胃交界之腺癌。
- 如請求項1至15中任一項之方法,其中該癌症表現CKB。
- 如請求項1至16中任一項之方法,其中個體經鑒定為患有轉移癌或處於患有轉移癌之風險下。
- 如請求項1至17中任一項之方法,其中該癌症對一或多種治療劑具有抗性。
- 如請求項1至18中任一項之方法,其中該癌症在使用一或多種抗癌療法之治療時或之後進展。
- 如請求項1至19中任一項之方法,其中該β-GPA或其醫藥上可接受之鹽係β-GPA之琥珀酸鹽。
- 如請求項20之方法,其中β-GPA之該琥珀酸鹽係β-GPA之2:1琥珀酸鹽。
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