CN103826634A - 4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1h-苯并咪唑-2-基]-1h-喹啉-2-酮在治疗中度肝损伤患者癌症中的应用 - Google Patents
4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1h-苯并咪唑-2-基]-1h-喹啉-2-酮在治疗中度肝损伤患者癌症中的应用 Download PDFInfo
- Publication number
- CN103826634A CN103826634A CN201280044613.4A CN201280044613A CN103826634A CN 103826634 A CN103826634 A CN 103826634A CN 201280044613 A CN201280044613 A CN 201280044613A CN 103826634 A CN103826634 A CN 103826634A
- Authority
- CN
- China
- Prior art keywords
- patient
- amino
- compound
- treatment
- administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 21
- 201000011510 cancer Diseases 0.000 title claims abstract description 16
- 230000001771 impaired effect Effects 0.000 title abstract description 6
- 230000002440 hepatic effect Effects 0.000 title abstract description 3
- PIQCTGMSNWUMAF-UHFFFAOYSA-N chembl522892 Chemical compound C1CN(C)CCN1C1=CC=C(NC(=N2)C=3C(NC4=CC=CC(F)=C4C=3N)=O)C2=C1 PIQCTGMSNWUMAF-UHFFFAOYSA-N 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 108010082126 Alanine transaminase Proteins 0.000 claims description 19
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 claims description 18
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 17
- 210000004185 liver Anatomy 0.000 claims description 17
- 108010003415 Aspartate Aminotransferases Proteins 0.000 claims description 14
- 102000004625 Aspartate Aminotransferases Human genes 0.000 claims description 14
- 230000007812 deficiency Effects 0.000 claims description 14
- 230000003203 everyday effect Effects 0.000 claims description 7
- 210000002381 plasma Anatomy 0.000 claims description 6
- 238000008050 Total Bilirubin Reagent Methods 0.000 claims description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 235000014655 lactic acid Nutrition 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 37
- 231100000753 hepatic injury Toxicity 0.000 description 20
- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 description 14
- 238000011160 research Methods 0.000 description 12
- 210000003494 hepatocyte Anatomy 0.000 description 11
- 230000003908 liver function Effects 0.000 description 10
- 238000011156 evaluation Methods 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000007115 recruitment Effects 0.000 description 5
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 3
- 201000008275 breast carcinoma Diseases 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 208000000857 Hepatic Insufficiency Diseases 0.000 description 2
- 206010019663 Hepatic failure Diseases 0.000 description 2
- 206010067125 Liver injury Diseases 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 210000000941 bile Anatomy 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 201000009613 breast lymphoma Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YUDPTGPSBJVHCN-DZQJYWQESA-N 4-methylumbelliferyl beta-D-galactoside Chemical compound C1=CC=2C(C)=CC(=O)OC=2C=C1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O YUDPTGPSBJVHCN-DZQJYWQESA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000008142 Cytochrome P-450 CYP1A1 Human genes 0.000 description 1
- 108010074918 Cytochrome P-450 CYP1A1 Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 108091008794 FGF receptors Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 101710107035 Gamma-glutamyltranspeptidase Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 101710173228 Glutathione hydrolase proenzyme Proteins 0.000 description 1
- 206010019670 Hepatic function abnormal Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- -1 LDH Proteins 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 description 1
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 101710098398 Probable alanine aminotransferase, mitochondrial Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000037058 blood plasma level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000013170 computed tomography imaging Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 238000004980 dosimetry Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 102000006640 gamma-Glutamyltransferase Human genes 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000010197 meta-analysis Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 238000000611 regression analysis Methods 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 231100000748 severe hepatic injury Toxicity 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 108010002164 tyrosine receptor Proteins 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通过给予4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮、或其互变异构体、或其中任意一种的盐来治疗有此需要的患者中癌症的方法，其中所述患者是中度肝损伤患者。
Description
本发明涉及通过给予4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮、或其互变异构体、或其中任意一种（化合物I）的盐来治疗有此需要的患者中癌症的方法，其中所述患者是中度肝损伤患者。
提供下列描述以帮助读者理解。本文提供的信息或引用的参考文献不视作承认是本技术的在先技术。
4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮具有式I所示结构：
式I化合物抑制多种蛋白激酶，如酪氨酸受体蛋白激酶。此化合物和其盐（包括单乳酸盐）的应用及制备描述于美国专利号6,605,617、6,774,237、7,335,774和7,470,709以及美国专利申请系列号10/982,757、10/982,543和10/706,328以及2006年11月30日公开的PCT公开申请WO2006/127926和2009年9月24日公开的WO2009/115562，各文献通过引用全文纳入本文。晶形和其制备描述于US11/915005，特别是B型。
根据来自I和II期研究的化合物I的PK和安全性数据，选择500毫克/天、5天给药/2天停药的方案用于治疗组1（正常肝功能）和2（轻度肝损伤），以确保这2组癌患者的最优全身性暴露。事实上，由于其性质，化合物I在连续每日给药方案后于25-600mg的所有测试剂量显示时间依赖性血浆药代动力学，在400毫克/天及以上剂量观察到延长的超比例化合物I暴露。引入5天给药/2天停药的方案以防止随着剂量递增出现所述延长的超比例化合物I暴露积累。对于有中度肝损伤的患者，没有数据表明化合物I是否能以与正常肝功能和轻度肝损伤患者相同的剂量给予这些患者。肝损伤患者消除化合物I能力降低的风险可能更高。器官功能受损引起的药物消除减少能导致全身性暴露和可能的毒性增加。
本发明人用本发明解决当前问题。本发明涉及化合物I在有此需要的患者内治疗癌症中的应用，其中所述患者是中度肝损伤患者且给药剂量为每天400mg以及给药方案为5天给药和2天停药。
本发明涉及化合物I在有此需要的患者内治疗癌症中的应用，其中所述患者是中度肝损伤患者且给药剂量为每天500mg以及给药方案为5天给药和2天停药。
本发明涉及化合物I在有此需要的患者内治疗癌症中的应用，其中所述患者是中度肝损伤患者且给药剂量为每天300mg以及给药方案为5天给药和2天停药。
本发明涉及通过给予4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮、或其互变异构体、或其中任意一种的盐来治疗癌症患者的方法，其中所述患者是中度肝损伤患者且剂量为每天300mg、400mg或500mg以及给药方案为5天给药和2天停药。
本发明涉及4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮、或其互变异构体、或其中任意一种的盐在制备治疗癌症药物中的应用，其中所述患者是中度肝损伤患者且给药剂量为每天300mg或400mg或500mg以及给药方案为5天给药和2天停药。
根据本发明治疗的癌症包括实体瘤，如肾癌、乳腺癌、膀胱癌、前列腺癌和多发性骨髓瘤。
根据本发明，中度肝损伤患者是具有下列血浆特性的患者：1.5x ULN<TBL≤3.0x ULN和/或AST和ALT≤5x ULN，其中ULN指正常上限，TBL指总胆红素，AST指天冬氨酸转氨酶，ALT指丙氨酸转氨酶。
丙氨酸转氨酶（ALT）也称为血清谷氨酸丙酮酸转氨酶（SGPT）或丙氨酸氨基转移酶（ALAT），是一种在肝细胞（肝脏细胞）中存在的酶。细胞受损时，将此酶释放入血液，在其中进行测量。ALT在急性肝损伤，如病毒性肝炎或扑热息痛（对乙酰氨基酚）过量中急剧上升。上升通常在正常上限（ULN）倍数内测得。ALT的参考范围是9-40IU/L（国际单位/升）
天冬氨酸转氨酶（AST）也称为血清谷草转氨酶（SGOT）或天冬氨酸氨基转移酶（ASAT），与ALT类似，因为它是与肝实质细胞相关的另一酶。其在急性肝损伤中上升。AST的参考范围是10-35IU/L。
胆红素是亚铁血红素（红细胞中血红蛋白的一部分）降解产物。肝负责清除胆红素的血液。这通过以下机制完成：胆红素被摄入肝细胞，结合（修饰从而变为水溶性），分泌入胆汁，胆汁被排入肠内。总胆红素增加导致黄疸，且可能指示许多问题。肝的问题反映为胆红素代谢不足（如肝细胞摄取减少，胆红素结合受损，肝细胞分泌胆红素降低）。总胆红素的正常水平的参考范围是例如0.2-1.2mg/dL。
本领域技术人员了解测量AST、ALT和/或TBL的血液和/或血浆水平的手段、测量方法和试剂盒，如根据FDA和/或EMEA标准，且了解如何基于AST、ALT和/或TBL的测量结果来对患者如中度损伤患者进行分级。
化合物I作为盐给予时，剂量表示4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮的毫克数。合适的盐包括任何药学上可接受盐，特别是乳酸盐形式，如单乳酸盐形式。其他药学上可接受盐为本领域技术人员已知。
根据本发明，化合物I的乳酸盐可以是4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮乳酸盐的B型晶体，如US11/915005所述。
实施例1：4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮或其互变异构体（如其乳酸盐形式）在有正常和中度受损肝功能的成年癌患者中的药代动力学
主要目标：评估轻度或中度肝损伤相比正常肝功能对化合物I在晚期实体瘤患者中药代动力学的影响
次要目标：
评价与肝功能正常的患者相比，轻度或中度肝损伤的成年癌患者中根据5天给药/2天停药方案的化合物I给药的安全性和耐受性；
评价中度肝损伤的成年癌患者中根据5天给药/2天停药方案的化合物I给药的药代动力学（PK）、安全性和耐受性；
适当时使用回归分析研究PK和肝功能异常之间的关系（即胆红素，(丙氨酸氨基转移酶/谷丙转氨酶/GPT)/ALT/AST，和Child-Pugh分级）
评估化合物I在所研究患者群中的初步抗肿瘤活性
探索性目标：用于确定轻度、中度或严重肝损伤患者相比肝功能正常患者中化合物I的血浆结合部分（给药前样品）。
研究人群：有晚期实体瘤（除了乳腺癌和淋巴瘤）的成年患者，所述瘤难以由标准疗法治疗或没有可用疗法，其根据NCI指南有不同程度的肝损伤并与肝功能正常的癌症患者匹配。
患者数量：约18-48名患者
研究设计概述：
这是一种多中心、开放标签研究，用于评价轻度、中度肝损伤的成年癌症患者相对于正常肝功能患者的单剂量和稳态化合物I的PK。所述研究还评价中度肝损伤患者中化合物I的PK、安全性和耐受性，只要认为以根据轻度和中度肝损伤组的评估和安全性结果来评价该组是安全的。
从肝功能正常和受损患者中收集化合物I的单剂量PK。由于化合物I的时间依赖性PK（自诱导CYP1A1/A2），化合物I的稳态PK也在3周或4周（若患者在3周给药后错失或不能进行令人满意的PK取样）多次给药化合物I后，于这些患者中测定。所述研究由4个治疗组，包括治疗组1（正常肝功能）和2（轻度肝损伤）、3（中度肝损伤）组成。所有治疗组招募有任意实体瘤（除了乳腺癌和淋巴瘤）的患者。
治疗组3（中度肝功能障碍）选择400毫克/天（5天给药/2天停药方案）作为初始剂量。然而，可根据此研究所得的安全性、耐受性和PK数据，在中度肝功能障碍患者中研究其他剂量水平（500毫克/天或300毫克/天）。
治疗持续时间包括单剂量PK期，其在第1周的第1天给药单剂量化合物I和用化合物I进行多剂量治疗期，如采用5天给药/2天停药方案，在第1周的第4天开始，直到疾病发展（如通过RECIST1.1评价）、毒性不可接受、死亡或出于任何其他原因无法继续研究治疗。
约18-48个患者根据其基线/筛选时的总胆红素和AST/ALT水平加入3个治疗组。下表详述各治疗组的患者分配和治疗剂量。治疗组1-3平行招募，每个治疗组有至少6个可评估的患者。轻度肝损伤组需要6-12个可评估的患者。中度肝损伤组可能需要6-18个可评估的患者。
至少6个患者在已鉴定的耐受的化合物I剂量评估PK。治疗组1（对照）的招募应尽可能与治疗组2（轻度肝损伤）和3（中度肝损伤）的招募在年龄（±10岁）和体重（±10Kg）方面相当（或类似）。因此，治疗组1（正常肝功能）的招募保持开放，直到轻度和中度肝损伤组的招募完成，并且获得足够数量的匹配对照用于比较，此治疗组中最少有6个可评估的患者。若初始剂量不耐受，治疗组2（轻度肝损伤）允许剂量递减至400mg，治疗组3（中度肝损伤）允许剂量递减至300mg。剂量限制性毒性（DLT）标准用于指导剂量递增或剂量递减以根据此研究中评价的剂量水平来鉴定治疗组2和3的耐受化合物I剂量。需要可评估的患者完成安全性（DLT评估）和PK评价。如果在单剂量PK期和稳态获得完整PK分布，则认为患者是PK可评估的。如果患者完成4周化合物I治疗，其根据5天给药/2天停药方案接受至少16剂计划剂量，或在5天给药/2天停药方案的4周内由于DLT而中止化合物I治疗，则认为患者就DLT而言可评估。
药代动力学（PK）和蛋白结合评价：
对于PK评价：开始化合物I治疗后对每个患者收集总共17个时间点和约34mL血液。在以下时间点取血液样品（每样品2mL）：
·单剂量PK期（单剂量后第1周的第1天）：给药前，给药后2、4、6、8、24、48和72小时；
·稳态（第三个5天给药/2天停药方案的多个剂量后第4周的第1天）：给药前，给药后2、4、6、8、24、48和72小时。
·若患者错失或不能进行令人满意的第4周PK取样（如归因于剂量中断、患者呕吐等），可以在第四个5天给药/2天停药方案的多个剂量后第5周的第1天-第4天收集稳态PK）：给药前，给药后2、4、6、8、24、48和72小时。
·谷浓度（第7周的第1天）：给药前
对于蛋白结合评价：在第1周第1天给药前和第4周第1天（如适用，或者第5周第1天）给药前收集样品
安全性和耐受性评价：
·不良事件（AE）和严重不良事件（SAE）的常规安全性检测；
·血液学（血红蛋白、WBC、血小板、和差异）、血清化学（尿素/BUN、肌酸酐、总和直接胆红素、ALT、AST、碱性磷酸酶、γ-谷氨酰转肽酶、白蛋白、钙、钠、镁、磷、葡萄糖、LDH、淀粉酶和脂肪酶）、凝血（PT/INR、PTT和纤维蛋白原）、和尿分析的实验室试验；
·生命体征、机能状态、和身体检查的测量；
·ECG评估（给药前（一式三份，间隔5-10分钟），给药后2h和6hPK取样后的1小时内）；
·HCC患者中的MUGA/ECHO扫描，和HBV及HCV筛选；
·根据放射学肿瘤测量（如计算机断层扫描或磁共振成象扫描）使用RECIST1.1每8周进行疗效评价
·其他评价包括评估FGFR和VEGFR抑制的血浆生物标志物以及通
过生物标志物分析从血浆样品鉴定可能受益于治疗的患者。
数据分析：
对化合物I的完整PK分布进行非隔室分析。按照肝组以及用于单剂量和稳态的剂量显示各预定时间点处化合物I血浆浓度的概括统计量和平均（SD）图。药代动力学参数如Cmax、Tmax、AUClast、单剂量AUCinf、HL、Vz/F、CL/F按照肝组和剂量总结。比较轻度和中度肝损伤组与对照组（正常肝功能）的PK参数，包括Cmax、Tmax、AUClast、和单剂量AUCinf。将固定影响ANOVA模型与来自对照、轻度和中度肝损伤组的经log-转换剂量标准化的主要PK参数（Cmax、AUClast和单剂量AUCinf）拟合，其中肝功能作为固定影响，条件是合理假设剂量比例性（DP）。计算对照组和各肝损伤组之间平均差异的点估计和对应的90%置信区间。这是反对数的，从而在未转换量度上就几何平均数比例获得点估计和90%置信区间。如果存在关于DP假设的进一步证据，如所述进行初步分析。否则，适当时可采用其他基于线性和/或非线性模型的分析以评价肝功能对化合物I PK参数的影响。必要时，研究基线协变量如年龄和重量的影响。此外，产生自此研究的PK数据有助于未来的荟萃分析，用于正常或中等肝功能患者中化合物I的探索性PK群。
安全性分析由AE总结（频率表）和列表、实验室异常总结（基线到最差基线后的位移表）和列表、其他测试（如心电图或生命体征）列表中显著值下降。安全性组用于安全性分析。用剂量测定组列出DLT。
统计学考虑/样本大小计算：此研究的样本大小主要由以根据所述研究评价的剂量水平来鉴定治疗组2和3的耐受化合物I剂量的可行性和简单剂量发现过程来推动。约18-48个患者加入所述研究，治疗组1、2和3中最少有6个可评估的患者。采用500毫克/天，5天给药/2天停药方案的情况下，AUC的受试对象间变异系数（CV%）为约50%。使用50%的受试对象间CV%估计值和6个/治疗组的样本大小，以log量度上（肝功能受损）-（肝功能正常）比较的90%置信区间（CI）的精确值或半宽从所观察平均差异延伸0.494。此计算是基于2样品t检验，I型误差率为10%。对于多重比较没有做出调整。上述半宽转化成以下药代动力学参数比率的90%置信区间（CI），假设所观察比率不同。
| 比率 | 90%CI的下限 | 90%CI的上限 |
| 0.5 | 0.31 | 0.82 |
| 1.00 | 0.61 | 1.64 |
| 1.50 | 0.92 | 2.46 |
| 2.00 | 1.22 | 3.28 |
尽管已阐明和描述了某些实施方式，应理解能根据本领域普通技术在不偏离本技术情况下在其更广的方面做出改变和修改，如下列权利要求所定义。
Claims (6)
1.一种通过给予4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮、或其互变异构体、或其中任意一种的盐来治疗有此需要的患者中癌症的方法，其中所述患者是中度肝损伤患者。
2.如权利要求1所述的方法，其特征在于，-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮、或其互变异构体、或其中任意一种的盐以每天300mg、400mg或500mg剂量给药且给药方案为5天给药和2天停药。
3.如权利要求1或2所述的方法，其特征在于，所述中度肝损伤患者由以下血浆特性表征：1.5x ULN<TBL≤3.0x ULN和/或AST和ALT≤5x ULN，其中ULN指正常上限，TBL指总胆红素，AST指天冬氨酸转氨酶，ALT指丙氨酸转氨酶。
4.如权利要求1-3中任一项所述的方法，其特征在于，4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮、或其互变异构体采用其乳酸盐形式。
5.如权利要求4所述的方法，其特征在于，所述乳酸是D,L-乳酸。
6.如权利要求1-5中任一项所述的方法，其特征在于，所述4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1H-苯并咪唑-2-基]-1H-喹啉-2-酮乳酸采用B型晶型。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161535142P | 2011-09-15 | 2011-09-15 | |
| US61/535,142 | 2011-09-15 | ||
| PCT/US2012/054046 WO2013039764A1 (en) | 2011-09-15 | 2012-09-07 | Use of 4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1h-benzimidazol-2-yl]-1h-quinolin-2-one in the treatment of cancer in moderate hepatic impaired patients |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103826634A true CN103826634A (zh) | 2014-05-28 |
Family
ID=46846036
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201280044613.4A Pending CN103826634A (zh) | 2011-09-15 | 2012-09-07 | 4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1h-苯并咪唑-2-基]-1h-喹啉-2-酮在治疗中度肝损伤患者癌症中的应用 |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US20140221389A1 (zh) |
| EP (1) | EP2755655A1 (zh) |
| JP (1) | JP2014526506A (zh) |
| KR (1) | KR20140062485A (zh) |
| CN (1) | CN103826634A (zh) |
| AU (1) | AU2012308993A1 (zh) |
| BR (1) | BR112014005653A2 (zh) |
| CA (1) | CA2848210A1 (zh) |
| IN (1) | IN2014DN02060A (zh) |
| MX (1) | MX2014003182A (zh) |
| RU (1) | RU2014114827A (zh) |
| WO (1) | WO2013039764A1 (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2764866A1 (en) | 2013-02-07 | 2014-08-13 | IP Gesellschaft für Management mbH | Inhibitors of nedd8-activating enzyme |
| EP3093014A1 (en) * | 2015-05-13 | 2016-11-16 | Aventis Pharma S.A. | Cabazitaxel and its use for treating cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004105763A2 (en) * | 2003-05-27 | 2004-12-09 | Haegerkvist Robert Per | Use of tyrosine kinase inhibitor to treat diabetes |
| CN1711088A (zh) * | 2002-11-13 | 2005-12-21 | 希龙公司 | 治疗癌症的方法及相关方法 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EA006711B1 (ru) | 2000-09-11 | 2006-02-24 | Чирон Корпорейшн | Хинолиноновые производные в качестве ингибиторов тирозинкиназы |
| AU2003288899B2 (en) | 2002-08-23 | 2009-09-03 | Novartis Vaccines And Diagnostics, Inc. | Benzimidazole quinolinones and uses thereof |
| EP1565187A4 (en) * | 2002-11-13 | 2010-02-17 | Novartis Vaccines & Diagnostic | CANCER TREATMENT METHODS AND RELATED METHODS |
| KR101368519B1 (ko) | 2005-05-23 | 2014-02-27 | 노파르티스 아게 | 결정형 및 기타 형태의 4-아미노-5-플루오로-3-［6-(4-메틸피페라진-1-일)-1ｈ-벤즈이미다졸-2-일］-1ｈ-퀴놀린-2-온 락트산염 |
| AR070924A1 (es) | 2008-03-19 | 2010-05-12 | Novartis Ag | Formas cristalinas y dos formas solvatadas de sales del acido lactico de 4- amino -5- fluoro-3-(5-(4-metilpiperazin-1-il ) -1h- bencimidazol-2-il) quinolin -2-(1h) - ona |
| JP6220126B2 (ja) * | 2009-11-23 | 2017-10-25 | セルリアン・ファーマ・インコーポレイテッド | 治療的送達のためのシクロデキストリンに基づく重合体 |
-
2012
- 2012-09-07 EP EP12758976.0A patent/EP2755655A1/en not_active Withdrawn
- 2012-09-07 BR BR112014005653A patent/BR112014005653A2/pt not_active IP Right Cessation
- 2012-09-07 IN IN2060DEN2014 patent/IN2014DN02060A/en unknown
- 2012-09-07 KR KR1020147006625A patent/KR20140062485A/ko not_active Application Discontinuation
- 2012-09-07 AU AU2012308993A patent/AU2012308993A1/en not_active Abandoned
- 2012-09-07 WO PCT/US2012/054046 patent/WO2013039764A1/en active Application Filing
- 2012-09-07 RU RU2014114827/15A patent/RU2014114827A/ru not_active Application Discontinuation
- 2012-09-07 CN CN201280044613.4A patent/CN103826634A/zh active Pending
- 2012-09-07 US US14/342,612 patent/US20140221389A1/en not_active Abandoned
- 2012-09-07 JP JP2014530703A patent/JP2014526506A/ja active Pending
- 2012-09-07 CA CA2848210A patent/CA2848210A1/en not_active Abandoned
- 2012-09-07 MX MX2014003182A patent/MX2014003182A/es not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1711088A (zh) * | 2002-11-13 | 2005-12-21 | 希龙公司 | 治疗癌症的方法及相关方法 |
| WO2004105763A2 (en) * | 2003-05-27 | 2004-12-09 | Haegerkvist Robert Per | Use of tyrosine kinase inhibitor to treat diabetes |
Also Published As
| Publication number | Publication date |
|---|---|
| BR112014005653A2 (pt) | 2017-03-28 |
| RU2014114827A (ru) | 2015-10-20 |
| WO2013039764A1 (en) | 2013-03-21 |
| IN2014DN02060A (zh) | 2015-05-15 |
| AU2012308993A1 (en) | 2014-03-27 |
| EP2755655A1 (en) | 2014-07-23 |
| CA2848210A1 (en) | 2013-03-21 |
| KR20140062485A (ko) | 2014-05-23 |
| US20140221389A1 (en) | 2014-08-07 |
| JP2014526506A (ja) | 2014-10-06 |
| MX2014003182A (es) | 2014-09-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Judson et al. | A human capecitabine excretion balance and pharmacokinetic study after administration of a single oral dose of 14C-labelled drug | |
| Sarkaria et al. | North Central Cancer Treatment Group Phase I trial N057K of everolimus (RAD001) and temozolomide in combination with radiation therapy in patients with newly diagnosed glioblastoma multiforme | |
| Hamaguchi et al. | A phase II study of NK012, a polymeric micelle formulation of SN-38, in unresectable, metastatic or recurrent colorectal cancer patients | |
| Galvin et al. | Neurofibromatosis in the era of precision medicine: development of MEK inhibitors and recent successes with selumetinib | |
| Rajakariar et al. | Post transplant T-cell lymphoma: a case series of four patients from a single unit and review of the literature | |
| Benadiba et al. | Growth inhibitory effects of the Diruthenium-Ibuprofen compound,[Ru 2 Cl (Ibp) 4], in human glioma cells in vitro and in the rat C6 orthotopic glioma in vivo | |
| Duncan et al. | 18F-FDG-PET/CT imaging in an IL-6-and MYC-driven mouse model of human multiple myeloma affords objective evaluation of plasma cell tumor progression and therapeutic response to the proteasome inhibitor ixazomib | |
| CN103826634A (zh) | 4-氨基-5-氟-3-[6-(4-甲基哌嗪-1-基)-1h-苯并咪唑-2-基]-1h-喹啉-2-酮在治疗中度肝损伤患者癌症中的应用 | |
| Markovic et al. | Phase II trial of KW2189 in patients with advanced malignant melanoma | |
| Deng et al. | Clinical observation of crizotinib in the treatment of ALK-positive advanced non-small cell lung cancer | |
| CN115105501A (zh) | 西奥罗尼用于小细胞肺癌的治疗 | |
| Viertl et al. | Increase of [18 F] FLT tumor uptake in vivo mediated by FdUrd: Toward improving cell proliferation positron emission tomography | |
| Turcotte et al. | Toxicology evaluation of radiotracer doses of 3'-deoxy-3'-[18 F] fluorothymidine (18 F-FLT) for human PET imaging: Laboratory analysis of serial blood samples and comparison to previously investigated therapeutic FLT doses | |
| CN114814223A (zh) | 一种用于监测及控制疟原虫治疗的系统及设备 | |
| Muto et al. | A patient with intravascular lymphoma presenting with cerebral infarction and a high serum MPO-ANCA level | |
| Sadahiro et al. | Oral S-1 with 24-h infusion of irinotecan plus bevacizumab versus FOLFIRI plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer: an open-label randomized phase II trial | |
| Dogan et al. | Fatal lactic acidosis due to leukemic transformation in a patient with non-Hodgkin’s lymphoma: case report | |
| Yoo et al. | Phase II study of paclitaxel in combination with carboplatin for patients with recurrent or persistent uterine sarcoma | |
| Kimura et al. | Evaluation of the therapeutic effects and tolerability of modified lenvatinib administration methods for unresectable hepatocellular carcinoma: A preliminary study | |
| Friday et al. | A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors | |
| WO2019214328A1 (zh) | Larp7基因在癌症诊断和治疗中的应用 | |
| Shafie et al. | Burkitt lymphoma presenting as cecum mass and spontaneous tumor lysis syndrome with hypercalcemia | |
| Imperiale et al. | Metabolic response to BRAF-MEK combination therapy in cecal neuroendocrine carcinoma with BRAFV600E mutation and refractory lactic acidosis | |
| EP3752154A1 (en) | Methods and combination therapy to treat biliary tract cancer | |
| CN113694205B (zh) | 5-ht受体抑制剂和顺铂在制备治疗肝癌的药物中的应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140528 |