TWI415610B - 3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮在治療特定白血病之用途 - Google Patents
3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮在治療特定白血病之用途 Download PDFInfo
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- 229950006929 uredepa Drugs 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
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- 206010046766 uterine cancer Diseases 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
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- XLQGICHHYYWYIU-UHFFFAOYSA-N veramine Natural products O1C2CC3C4CC=C5CC(O)CCC5(C)C4CC=C3C2(C)C(C)C21CCC(C)CN2 XLQGICHHYYWYIU-UHFFFAOYSA-N 0.000 description 1
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Description
本發明係關於用化學名稱為3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮之免疫調節化合物(其亦稱為雷利明(Revlimid)或Revimid)治療、預防或控制白血病之方法。特定言之,本發明包含使用該化合物單獨作為治療劑治療、預防或控制白血病之方法,包括但不限於慢性淋巴細胞白血病、慢性骨髓細胞白血病、急性淋巴母細胞白血病、急性骨髓性白血病及急性骨髓母細胞白血病。
本發明亦包含使用雷利明(Revlimid)與其他療法(例如,放射線療法或其他化學治療劑,包括但不限於抗癌劑、免疫抑制劑及諸如類固醇之消炎藥)之特定組合或"雞尾療法"。本發明亦係關於醫藥組合物及單獨用該化合物作為治療劑之給藥方案。
癌症之特徵主要為源自特定正常組織之異常細胞之數量增加,該等異常細胞侵入鄰近組織,或惡性細胞藉由淋巴或血液擴散至局部淋巴結且至遠處位點(轉移)。臨床資料及分子生物學研究顯示癌症為一種多步過程,其從微小贅瘤前變化開始,該微小贅瘤前變化可在一定條件下發展至贅瘤形成。贅瘤病變可無性系地發展且逐步顯現漸增之侵襲、生長、轉移及異質性能力,尤其在瘤性細胞逃脫宿主之免疫監視的條件下。Roitt,I.、Brostoff,J.及Kale,D.,Immunology
,17.1-17.12(第3版,Mosby,St.Louis,Mo.,1993)。
存在眾多在醫學文獻中詳細描述之癌症。實例包括血癌、肺癌、結腸癌、直腸癌、前列腺癌、乳癌、腦癌及腸癌。癌症(諸如,白血病)之各種形態係描述於2002年5月17日申請之美國臨時申請案第60/380,842號中,該案之全文以引用的方式併入本文中(參見
(例如
)第2.2節:Types of Cancers)。
特定言之,白血病係指造血組織之惡性贅瘤。儘管據報導病毒在動物中引發數種類型之白血病,然在人中白血病之病因在很大程度上係未知的。The Merck Manual
,944-952(第17版,1999)。惡性轉型作用通常經由兩步或兩步以上發生在一單個細胞中,隨後增殖且無性系地擴張。在一些白血病中,已用一致白血病細胞形態及特殊臨床特徵確認特異性染色體易位(例如
,在慢性骨髓細胞白血病中9與22之易位,及在急性前髓細胞白血病中15及17之易位)。急性白血病主要為未分化細胞群體且慢性白血病為更成熟之細胞形態。
急性白血病分為淋巴母細胞(ALL)類型及非淋巴母細胞(ANLL)類型。The Merck Manual
,946-949(第17版,1999)。其可根據英美法(FAB)分類法或根據其分化之類型及程度藉由其形態學及細胞化學外形進一步細分。使用特異性B細胞及T細胞及骨髓抗原單株抗體最為有助於分類。ALL主要為一種兒童疾病,其由實驗室研究結果及骨髓檢查確定。ANLL(亦稱為急性骨髓性白血病或急性骨髓母細胞白血病(AML))在所有年齡皆可發生,且在成年人中為更常見之急性白血病;其為通常與輻射為病原體相關之形態。
將慢性白血病描述為慢性淋巴細胞白血病(CLL)或慢性骨髓細胞白血病(CML)。The Merck Manual
,949-952(第17版,1999)。CLL之特徵為在血液、骨髓及淋巴器官中之成熟淋巴細胞之出現。CLL之特點為持續、絕對之淋巴細胞增多(>5,000/μL)及在骨髓中之淋巴細胞增多。大多數CLL患者之具有B細胞特徵之淋巴細胞亦無性系地擴張。CLL為一種中年或老年疾病。在CML中,典型特徵為在血液、骨髓、肝臟、脾及其他器官中之所有分化階段之顆粒性細胞優勢顯著。在經診斷之表現症狀之患者中,總WBC數通常為約200,000/μL,但可達至1,000,000/μL。CML因存在費城染色體,故相對易於診斷。
隨著總人口老齡化,隨著新癌症逐步顯現且隨著易受影響之人口(例如
,感染AIDS或過度曝露至日光之人群)增多,癌症之發病率持續上升。特定言之,慢性淋巴細胞白血病為一種無法治癒之白血病,對罹患復發或難治癒疾病之患者而言治療劑選擇有限。因此對可用於治療罹患癌症(包括白血病)之患者的新型方法及組合物存在極大需求。
許多類型之癌症與新血管形成(一種稱為血管生成之過程)有關。已闡明涉及腫瘤誘導血管生成之機制中之數者。該等機制中最直接者為由腫瘤細胞分泌具有血管生成性質之細胞激素。該等細胞激素之實例包括酸性及鹼性纖維母細胞生長因子(a,b-FGF)、血管生成素、血管內皮生長因子(VEGF)及TNF-α。或者,腫瘤細胞可經由產生蛋白酶且隨後分解其中儲存一些細胞激素(例如
,b-FGF)之細胞外基質來釋放血管生成肽。血管生成亦可經由招募炎性細胞(特別係巨噬細胞)且炎性細胞隨後釋放血管生成細胞激素(例如
,TNF-α、bFGF)來間接誘導。
因此,可控制血管生成或抑制特定細胞激素(包括TNF-α)產生之化合物可用於治療及預防多種癌症。
當前癌症療法可包括外科手術、化學療法、激素療法及/或放射線治療以在患者中根除瘤性細胞(參見,例如,Stockdale,1998,Medicine
,第3卷,Rubenstein及Federman編,第12章,第IV節)。近來,癌症療法亦可包括生物學療法或免疫療法。所有該等方法皆對患者造成重大不利影響。外科手術(例如)歸因於患者之健康可被視為禁忌或可對患者而言無法接受。另外,外科手術可能無法完全移除贅瘤組織。放射線療法僅當贅瘤組織比正常組織對放射線呈現更高敏感性時方有效。放射線療法亦常可引起嚴重副作用。激素療法很少用作單一療法。儘管激素療法可係有效的,然其常用於在其他治療已移除大部分癌細胞後預防或延緩癌症復發。生物學療法及免疫療法在數量上係有限的,且可產生副作用,諸如,皮疹或腫脹、類流感症狀(包括發熱、寒冷及疲勞)、消化道問題或過敏性反應。
就化學療法而言,存在多種可用於治療癌症之化學治療劑。大部分癌症化學治療劑藉由直接或間接抑制脫氧核糖核苷酸三磷酸前驅體之生物合成來抑制DNA合成以阻止DNA複製及伴隨之細胞分裂而發揮作用。Gilman等人,Goodman and Gilman's:The Pharmacological Basis of Therapeutics
,第10版(McGraw Hill,New York)。
儘管可用多種化學治療劑,然化學療法有許多缺點。Stockdale,Medicine
,第3卷,Rubenstein及Federman編,第12章,第10節,1998。幾乎所有化學治療劑皆有毒性,且化學療法引起顯著且常常危險之副作用,包括嚴重噁心、骨髓抑制及免疫抑制。另外,即使投予化學治療劑之組合,許多腫瘤細胞仍對化學治療劑有抗性或逐步對化學治療劑顯現抗性。事實上,對在治療方案中所使用之特定化學治療劑有抗性之彼等細胞常證實亦對其他藥物有抗性,即使彼等藥劑藉由與彼等在特定治療中所使用之藥物不同之機制來發揮作用。該現象稱為多效耐藥性或多藥耐藥性。由於耐藥性,許多癌症證實以標準化學治療劑之治療方案難治癒。
對治療、預防及控制癌症,特別係對標準治療(諸如,外科手術、放射線療法、化學療法及激素療法)難治癒之疾病,同時降低或避免與習知療法相關之毒性及/或副作用之安全且有效的方法仍存在顯著需求。
已進行許多目標為提供可安全且有效用於治療與TNF-α之異常產生相關之疾病的化合物的研究。參見
(例如
)Marriott,J.B.等人,Expert Opin.Biol.Ther.
1(4):1-8(2001);G.W.Muller等人,Journal of Medicinal Chemistry
39(17):3238-3240(1996);及G.W.Muller等人,Bioorganic & Medicinal Chemistry Letters
8:2669-2674(1998)。一些研究已將焦點集中於一組選定化合物,因該等化合物能有效抑制由LPS刺激之PBMC產生之TNF-α。L.G.Corral等人,Ann.Rheum.Dis.
58:(Suppl I)1107-1113(1999)。該等稱為IMiDs(Celgene Corporation)或免疫調節藥物之化合物顯示不但有效抑制TNF-α,而且抑制LPS誘導之單核細胞IL1β及IL12之產生。LPS誘導之IL6亦由本發明之免疫調節化合物抑制,雖然僅為部分抑制。該等化合物為LPS誘導之IL10之有效刺激劑。同上,IMiDs之特定實例包括但不限於在頒予G.W.Muller等人之美國專利第5,635,517號、第6,281,230號及第6,316,471號中所述之經取代之2-(2,6-二酮基哌啶-3-基)鄰苯二甲醯亞胺及經取代之2-(2,6-二酮基哌啶-3-基)-1-酮基異吲哚。
本發明包含治療、預防或控制特定類型癌症(包括原發性癌症及轉移性癌症及復發、習知化學療法難治癒或有抗性之癌症)之方法。特定言之,本發明之方法包含治療、預防或控制包括復發、難治癒或有抗性之白血病之多種形態之白血病(諸如,慢性淋巴細胞白血病、慢性骨髓細胞白血病、急性淋巴母細胞白血病、急性骨髓性白血病及急性骨髓母細胞白血病)之方法。
該等方法包含將治療或預防有效量之本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥投予需要該治療、預防或控制之患者。在一較佳實施例中,單獨(意即,在無其他化學治療劑下)使用該免疫調節化合物。
在本發明之另一些方法中,本發明之免疫調節化合物係與習知用於治療、預防或控制癌症之療法組合來投藥。該等習知療法之實例包括但不限於外科手術、化學療法、放射線療法、激素療法、生物學療法、免疫療法及其組合。
本發明亦包含包含本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥及一種第二或額外活性劑之醫藥組合物、單一單位劑型及給藥方案。第二活性劑包括藥物或療法或兩者之特定組合或"雞尾療法"。
在方法及組合物中待使用之較佳化合物為3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))。
本發明之第一實施例包含治療、控制或預防癌症之方法,其包含將治療或預防有效量之本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥投予需要該治療、控制或預防之患者。特定言之,本發明之方法包含治療、預防或控制多種形態之白血病(包括但不限於慢性淋巴細胞白血病、慢性骨髓細胞白血病、急性淋巴母細胞白血病、急性骨髓性白血病及急性骨髓母細胞白血病)之方法。在一實施例中,該白血病為難治癒之白血病、復發之白血病,或對化學療法(除本發明之免疫調節化合物以外)有抗性之白血病。
在本發明之一獨立及獨特之實施例中,本發明之免疫調節化合物係與用於治療、控制或預防癌症之另一藥物("第二活性劑")或另一療法組合來投藥。第二活性劑包括小分子及大分子(例如,蛋白質及抗體),其之實例提供於本文中,同時亦包括幹細胞或臍血。可與本發明之免疫調節化合物之投藥組合使用之方法或療法包括但不限於外科手術、輸血、免疫療法、生物學療法、放射線療法及其他目前用於治療、預防或控制癌症之基於非藥物之療法。
本發明亦包含可在本文所揭示之方法中使用之醫藥組合物(例如,單一單位劑型)。特定醫藥組合物包含本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥及一種第二活性劑。
本發明中所使用之化合物包括外消旋化合物、立體異構上富集之化合物或立體異構上純的化合物。在一些實施例中,包括其醫藥學上可接受之鹽、溶劑合物、水合物、籠形物及前藥。本發明中所使用之較佳化合物為分子量小於約1,000 g/mol之小有機分子,且不為蛋白質、肽、寡核苷酸、寡醣或其他大分子。
如本文所使用且除非另有說明,術語"免疫調節化合物"及"IMiDs"(Celgene公司)包含明顯抑制TNF-α、LPS誘導之單核細胞IL1β及IL12且部分抑制IL6產生之小有機分子。本發明之特定免疫調節化合物如下所述。
在最佳實施例中,"本發明之免疫調節化合物"係指3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(來那度胺(lenalidomide),亦稱為雷利明(Revlimid)或Revimid)。該化合物3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮具以下化學結構:
免疫調節化合物之特定實例包括但不限於經取代之苯乙烯的氰基及羧基衍生物,諸如彼等在美國專利第5,929,117號中所揭示者;1-酮基-2-(2,6-二酮基-3-氟哌啶-3-基)異吲哚啉及1,3-二酮基-2-(2,6-二酮基-3-氟哌啶-3-基)異吲哚啉,諸如彼等在美國專利第5,874,448號中所揭示者;美國專利第5,798,368號中所述之經四取代之2-(2,6-二酮基哌啶-3-基)-1-酮基異吲哚啉;1-酮基及1,3-二酮基-2-(2,6-二酮基哌啶-3-基)異吲哚啉,包括但不限於彼等在美國專利第5,635,517號中所揭示者;經取代之2-(2,6-二酮基哌啶-3-基)鄰苯二甲醯亞胺及經取代之2-(2,6-二酮基哌啶-3-基)-1-酮基異吲哚,諸如在美國專利第6,281,230號及第6,316,471號中所述者;美國專利第5,698,579號及第5,877,200號中所揭示之一類非多肽環醯胺;沙立度胺(thalidomide)類似物,包括沙立度胺之水解產物、代謝物及前軀體,諸如彼等在頒予D'Amato之美國專利第5,593,990號、第5,629,327號及第6,071,948號中所述者;及異吲哚-醯亞胺化合物,諸如彼等在美國專利公開案第2003/0096841號及國際申請案第PCT/US01/50401號(國際公開案第WO 02/059106號)中所述者。在此所確認之專利及專利申請案中之每一者之全文以引用的方式併入本文中。本發明之免疫調節化合物不包括沙立度胺。
本發明之免疫調節化合物可購得抑或根據本文中所揭示之專利或專利申請案中所述之方法製備(參見
,例如
美國專利第5,635,517號,其以引用的方式併入本文中)。此外,光學純的化合物可不對稱合成或使用已知解析劑或對掌性管柱以及其他標準合成有機化學技術解析。
如本文所使用且除非另有說明,術語"醫藥學上可接受之鹽"包含術語所指化合物之無毒性酸加成鹽及鹼加成鹽。可接受之無毒性酸加成鹽包括彼等自該項技術中已知之有機及無機酸或鹼(其包括,例如,鹽酸、氫溴酸、磷酸、硫酸、甲磺酸、乙酸、酒石酸、乳酸、丁二酸、檸檬酸、蘋果酸、順丁烯二酸、山梨酸、烏頭酸、水楊酸、鄰苯二甲酸、胚胎酸(embolic acid)、庚酸及其類似物)衍生之鹽。
本質上為酸性之化合物能與多種醫藥學上可接受之鹼形成鹽。可用於製備該等酸性化合物之醫藥學上可接受之鹼加成鹽的鹼為彼等形成無毒性鹼加成鹽(亦即,含有藥理學上可接受之陽離子之鹽,諸如但不限於鹼金屬或鹼土金屬鹽且特別係鈣、鎂、鈉或鉀鹽)之鹼。合適有機鹼包括但不限於N,N-二苄基乙二胺、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、甲葡胺(N-甲基葡糖胺)、離胺酸及普魯卡因。
如本文所使用且除非另有說明,術語"前藥"意謂化合物之衍生物,該衍生物可在生物學條件下(活體外或活體內)水解、氧化或以別的方式反應以提供該化合物。前藥之實例包括但不限於本發明之免疫調節化合物之包含可生物水解部分的衍生物,諸如,可生物水解之醯胺、可生物水解之酯、可生物水解之胺基甲酸酯、可生物水解之碳酸酯、可生物水解之醯脲及可生物水解之磷酸酯類似物。前藥之其他實例包括本發明之免疫調節化合物之包含-NO、-NO2
、-ONO或-ONO2
部分的衍生物。前藥通常可使用熟知之方法製備,諸如彼等在Burger's Medicinal Chemistry and Drug Discovery
,172-178,949-982(Manfred E.Wolff編,第5版,1995)及Design of Prodrugs
(H.Bundgaard編,Elselvier,New York 1985)中所述之方法。
如本文所使用且除非另有說明,術語"可生物水解之醯胺"、"可生物水解之酯"、"可生物水解之胺基甲酸酯"、"可生物水解之碳酸酯"、"可生物水解之醯脲"、"可生物水解之磷酸酯"分別意謂化合物之醯胺、酯、胺基甲酸酯、碳酸酯、醯脲或磷酸酯,其:1)不干擾化合物之生物學活性但可使彼化合物在活體內具有利性質,諸如,吸收、作用持續時間或作用開始;抑或2)在生物學上無活性,但在活體內轉變成生物學上有活性的化合物。可生物水解之酯之實例包括但不限於低碳烷基酯、低碳醯氧基烷基酯(諸如,乙醯氧基甲酯、乙醯氧基乙酯、胺基甲醯氧基甲酯、特戊醯氧甲酯及特戊醯氧乙酯)、內酯基酯(諸如,酞基及硫代酞基酯)、低碳烷氧基醯氧基烷基酯(諸如,甲氧基甲醯氧基甲酯、乙氧基甲醯氧基乙酯及異丙氧基甲醯氧基乙酯)、烷氧基烷基酯、膽鹼酯及醯胺基烷基酯(諸如,乙醯胺基甲酯)。可生物水解之醯胺之實例包括但不限於低碳烷基醯胺、α-胺基酸醯胺、烷氧基醯基醯胺及烷胺基烷基羰基醯胺。可生物水解之胺基甲酸酯之實例包括但不限於低碳烷基胺、經取代之乙二胺、胺基酸、羥烷基胺、雜環胺及雜芳族胺及聚醚胺。
本發明之免疫調節化合物含有一對掌性中心,且因此可作為R與S對映異構體之外消旋混合物而存在。本發明包含使用本化合物之立體異構上純的形態,同時亦包含使用彼等形態之混合物。例如,包含等量或不等量對映異構體之混合物可用於本發明之方法及組合物中。該等異構體可不對稱合成或使用標準技術(諸如,對掌性管柱或對掌性解析劑)解析。參見
(例如
)Jacques,J.等人,Enantiomers,Racemates and Resolutions
(Wiley-Interscience,New York,1981);Wilen,S.H.等人,Tetrahedron
33:2725(1977);Eliel,E.L.,Stereochemistry of Carbon Compounds
(McGraw-Hill,NY,1962);及Wilen,S.H.,Tables of Resolving Agents and Optical Resolutions
,第268頁(E.L.Eliel編,Univ.of Notre Dame Press,Notre Dame,IN,1972)。
除非另有說明,本文所使用術語"立體異構上純"意謂包含化合物之一種立體異構體且大體上無該化合物之其他立體異構體的組合物。例如,具有一個對掌性中心之化合物之立體異構上純的組合物大體上無該化合物之相反的對映異構體。具有兩個對掌性中心之化合物之立體異構上純的組合物大體上無該化合物之其他非對映異構體。典型立體異構上純的化合物包含大於約80重量%的該化合物的一種立體異構體及小於約20重量%的該化合物的其他立體異構體,更佳為包含大於約90重量%的該化合物的一種立體異構體及小於約10重量%的該化合物的其他立體異構體,尤佳為包含大於約95重量%的該化合物的一種立體異構體及小於約5重量%的該化合物的其他立體異構體,且最佳為包含大於97重量%的該化合物的一種立體異構體及小於約3重量%的該化合物的其他立體異構體。除非另有說明,本文所使用術語"立體異構上富集"意謂一種組合物,其包含大於約60重量%的化合物的一種立體異構體,較佳為大於約70重量%,更佳為大於約80重量%的化合物的一種立體異構體。除非另有說明,本文所使用術語"對映異構上純"意謂具有一個對掌性中心之化合物之對映異構上純的組合物。同樣地,術語"立體異構上富集"意謂具有一個對掌性中心之化合物之立體異構上富集的組合物。換言之,本發明包含在該等方法中使用免疫調節化合物之R或S對映異構體。
應注意若圖示結構與賦予彼結構的名稱之間存在差異,則應更加以該圖示結構為準。此外,若某一結構或某一結構之部分的立體化學未用(例如)粗線或虛線表示,則應將該結構或該結構之部分理解為包含其所有立體異構體。
本發明之免疫調節化合物可在本發明之方法及組合物中與其他藥理學上活性之化合物("第二活性劑")一起或組合使用。咸信特定組合在治療特殊類型癌症及特定與不恰當之血管生成相關,或特徵為不恰當之血管生成之疾病及病症中發揮增效作用。本發明之免疫調節化合物亦可用來減輕與特定第二活性劑相關之副作用,且一些第二活性劑可用於減輕與本發明之免疫調節化合物相關之副作用。
一或多種第二活性成份或藥劑可與本發明之免疫調節化合物一起用於本發明之方法及組合物中。第二活性劑可為大分子(例如
,蛋白質)或小分子(例如
,合成無機分子、有機金屬分子或有機分子)。
大分子活性劑之實例包括但不限於造血生長因子、細胞激素及單株抗體以及多株抗體。典型大分子活性劑為生物學分子,諸如自然存在或人造之蛋白質。特別可用於本發明之蛋白質包括在活體外或活體內刺激造血前體細胞及免疫學上活性之造血細胞存活及/或增殖的蛋白質。其他則在活體外或活體內刺激細胞中之定向紅血球系祖細胞分裂及分化。特定蛋白質包括但不限於:介白素,諸如IL-2(包括重組體IL-II("rIL2")及金絲雀痘IL-2)、IL-10、IL-12及IL-18;干擾素,諸如干擾素α-2a、干擾素α-2b、干擾素α-n1、干擾素α-n3、干擾素β-I a及干擾素γ-I b;GM-CF及GM-CSF;及EPO。
可用於本發明之方法及組合物之特定蛋白質包括但不限於:非格司亭(filgrastim),其以商標名Neupogen(Amgen,Thousand Oaks,CA)在美國出售;沙格司亭(sargramostim),其以商標名Leukine(Immunex,Seattle,WA)在美國出售;及重組體EPO,其以商標名Epogen(Amgen,Thousand Oaks,CA)在美國出售。
GM-CSF之重組體及突變形態可如美國專利第5,391,485號、第5,393,870號及第5,229,496號中所述製備,所有該等專利皆以引用的方式併入本文中。G-CSF之重組體及突變形態可如美國專利第4,810,643號、第4,999,291號、第5,528,823號及第5,580,755號中所述製備,所有該等專利皆以引用的方式併入本文中。
本發明包含使用天然、自然存在之蛋白質及重組蛋白質。本發明進一步包含自然存在之蛋白質之在活體內展現其所基於之蛋白質的至少一些藥理學活性的突變體及衍生物(例如,改質形態)。突變體之實例包括但不限於具有一或多個不同於蛋白質之自然存在形態中相應殘基之胺基酸殘基的蛋白質。術語"突變體"亦包含缺乏通常以其自然存在形態存在之碳水化合物部分的蛋白質(例如,非糖基化形態)。衍生物之實例包括但不限於聚乙二醇化衍生物及融合蛋白質,諸如藉由將IgG1或IgG3與感興趣之蛋白質或該蛋白質之活性部分融合而形成之蛋白質。參見(例如)Penichet,M.L.及Morrison,S.L.,J.Immunol.Methods
248:91-101(2001)。
可用於與本發明之化合物組合使用之抗體包括單株抗體及多株抗體。抗體之實例包括但不限於曲妥珠單抗(trastuzumab,Herceptin)、利妥昔單抗(rituximab,Rituxan)、貝伐單抗(bevacizumab,AvastinT M
)、帕妥珠單抗(pertuzumab,OmnitargT M
)、托西莫單抗(tositumomab,Bexxar)、依決洛單抗(edrecolomab,Panorex)及G250。本發明之化合物亦可組合抗TNF-α抗體或與抗TNF-α抗體組合使用。
大分子活性劑可以抗癌疫苗形式投藥。例如,可分泌諸如IL-2、G-CSF及GM-CSF之細胞激素或導致該等細胞激素之分泌的疫苗可用於本發明之方法、醫藥組合物及套組中。參見(例如)Emens,L.A.等人,Curr.Opinion Mol.Ther.
3(1):77-84(2001)。
在本發明之一實施例中,大分子活性劑減輕、消除或預防與本發明之免疫調節化合物之投藥相關之不利作用。視本發明之特定免疫調節化合物及開始治療之疾病或病症而定,不利作用可包括但不限於困倦及嗜眠、頭腦昏沉及起立性低血壓、嗜中性球減少症、由嗜中性球減少症引起之感染、增加之HIV病毒負荷、心跳遲緩、史蒂芬-瓊森(Stevens-Johnson)症候群及中毒性表皮壞死溶解,及抽搐(例如
,癲癇大發作抽搐)。特定不利作用為嗜中性球減少症。
小分子第二活性劑亦可用於減輕與本發明之免疫調節化合物之投藥相關之不利作用。然而,與一些大分子相似,據信許多小分子能在與本發明之免疫調節化合物一起(例如,在本發明之免疫調節化合物投藥之前、之後或同時)投藥時提供協同作用。小分子第二活性劑之實例包括但不限於抗癌劑、抗生素、免疫抑制劑及類固醇。
抗癌劑之實例包括但不限於:阿西維辛(acivicin);阿柔比星(aclarubicin);鹽酸阿考達唑(acodazole hydrochloride);阿克羅寧(acronine);阿多來新(adozelesin);阿地白介素(aldesleukin);六甲蜜胺(altretamine);安波黴素(ambomycin);乙酸阿美蒽醌(ametantrone acetate);安吖啶(amsacrine);安美達錠(anastrozole);安麯黴素(anthramycin);天門冬醯胺酶;曲林菌素(asperlin);阿紮胞苷(azacitidine);阿紮替派(azetepa);阿佐黴素(azotomycin);巴馬司他(batimastat);苯佐替派(benzodepa);比卡魯胺(bicalutamide);鹽酸比生群(bisantrene hydrochloride);雙奈法德(bisnafide)二甲磺酸鹽;比折來新(bizelesin);硫酸博萊黴素(bleomycin sulfate);布喹那鈉(brequinar sodium);溴匹立明(bropirimine);白消安(busulfan);放線菌素C(cactinomycin);卡普睾酮(calusterone);卡醋胺(caracemide);卡貝替姆(carbetimer);卡鉑(carboplatin);卡莫司汀(carmustine);鹽酸卡柔比星(carubicin hydrochloride);卡折來新(carzelesin);西地芬戈(cedefingol);賽利克西(celecoxib,COX-2抑制劑);苯丁酸氮芥(chlorambucil);西羅黴素(cirolemycin);順鉑(cisplatin);克拉屈濱(cladribine);克司那托(crisnatol)甲磺酸鹽;環磷醯胺;阿糖胞苷(cytarabine);達卡巴嗪(dacarbazine);放線菌素D(daetinomycin);鹽酸道諾黴素(daunorubicin hydrochloride);地西他濱(decitabine);右奧馬鉑(dexormaplatin);地紮胍寧(dezaguanine);地紮胍寧甲磺酸鹽;地吖醌(diaziquone);多西他賽(docetaxel);阿黴素(doxorubicin);鹽酸阿黴素;屈洛昔芬(droloxifene);檸檬酸屈洛昔芬;丙酸屈他雄酮(dromostanolone);偶氮黴素(duazomycin);依達曲沙(edatrexate);鹽酸依氟鳥胺酸(eflornithine hydrochloride);依沙蘆星(elsamitrucin);恩絡鉑(enloplatin);恩普胺酯(enpromate);依匹哌啶(epipropidine);鹽酸表柔比星(epirubicin hydrochloride);厄布洛唑(erbulozole);鹽酸依索比星(esorubicin hydrochloride);雌莫司汀(estramustine);雌莫司汀磷酸鈉;依他硝唑(etanidazole);依託泊苷(etoposide);磷酸依託泊苷;依託平(etoprine);鹽酸法屈唑(fadrozole hydrochloride);法紮拉濱(fazarabine);芬維A胺(fenretinide);氟尿苷(floxuridine);氟達拉賓磷酸鹽(fludarabine phosphate);氟尿嘧啶(fluorouracil);氟西他濱(flurocitabine);磷喹酮(fosquidone);福司曲星鈉(fostriecin soudium);吉西他濱(gemcitabine);鹽酸吉西他濱;羥基脲;鹽酸黃膽素(idarubicin hydrochloride);異環磷醯胺;伊莫福新(ilmofosine);異丙鉑(iproplatin);伊立替康(irinotecan);鹽酸伊立替康;乙酸蘭瑞肽(lanreotide acetate);來曲唑(letrozole);乙酸亮丙瑞林(leuprolide acetate);鹽酸利阿唑(liarozole hydrochloride);洛美曲索鈉(lometrexol sodium);洛莫司汀(lomustine);鹽酸洛索蒽醌(losoxantrone hydrochloride);馬索羅酚(masoprocol);美登素(maytansine);鹽酸氮芥(mechlorethamine hydrochloride);乙酸甲地孕酮(megestrol acetate);乙酸美侖孕酮(melengestrol acetate);美法侖(melphalan);美諾立爾(menogaril);巰嘌呤;甲胺喋呤;甲胺喋呤鈉;美托平(metoprine);美妥替哌(meturedepa);米丁度胺(mitindomide);米托卡星(mitocarcin);米托考明(mitocromin);米托潔林(mitogillin);米托馬星(mitomalcin);絲裂黴素(mitomycin);米托司培(mitosper);米托坦(mitotane);鹽酸米托蒽醌(mitoxantrone hydrochloride);黴酚酸;諾考達唑(nocodazole);諾加黴素(nogalamycin);奧馬鉑(ormaplatin);奧昔舒侖(oxisuran);紫杉醇(paclitaxel);培門冬酶(pegaspargase);培利黴素(peliomycin);奈莫司汀(pentamustine);硫酸培洛黴素(peplomycin sulfate);培磷醯胺(perfosfamide);哌泊溴烷(pipobroman);哌泊舒凡(piposulfan);鹽酸吡羅蒽醌(piroxantrone hydrochloride);普卡黴素(plicamycin);普洛美坦(plomestane);蔔吩姆鈉(porfimer sodium);甲基絲裂黴素(porfiromycin);潑尼莫司汀(prednimustine);鹽酸甲基苄肼;嘌呤黴素;鹽酸嘌呤黴素;吡唑呋喃菌素;利波腺苷(riboprine);沙芬戈(safingol);鹽酸沙芬戈;司莫司汀(semustine);辛曲秦(simtrazene);司巴福賽鈉(sparfosate sodium);稀疏黴素(sparsomycin);鹽酸鍺螺胺(spirogermanium hydrochloride);螺莫司汀(spiromustine);螺鉑(spiroplatin);鏈黑菌素;鏈脲黴素(streptozocin);磺氯苯脲(sulofenur);他利黴素(talisomycin);泰克戈蘭鈉(tecogalan sodium);克癌易(taxotere);喃氟啶(tegafur);鹽酸替洛蒽醌(teloxantrone hydrochloride);替莫泊芬(temoporfin);替尼泊甙(teniposide);替羅昔隆(teroxirone);睾內酯(testolactone);塞米平(thiamiprine);硫鳥嘌呤;噻替派(thiotepa);噻唑羧胺核苷;替拉紮明(tirapazamine);檸檬酸托瑞米芬(toremifene citrate);乙酸曲托龍(trestolone acetate);磷酸曲西立濱(triciribine phosphate);三甲曲沙(trimetrexate);三甲曲沙葡糖醛酸鹽;曲普瑞林(triptorelin);鹽酸妥布氯唑(tubulozole hydrochloride);烏拉莫司汀(uracil mustard);烏瑞替派(uredepa);伐普肽(vapreotide);維替泊芬(verteporfin);硫酸長春鹼;硫酸長春新鹼;長春地辛(vindesine);硫酸長春地辛;硫酸長春匹定(vinepidine sulfate);硫酸長春甘酯(vinglycinate sulfate);硫酸長春羅新(vinleurosine sulfate);酒石酸長春瑞賓(vinorelbine tartrate);硫酸長春羅定(vinrosidine sulfate);硫酸長春利定(vinzolidine sulfate);伏羅唑(vorozole);折尼鉑(zeniplatin);淨司他丁(zinostatin);及鹽酸佐柔比星(zorubicin hydrochloride)。
其他抗癌藥物包括但不限於:20-表-1,25二羥維生素D3;5-乙炔尿嘧啶;阿比特龍(abiraterone);阿柔比星;阿塞弗威(acylfulvene);阿丹斯弗(adecypenol);阿多來新;阿地白介素(aldesleukin);ALL-TK拮抗劑;六甲蜜胺;胺莫司汀(ambamustine);羥胺;阿米福汀(amifostine);胺基乙醯丙酸;胺柔比星(amrubicin);安吖啶;阿那格雷(anagrelide);安美達錠;穿心蓮內酯(andrographolide);血管生成抑制劑;拮抗劑D;拮抗劑G;安泰立克(antarelix);抗背部化形態發生蛋白-1;抗雄激素(前列腺癌);抗雌激素;抗新普拉通(antineoplaston);反義寡核苷酸;甘胺酸阿非迪黴素(aphidicolin glycinate);細胞凋亡基因調節劑;細胞凋亡調控劑;脫嘌呤核酸;ara-CDP-DL-PTBA;精胺酸脫胺酶;阿蘇拉昆(asulacrine);阿他美坦(atamestane);阿莫司汀(atrimustine);阿司他丁(axinastatin)1;阿司他丁2;阿司他丁3;阿紮司瓊(azasetron);阿紮毒素(azatoxin);重氮酪胺酸;漿果赤黴素III衍生物;巴拉諾(balanol);巴馬司他(batimastat);BCR/ABL拮抗劑;苯幷二氫卟吩(benzochlorin);苄醯基星形孢菌素;β-內醯胺衍生物;β-阿立賽恩(beta-alethine);β-卡拉黴素B(betaclamycin B);白樺脂酸(betulinic acid);bFGF抑制劑;必卡特醯胺(bicalutamide);比生群(bisantrene);比沙自丁精胺(bisaziridinylspermine);雙奈法德;比司徒汀A(bistratene A);比折來新;比福來特(breflate);溴匹立明;布度鈦(budotitane);丁硫胺酸亞碸胺(buthionine sulfoximine);鈣泊三醇(calcipotriol);卡福司汀C(calphostin C);喜樹鹼(camptothecin)衍生物;卡西他賓(capecitabine);羧醯胺-胺基-三唑;羧基胺咪唑;卡瑞司特M3(CaRest M3);CARN 700;軟骨源抑制劑;卡折來新;酪蛋白激酶抑制劑(ICOS);栗樹精胺(castanospermine);抗菌肽天蠶素B(cecropin B);西曲瑞克(cetrorelix);克羅瑞林(chlorlns);氯喹喏啉磺醯胺;西卡前列素(cicaprost);順卟啉;克拉屈濱(cladribine);氯米芬(clomifene)類似物;克黴唑(clotrimazole);克裏司黴素A(collismycin A);克裏司黴素B;康布瑞塔卡汀A4(combretastatin A4);康布瑞塔卡汀類似物;克那介寧(conagenin);克然姆貝司丁(crambescidin)816;克司那托;克來普拓素8(cryptophycin 8);克來普拓素A衍生物;庫若司A(curacin A);環戊蒽醌;環普蘭他姆(cycloplatam);賽匹黴素(cypemycin);阿糖胞苷奧克佛司非特(cytarabine ocfosfate);溶胞因子;細胞抑制素;達昔單抗(dacliximab);地西他濱;脫氫膜海鞘素B(dehydrodidemnin B);地洛瑞林(deslorelin);地塞米松(dexamethasone);右異環磷醯胺;右雷佐生(dexrazoxane);右維拉帕米(dexverapamil);地吖醌;膜海鞘素B;代道克司(didox);二乙基諾精胺(diethylnorspermine);二氫-5-氮雜胞苷(dihydro-5-azacytidine);9-二氫紫杉醇(dihydrotaxol);二噁黴素(dioxamycin);二苯基螺莫司汀;多西他賽;二十二烷醇(docosanol);多拉司瓊(dolasetron);去氧氟尿苷;阿黴素;屈洛昔芬;屈大麻酚(dronabinol);多卡黴素SA(duocarmycin SA);依布硒(ebselen);依考莫司汀(ecomustine);依地福新(edelfosine);依決洛單抗;依氟鳥胺酸;欖香烯(elemene);乙嘧替氟(emitefur);表柔比星;愛普列特(epristeride);雌莫司汀類似物;雌激素促效劑;雌激素拮抗劑;依他硝唑;依託泊苷磷酸鹽;依西美坦(exemestane);法屈唑;法紮拉濱;芬維A胺;非格司亭;非那雄安(finasteride);弗來匹日多(flavopiridol);氟卓斯汀(flezelastine);弗斯特榮(fluasterone);氟達拉賓;鹽酸氟道諾黴素;福酚美克(forfenimex);福美司坦(formestane);福司曲星;福莫司汀(fotemustine);德卟啉釓(gadolinium texaphyrin);硝酸鎵;加洛他濱(galocitabine);加尼瑞克(ganirelix);明膠酶抑制劑;吉西他濱;麩胱甘肽抑制劑;赫普薩發(hepsulfam);赫穀林(heregulin);六亞甲基二乙醯胺;金絲桃素(hypericin);伊班膦酸(ibandronic acid);黃膽素;艾多昔芬(idoxifene);伊決孟酮(idramantone);伊莫福新;伊洛馬司他(ilomastat);伊馬替尼(imatinib)(例如,Gleevec);咪喹莫特(imiquimod);免疫刺激肽;胰島素樣生長因子-1受體抑制劑;干擾素促效劑;干擾素;介白素;碘苄胍(iobenguane);碘阿黴素(iododoxorubicin);4-甘薯醇(4-ipomeanol);伊羅普拉(iroplact);異苯各唑(isobengazole);異同源軟海綿素B(isohomohalicondrin B);伊他司瓊(itasetron);加斯普勒肯萊德(jasplakinolide);卡哈拉裏得F(kahalalide F);三乙酸層狀素N(lamellarin-N triacetate);蘭瑞肽;雷那黴素(leinamycin);來格司亭(lenograstim);硫酸香菇多糖(lentinan sulfate);樂普托司他丁(leptolstatin);來曲唑;白血病抑制因子;白細胞α干擾素;亮丙瑞林(leuprolide)+雌激素+孕酮;亮丙瑞林(leuprorelin);左旋咪唑(levamisole);利阿唑;線性多胺類似物;親脂性雙糖肽;親脂性鉑化合物;利塞克林醯胺7(lissoclinamide 7);洛鉑(lobaplatin);蚯蚓胺酸(lombricine);洛美曲索;氯尼達明(lonidamine);洛索蒽醌;洛索立賓(loxoribine);勒托替康(lurtotecan);德卟啉鑥(lutetium texaphyrin);立塞福林(lysofylline);溶菌肽(lytic peptide);美坦新(maitansine);麻那司他丁A(mannostatin A);馬立馬司他(marimastat);馬索羅酚;麥斯平(maspin);基質金屬蛋白酶7(matrilysin)抑制劑;基質金屬蛋白酶抑制劑;美諾立爾;麥爾巴隆(merbarone);麥特瑞林(meterelin);蛋胺酶(methioninase);甲氧氯普胺(metoclopramide);MIF抑制劑;美服培酮(mifepristone);米替福新(miltefosine);米立司亭(mirimostim);米托胍腙(mitoguazone);二溴衛矛醇(mitolactol);絲裂黴素類似物;米托萘胺(mitonafide);米托毒素(mitotoxin)成纖維細胞生長因子-沙泊寧(saporin);米托蒽醌;莫法羅汀(mofarotene);莫拉司亭(molgramostim);艾比特思(Erbitux);人絨毛膜促性腺激素;單磷醯脂A+分枝桿菌細胞壁鏈激酶;莫哌達醇(mopidamol);莫司汀(mustard)抗癌劑;印度洋海綿B(mycaperoxide B);分枝桿菌細胞壁提取物;米瑞普榮(myriaporone);N-乙醯基地那林(N-acetyldinaline);N-經取代之苄醯胺;那法瑞林(nafarelin);那格瑞斯替(nagrestip);納洛酮(naloxone)+戊唑星(pentazocine);那帕威(napavin);那福特平(naphterpin);那托司亭(nartograstim);奈達鉑(nedaplatin);奈莫柔比星(nemorubicin);奈立膦酸(neridronic acid);尼魯米特(nilutamide);尼沙黴素(nisamycin);氧化氮調節劑;氮氧化物抗氧化劑;尼曲林(nitrullyn);奧利默森(Genasense);O6
-苄基鳥嘌呤;奧曲肽(octreotide);奧克斯諾(okicenone);寡核苷酸;奧那司酮(onapristone);昂丹司瓊(ondansetron);昂丹司瓊;奧讓司(oracin);口服細胞激素誘導劑;奧馬鉑(ormaplatin);奧沙特隆(osaterone);奧賽力鉑(oxaliplatin);奧克諾黴素(oxaunomycin);紫杉醇(paclitaxel);紫杉醇類似物;紫杉醇衍生物;帕拉胺(palauamine);十六醯基利索新(palmitoylrhizoxin);帕米膦酸(pamidronic acid);人參三醇(panaxytriol);帕諾米芬(panomifene);副菌鐵素(parabactin);帕折普汀(pazelliptine);培門冬酶;培爾得辛(peldesine);聚戊醣多硫化鈉;噴司他丁(pentostatin);噴曲唑(pentrozole);全氟溴烷(perflubron);培磷醯胺;芥子醇(perillyl alcohol);菲那嗪黴素(phenazinomycin);苯乙酸酯;磷酸酶抑制劑;必醫你舒(picibanil);鹽酸毛果芸香鹼(pilocarpine hydrochloride);吡柔比星(pirarubicin);吡曲克辛(piritrexim);普萊斯汀A(placetin A);普萊斯汀B;血纖維蛋白溶酶原活化因子抑制劑;鉑錯合物;鉑化合物;鉑-三胺錯合物;蔔吩姆鈉;甲基絲裂黴素;潑尼松(prednisone);丙基雙-吖啶酮;前列腺素J2;蛋白酶體抑制劑;基於蛋白質A之免疫調節劑;蛋白激酶C抑制劑;蛋白激酶C抑制劑;微藻;蛋白酪胺酸磷酸酶抑制劑;嘌呤核苷酸磷酸化酶抑制劑;羥基茜草素(purpurin);9-甲氧基吡唑啉吖啶(pyrazoloacridine);吡啶氧基化血色素聚氧伸乙基共軛物;raf拮抗劑;雷替曲塞(raltitrexed);拉莫司瓊(ramosetron);ras法呢基(farnesyl)蛋白質轉移酶抑制劑;ras抑制劑;ras-GAP抑制劑;脫甲基之若特立普汀(retelliptine);錸Re 186依替膦酸鹽;利索新;核糖核酸酶;維生素A醯胺II(RII retinamide);羅希吐鹼(rohitukine);羅莫肽(romurtide);羅喹美克(roquinimex);羅必金B1(rubiginone B1);羅泊奧克司(ruboxyl);沙芬戈;賽恩托平(saintopin);SarCNU;薩克菲托A(sarcophytol A);沙格司亭;Sdi 1模擬劑;司莫司汀;衰老源抑制劑1;正義寡核苷酸;信號轉導抑制劑;西佐喃(sizofiran);索布佐生(sobuzoxane);硼卡鈉(sodium borocaptate);苯乙酸鈉;索戊繞(solverol);生長介素結合蛋白;索納明(sonermin);斯帕福斯酸(sparfosic acid);斯必克黴素D(spicamycin D);螺莫司汀;斯泊萊諾噴汀(splenopentin);斯泊基司他丁1(spongistatin 1);角鯊胺(squalamine);斯第匹醯胺(stipiamide);基質溶素抑制劑;薩菲諾辛(sulfinosine);超活性血管活性腸肽拮抗劑;蘇若第斯他(suradista);蘇拉明(suramin);苦馬豆素(swainsonine);他莫司汀(tallimustine);它莫西芬甲碘化物(tamoxifen methiodide);牛磺莫司汀(tauromustine);他紮羅汀(tazarotene);泰克戈蘭鈉;喃氟啶;泰勒阿匹日列(tellurapyrylium);端粒酶抑制劑;替莫泊芬;替尼泊甙;四氯代可奧克賽(tetrachlorodecaoxide);四舟閩(tetrazomine);薩立布拉斯汀(thaliblastine);賽克讓林(thiocoraline);血小板生成素;血小板生成素模擬劑;胸腺法新(thymalfasin);促胸腺生成素受體促效劑;胸腺曲南(thymotrinan);促甲狀腺激素;乙基錫初紫紅素(tin ethyl etiopurpurin);替拉紮明;二氯二茂鈦(bichloride);托普賽汀(topsentin);托瑞米芬;翻譯抑制劑;維生素A酸(tretinoin);三乙醯尿苷(triacetyluridine);曲西立濱;三甲曲沙;曲普瑞林;托烷司瓊(tropisetron);妥羅雄脲(turosteride);酪胺酸激酶抑制劑;酪胺酸磷酸化抑制劑(tyrphostin);UBC抑制劑;烏苯美司(ubenimex);尿生殖竇源生長抑制因子;尿激酶受體拮抗劑;伐普肽(vapreotide);烏瑞林B(variolin B);維拉雷瑣(velaresol);烏厄胺(veramine);綠素(verdin);維替泊芬;長春瑞濱;維克塞汀(vinxaltine);維特新(vitaxin);伏羅唑;紮諾特隆(zanoterone);折尼鉑(zeniplatin);亞苄維C(zilascorb);及淨司他丁斯酯(zinostatin stimalamer)。
特定第二活性劑包括但不限於利妥昔單抗、奧利默森(Genasense)、英利昔單抗(remicade)、多西他賽、賽利克西、美法侖、地塞米松(Decadron)、類固醇、吉西他濱、順鉑(cisplatinum)、替莫唑胺(temozolomide)、依託泊苷、環磷醯胺、替莫唑胺(temodar)、卡鉑、甲基苄肼、卡莫司汀(gliadel)、它莫西芬、拓朴替康(topotecan)、甲胺喋呤、Arisa、紫杉醇鹼、克癌易、氟尿嘧啶、亞葉酸鈣(leucovorin)、伊立替康、希羅達(xeloda)、CPT-11、干擾素α、聚乙二醇化干擾素α(例如,PEG INTRON-A)、卡西他賓、順鉑(cisplatin)、噻替派、氟達拉賓、卡鉑、脂質體道諾黴素、阿糖胞苷、道克司他可(doxetaxol)、紫杉醇(pacilitaxel)、長春鹼、IL-2、GM-CSF、達卡巴嗪、長春瑞濱、唑來膦酸(zoledronic acid)、帕米曲內特(palmitronate)、巴厄新(biaxin)、白消安(busulphan)、潑尼松、雙膦酸鹽、三氧化二砷、長春新鹼、阿黴素(Doxil)、紫杉醇(paclitaxel)、更昔洛韋(ganciclovir)、阿黴素(adriamycin)、雌莫司汀磷酸鈉(Emcyt)、舒林酸(sulindac)及依託泊苷。
本發明之方法包含治療、預防或控制多種類型之癌症之方法。在一較佳實施例中,本發明之方法包含治療、預防或控制多種類型之白血病(諸如,慢性淋巴細胞白血病、慢性骨髓細胞白血病、急性淋巴母細胞白血病、急性骨髓性白血病及急性骨髓母細胞白血病)之方法。
如本文所使用,除非另有規定,術語"治療"係指在特定疾病或病症之症狀發作後投予本發明之化合物或其他額外活性劑。如本文所使用,除非另有視定,術語"預防"係指在症狀發作前投藥,特別對處於患癌症(且尤其係白血病)風險中之患者而言。術語"預防"包括抑制特定疾病或病症之症狀。有癌症或白血病家族史之患者尤其為預防性療法之較佳候選人。如本文所使用且除非另有說明,術語"控制"包含在已罹患特定疾病或病症之患者中預防該疾病或病症復發,延長已罹患該疾病或病症之患者保持在症狀緩解下之時間,及/或降低患者之死亡率。
如本文所使用,術語"癌症"包括但不限於實體腫瘤及血液生腫瘤。術語"癌症"係指皮膚組織、器官、血液及脈管之疾病,包括但不限於膀胱癌、骨癌或血癌、腦癌、乳癌、子宮頸癌、胸癌、結腸癌、子宮內膜癌、食道癌、眼癌、頭部癌、腎癌、肝癌、淋巴結癌、肺癌、口腔癌、頸部癌、卵巢癌、胰腺癌、前列腺癌、直腸癌、胃癌、睾丸癌、喉癌及子宮癌。
術語"白血病"係指造血組織之惡性腫瘤。白血病包括但不限於慢性淋巴細胞白血病、慢性骨髓細胞白血病、急性淋巴母細胞白血病、急性骨髓性白血病及急性骨髓母細胞白血病。白血病可復發,以習知療法難治癒或有抗性。術語"復發"係指在治療後白血病症狀已緩解之患者骨髓中之白血病細胞恢復且正常血細胞減少的狀況。術語"難治癒或有抗性"係指即使在強化治療後患者之骨髓中仍有殘餘白血病細胞之狀況。
多種類型之癌症係描述於2002年5月17日申請之美國臨時申請案第60/380,842號中,該案之全文以引用的方式併入本文中(參見
,例如
第2.2節:Types of Cancers)。特殊癌症包括但不限於白血病(諸如,慢性淋巴細胞白血病、慢性骨髓細胞白血病、急性淋巴母細胞白血病、急性骨髓性白血病及急性骨髓母細胞白血病);晚期惡性腫瘤、澱粉樣變性病、神經母細胞瘤、腦膜瘤、血管外皮瘤、多發性腦轉移瘤、多形性膠質母細胞瘤、神經膠母細胞瘤、腦幹膠質細胞瘤、不良預後惡性腦瘤、惡性神經膠質瘤、復發之惡性神經膠質瘤、惡性星細胞瘤、惡性少突神經膠質瘤、神經內分泌腫瘤、直腸腺癌、杜克斯(Dukes)C & D結直腸癌、不能切除之結直腸癌、轉移性肝細胞癌、卡波西氏肉瘤(Kaposi's sarcoma)、卡羅型(karotype)急性骨髓母細胞白血病、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤、皮膚T-細胞淋巴瘤、皮膚B-細胞淋巴瘤、彌漫性大B細胞淋巴瘤、低分級濾泡性淋巴瘤、惡性黑素瘤、惡性間皮瘤、惡性胸膜滲出液間皮瘤綜合症、腹膜癌、漿液性乳頭狀癌、婦科肉瘤、軟組織肉瘤、硬皮病、皮膚血管炎、朗格漢斯(Langerhans)細胞性組織細胞增生症、平滑肌肉瘤、進行性肌肉骨化症、激素抵抗性前列腺癌、可切除之高風險軟組織肉瘤、不可切除之肝細胞癌、瓦爾登斯特倫巨球蛋白血症(Waldenstrom's macroglobulinemia)、隱匿性骨髓瘤、緩慢型骨髓瘤、輸卵管癌、雄激素非依賴性前列腺癌、雄激素依賴性IV期非轉移性前列腺癌、對激素不敏感之前列腺癌、對化學療法不敏感之前列腺癌、乳突狀甲狀腺癌、濾泡狀甲狀腺癌、髓質性甲狀腺癌及平滑肌瘤。在一實施例中,該癌症為原發性或轉移性癌症。在另一實施例中,該癌症為復發癌症,化學療法或放射線難治癒或有抗性之癌症,特別係以沙立度胺難治癒者。本文所使用之術語"癌症"不包括骨髓發育不良綜合症或MDS。
本發明包含治療先前已進行癌症治療但對標準療法不起反應之患者以及彼等先前未經治療之患者的方法。本發明亦包含與患者年齡無關之治療患者之方法,儘管一些疾病或病症在特定年齡組中更常見。本發明進一步包含治療已試圖進行尚有爭議之外科手術以治療疾病或病症之患者以及彼等未經外科手術之患者的方法。因患癌症之患者具有異質臨床表現及可變之臨床結果,故提供至患者之治療可視他/她之預後而變化。有經驗之臨床醫師無需過多試驗就能容易地確定可有效用於治療患癌症之個別患者之特定第二藥劑、外科手術類型及基於非藥物之標準療法之類型。
本發明所包含之方法包含將一或多種本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥投予罹患或可能罹患癌症(特別係白血病)之患者(例如,人)。
在本發明之一實施例中,可將量為約0.10毫克/天至約150毫克/天之本發明之免疫調節化合物之每日劑量單次或分次經口投藥。在一較佳實施例中,3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))可以約0.10毫克/天至150毫克/天,約1毫克/天至約50毫克/天,或約5毫克/天至約25毫克/天之量投藥。每日之特定劑量包括1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50毫克/天。
在一較佳實施例中,3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))可以約1毫克/天至50毫克/天或約5毫克/天至約25毫克/天之量投予患各種類型白血病(諸如,慢性淋巴細胞白血病、慢性骨髓細胞白血病、急性淋巴母細胞白血病、急性骨髓性白血病及急性骨髓母細胞白血病)之患者。
特定言之,3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))可以約1毫克/天至約50毫克/天或約5毫克/天至約25毫克/天之量投予患慢性淋巴細胞白血病之患者。在一特定實施例中,3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))可以約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50毫克/天之量投予患慢性淋巴細胞白血病之患者。在一特定實施例中,雷利明(Revlimid)可以約25毫克/天之量投予患慢性淋巴細胞白血病之患者。
在一實施例中,3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))之推薦起始劑量為10毫克/天。每週可將劑量逐步增加至15、20、25、30、35、40、45及50毫克/天。一開始服藥10 mg且在開始用雷利明(Revlimid)治療的前四週之內或之後逐漸顯現血小板減少症或嗜中性球減少症之患者可根據血小板數或嗜中性球絕對數(ANC)調節其劑量。
本發明之特定方法包含將本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥與一或多種第二活性劑組合,及/或與放射線療法、輸血或外科手術組合來投藥。本發明之免疫調節化合物之實例揭示於本文中(參見,例如[實施方式]第1節)。第二活性劑之實例亦揭示於本文中(參見,例如[實施方式]第2節)。
本發明之免疫調節化合物及第二活性劑可同時或按順序經由相同或不同投藥途徑投予患者。特定活性劑所採用之特定投藥途徑之適用性將視活性劑自身(例如,其是否可經口投藥而在進入血流之前不分解)及所治療之疾病而定。本發明之免疫調節化合物之較佳投藥途徑為經口投藥。本發明之第二活性劑或成份之較佳投藥途徑對一般熟習此項技術者而言係已知的。參見
(例如
)Physicians' Desk Reference
,1755-1760(第56版,2002)。
在本發明之一實施例中,第二活性劑可經靜脈內或皮下且每日一次或每日兩次以約1 mg至約1,000 mg、約5 mg至約500 mg、約10 mg至約375 mg或約50 mg至約200 mg之量投藥。第二活性劑之特定劑量將視所使用之特定藥劑、所治療或控制之疾病類型、疾病之嚴重程度及階段及本發明之免疫調節化合物之量以及同時投予患者之任何視情況之額外活性劑而定。在一特定實施例中,第二活性劑為利妥昔單抗、奧利默森(oblimersen,Genasense)、GM-CSF、G-CSF、EPO、克癌易、伊立替康、達卡巴嗪、反式維甲酸、拓朴替康、配妥西菲林(pentoxifylline)、環丙沙星(ciprofloxacin)、地塞米松、長春新鹼、阿黴素、COX-2抑制劑、IL2、IL8、IL18、IFN、Ara-C、長春瑞濱或其組合。
在一特定實施例中,本發明之免疫調節化合物與利妥昔單抗組合投予患白血病之患者。在一特定實施例中,雷利明(Revlimid)以約5毫克/天至約25毫克/天之劑量與量為375 mg/m2
之利妥昔單抗組合投予患慢性淋巴細胞白血病之患者。
在另一實施例中,本發明之免疫調節化合物與氟達拉賓、卡鉑及/或拓朴替康組合投予患難治癒或復發或高風險之急性骨髓性白血病的患者。
在另一實施例中,本發明之免疫調節化合物與脂質體道諾黴素、拓朴替康及/或阿糖胞苷組合投予患不利卡羅型急性骨髓母細胞白血病之患者。
在另一實施例中,本發明之免疫調節化合物可單獨或與諸如長春鹼或氟達拉賓之第二活性成份組合投予患各種類型淋巴瘤(包括但不限於霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、皮膚T-細胞淋巴瘤、皮膚B-細胞淋巴瘤、彌漫性大B細胞淋巴瘤或復發或難治癒之低分級濾泡性淋巴瘤)之患者。
在另一實施例中,GM-CSF、G-CSF或EPO可在四週或六週週期內之約5天期間以每天約1 mg/m2
至每天約750 mg/m2
之量,較佳以每天約25 mg/m2
至每天約500 mg/m2
之量,更佳以每天約50 mg/m2
至每天約250 mg/m2
之量,且最佳以自每天約50 mg/m2
至每天約200 mg/m2
之量經皮下投藥。在一特定實施例中,GM-CSF可以約60 mcg/m2
至約500 mcg/m2
之量歷經2小時經靜脈投藥,或以每天約5 mcg/m2
至每天約12 mcg/m2
之量經皮下投藥。在一特定實施例中,G-CSF初始可以每天約1 mcg/kg之量經皮下投藥且可視總粒細胞數上升而調節。G-CSF可以量為約300 mcg(在年齡小之患者中)或480 mcg之維持劑量經皮下投藥。在一特定實施例中,EPO可每週三次以10,000單位之量經皮下投藥。
本發明亦包含一種增加可安全且有效地投予患者之抗癌藥物或藥劑之劑量的方法,其包含將本發明之免疫調節化合物或其醫藥學上可接受之衍生物、鹽、溶劑合物、籠形物、水合物或前藥投予患者(例如
,人)。可受益於該方法之患者為彼等可能遭受與用於治療特殊癌症(血癌、皮膚癌、皮下組織癌、淋巴結癌、腦癌、肺癌、肝癌、骨癌、腸癌、結腸癌、心臟癌、胰腺癌、腎上腺癌、腎癌、前列腺癌、乳癌、結直腸癌或其組合)之抗癌藥物相關之不利作用的患者。投予本發明之免疫調節化合物減輕或降低嚴重至否則將限制抗癌藥物之劑量的不利作用。
在一實施例中,本發明之免疫調節化合物可在與將抗癌藥物投予患者相關之不利作用出現之前、期間或之後以約0.10 mg至約150 mg之量,且較佳以約1 mg至約50 mg之量,更佳以約5 mg至約25 mg之量經口且每日投藥。在一特定實施例中,本發明之免疫調節化合物與特定藥劑(諸如,肝素、阿司匹林、可邁丁(coumadin)或G-CSF)組合投藥以避免與抗癌藥物相關之不利作用(諸如但不限於嗜中性球減少症或血小板減少症)。
在另一實施例中,本發明包含一種治療、預防及/或控制癌症之方法,其包含將本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥與習知療法(包括但不限於外科手術、免疫療法、生物學療法、放射線療法或目前用於治療、預防或控制癌症之其他基於非藥物之療法)結合(例如
,在習知療法之前、期間或之後)投藥。本發明之免疫調節化合物與習知療法之組合使用可在特定患者中提供一種獨特且意外地有效之治療方案。在不受理論限制下,咸信本發明之免疫調節化合物在與習知療法同時供給時可提供附加或協同作用。
如本文他處所述,本發明包含一種減輕、治療及/或預防與習知療法(包括但不限於外科手術、化學療法、放射線療法、激素療法、生物學療法及免疫療法)相關之不利作用或不恰當之作用。本發明之免疫調節化合物及其他活性成份可在與習知療法相關之不利作用出現之前、期間或之後投予患者。
在一實施例中,本發明之免疫調節化合物可以約0.10 mg至約150 mg之量,且較佳以約1 mg至約50 mg之量,更佳以約5 mg至約25 mg之量單獨或與本文所揭示之第二活性劑(參見
,例如
[實施方式]第2節)組合在使用習知療法之前、期間或之後經口且每日投藥。
本發明之化合物可用於降低移植物抗宿主疾病(GVHD)之風險。因此,本發明包含一種治療、預防及/或控制癌症之方法,其包含將本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥與移植療法結合投藥。
如一般熟習此項技術者所瞭解,癌症之治療常基於疾病之階段及機制。例如,因不可避免之白血病轉型在癌症之某些階段發展,故可能必需移植末梢血液幹細胞、造血幹細胞製劑或骨髓。本發明之免疫調節化合物與移植療法之組合使用提供獨特且意想不到之協同作用。特定言之,本發明之免疫調節化合物呈現免疫調節活性,其可在與移植療法同時供給時在患癌症的患者中提供附加或協同作用。
本發明之免疫調節化合物可與移植療法組合而發揮減少與侵入性移植手術相關之併發症及GVHD之風險的作用。本發明包含一種治療、預防及/或控制癌症之方法,其包含將本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥在移植臍帶血、胎盤血、末梢血液幹細胞、造血幹細胞製劑或骨髓之前、期間或之後投予患者(例如
,人)。適於在本發明之方法中使用之幹細胞之實例由R.Hariri等人揭示於美國專利公開案第2002/0123141號、第2003/0235909號及第2003/0032179號中,該等公開案之全文以引用的方式併入本文中。
在該方法之一實施例中,本發明之免疫調節化合物在移植自體性末梢血液祖細胞之前、期間或之後投予患白血病之患者。
在另一實施例中,本發明之免疫調節化合物在幹細胞移植之後投予患復發白血病之患者。
在特定實施例中,本發明之預防劑或治療劑可週期性地投予患者。週期性療法包括投予活性劑一段時間,接著停藥一段時間,且重複該依序投藥。週期性療法可減緩對一或多種療法產生之抗性之發展,避免或減小其中該等療法中之一者之副作用,且/或改良治療功效。
因此,在本發明之一特定實施例中,本發明之免疫調節化合物在四至六週之週期中,每日單次或分次投藥,其中停藥約一週或兩週。本發明進一步允許增加給藥週期之頻率、數量及持續時間。因此,本發明之另一特定實施例包含本發明之免疫調節化合物可以比在其單獨投藥時之典型週期數更多之週期數來投藥。在本發明之又一特定實施例中,本發明之免疫調節化合物還可以比通常會在亦不能向其投予第二活性成份之患者中引起劑量限制性毒性之週期數更多之週期數來投藥。
在一實施例中,本發明之免疫調節化合物以約0.10毫克/天至約150毫克/天之劑量每日投藥且持續三週或四週,接著停藥一週或兩週。在一特定實施例中,本發明之免疫調節化合物在四週或六週之週期中,以約1毫克/天至約50毫克/天之量,較佳以約25毫克/天之量投藥三週至四週,接著停藥一週或兩週。
在一較佳實施例中,3-(4-胺基-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))在28天之週期中以約0.10毫克/天至約150毫克/天之量投予患白血病之患者歷經21天,接著停藥7天。在最佳實施例中,3-(4-胺基-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))在28天之週期中以約25毫克/天之量投予患難治癒或復發之慢性淋巴細胞白血病之患者歷經21天,接著停藥7天。
在本發明之一實施例中,在四至六週週期期間經口投予本發明之免疫調節化合物及第二活性成份,其中在投予第二活性成份之前30分鐘至60分鐘投予本發明之免疫調節化合物。在本發明之另一實施例中,本發明之免疫調節化合物係經口投藥且第二活性成份係藉由靜脈內輸液而投藥。
在一特定實施例中,一個週期包含每日投予約10毫克/天至約25毫克/天之雷利明(Revlimid)及每天約50 mg/m2
至每天約750 mg/m2
之第二活性成份歷經三至四週且接著停藥一週或兩週。在一較佳實施例中,利妥昔單抗可作為額外活性劑以375 mg/m2
之劑投予患難治癒或復發之慢性淋巴細胞白血病之患者。通常,將組合治療投予患者期間之週期數將為約1個週期至約24個週期,更通常為約2個週期至約16個週期,且甚至更通常為約4個週期至約3個週期。
醫藥組合物可用於個別之單一單位劑型之製劑中。本發明之醫藥組合物及劑型包含本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥。本發明之醫藥組合物及劑型可進一步包含一或多種賦形劑。
本發明之醫藥組合物及劑型亦可包含一或多種額外活性成份。因此,本發明之醫藥組合物及劑型包含本文中所揭示之活性成份(例如
,本發明之免疫調節化合物及第二活性劑)。本文中揭示視情況之第二或額外活性成份之實例(參見
,例如
[實施方式]第2節)。
本發明之單一單位劑型適於經口、黏膜(例如
,鼻、舌下、陰道、口腔或直腸之黏膜)、非經腸(例如
,皮下、靜脈內、快速注射、肌內或動脈內)、局部(例如
,滴眼劑或其他眼用製劑)、經皮或經皮膚投予患者。劑型之實例包括但不限於:錠劑;囊片;膠囊,諸如,軟彈性明膠膠囊;扁囊劑;口含錠;口含劑;分散液;栓劑;粉劑;氣溶膠(例如
,鼻噴劑或吸入劑);凝膠;適於經口或黏膜投予患者之液體劑型,包括懸浮液(例如
,水性或非水性液體懸浮液、水中油型乳液,或油中水型液體乳液)、溶液及酒劑;適於非經腸投予患者之液體劑型;適於局部投藥之滴眼劑或其他眼用製劑;及可經加水再組以提供適於非經腸投予患者之液體劑型的無菌固體(例如
,結晶或非晶形固體)。
本發明劑型之組成、形狀及類型通常將視其用途而變化。例如,用在疾病之急性治療中之劑型較之用於同一疾病之慢性治療中之劑型可含有更多量之一或多種其所包含之活性成份。同樣地,非經腸劑型較之用於治療同一疾病中之口服劑型可含有更少量之一或多種其所包含之活性成份。熟習此項技術者將易瞭解本發明所包含之特定劑型之該等及其他方式將在彼此之間變化。參見
(例如
)Remington's Pharmaceutical Sciences
,第18版,Mack Publishing,Easton PA(1990)。
典型醫藥組合物及劑型包含一或多種賦形劑。熟習藥劑學技術者熟知合適賦形劑,且合適賦形劑之非限制性實例於本文中提供。特定賦形劑是否適於併入醫藥組合物或劑型視多種此項技術中熟知之因素而定,該等因素包括但不限於將該劑型投予患者之方式。例如,諸如錠劑之口服劑型可含有不適於在非經腸劑型中使用之賦形劑。特定賦形劑之適用性亦可視劑型中之特定活性成份而定。例如,一些活性成份可由一些諸如乳糖之賦形劑加速分解或在曝露至水時加速分解。包含第一胺或第二胺之活性成份特別易受該加速之分解影響。因此,本發明包括含有很少(若有)乳糖、其他單醣或二醣之醫藥組合物及劑型。如本文所使用,術語"無乳糖"意謂存在(若有)之乳糖量不足以大體上增加活性成份之降解速率。
本發明之無乳糖組合物可包含在此項技術中熟知之賦形劑及(例如)於U.S.Pharmacopeia
(USP)25-NF20(2002)中所列之賦形劑。通常,無乳糖組合物包含醫藥學上相容且醫藥學上可接受之量的活性成份、黏合劑/填充劑及潤滑劑。較佳之無乳糖劑型包含活性成份、微晶纖維素、預膠凝澱粉及硬脂酸鎂。
本發明進一步包括包含活性成份之無水醫藥組合物及劑型,因水可促使一些化合物降解。例如,在醫藥學技術中廣泛接受添加水(例如
,5%)作為模擬長期儲存之方法以便確定諸如調配物隨時間之儲放時限或穩定性之特徵。參見
,(例如
)Jens T.Carstensen,Drug Stability:Principles & Practice
,第2版,Marcel Dekker,NY,NY,1995,第379-80頁。實際上,水及熱皆可加速一些化合物之分解。因此,水對調配物之影響非常重要,因在製造、加工、包裝、儲存、裝運及使用調配物期間常會遇到水分及/或濕氣。
本發明之無水醫藥組合物及劑型可使用無水或含低水分之成份且在低水分或低濕氣條件下製備。若預期在製造、包裝及/或儲存期間會與水分及/或濕氣發生實質接觸,則包含乳糖及至少一種包含第一胺或第二胺之活性成份的醫藥組合物及劑型較佳無水。
無水醫藥組合物應經製備且儲存以保持其無水性。因此,無水組合物較佳使用已知用於防止曝露至水之材料包裝使得其可包括在合適配方之套組中。合適包裝之實例包括但不限於密封箔、塑膠、單位劑量容器(例如,小瓶)、發泡包裝及包裝帶包裝。
本發明進一步包括包含一或多種降低活性成份分解速率之化合物的醫藥組合物及劑型。該等化合物(在本文中稱為"穩定劑")包括但不限於諸如抗壞血酸之抗氧化劑、pH緩衝劑或鹽緩衝劑。
與賦形劑之量及類型相似,劑型中之活性成份之量及特定類型可視諸如但不限於待投予患者之途徑的因素而不同。然而,本發明之典型劑型包含約0.10 mg至約150 mg之量的本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥。典型劑型包含約0.1、1、2.5、5、7.5、10、12.5、15、17.5、20、25、50、100、150或200 mg之量的本發明之免疫調節化合物或其醫藥學上可接受之鹽、溶劑合物、水合物、立體異構體、籠形物或前藥。在一特定實施例中,較佳劑型包含約1、2.5、5、10、15、20、25或50 mg之量的3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))。典型劑型包含1 mg至約1000 mg、約5 mg至約500 mg、約10 mg至約350 mg或約50 mg至約200 mg之量的第二活性成份。當然,抗癌藥物之特定量將視所使用之特定藥劑、所治療或控制之癌症之類型及本發明之免疫調節化合物及任何同時投予患者之視情況之額外活性劑之量而定。
適於口服投藥之本發明之醫藥組合物可呈離散劑型,諸如但不限於錠劑(例如,可咀嚼之錠劑)、囊片、膠囊及液體(例如,調味糖漿)。該等劑型含有預定量之活性成份,且可藉由熟習此項技術者所熟知之藥劑學方法製備。通常參見Remington's Pharmaceutical Sciences
,第18版,Mack Publishing,Easton PA(1990)。
在一實施例中,較佳劑型為包含約1、2.5、5、10、15、20、25或50 mg之量的3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))的膠囊或錠劑。在一特定實施例中,較佳膠囊或錠劑劑型包含約5 mg或10 mg之量的3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))。
本發明之典型口服劑型係根據習知醫藥配合技術藉由將均勻混雜物中之活性成份與至少一種賦形劑組合而製備。賦形劑視投藥所要之劑型可呈廣泛多種形態。例如,適於在口服液體或氣溶膠劑型中使用之賦形劑包括但不限於水、二醇、油、醇、調味劑、防腐劑及著色劑。適於在固體口服劑型(例如
,粉劑、錠劑、膠囊及囊片)中使用之賦形劑之實例包括但不限於澱粉、糖、微晶纖維素、稀釋劑、成粒劑、潤滑劑、黏合劑及崩解劑。
錠劑及膠囊因其投藥之便利性故表現為最具優勢之口服單位劑型,在該狀況下採用固體賦形劑。若需要,錠劑可藉由標準水性或非水性技術塗覆。該等劑型可藉由任何藥劑學方法製備。通常,醫藥組合物及劑型藉由均一且均勻混雜活性成份與液體載劑、經精細分開之固體載劑或兩者,且若有必要則接著使產物成形為所要外形而製備。
例如,錠劑可藉由壓縮或模製來製備。壓縮錠劑可藉由在一合適機器中壓縮呈自由流動形態(諸如,粉劑或顆粒)之活性成份(視情況與賦形劑混合)而製備。模製錠劑可藉由在一合適機器中模製用惰性液體稀釋劑潤濕之粉末化合物的混合物而製成。
可在本發明之口服劑型中使用之賦形劑之實例包括但不限於黏合劑、填充劑、崩解劑及潤滑劑。適於在醫藥組合物及劑型中使用之黏合劑包括但不限於玉米澱粉、馬鈴薯澱粉或其他澱粉、明膠、天然及合成膠(諸如,阿拉伯膠、海藻酸鈉、褐藻酸、其他海藻酸鹽、粉末黃耆膠、瓜爾膠)、纖維素及其衍生物(例如
,乙基纖維素、乙酸纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉)、聚乙烯吡咯啶酮、甲基纖維素、預膠凝澱粉、羥丙基甲基纖維素(例如
第2208號、第2906號、第2910號)、微晶纖維素及其混合物。
合適類型之微晶纖維素包括但不限於以AVICEL-PH-101、AVICEL-PH-103 AVICEL RC-581、AVICEL-PH-105(自FMC Corporation,American Viscose Division,Avicel Sales,Marcus Hook,PA購得)出售之材料及其混合物。一種特定黏合劑為微晶纖維素及羧甲基纖維素鈉之以AVICEL RC-581出售的混合物。合適之無水或低水分賦形劑或添加劑包括AVICEL-PH-103T M
及Starch 1500 LM。
適於在本文所揭示之醫藥組合物及劑型中使用之填充劑之實例包括但不限於滑石粉、碳酸鈣(例如
,顆粒或粉劑)、微晶纖維素、粉狀纖維素、葡萄糖結合劑、高嶺土、甘露醇、矽酸、山梨糖醇、澱粉、預膠凝澱粉及其混合物。在本發明之醫藥組合物中之黏合劑或填充劑通常以醫藥組合物或劑型之約50重量%至約99重量%之量存在。
在本發明之組合物中使用崩解劑以提供在曝露至水性環境時崩解之錠劑。含有過多崩解劑之錠劑在儲存中可崩解,而彼等含有過少崩解劑之錠劑不可以所要速率崩解或不可在所要條件下崩解。因此,應使用充足量之崩解劑以形成本發明之固體口服劑型,崩解劑既不過多亦不過少,以便不會不利地改變活性成份的釋放。所使用之崩解劑之量基於調配物類型而變化,且一般熟習此項技術者容易辨別該量。典型醫藥組合物包含約0.5重量%至約15重量%之崩解劑,較佳為約1重量%至約5重量%之崩解劑。
可在本發明之醫藥組合物及劑型中使用之崩解劑包括但不限於瓊脂、褐藻酸、碳酸鈣、微晶纖維素、交聯羧甲基纖維素鈉、交聯聚乙烯吡咯酮、波拉克林鉀(polacrilin potassium)、羥乙酸澱粉鈉、馬鈴薯或木薯澱粉、其他澱粉、預膠凝澱粉、其他澱粉、黏土、其他褐藻酸、其他纖維素、膠狀物及其混合物。
可用在本發明之醫藥組合物及劑型中之潤滑劑包括但不限於硬脂酸鈣、硬脂酸鎂、礦物油、輕礦物油、甘油、山梨糖醇、甘露醇、聚乙二醇、其他二醇、硬脂酸、月桂基硫酸鈉、滑石粉、氫化植物油(例如
,花生油、棉籽油、向日葵籽油、芝蔴油、橄欖油、玉米油及大豆油)、硬脂酸鋅、油酸乙酯、月桂酸乙酯、瓊脂及其混合物。其他潤滑劑包括(例如)syloid矽膠(AEROSIL200,由W.R.Grace Co.of Baltimore,MD製造)、合成矽石之凝結氣溶膠(由Degussa Co.of Piano,TX出售)、CAB-O-SIL(由Cabot Co.of Boston,MA出售之熱解二氧化矽產品)及其混合物。實際使用時,通常使用量小於在其所併入之醫藥組合物或劑型之約1重量%的潤滑劑。
本發明之較佳固體口服劑型包含本發明之免疫調節化合物、無水乳糖、微晶纖維素、聚乙烯吡咯啶酮、硬脂酸、無水膠狀二氧化矽及明膠。
本發明之活性成份可藉由控制釋放方式或藉由一般熟習此項技術者所熟知之傳遞設備來投藥。實例包括但不限於彼等在美國專利第3,845,770號;第3,916,899號;第3,536,809號;第3,598,123號;及第4,008,719號、第5,674,533號、第5,059,595號、第5,591,767號、第5,120,548號、第5,073,543號、第5,639,476號、第5,354,556號及第5,733,566號中所述者,該等專利中之每一者皆以引用的方式併入本文中。該等劑型可用於使用(例如)氫丙基甲基纖維素、其他聚合物基質、凝膠、滲透膜、滲透性體系、多層塗層、微粒、脂質體、微球體或其組合以提供一或多種活性成份之緩慢或控制釋放,從而以變化之比例提供所要之釋放曲線。易於選擇一般熟習此項技術者已知之合適控制釋放調配物(包括彼等本文中所述者)以便與本發明之活性成份一起使用。本發明因此包含適於口服投藥之單一單位劑型,諸如但不限於適於控制釋放之錠劑、膠囊、膠囊錠及囊片。
所有控制釋放醫藥產品皆具改良藥物療法以超越由其非控制性對應物所達成者之共同目標。理想地,在醫學治療中使用最佳設計之控制釋放製劑之特徵為採用最少量之藥物以最短的時間治癒或控制病症。控制釋放調配物之優點包括藥物活性擴展,給藥頻率下降及患者順應性增強。此外,控制釋放調配物可用於影響作用開始時間或其他特徵,諸如,藥物之血液含量,且可因此影響副(例如
,不利)作用之發生。
大多數控制釋放調配物經設計以便初始釋放迅速產生所要治療效果之一定量之藥物(活性成份),且逐漸及持續地釋放其餘量之藥物以維持該程度之治療或預防效果一段延長之時間。為在體內維持藥物之該恆定含量,藥物必須以將替代經代謝且自體內排泄之藥物量的速率自劑型釋放。可由各種條件刺激活性成份之控制釋放,包括但不限於pH、溫度、酶、水或其他生理學條件或化合物。
非經腸劑型可藉由各種途徑(包括但不限於皮下、靜脈內(包括快速注射)、肌內及動脈內)投予患者。因投予非經腸劑型時通常避開免患者對污染物之自發抵禦,故其在投予患者之前較佳為無菌或能被滅菌之劑型。非經腸劑型之實例包括但不限於注射用溶液、可溶解或懸浮於用於注射之醫藥學上可接受之媒劑中的乾燥產品、注射用懸浮液,及乳液。
熟習此項技術者熟知可用於提供本發明之非經腸劑型之合適媒劑。實例包括但不限於:注射用水USP;水性媒劑,諸如但不限於氯化鈉注射劑、林格氏注射劑(Ringer's Injection)、葡萄糖注射劑、葡萄糖及氯化鈉注射劑及乳酸化林格氏注射劑;易與水混合之媒劑,諸如但不限於乙醇、聚乙二醇及聚丙二醇;及非水性載劑,諸如但不限於玉米油、棉籽油、花生油、芝蔴油、油酸乙酯、十四烷酸異丙酯及苯甲酸苯甲酯。
亦可將增加一或多種本文所揭示之活性成份之溶解度的化合物併入本發明之非經腸劑型。例如,環糊精及其衍生物可用於增加本發明之免疫調節化合物及其衍生物之溶解度。參見
(例如
)美國專利第5,134,127號,其以引用的方式併入本文中。
本發明之局部及黏膜劑型包括但不限於噴霧劑、氣溶膠、溶液、乳液、懸浮液、滴眼劑或其他眼用製劑或其他熟習此項技術者已知之劑型。參見
(例如
)Remington's Pharmaceutical Sciences
,第16版及第18版,Mack Publishing,Easton PA(1980 & 1990);及Introduction to Pharmaceutical Dosage Forms
,第4版,Lea & Febiger,Philadelphia(1985)。適於治療口腔內黏膜組織之劑型可調配為漱口藥或調配為口服凝膠。
可用於提供本發明所包含之局部及黏膜劑型的合適賦形劑(例如
,載劑及稀釋劑)及其它材料為彼等熟習醫藥上之技術者所熟知,且可視給定醫藥組合物或劑型將應用之特定組織而定。應瞭解典型賦形劑包括但不限於水、丙酮、乙醇、乙二醇、丙二醇、丁-1,3-二醇、十四烷酸異丙酯、棕櫚酸異丙酯、礦物油及其混合物以形成無毒性且醫藥學上可接受之溶液、乳液或凝膠。若需要,則亦可將增濕劑或保濕劑添加至醫藥組合物及劑型。該等額外成份之實例在該項技術中為吾人所熟知。參見
(例如
)Remington's Pharmaceutical Sciences
,第16版及第18版,Mack Publishing,Easton PA(1980 & 1990)。
亦可調節醫藥組合物或劑型之pH以改良一或多種活性成份之傳遞。同樣地,可調節溶劑載劑之極性、其離子強度或張力以改進傳遞。亦可將諸如硬脂酸鹽之化合物添加至醫藥組合物或劑型以有利地改變一或多種活性成份之親水性或親脂性,從而改良傳遞。就此點而言,硬脂酸鹽可充當調配物之液體媒劑,充當乳化劑或界面活性劑,及充當傳遞增強劑或滲透增強劑。活性成份之不同鹽、水合物或溶劑合物可用於進一步調節所得組合物之性質。
本發明之特定實例藉由以下非限制性實例說明。
在經麻醉之犬中研究3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))對心臟血管及呼吸功能之影響。使用兩組米格魯犬(Beagle dog)(2個/性別/組)。一組僅接受3種劑量之媒劑而另一組接受3種上升劑量之3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(2 mg/kg、10 mg/kg及20 mg/kg)。在所有狀況下,各劑量之3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮或媒劑相隔至少30分鐘經由頸靜脈之輸液而連續地投藥。
當與媒劑對照組相比較時,在所有劑量下由3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮引起之心臟血管及呼吸變化皆極小。媒劑組與治療組之間的僅有之統計上顯著差異為在投予低劑量之3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮後動脈血壓稍微上升(自94 mmHg至101 mmHg)。該作用持續大致15分鐘且在更高劑量下未出現。股動脈血流、呼吸參數及Qtc間隔之偏差對對照組及治療組而言係共同的且不認為與治療有關。
5.2.1慢性淋巴細胞白血病之治療
3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))在28天之週期中以25毫克/天之量經口投予患難治癒或復發之慢性淋巴細胞白血病(CLL)之患者歷經21天,接著停藥7天。共27位中值年齡為64歲(範圍:47-75歲)之患者參與。17位患者患III期或IV期之疾病。在第0天、第7天及第30天時量測絕對淋巴細胞數。在第30天及其後每月一次使用NCI-WG 1996標準評價響應。病情穩定或響應較好之患者繼續治療最多12個月,而彼等病情更加嚴重之患者接受添加至雷利明(Revlimid)之利妥昔單抗(375 mg/m2
)。若患者完成至少兩個月之治療,則認為可評價其響應。
所有患者皆接受毒性評價且18位患者中之13位接受響應評價。9位治療中之患者先接受響應評價。5位患者達成完全響應且4位患者達成部分響應。3位患者病情得到穩定(繼續治療)。13位可評價患者中之總響應率為69%,而目標響應率界定為(完全響應、部分響應及病情穩定)為92.3%。僅1位患者在治療3週後病情更加嚴重。
毒性概況可預測且可控制。紅腫反應(例如,淋巴結之觸痛腫脹、鼻竇炎及/或皮疹)為應注意之常見副作用。其他副作用為腫瘤溶解症候群、3/4級血液科毒性及發熱性嗜中性球減少症。
該研究結果顯示雷利明(Revlimid)有效於治療白血病,尤其有效於治療慢性淋巴細胞白血病。
5.2.2復發之多發性骨髓瘤之治療
將4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮(ActimidT M
)投予患復發/難治癒之多發性骨髓瘤之患者。研究遵照藥物臨床試驗質量管理規範(Good Clinical Practice)進行。患者至少為18歲,已診斷為多發性骨髓瘤(血清及/或尿液中有異常蛋白質),且在至少兩個週期治療後被視為該治療難治癒,或已在兩個週期治療後復發。
根據Southwest Oncology Group(SWOG)標準,採用先前療法而病情更加嚴重之患者被視為該治療難治癒。界定症狀緩解後之復發為M組份自基線含量增加>25%;先前已消失之M異常蛋白質重新出現;或射線照片上所辨別之溶骨病變之尺寸明確增大且數量明確增多。若患者能耐受治療,則其可能先前已用沙立度胺進行治療。所有患者皆需要Zubrod體能狀況為0至2。
將4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮以1、2、5或10毫克/天之劑量投予患者歷經多至四週;在各劑量位準下,初始參與者為3位患者。給藥大致在每個早晨之同一時間進行;所有劑量皆在禁食狀態下(在投藥前至少2小時及在投藥後2小時不吃食物)投藥。4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮劑量係以上升之方式投藥,故在第一用藥群中之患者接受最低劑量之4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮(1毫克/天)且僅在當前劑量下確定安全且有耐受性後才增加至下一更高劑量位準。在任何劑量位準下若3位患者中有1位經受劑量限制性毒性(DLT),則在彼劑量下有另外3位患者參與。若該等另外3位患者無一經受DLT,則增加至下一劑量位準;以類似方式繼續增加劑量直至確定MTD或達至最高日劑量(10毫克/天)。然而,若所參與之該等另外3位患者中有1位經受DLT,則已達至MTD。若所參與之該等另外3位患者中有2位或2位以上經受DLT,則判斷已超過MTD且在先前劑量位準下有另外3位患者參與以確定MTD。確定MTD之後,在彼劑量位準下有另外4位患者參與,以使得在MTD下共有10位患者進行治療。
根據以下取樣時間進度在第1天及第28天取血樣以用於分析藥物動力學參數:給藥前、給藥後0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、10、12、18及24小時。在每週就診時收集額外血樣以用於測定4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮含量。亦經由根據給藥後以下之時間間隔來集尿而進行全部尿液收集:0小時至4小時、4小時至8小時、8小時至12小時及12小時至24小時。安全性評價藉由監控研究期間之不利現象、極重要之症狀、ECG、臨床實驗室評估(血液化學、血液學、淋巴細胞表型及尿分析)及在特定時期之身體檢查而進行。
在將單劑量及多劑量之4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮投予多發性骨髓瘤患者後獲得之中間藥物動力學分析結果呈現於下表1及2中。該等資料顯示在復發之多發性骨髓瘤患者中,在所有劑量位準下之4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮皆被穩定地吸收。最高血漿濃度在第1天給藥後2.5小時與2.8小時之間及第4週給藥後3小時與4小時之間的中值Tm a x
出現。在所有劑量下,血漿濃度達至Cm a x
後皆以單調方式下降。消除期之起點分別在第1天及第4週給藥後3小時與10小時之間出現。
該等資料亦顯示在給藥4週後,4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮以很小程度積累(對Cm a x
及AUC( 0 - τ )
而言,平均積累率分別為~1.02至1.52及~0.94至1.62)。隨劑量之增加,AUC( 0 - τ )
及Cm a x
值幾乎與劑量成比例增加。在第1天及第4週時,5倍更高劑量之4-(胺基)-2-(2,6-二酮基(3-哌啶基))-異吲哚啉-1,3-二酮引起Cm a x
分別增加3.2倍及2.2倍。同樣地,在第1天及第4週時,劑量增加5倍分別引起AUC( 0 - τ )
增加3.6倍及2.3倍。
5.2.3復發之多發性骨髓瘤之治療
已進行3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))之兩階段1臨床研究以在患難治癒或復發之多發性骨髓瘤之患者中確定最大耐受劑量(MTD)。該等研究亦已表徵在經口投予上升劑量之3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮歷經多至四週時3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮之安全概況。患者以5毫克/天開始3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮治療,隨後增加至10毫克/天、25毫克/天及50毫克/天。患者在其所分配之劑量下參與28天,其中彼等不展現疾病加重或經受劑量限制性毒性(DLT)之患者可選擇延長治療。在每次就診時評價患者之不利現象且根據National Cancer Institute(NCI)通用毒性標準(Common Toxicity Criteria)對該等現象之嚴重程度進行分級。患者若經受DLT(3級或3級以上非血液科毒性,或4級血液科毒性)則停止用藥。
在本研究中,有27位患者參與。所有患者皆患有復發之多發性骨髓瘤且18位(72%)以搶救療法難治癒。在該等患者中,15位先前已進行過自體性幹細胞移植且16位患者先前已接受沙立度胺治療。先前療法之中值為3(範圍為2至6)。
在第1天及第28天收集血液及尿液樣品以用於分析藥物動力學參數。根據以下取樣時間進度收集血樣:給藥前、給藥後0.25、0.5、0.75、1、1.5、2、2.5、3、4、6、8、10、12、18及24小時。此外,在每週臨床就診時收集血樣以用於測定3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮。根據以下給藥後之時間間隔收集及彙集全部尿液:0小時至4小時、4小時至8小時、8小時至12小時及12小時至24小時。對治療之響應藉由自血清及收集之24小時尿液定量M蛋白(藉由免疫電泳)及在篩選、基線、第2週及第4週、及其後每月(或提早停藥後)對肌酸酐清除及24小時之蛋白質進行計算而評價。基於最佳響應標準,若患者之異常蛋白質血清濃度或24小時尿蛋白排泄降至下一更低位準,則亦在第3個月、第6個月及第12個月時進行抽吸骨髓及/或活組織檢查。28天治療週期之初步結果概述如下。
基於該兩研究之初步藥物動力學分析顯示在多發性骨髓瘤患者中投予單劑量及多劑量後AUC及Cm a x
值隨劑量按比例增加(其在健康志願者中可見)。此外,多次給藥情況下無明顯積累,因單劑量AUC( 0 - ∞ )
相當於投予相同劑量3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮之後的多劑量AUC0 - τ
。類似於對健康志願者之研究,觀察到雙峰。基於Cm a x
及AUC值,多發性骨髓瘤患者較之健康男性志願者曝露似乎略高,同時多發性骨髓瘤患者中之清除性弱於健康之志願者,此與其腎功能更差相一致(兩者皆為其年齡及其疾病之結果)。最後,患者中3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮半衰期短於健康志願者(平均8小時,範圍為高至17小時)。
在本研究中,第一用藥群之3位患者以5毫克天治療28天,無任何劑量限制性毒性(DLT)。第二用藥群之3位患者隨後以10毫克/天開始治療。投予10毫克/天之3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮之第二用藥群中的患者耐受治療良好。
5.2.4復發或難治癒之多發性骨髓瘤之治療
患復發及難治癒之Dune-Salmon III期多發性骨髓瘤之患者先前已在至少三種療法中失敗或呈現較差之體能狀況、嗜中性球減少症或血小板減少症,對其每4至6週用美法侖(50 mg,靜脈內)、本發明之免疫調節化合物(每日口服約1 mg至150 mg)及地塞米松(第1天至第4天口服40毫克/天)之組合治療歷經多至四個週期。繼續採用由每日本發明之免疫調節化合物及每月地塞米松組成之維持治療直至疾病更加嚴重。將本發明之免疫調節化合物與美法侖及地塞米松組合使用之療法具有高度活性且通常為在其他方面預後差且經重度預治療之多發性骨髓瘤患者所耐受。
上述本發明之實施例係欲僅為例示性實施例,且熟習此項技術者將瞭解或將能僅使用常規實驗確定特定化合物、材料及方法之眾多相當物。所有該等相當物視為在本發明之範疇內且由隨附申請專利範圍包括。
圖1展示在活體外研究中3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮(雷利明(Revlimid))與沙立度胺(thalidomide)抑制多發性骨髓瘤(MM)細胞株增殖之作用的比較。量測不同MM細胞株(MM.1S,Hs Sultan,U266及RPMI-8226)對[3
H]-胸苷之吸收作為細胞增殖之指標。
Claims (22)
- 一種3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮用於製備治療人類白血病之藥劑之用途,其中該藥劑係製備為該化合物介於1毫克/天至10毫克/天之起始劑量至介於10毫克/天至20毫克/天之最大劑量之逐步增加之劑量投藥其中該白血病為慢性淋巴細胞白血病、急性淋巴母細胞白血病或急性骨髓性白血病。
- 如請求項1之用途,其中該起始劑量係介於1及5毫克/天。
- 如請求項2之用途,其中該起始劑量為2毫克/天。
- 如請求項2之用途,其中該起始劑量為5毫克/天。
- 如請求項1至4中任一項之用途,其中該劑量係每週逐步增加。
- 如請求項1至4中任一項之用途,其中該劑量係每28天逐步增加。
- 如請求項1之用途,其中該最大劑量為10毫克/天。
- 如請求項1之用途,其中該藥劑包含5或10毫克之3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮。
- 如請求項1之用途,其中該藥劑包含2.5、3、4、5、6、7、8、9、10、11、12、13、14或15毫克之3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮。
- 如請求項1至4中任一項之用途,其中該白血病為復發或治療無效之急性淋巴細胞白血病。
- 如請求項1至4中任一項之用途,其中該藥劑與第二活性 劑合併施予。
- 如請求項11之用途,其中該第二活性劑為抗體、造血生長因子、細胞激素、抗癌劑、抗生素、cox-2抑制劑、免疫調節劑、免疫抑制劑、皮質類固醇或其具有藥理學活性之突變體或衍生物,其中術語「突變體」係指蛋白質,其具有一或多個不同於自然存在形態蛋白質之相應殘基之胺基酸殘基或缺乏自然存在於自然形態蛋白質之碳水化合物部分,且其中術語「衍生物」係指聚乙二醇衍生物及融合蛋白質。
- 如請求項11之用途,其中該第二活性劑為利妥昔單抗(rituximab)。
- 如請求項11之用途,其中該第二活性劑為氟達拉賓(fludarabine)。
- 如請求項1至4中任一項之用途,其中該3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮係對映異構上純的。
- 如請求項15之用途,其中該3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮為S對映異構體。
- 如請求項15之用途,其中該3-(4-胺基-1-酮基-1,3-二氫-異吲哚-2-基)-哌啶-2,6-二酮為R對映異構體。
- 如請求項1至4中任一項之用途,其中該藥劑係為口服形式。
- 如請求項1至4中任一項之用途,其中該藥劑係為膠囊或錠劑形式。
- 如請求項1至4中任一項之用途,其中該藥劑係調配為投藥21天接著停藥7天之28天週期。
- 如請求項20之用途,其中該藥劑係調配為合併施予375mg/m2 之量之利妥昔單抗。
- 如請求項1至4中任一項之用途,其中該藥劑調配為以28天為週期之連續投藥。
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