TW201832766A - 用於增加血漿2′-去氧尿苷(dUrd)及胸苷酸合成酶抑制之方法 - Google Patents
用於增加血漿2′-去氧尿苷(dUrd)及胸苷酸合成酶抑制之方法 Download PDFInfo
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Abstract
本發明提供用於增加血漿dUrd含量之方法,其包含投與6R-MTHF。與等莫耳濃度LV相比增加血漿dUrd之方法增加dUrd含量。本發明亦提供用於增加TS抑制之方法,其包含投與6R-MTHF。
Description
本發明係關於治療人類中之固態腫瘤,諸如癌症,其涉及在5-氟尿嘧啶(5-FU)基化療中投與[6R]-5,10-亞甲基四氫葉酸(6R-MTHF)。
5-氟尿嘧啶(5-FU)最初在1957年引入且仍然是在包括結腸直腸癌(CRC)之固態腫瘤治療中之支柱。5-FU主要藉由抑制胸苷酸合成酶(TS)且此外在一定程度上藉由將代謝物併入至RNA發揮細胞毒活性。(Ford等人(2002) Clinical Cancer Research 2002; 8(1): 103-109)。單獨的5-FU總體反應率非常受限(10-15%)且已開發出調制策略以提高5-FU之抗癌活性。(Johnston等人Anticancer Drugs 2001, 12: 639-646)。使用最廣泛之策略中之一者涉及葉酸5-甲醯四氫葉酸(醛葉酸或亞葉酸或LV)與5-FU共同投與。(Romanini等人(1991) Cancer Res., 51: 789-793; Keyomarsi等人(1988) J. Biol. Chem., 263: 14402-14409)。LV使抑制DNA合成必需之胸苷酸合成酶(TS)之三元錯合物穩定。(Longley等人(2003) Nat. Rev. Cancer, 3(5):330-8)。藉由向5-FU添加LV總體反應率提高至超過20%。(Id.)。 基於直接投與還原葉酸鹽亞甲基THF代替LV可提供在臨床活性方面顯著優點之假設,已建議還原葉酸鹽福特克林(fotrexorin)鈣(CoFactor®)((dl)-5,10,-亞甲基喋醯基-單麩胺酸鈣鹽,或[6R,S]-5,10-亞甲基-THF Ca鹽),亦稱為外消旋亞甲基THF,作為LV之替代方案。CoFactor®係兩種非對映異構體之1:1混合物(Odin, E., Carlsson, G., Frösing, R., Gustavsson, B., Spears, C.P., Larsson, P.A., 1998. Chemical stability and human plasma pharmacokinetics of reduced folates. Cancer Invest. 16, 447-455)。因為[6R]-異構體係TS之直接活性共受質,預見到投與CoFactor®而非甲醯四氫葉酸將為有利的,此係由於考慮臨床安全及功效較低之患者間及患者內變異率。 實際上,在此前未經治療之轉移性結腸直腸癌之II期試驗中,發現CoFactor®之反應率為35% (Saif, M.W, Merritt, J, Robbins J, Stewart J., Schupp, J, 2006. Phase III Multicenter Randomized Clinical Trial to Evaluate the Safety and Efficacy of CoFactor®/5-Fluorouracil/Bevacizumab Versus Leucovorin/5-Fluorouracil/ Bevacizumab as Initial Treatment for Metastatic Colorectal Carcinoma Clinical Colorectal Cancer, Vol. 6, No. 3, 229-234, 2006),在另一個I/II期臨床試驗中展現在40%之患者中與5-FU組合之CoFactor®顯示在胰腺癌中之臨床益處,其被定義為安定疾病或腫瘤反應(Saif, M.W., Makrilia N., Syrigos K., 2010. CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy. Journal of Oncology Vol. 1-5)。然而,除表現不必要的肝解毒負擔之外,考慮其作為TS共受質之效應非天然(6S)-異構體為天然[6R]-異構體部分競爭性抑制劑(Leary, R.P., Gaumont, Y., Kisliuk, R.L., 1974. Effects of the diastereoisomers of methylenetetrahydrofolate on the reaction catalyzed by thymidylate synthetase. Biochem. Biophys. Res. Commun. 56, 484-488)。此外,在一個IIb期研究中在結腸直腸癌中CoFactor®未展現比甲醯四氫葉酸更有效,因為不能發現在研究組之間關於功效或安全之顯著差異,且一個計劃III期研究結腸直腸癌在完成之前中止(新聞稿:ADVENTRX Provides Update on Cofactor Program. Nov 2, 2007)。 繼續存在對用於穩定三元錯合物且增加對TS抑制之組成物及方法的較大需要。本發明者出人意料地發現與投與等莫耳濃度之LV相比投與6R-MTHF增加2'-去氧尿苷(dUrd)血漿含量。出人意料地,本發明者發現與投與等莫耳濃度之LV相比投與6R-MTHF增加對TS之抑制。
本發明者發現當與5-FU共同投與時等莫耳劑量6R-MTHF與LV相比出人意料地在血漿中產生顯著較高之dUrd含量。血漿2'-去氧尿苷(dUrd)之升高係TS抑制之標誌。(Ford等人(2002) Clinical Cancer Research, 8(1): 103-109)。本發明出人意料地提供包含投與6R-MTHF之用於增加血漿dUrd含量之方法。與等莫耳濃度LV相比,增加血漿dUrd之方法增加含量。本發明亦提供包含投與6R-MTHF之用於增加TS抑制之方法。 作為TS抑制之替代標誌,血漿dUrd升高逐漸變為精選的生物標記。藉由血液取樣及LC-MS/MS分析,進行分析亦相對簡單。使用TS抑制劑如5-FU治療造成TS受質dUMP之細胞內池上升,其反映在相對應的核苷dUrd之升高的含量中,該升高的含量大部分在細胞外且可在血漿中量測。此外,已展示血漿dUrd升高緊隨著TS抑制劑之投與,且由此為TS抑制之替代標誌(Ford等人(2002))。 本發明者理解在5-FU治療期間血漿dUrd含量升高直接映射當前體內整合的腫瘤TS抑制狀態,反映包括轉移之所有存在之腫瘤部位。 藉由發現在腫瘤中TS之基本活性遠高於在黏膜中且在5-FU治療期間在腫瘤中比在黏膜及其他身體細胞中代謝物5-氟去氧尿苷單磷酸酯(FdUMP)與TS之結合及TS抑制效應高得多強有力地支持以上所述。值得注意的是在不添加外生性葉酸鹽(MTHF)的情況下幾乎觀測不到FdUMP之結合(Peters等人(1991) Eur J Cancer, 27(3): 263-267)。 因此,作為TS抑制之替代標誌,血漿dUrd含量相對於基於例如僅局限於例如腫瘤或黏膜或分離之TS酶之生物檢體之體外研究的3
H-FdUMP TS結合的早期測定顯然突出。當今此等基於放射性標記之結合分析若有也很少使用且與極大程度變化強烈相關(Peters等人(1991) Eur J Cancer, 27(3): 263-267)且難以獲得用於測定之必需材料。 本發明者認為90%以上之TS抑制程度對腫瘤進入發生腫瘤壞死所需之細胞凋亡狀態係必需的。 進一步認為6R-MTHF能夠使以上抑制性三元錯合物穩定至獲得90%含量及以上之TS抑制之所需含量。
本申請案主張於2017年2月14日申請之美國臨時申請案第62/458,868號之優先權,該申請案以全文引用之方式併入本文中。 在一個實施例中,採用[6R]-5,10-亞甲基四氫葉酸(6R-MTHF)或其醫藥學上可接受之鹽,其呈可溶於水之固體形式或凍乾物形式,視情況藉由一或多種合適賦形劑及/或抗氧化劑諸如檸檬酸或抗壞血酸或其鹽形式穩定。在一個實施例中,6R-MTHF作為一或多種靜脈內集團投與,各集團含有5-1000 mg/m2
BSA(體表面積),諸如5 mg/m2
BSA,諸如7 mg/m2
BSA,諸如10 mg/m2
BSA,諸如15 mg/m2
BSA,諸如30 mg/m2
BSA,諸如60 mg/m2
BSA,諸如120 mg/m2
BSA,諸如240 mg/m2
BSA,諸如480 mg/m2
BSA,諸如720 mg/m2
BSA或諸如960 mg/m2
BSA。如本文所使用,「集團」意謂一種靜脈內投與方法,其中醫藥組合物之單次劑量一次全部給與,不同於靜脈內輸注,其中單次劑量以恆定濃度在一時段內給與。 劑量取決於治療形式、製劑施加形式及患者年齡、重量、營養及病況。治療可以低於最優量之較小量開始,該量可提高以便獲得最優效果。療法中所用之較佳劑量在每日10 mg與每日3,000 mg,尤其在每日50 mg與每日500 mg範圍內。可以單次劑量形式或反覆劑量形式進行投與。 在一個實施例中,6R-MTHF可呈游離酸形式,呈醫藥學上可接受之鹽,尤其酸鹽以及鹼或鹼土金屬鹽形式。 在另一實施例中,MTHF包含兩種非對映異構性異構體,尤其非對映異構體純之天然6R-MTHF。如本文所使用,術語「非對映異構體純」意謂6R-MTHF或其鹽相比於其他異構體異構過量大於約80%,較佳大於約90%,較佳大於約95%,更佳大於約97%,甚至更佳大於約99%,更佳大於約99.5 %或更大且最佳高達100%,其中其餘部分係其他6S-MTHF異構體。 在另一實施例中,6R-MTHF為化學純。如本文所使用,術語「化學純」意謂如藉由HPLC所測定,化合物呈約80%化學純度,較佳約90%,更佳約95%,更佳約97%,更佳約98%化學純度且最佳99%或高於99%,例如,99.5、99.6、99.7、99.8、99.9或高達100%化學純度。化學雜質可包括未反應之起始物質(包括溶劑)、6R-MTHF降解產物(諸如四氫葉酸及其降解產物)等。 視情況,包含6R-MTHF之醫藥組合物例如可進一步包含至少一種抗癌化合物。抗癌化合物可包括(但不限於)一或多種化學治療劑,諸如(但不限於):核酸,尤其氟化核酸(例如5 -氟脲嘧啶(5-FU)或其類似物或前驅藥),抗葉酸劑(例如培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)、洛美曲索(lometrexol)),拓樸異構酶抑制劑(例如伊立替康(irinotecan)、拓朴替康(topotecan)),抗代謝物藥物(例如甲胺喋呤(methotrexate)、吉西他濱(gemcitabine)、替紮他濱(tezacitabine)),5-FU調節劑,烷基化劑(例如環磷醯胺、卡莫司汀(carmustine)),核酸生物合成抑制劑(諸如絲裂黴素(mitomycin)、蒽環黴素(anthracyclines)(例如表阿黴素(epirubicin)、小紅莓(doxorubicin)))、鉑衍生物(例如順鉑(cisplatin)、奧賽力鉑(oxaliplatin)、卡鉑(carboplatin))、微管干擾藥物(例如紫杉醇、多西他賽(docetaxel)、長春瑞濱(vinolrebine)、長春新鹼(vincristine),激素阻斷藥物(例如他莫昔芬(tamoxifen)),包括(但不限於)受體及非受體酪胺酸激酶之激酶抑制劑(例如易瑞沙(Iressa)、特羅凱(Tarceva)、SU5416、PTK787、格列維克(Gleevec)),蛋白酶體抑制劑(例如硼替佐米(bortezomib)),免疫調節劑(例如左旋咪唑),消炎藥,血管形成抑制劑,細胞介素(例如介白素、腫瘤壞死因子)及抑制細胞介素、激素或細胞介素或激素之受體之活性之藥物(例如抗VEGF抗體貝伐單抗(bevacizumab)或「阿瓦斯汀(Avastin)」) 。抗癌化合物亦可包括單株抗體,諸如(但不限於)與細胞介素、激素或激素受體結合之單株抗體(例如阻斷EGF或VEGF生長因子活化之抗體,諸如阿瓦斯汀、艾必妥(Erbitux)、賀癌平(herceptin))等。在一個實施例中,6R-MTHF與治療有效量之至少一種抗癌化合物組合投與。當6R-MTHF與治療有效量之至少一種抗癌化合物組合投與時,一般熟習此項技術者將理解該至少一種抗癌化合物可在6R-MTHF之前、之後或同時投與。實例
以下實例僅指示本發明之性質,且不應視為以任何方式限制本發明或所附申請專利範圍之範疇。實例 1-- 用 5-FU 及葉酸治療。 1. 研究設計。
在患有IV期結腸直腸癌(mCRC)之患者中在開放標記、多位點、I/II期劑量組試驗(ISO-CC-005)中分析[6R]-5,10-亞甲基四氫葉酸([6R]-MTHF)之安全性及功效以測定在患有IV期結腸直腸癌之患者中單獨或與固定劑量之貝伐單抗、奧賽力鉑或伊立替康組合之6R-MTHF與標準劑量5-FU(500 mg/m2
)組合之安全及可耐受靜脈內集團劑量。在患者群組(n≥3)中,在以標準劑量給與之細胞毒劑、單獨的5-FU或5-FU外加奧賽力鉑、貝伐單抗或伊立替康之不同排列存在下,評估30-240 mg/m2
BSA之遞升之6R-MTHF劑量。研究預期至2017年底完成。研究設計之概述及各研究隊組在以下表1中描繪。表 1 : 化療劑 ( 貝伐單抗、奧賽力鉑、伊立替康及 / 或 5-FU) 及研究藥物 (6R-MTHF) 之初始劑量
縮寫:N/A
:不適用,SP2D
:所選擇之2期劑量。 ¶ 必要時奧賽力鉑投與之時間點窗口將擴展至允許至多120分鐘之輸注時間。 # 必要時伊立替康投與之時間點窗口將擴展至允許至多90分鐘之輸注時間。 § 無關於體表面積,投與之集團5-FU劑量不應超出1000 mg之最大建議每日劑量。 * 已抹除原先包括於此臨床研究方案早期版本中之組#3、組#10、及組#11。a 在治療隊組#4(組#12、#13及#14)及隊組#5(組#15)中6R-MTHF之總劑量將被分成分別在5-FU團注(在0分鐘)投與之後約30及60分鐘配製之兩個(2)靜脈內團注。連續5-FU輸注將為6R-MTHF之第二次注射投與而暫停。 b 在治療隊組#4(MOFOX)中之6R-MTHF劑量評定為具有對於以下研究最有利之分佈的劑量。 已收集在Gothenburg幾乎二十年所有患有CRC之患者之臨床、治療及結果數據。血漿及組織樣品已在用於長期儲存之適當之物理條件下儲存於生物樣本庫中。資料庫及生物樣本庫在相關道德及監管權限的支持下運行。從資料庫中隨機抽出已經標準5-FU劑量500 mg/m2
外加靜脈內集團LV 60 mg/m2
(等效於30 mg/m2
LLV)治療之患者。 對於所有患者,儲存之血漿樣品用於測定dUrd。 本研究係歷史群組比較研究。所有患者已經以團注形式給與之500 mg 5-FU之標準劑量外加亦以團注形式給與之相應葉酸6R-MTHF或LV治療。2. 經 6R-MTHF 治療之患者。
已在使用5-FU之兩個連續治療循環期間量測所有患者。在即將注入5-FU之前(t0
)及在24小時之後(t24
)量測dUrd值。分別計算以30及60 mg/m2
6R-MTHF各劑量給藥之患者在t24
與t0
之間的差異的平均值及標準差。亦對240 mg/m2
6R-MTHF測定且計算一些值。3. 經 LV 治療之患者。
從資料庫中隨機抽出二十四個經5-FU外加60 mg/m2
LV治療之患有轉移性結腸直腸癌(mCRC)之患者,且對於各患者自兩個治療循環在t0
及t24
時測定dUrd含量,且以與6R-MTHF患者相同之方式計算在t24
與t0
之間差異之平均值及標準差。由於LV係天然(l-甲醯基-四氫葉酸)與非天然(d-甲醯基-四氫葉酸)異構體之50:50混合物,因此活性異構體構成給與之LV劑量的二分之一。LV及6R-MTHF之分子量極類似且因此60 mg LV可視為與30 mg 6R-MTHF等莫耳。4. 統計方法。
藉助於Friedman雙向差異分析測試所有四個群組之間的差異且其後藉助於Mann-Whitney U測試來測試兩個等莫耳群組LV 60 mg/m2
與6R-MTHF 30 mg/m2
之間的差異。p值小於0.05視為顯著。3. 血漿 dUrd 之測定
血漿dUrd藉由包含液相層析接著串聯式質譜法之方法測定,大體上概述如下: 將血漿樣品從-80℃之冷凍器中移出,將三氯乙酸添加至血漿中且將樣品混合及離心。上澄液經10 kDa分子量截斷過濾膜過濾且再次離心30 min。隨後試管底部之溶液準備進行LC-MS/MS分析。以相同方式使用空白血漿樣品及不同內標濃度製備校準樣品。進入LC-MS/MS之注射體積為40 μl。藉由負模式電噴霧電離去氧尿苷及氯去氧尿苷。為了所有葉酸之最大反應優化MS參數。採用MS/MS採集方法(多反應監測)。實例 2-TS 抑制。
前三個群組之間的差異顯著(p = 0.04)且兩個等莫耳群組LV 60 mg/m2
與[6R]-MTHF 30 mg/m2
之間的差異亦顯著(p = 0.03)。等莫耳劑量之[6R]-MTHF連同5-FU產生比LV顯著更高含量之dUrd。此外,在增加[6R]-MTHF劑量與增加TS抑制含量之間似乎存在劑量-反應關係,如由增加之血漿dUrd含量反映(見表 2
及圖 1
)。表 2. 在團注 5-FU 外加 LLV 或 6R-MTHF 之後 24 小時 dUrd 增量 1
除240 mg/m2
群組外。 此研究表明5-FU與6R-MTHF而非LV之生物調控引起較高血漿dUrd及增加之TS抑制。此觀測結果藉由在增加6R-MTHF劑量之後的TS之劑量相關抑制進一步支持。 60 mg/m2
LV集團劑量係在Scandinavia廣泛使用之所謂的北歐療法中所用之標準劑量。臨床結果類似於當藉由輸注投與,通常400 mg歷時兩小時時之其他方案獲得之彼等。(Gustavsson等人,(2015) Clinical Colorectal Cancer, 14: 1-10)。引起關注的是注意在6R-MTHF之後高得多的TS抑制(圖 2
)。
圖 1
:在投與5-FU與30及60 mg/m2
6R-MTHF(表示為「6R」)後與30 mg/m2
l-LV(「LLV」)(表示為「LLV 30」)相比,與60 mg/m2
外消旋(d、l-LV或LV)相比提高之TS抑制。圖 2
:在投與5-FU與30及60 mg/m2
6R-MTHF(表示為「6R」)後相對於30 mg/m2
LLV (60 mg/m2
d、l-LV或LV或LV 60)血漿dUrd含量。圖 3
:LV與6R-MTHF等莫耳比較,顯示為在連同團注30 mg/m2
l-LV(表示為「LLV30」)(60 mg/m2
d、l-LV或LV)或30 mg/m2
6R-MTHF(表示為「M30」)投與之集團5-FU 500 mg/m2
之後24小時增加之血漿dUrd含量。增量經計算為對LLV循環(n=48)及6R-MTHF循環(n=18)在24小時(t24
)時dUrd血漿濃度減在即將注入之前(t0
)血漿dUrd濃度之間的個體差異。LLV係LV之活性天然異構體,LV係LLV與非天然、無(顯著)活性d-LV之50:50混合物。6R-MTHF及LLV之分子量足夠類似以作為等莫耳比較之基礎。已使用Mann-Whitney U測試(p<0.05)測試群組之間的差異。圖 4
:在連同團注30 mg/m2
l-LV(表示為「LLV30」)(60 mg/m2
d、l-LV或LV)或30 mg/m2
(表示為「M30」)或60 mg/m2
6R-MTHF(表示為「M60」)投與之團注5-FU 500 mg/m2
之後24小時增加之血漿dUrd含量6R-MTHF劑量相關增加。增量經計算為對LLV循環(30 mg/m2
n=48)及6R-MTHF循環(30 mg/m2
n = 18; 60 mg/m2
n = 16)在24小時(t24
)時dUrd血漿濃度減在即將注入之前(t0
)血漿dUrd濃度之間的個體差異。在群組之間的差異顯著且已使用Friedman雙向差異分析(p<0.05)測試。
Claims (15)
- 一種增加人類個體中之dUrd之血漿濃度之方法,其包含: a. 向該人類個體靜脈內投與包含與治療有效量之至少一種抗癌劑組合之5-1000 mg/m2 劑量之6R-MTHF的醫藥組合物之步驟; 其中該投與產生增加之dUrd之血漿濃度。
- 如請求項1之方法,其中在該人類個體中之dUrd之血漿濃度相對於等莫耳投與LV之後在人類個體中的dUrd血漿含量增加。
- 如請求項1之方法,其中在該人類個體中dUrd之平均血漿含量大於在等莫耳投與LV之後在人類個體中產生之平均血漿含量。
- 如請求項1之方法,其中該醫藥組合物係以集團形式投與。
- 如請求項1之方法,其中該人類個體罹患癌症。
- 如請求項5之方法,其中該癌症為結腸直腸癌。
- 如請求項1之方法,其進一步包含投與至少一種額外抗癌化合物。
- 如請求項7之方法,其中該一種額外抗癌化合物係選自由以下組成之群:奧賽力鉑(oxaliplatin)、伊立替康(irinotecan)及貝伐單抗(bevacizumab)。
- 一種在人類個體中抑制胸苷酸合成酶(TS)之方法,其包含: a. 向該人類個體靜脈內投與包含與治療有效量之至少一種抗癌劑組合之5-1000 mg/m2 劑量之6R-MTHF的醫藥組合物之步驟; 其中相對於接受等莫耳劑量LV之人類個體,該投與產生增加之TS之抑制。
- 如請求項9之方法,其中該醫藥組合物係以集團形式投與。
- 如請求項9之方法,其中該人類個體罹患癌症。
- 如請求項11之方法,其中該癌症為結腸直腸癌。
- 如請求項9之方法,其中該至少一種抗癌劑為5-氟脲嘧啶(5-FU)。
- 如請求項13之方法,其進一步包含投與至少一種額外抗癌化合物。
- 如請求項14之方法,其中該一種額外抗癌化合物係選自由以下組成之群:奧賽力鉑、伊立替康及貝伐單抗。
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CA3053293C (en) | 2023-01-03 |
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US20190240224A1 (en) | 2019-08-08 |
RU2019126648A (ru) | 2021-03-16 |
WO2018150264A1 (en) | 2018-08-23 |
SG11201907442UA (en) | 2019-09-27 |
JP2020505316A (ja) | 2020-02-20 |
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IL268439B1 (en) | 2023-12-01 |
AU2018220861A1 (en) | 2019-09-05 |
NZ756408A (en) | 2024-01-26 |
IL268439A (en) | 2019-09-26 |
US11389452B2 (en) | 2022-07-19 |
KR20190112711A (ko) | 2019-10-07 |
US20180289711A1 (en) | 2018-10-11 |
EP3848036A3 (en) | 2021-08-18 |
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