CN105999264A - 用于乳腺癌的利用奈拉替尼的治疗方案 - Google Patents
用于乳腺癌的利用奈拉替尼的治疗方案 Download PDFInfo
- Publication number
- CN105999264A CN105999264A CN201610444390.0A CN201610444390A CN105999264A CN 105999264 A CN105999264 A CN 105999264A CN 201610444390 A CN201610444390 A CN 201610444390A CN 105999264 A CN105999264 A CN 105999264A
- Authority
- CN
- China
- Prior art keywords
- hki
- treatment
- scheme
- positive
- patient
- 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
- 229950008835 neratinib Drugs 0.000 title claims abstract description 95
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 title claims abstract description 88
- 206010006187 Breast cancer Diseases 0.000 title claims description 34
- 208000026310 Breast neoplasm Diseases 0.000 title claims description 34
- 238000011269 treatment regimen Methods 0.000 title 1
- 238000011282 treatment Methods 0.000 claims abstract description 87
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 36
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 29
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims abstract description 22
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims abstract description 21
- 201000011510 cancer Diseases 0.000 claims abstract description 17
- 229940022353 herceptin Drugs 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 40
- 230000004083 survival effect Effects 0.000 claims description 25
- 201000010099 disease Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 238000002512 chemotherapy Methods 0.000 claims description 11
- 229960000575 trastuzumab Drugs 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- OCINXEZVIIVXFU-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[4-(trifluoromethylthio)phenoxy]phenyl]-1,3,5-triazinane-2,4,6-trione Chemical compound CC1=CC(N2C(N(C)C(=O)NC2=O)=O)=CC=C1OC1=CC=C(SC(F)(F)F)C=C1 OCINXEZVIIVXFU-UHFFFAOYSA-N 0.000 claims description 7
- 229960000898 toltrazuril Drugs 0.000 claims description 7
- 208000028715 ductal breast carcinoma in situ Diseases 0.000 claims description 6
- 230000003203 everyday effect Effects 0.000 claims description 6
- 208000017891 HER2 positive breast carcinoma Diseases 0.000 claims description 5
- 208000037396 Intraductal Noninfiltrating Carcinoma Diseases 0.000 claims description 5
- 239000003817 anthracycline antibiotic agent Substances 0.000 claims description 5
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 4
- 239000002136 L01XE07 - Lapatinib Substances 0.000 claims description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
- 229960003668 docetaxel Drugs 0.000 claims description 4
- 229960004891 lapatinib Drugs 0.000 claims description 4
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims description 3
- 208000029725 Metabolic bone disease Diseases 0.000 claims description 3
- 206010049088 Osteopenia Diseases 0.000 claims description 3
- 229930012538 Paclitaxel Natural products 0.000 claims description 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 3
- 229960004562 carboplatin Drugs 0.000 claims description 3
- 229960004397 cyclophosphamide Drugs 0.000 claims description 3
- 108010038795 estrogen receptors Proteins 0.000 claims description 3
- 229960001592 paclitaxel Drugs 0.000 claims description 3
- 102000005962 receptors Human genes 0.000 claims description 3
- 108020003175 receptors Proteins 0.000 claims description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 3
- 206010073094 Intraductal proliferative breast lesion Diseases 0.000 claims description 2
- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 102100025803 Progesterone receptor Human genes 0.000 claims description 2
- 229960004679 doxorubicin Drugs 0.000 claims description 2
- 201000007273 ductal carcinoma in situ Diseases 0.000 claims description 2
- 238000009261 endocrine therapy Methods 0.000 claims description 2
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 0.000 claims description 2
- 108090000468 progesterone receptors Proteins 0.000 claims description 2
- 102000015694 estrogen receptors Human genes 0.000 claims 2
- 229940088597 hormone Drugs 0.000 claims 2
- 239000005556 hormone Substances 0.000 claims 2
- 229960000397 bevacizumab Drugs 0.000 claims 1
- 230000002354 daily effect Effects 0.000 claims 1
- 108091008039 hormone receptors Proteins 0.000 claims 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 claims 1
- 238000009098 adjuvant therapy Methods 0.000 abstract description 2
- 239000002585 base Substances 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 19
- 201000008275 breast carcinoma Diseases 0.000 description 17
- 230000008569 process Effects 0.000 description 17
- -1 HKI-272 compound Chemical class 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 230000003321 amplification Effects 0.000 description 14
- 238000003199 nucleic acid amplification method Methods 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 10
- 239000003814 drug Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000002253 acid Substances 0.000 description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 238000004806 packaging method and process Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 241001597008 Nomeidae Species 0.000 description 3
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007894 caplet Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 239000000902 placebo Substances 0.000 description 3
- 229940068196 placebo Drugs 0.000 description 3
- 206010038038 rectal cancer Diseases 0.000 description 3
- 201000001275 rectum cancer Diseases 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 206010055113 Breast cancer metastatic Diseases 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 101150039808 Egfr gene Proteins 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 201000010989 colorectal carcinoma Diseases 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000001165 lymph node Anatomy 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229940049964 oleate Drugs 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 201000001514 prostate carcinoma Diseases 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000007115 recruitment Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- OBSLWIKITOYASJ-AZEWMMITSA-N (2r,3s,4s,5r,6s)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical compound CN[C@@H]1[C@H](O)O[C@@H](CO)[C@H](O)[C@H]1O OBSLWIKITOYASJ-AZEWMMITSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-M 9-cis,12-cis-Octadecadienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O OYHQOLUKZRVURQ-HZJYTTRNSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 244000050510 Cunninghamia lanceolata Species 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 102000056372 ErbB-3 Receptor Human genes 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 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
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 238000011226 adjuvant chemotherapy Methods 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- VFNGKCDDZUSWLR-UHFFFAOYSA-L disulfate(2-) Chemical compound [O-]S(=O)(=O)OS([O-])(=O)=O VFNGKCDDZUSWLR-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 108700020302 erbB-2 Genes Proteins 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 229940114119 gentisate Drugs 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000024312 invasive carcinoma Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 239000013038 irreversible inhibitor Substances 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940049918 linoleate Drugs 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-M linolenate Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC([O-])=O DTOSIQBPPRVQHS-PDBXOOCHSA-M 0.000 description 1
- 229940040452 linolenate Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000000394 phosphonato group Chemical group [O-]P([O-])(*)=O 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- WDXARTMCIRVMAE-UHFFFAOYSA-N quinoline-2-carbonitrile Chemical class C1=CC=CC2=NC(C#N)=CC=C21 WDXARTMCIRVMAE-UHFFFAOYSA-N 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical group C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000002426 superphosphate Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 230000003612 virological effect Effects 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
描述了用于治疗过表达/扩增HER‑2/neu的癌症的扩展方案，其包括在完成手术和辅助治疗之后将奈拉替尼治疗过程递送至过表达/扩增HER‑2/neu的癌症患者。奈拉替尼方案可持续长达12个月至5年。还提供了经设计用以促进对方案的顺从性的药物试剂盒。
Description
本申请是申请日为2010年03月24日、申请号为201080014916.2、名称为“用于乳腺癌的利用奈拉替尼的治疗方案”的发明申请的分案。
发明背景
乳腺癌是妇女中诊断频率最高的恶性肿瘤并且是全世界妇女中癌症死亡率的首要原因。乳腺癌的全球发病率据估计在下一个十年达到5百万妇女[Parkin,DM和Fernandez LM,Use of statistics to assess theglobal burden of breast cancer.Breast Journal.2006；(12,Suppl 1):S70-80；World Health Statistics.2008,世界卫生组织]。在2007年，乳腺癌在世界范围导致大约540,000例死亡[World Health Organization Fact SheetNo.297.2008；可从WHO网站获得]。
TKI(酪氨酸激酶抑制剂)的erbB(成红细胞白血病病毒癌基因同源物)家族由4个成员组成：erbB-1(EGFR[表皮生长因子受体])、erbB-2(HER-2,neu)、erbB-3(HER-3)和erbB-4(HER-4)。受体的erbB家族参与细胞增殖、肿瘤发生和转移，并且在多个肿瘤类型中异常表达。HER2-阳性的乳腺癌，即，对于称为人EGFR的蛋白质检测为阳性的乳腺癌，与Erb-2-蛋白过表达相关，或乳腺癌肿瘤中erbB-2基因的扩增与更具侵袭性的临床疾病和更糟的预后相关[Slamon D,Human breast cancer:correlation of relapse and survival with amplification of the HER-2/neuoncogene.Science.1987(235):177-182]。
曲妥珠单抗，选择性结合人erbB-2受体的人源化单克隆抗体，改善了患有erbB-2-阳性乳腺癌的妇女的预后。在患有过表达erbB-2的转移性乳腺癌的患者中，与化学治疗组合的曲妥珠单抗，与单独的化学治疗相比较，促进肿瘤消退，延长肿瘤进展的时间和延长中位存活(mediansurvival)，从而导致其被批准为转移背景中的一线疗法。[Ligibel JA和Winer EP,trastuzumab/chemotherapy combinations in metastatic breastcancer.Seminars in Oncology.2002；29(3Suppl 11):38-43]。赫赛汀(曲妥珠单抗)[Package insert,Genentech(2008)]。曲妥珠单抗也被批准与用于治疗过表达erbB-2的淋巴结阳性或淋巴结阴性(雌激素受体/孕酮受体[ER/PgR]阴性)转移性乳腺癌的其他药物组合用于辅助背景。因此，曲妥珠单抗已被用作治疗方案的部分，所述治疗方案由下列组成：(a)多柔比星，环磷酰胺，以及紫杉酚或多西他赛，(b)利用多西他赛和卡铂的方案，和(c)在基于多模式蒽环类抗生素的治疗后作为单一试剂。
在确诊HER+乳腺癌后目前的护理标准是手术，然后进行一年的辅助治疗。标准辅助治疗是ER/PR阳性疾病的激素治疗、化学治疗、辐射与曲妥珠单抗的一些组合。尽管完成了辅助治疗，但早期乳腺癌患者仍然处于复发的风险中。曲妥珠单抗治疗的公开报导显示，无疾病存活率为3年的80.6％[Smith I等人2-year follow-up of trastuzumab afteradjuvant chemotherapy in HER2-positive breast cancer:a randomizedcontrolled trial.Lancet.2007；369:29-36]至4年的85.9％至82％[Perez EA等人,Updated results of the combined analysis of NCCTG N9831andNSABP B-31adjuvant chemotherapy with/without trastuzumab in patientswith HER2-positive breast cancer.Journal of Clinical Oncology.ASCOAnnual Meeting Proceedings.2007；25(18S):512，和Slamon D等人,PhaseIII trial comparing AC-T with AC-TH and with TCH in the adjuvanttreatment of HER2positive early breast cancer patients:second interimefficacy analysis.Presentation by Slamon D.SABCC 2006]。
已描述了HKI-272(奈拉替尼)用于肿瘤的治疗[美国专利6,288,082]。奈拉替尼(neratinib)是有效的、不可逆的泛erbB抑制剂。奈拉替尼为口服可用的小分子，其在胞内酪氨酸激酶结构域上抑制erbB-1、erbB-2和erbB-4，作用机制与曲妥珠单抗不同。奈拉替尼降低erbB-1和erbB-2自磷酸化、下游信号转导以及erbB-1和erbB-2依赖性细胞系的生长。临床前数据表明，奈拉替尼在表达erbB-1和/或erbB 2的癌细胞系中具有抗肿瘤活性，细胞IC50<100nM[Rabindran SK等人.Antitumor activity of HKI-272,an orally active,irreversible inhibitor of theHER-2tyrosine kinase.Cancer Research.2004；64(11):3958-65]。
所需要的是提高患者存活率的药物和方案和/或在基本治疗(primary treatment)和辅助治疗完成后减少乳腺癌复发的药物和方案。
发明概述
在一个方面中，本发明提供了用于治疗过表达/扩增HER-2/neu的肿瘤的方案，其包括将奈拉替尼治疗过程作为曲妥珠单抗辅助治疗的延伸，递送至过表达/扩增HER-2/neu的癌症患者，例如，在完成手术和标准辅助治疗之后递送奈拉替尼。
在另一个方面中，本发明提供了用于降低患者的过表达/扩增HER-2/neu的乳腺癌的复发率(与只接受基本治疗和曲妥珠单抗辅助治疗的患者相比较)的方法或方案。该方法包括在基本治疗和利用曲妥珠单抗的标准辅助治疗之后将奈拉替尼递送至所述患者。在一个实施方案中，所述方法还在一个或多个常规新辅助疗法或标准辅助治疗完成之后进行。
在另一个方面中，本发明提供了用于改善无侵袭性疾病存活(invasive disease free survival)的方案，其包括在完成基本治疗和利用曲妥珠单抗的标准辅助治疗后，用奈拉替尼治疗癌症患者。在一个实施方案中，利用奈拉替尼的治疗在手术后和利用曲妥珠单抗的标准辅助治疗后2周至48个月内开始。
根据下列发明详述，本发明的其他方面和优点将变得显而易见。
发明详述
在一个实施方案中，本发明提供了用于治疗过表达/扩增HER-2/neu的癌症的扩展的辅助方案，其包括将奈拉替尼治疗过程递送至过表达/扩增HER-2/neu的癌症患者。这样的扩展辅助治疗包括，在利用曲妥珠单抗的辅助治疗完成后开始奈拉替尼治疗。该扩展辅助治疗用于提供改善的无侵袭性疾病存活(IDFS)或无疾病存活(DFS)-原位导管癌(DCIS)和/或改善总存活(overall survival)、远处复发的时间(time todistant recurrence)和/或无远处疾病存活(distant disease-free survival)。
如本文中所使用的，无侵袭性疾病存活(IDFS)被定义为从随机化的日期至IDFS事件的日期的时间，所述IDFS事件包括：侵袭性同侧乳腺肿瘤复发、局部/区域性侵袭性复发、远处复发(distant recurrence)、任何原因引起的死亡、侵袭性对侧乳腺癌和第二原发性侵袭性癌(非乳腺)。DFS-DCIS被定义为从随机化至任何IDFS事件或原位导管癌的第一次发生的时间。无远处疾病存活(DDFS)为从随机化至第一次远处复发或任何原因引起的死亡的时间。远处复发的时间(TTDR)被定义为随机化与第一次远处肿瘤复发的日期之间的时间，不考虑局部复发和第二乳腺癌或非乳腺癌，并且把远处乳腺癌复发之前的死亡考虑为设限事件(censoring event)。
因此，利用奈拉替尼的本发明的扩展辅助治疗通过减少复发或死亡的风险而增加无疾病存活。在一个实施方案中，扩展奈拉替尼辅助治疗，与曲妥珠单抗治疗后的常规观察相比较，减少癌症复发或死亡的危险，即风险率，30％或20％。
在另一个实施方案中，通过使用本文中描述的扩展奈拉替尼方案，少于15％，少于10％和/或少于5％的已接受基本治疗和辅助治疗的患者在治疗开始后3年患癌症。在另一个实施方案中，通过使用本文中描述的扩展奈拉替尼方案，少于20％，少于15％和/或少于5％的已接受基本治疗和辅助治疗的患者在治疗开始后5年患癌症。
如本文中所使用的，奈拉替尼是指HKI-272，其具有下列核心结构:
以其游离碱形式存在。任选地，可使用其药学上可接受的盐或水合物。上文所示的核心结构为具体的HKI-272化合物，称为HKI-272或奈拉替尼，其具有化学名称[(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲氨基)丁-2-烯酰胺]。
虽然目前不太优选，但可使用另一种HKI-272化合物代替奈拉替尼。“HKI-272化合物"在一个实施方案中是指衍生自上文中所示的奈拉替尼的核心结构的化合物。适当的衍生物可包括例如酯、醚或氨基甲酸盐/酯。这样的HKI-272化合物可具有如下结构：
其中:
R1为卤素；
R2为吡啶基、苯硫基、嘧啶基、噻唑基或苯基，其中R2任选地被至多3个取代基取代；
R3为O或S；
R4为CH3或CH2CH2OCH3；
R5为CH3或CH2CH3；以及
n为0或1。
如本文中所使用的，术语"卤素"是指Cl、Br、I和F。
还包括的是，本文中描述的其他HKI化合物和/或奈拉替尼的药学上可接受的盐、水合物和前药。"药学上可接受的盐和酯"是指，其在药学上是可接受的并且具有期望的药理学性质的盐和酯。此类盐包括例如，当存在于化合物中的酸性质子能够与无机或有机碱反应时可形成的盐。适当的无机盐包括例如，与碱金属或碱土金属例如钠、钾、镁、钙、铝形成的盐。适当的有机盐包括例如，与有机碱例如胺碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等形成的盐以及与可形成N-四烷基铵盐例如N-四丁基铵盐的碱形成的盐。药学上可接受的盐还可包括，通过母体化合物中的碱性部分例如胺与无机酸(例如，盐酸和氢溴酸)和有机酸(例如，乙酸、柠檬酸、马来酸、丙酸、乳酸、酒石酸、琥珀酸、富马酸、马来酸、丙二酸、扁桃酸、苹果酸、苯二甲酸、盐酸、氢溴酸、磷酸、硝酸、硫酸以及烷烃-和芳烃-磺酸例如甲磺酸和苯磺酸、萘磺酸、甲苯磺酸、樟脑磺酸)的反应形成的酸加成盐。药学上可接受的盐的其他适当的实例包括但不限于，硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸性磷酸盐、异烟酸盐(isonicotinate)、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、单宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、延胡索酸盐、葡糖酸盐、glucaronate、蔗糖酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对-甲苯磺酸盐、双羟萘酸盐(即,1,1’-亚甲基-双-(2-羟基-3-萘甲酸盐))；和脂肪酸的盐例如己酸盐、月桂酸盐、肉豆蔻酸盐、棕榈酸盐、硬脂酸盐、油酸盐、亚油酸盐和亚麻酸盐。
药学上可接受的酯包括从存在于本发明的化合物中的羧基、磺酰氧基和膦酰氧基形成的酯，例如具有1至6个碳原子的直链烷基酯或包含1至6个碳原子的支链烷基酯，包括甲酯、乙酯、丙酯、丁酯、2-甲基丙酯和1,1-二甲基乙酯、环烷基酯、烷基芳基酯、苄酯等。当存在两个酸性基团时，药学上可接受的盐或酯可以是单-酸-单-盐或酯或二-盐或酯；并且类似地，当存在超过两个酸性基团时，可盐化或酯化一些或所有此类基团。本文中使用的化合物可以以未盐化(unsalified)或未酯化的形式或以盐化和/或酯化的形式存在，并且此类化合物的命名意欲包括原始(未盐化和未酯化的)化合物和其药学上可接受的盐和酯。同样地，本文中使用的一种或多种化合物可以以超过一种的立体异构形式存在，并且此类化合物的命名意欲包括所有单一的立体异构体和此类立体异构体的所有混合物(无论是消旋的还是未消旋的)。
HKI-272化合物(奈拉替尼是其中的一种)的制备详细地描述于美国专利申请公开案2005/0059678(其通过引用合并入本文)中。也参见美国专利6,288,082、美国专利6,002,008、美国专利6,297,258和美国专利申请公开案2007/0104721，其通过引用合并入本文。这些文献中描述的方法也可用于制备奈拉替尼和/或本文中使用的其他HKI-272和经取代的3-喹啉化合物，因而它们通过引用合并入本文。除了这些文献中描述的方法外，通过引用合并入本文的国际专利公开案WO-96/33978和WO-96/33980描述了可用于制备此类HKI-272化合物的方法。虽然此类方法描述了某些喹唑啉的制备，但它们也可用于制备相应地经取代的3-氰基喹啉，因而它们通过引用合并入本文。
术语“治疗”或“疗法”是指，给受试者施用奈拉替尼以预防或延迟、减轻或阻止或抑制与肿瘤相关的症状或病状的发展。
曲妥珠单抗，以及制造和配制其的方法已得到描述。参见，例如，美国专利6,821,515；美国专利6,399,063和美国专利6,387,371。曲妥珠单抗可在名称“赫赛汀(Herceptin)”下从Genentech商购获得。如本文中所使用的，术语“曲妥珠单抗”包括曲妥珠单抗以及曲妥珠单抗的改变的形式和衍生物。术语“曲妥珠单抗”包括这样的试剂，其靶向Her-2受体上与被曲妥珠单抗靶向的表位相同的表位。从H.S.Cho等人,Structure ofthe extracellular region of HER2alone and in complex with the HerceptinFab,Nature 421(2003),pp.756-760获知该表位。
如本文中所使用的，扩增/过表达erB-2(与Her-2和neu可互换使用)的肿瘤包括某些乳腺癌和其他肿瘤，其可包括卵巢癌、膀胱癌、胃癌、胰腺癌、结肠直肠癌、前列腺癌及肺癌，包括非小细胞肺癌。其中表达或过表达ErbB1的其他肿瘤包括多种人实体瘤，包括非小细胞肺癌(NSCL)、前列腺癌、乳腺癌、结肠直肠癌和卵巢癌。用于筛查样品以确定肿瘤是否过表达erb-1和/或erB-2/Her-2的方法对于本领域技术人员来说是已知的。
基本和辅助抗肿瘤治疗
如本文中所定义的，基本治疗是在确诊肿瘤例如过表达/扩增HER-2/neu的肿瘤后给患者提供的初始治疗(initial therapy)。基本治疗也称为限定性局部治疗(definitive local therapy)。用于过表达/扩增HER-2/neu的肿瘤的基本治疗包括手术(在乳腺癌的情况下，这可包括病灶切除术、改良的根治性乳房切除术、乳房切除术)和/或辐射(单独地或组合地)。辅助治疗是指在初始或基本治疗后常规地提供以增加治愈可能性的治疗。目前，用于过表达/扩增HER-2/neu的肿瘤的标准辅助治疗包括例如，化学治疗和/或抗体治疗。通常，如果在基本治疗(例如，手术)之前递送一个或多个此类辅助治疗，其被称为新辅助治疗。在本说明书的整个下面部分中，术语“新/辅助”用作表示新辅助治疗和标准辅助治疗的简写(shorthand)。可共同递送一个或多个类型的辅助治疗。
在一个实施方案中，患者可以已经历包括递送蒽环类抗生素或紫杉烷或任何环磷酰胺、氨甲蝶呤和5-氟尿嘧啶方案的化学治疗。此类化学治疗可包括下列的一种或多种：蒽环类抗生素例如多柔比星、环磷酰胺、紫杉酚、多西他赛和卡铂。另一种适当的新/辅助治疗是基于多模式蒽环类抗生素的治疗。其他新/辅助治疗包括拉帕替尼(Lapatinib)[二甲苯磺酸拉帕替尼,]、帕妥珠单抗[Roche,Genentech]、贝伐单抗[Genentech]、曲妥珠单抗-DM-1[Genentech]等等。新辅助治疗或辅助治疗的选择不是对本发明的限制。本发明的扩展辅助治疗在完成利用曲妥珠单抗的治疗后开始。通常在完成化学治疗后或与之同时递送曲妥珠单抗，作为维持治疗。关于曲妥珠单抗，包括单剂量和多剂量。在一个实施方案中，在第1天以90分钟静脉内输注施用在约4-5mg/kg的范围内的单个负荷剂量的曲妥珠单抗，然后从第8天开始每周施用约2mg/kg。通常，3周为一个周期。可在周期之间提供1至2至3周的间隔。在另一个实施方案中，使用8mg/kg作为负荷剂量和6mg/kg作为维持剂量，按照每3周的给药方案递送曲妥珠单抗。还可以以6mg/kg的剂量提供曲妥珠单抗，每3-4周1次。还可设计和利用其他曲妥珠单抗给药方案。
在一个实施方案中，患者可以已接受基本治疗以及除了曲妥珠单抗新/辅助治疗外，还已接受其他新/辅助治疗。在一个实施方案中，可在扩展辅助治疗过程中在完成曲妥珠单抗治疗后继续进行一个或多个辅助治疗。适当地，在开始本发明的扩展奈拉替尼方案之前，基本治疗和新/辅助治疗都不包括奈拉替尼治疗。
本发明的扩展奈拉替尼方案
在一个实施方案中，在基本治疗开始后约1年、约2年或约3年开始本文中描述的扩展奈拉替尼方案。在完成利用曲妥珠单抗的新/辅助治疗后开始扩展奈拉替尼辅助方案。
可在至少1个剂量、至少3周的周期、至少3个3周的周期、至少4个月、至少6个月、至少8个月或至少1年的曲妥珠单抗新/辅助治疗完成后开始本文中描述的扩展方案。在一个实施方案中，在完成曲妥珠单抗治疗后至少约2周、至少约1个月、至少约6个月、至少约9个月或至少约1年至4年开始扩展奈拉替尼方案。
如本文中描述的，扩展奈拉替尼方案用于减少患者的过表达/扩增HER-2/neu的乳腺癌的复发率。可在治疗开始后，在6个月、1年、3年或5年的时间点上测量这些复发率。该方案包括在基本治疗和新/辅助治疗后给这些患者提供奈拉替尼。在另一个实施方案中，扩展的奈拉替尼用于改善癌症患者的无侵袭性疾病存活、DFS-DCIS、无远处疾病存活和/或远处复发的时间。
本发明的扩展辅助治疗可以只包括在曲妥珠单抗治疗完成后的单个剂量的奈拉替尼。然而，在另一个实施方案中，在1个月、2个月、至少6个月、至少1年、至少18个月的时期内或根据需要或期望，在更长的时期内施用扩展奈拉替尼方案。在另一个实施方案中，用奈拉替尼治疗患者，进行约8个月至约5年，约12个月(1年)至约3年，或进行更长或更短的时期，如由医学专业人员确定的。
如本文中所使用的，就提供奈拉替尼而言，术语“提供”意指直接施用化合物或组合物，或施用可在体内形成有效量的奈拉替尼化合物的前药、衍生物或类似物。
如本文中所使用的以及除非另外指出，术语“个体”、“受试者”和“患者”可互换使用，并且是指任何动物，包括哺乳动物，优选小鼠、大鼠、其他啮齿类动物、兔、狗、猫、猪、牛、羊、马、非人灵长类动物和人。期望地，术语“个体”、“受试者”或“患者”是指人。在大多数实施方案中，受试者或患者需要治疗性治疗。因此，如本文中所用的，术语“受试者”或“患者”意指可对其施用所请求保护的方案的任何哺乳动物患者或受试者。
如本文中所使用的，术语“有效量”或“药学有效量”，当给受试者施用以治疗肿瘤时，足以抑制、减缓、减少或消除受试者的损伤或肿瘤生长，或抑制、减缓或减少疾病的进展和/或增加受试者的无进展存活率。
可以例如以约0.01至100mg/kg的剂量范围口服施用奈拉替尼(或所选择的HKI-272化合物)。在一个实施方案中，以约0.1至约90mg/kg的剂量范围施用奈拉替尼。在另一个实施方案中，以约1至约80mg/kg的剂量范围施用奈拉替尼。在其他实施方案中，以约10至约70mg/kg的剂量范围施用奈拉替尼。在另一个实施方案中，以约15至约60mg/kg的剂量范围施用奈拉替尼。在其他实施方案中，在施用其的周期内的天中，以每天约20至约240mg的剂量范围，以至少约40mg、至少约120mg或至少约160mg施用奈拉替尼。本领域技术人员可常规地进行经验活性测试来测定化合物在生物测定中的生物学活性，从而确定当通过另一种途径递送化合物时施用的剂量。
在一个实施方案中，奈拉替尼的口服剂量为至少约700mg/周。在另一个实施方案中，奈拉替尼的口服剂量为约800mg/周至至少约1700mg/周。在另一个实施方案中，奈拉替尼的口服剂量为约840mg/周至约1680mg/周。在另一个实施方案中，奈拉替尼的口服剂量为约900mg/周至约1600mg/周。在其他实施方案中，奈拉替尼的口服剂量为约1000mg/周至约1500mg/周。在另一个实施方案中，奈拉替尼的口服剂量为约1100mg/周至约1400mg/周。在其他实施方案中，奈拉替尼的口服剂量为约1200mg/周至约1300mg/周。精确的剂量由施用医生基于对要治疗的个体受试者的经验来确定。其他剂量方案和变型是可预见的，并且通过医生指导来确定。
对于奈拉替尼，期望化合物以单位剂量形式存在。可以以约0.01至100mg/kg的剂量范围或以0.1至10mg/kg的剂量范围来施用奈拉替尼。在一个实施方案中，每天1至6次，更常见地每天1至4次口服施用奈拉替尼。适当的单位剂量形式包括片剂、胶囊剂和药囊或小瓶中的粉剂。此类剂量单位形式可包含0.1至300mg奈拉替尼，2至100mg，以120mg至300mg/天，240mg/天的剂量。可选地，可通过另一种适当的途径例如静脉内途径施用奈拉替尼。在另一个实施方案中，每周1次施用奈拉替尼。在某些情况中，可在治疗过程中延迟或中断利用奈拉替尼的剂量给药，进行一段短暂的时间(例如，1、2或3周)。这样的延迟或中断在治疗过程中可发生1次或多次。有效量对于本领域技术人员来说是已知的；其也取决于化合物的形式。本领域技术人员可常规地进行经验活性试验以确定化合物在生物测定中的生物学活性，从而确定施用的剂量。
在一个实施方案中，本文中使用的药物载体的适当实例包括但不限于，赋形剂、稀释剂、填充剂、崩解剂、润滑剂和可用作载体的其他试剂。术语“药学上可接受的赋形剂”意指可用于制备通常为安全的、无毒性的和期望的药物组合物的赋形剂，并且包括对于兽医用途以及人药物用途是可接受的赋形剂。此类赋形剂可以为固体、液体、半固体或在气雾剂组合物的情况下，为气体。按照可接受的制药方法，例如Remingtons Pharmaceutical Sciences,第17版,ed.Alfonoso R.Gennaro,Mack Publishing Company,Easton,Pa.(1985)中描述的方法，制备药物组合物。药学上可接受的载体是与制剂中的其他成分相容并且为生物学上可接受的载体。用于片剂或小胶囊(caplet)制剂的适当的药学上可接受的赋形剂或载体包括例如，惰性赋形剂例如乳糖、碳酸钠、磷酸钙或碳酸钙；粒化剂和崩解剂例如玉米淀粉或海藻酸；粘合剂例如明胶或淀粉；润滑剂例如硬脂酸镁、硬脂酸或滑石；防腐剂例如4-羟基苯甲酸乙酯或丙酯；以及抗氧化剂例如抗坏血酸。可以不包被或包被片剂或小胶囊制剂以改变它们的崩解作用和随后活性成分在胃肠道内的吸收，或改善它们的稳定性和/或外观，使用本领域内公知的常规的包衣衣料(coatingagent)和方法。
在一个实施方案中，本发明提供了用于治疗过表达/扩增HER-2/neu的癌症的扩展方案，其包括将扩展的奈拉替尼治疗过程递送给过表达/扩增HER-2/neu的癌症患者。此类扩展治疗包括在完成手术和/或辅助治疗时开始奈拉替尼治疗。该扩展治疗用于提供改善的无侵袭性疾病存活和/或改善总存活、远处复发的时间和无远处疾病存活。
如本文中所描述的，在初始治疗开始后至少1年、至少2年或至少3年，开始扩展的奈拉替尼方案。在一个实施方案中，在基本治疗和标准新/辅助治疗完成后至少约2周和直至约4年，开始奈拉替尼治疗。
在一个实施方案中，可将所选择的伴随治疗与扩展奈拉替尼方案结合使用。例如，患者可进一步经历利用用于骨质减少(osteopenia)或骨质疏松症的双磷酸盐类的伴随治疗。在另一个实例中，患者可进一步经历伴随内分泌治疗。任选地，此类伴随治疗可以是非辅助治疗，而是用于治疗患者可能患有的其他病状或症状。
药物包装/试剂盒
本发明包括包含用于一个个体哺乳动物的抗肿瘤治疗过程的产品或药物包装，其包括一个或多个容器，所述容器具有1、1至4或更多个单位的奈拉替尼和任选地1、1至4或更多个单位的另一种活性剂。
在另一个实施方案中，药物包装包括用于一个个体哺乳动物的抗肿瘤治疗过程(疗程)，其包括具有以单位剂量形式存在的雷帕霉素单位的容器、具有奈拉替尼单位的容器和任选地，具有另一种活性剂的容器。
在某些实施方案中，本发明的药物组合物以可即时施用的形式存在于包装中。在其他实施方案中，本发明的组合物以浓缩的形式存在于包装中，任选地与制备用于施用的终溶液所需的稀释剂一起。在其他实施方案中，产品包括以固体形式存在的用于本发明的化合物和任选地单独的容器，所述容器具有用于本发明中使用的化合物的适当的溶剂或载体。
在其他实施方案中，上述包装/试剂盒包括其他成分，例如产品的稀释、混合和/或施用的说明书、其他容器、注射器、针头等。其他此类包装/试剂盒成分对于本领域技术人员来说是很显然的。
下列实施例举例说明了本发明的组合的用途。可容易地理解，可因本领域技术人员已知的理由，对例如成分的配制、递送途径和剂量进行改变或变动。
实施例
已在患有转移性erbB-2阳性乳腺癌的受试者的2期试验中研究了用作单一试剂的奈拉替尼。将66个具有在先的基于曲妥珠单抗的治疗的受试者招募进入组A(Arm A)；将70个不具有任何在先的曲妥珠单抗暴露的受试者招募进入组B。客观应答率和中位无进展存活用于评估抗肿瘤活性。
根据基于独立的放射学评估的初步数据，在具有在先的曲妥珠单抗治疗的受试者中，总应答率(ORR)为26％(95％置信指数(confidenceindex，CI))并且中位无进展存活(PFS)为23周(95％CI)。对于先前未暴露于曲妥珠单抗的受试者，ORR为57％(95％CI)并且中位PFS为40周(95％CI)。组A中的抗肿瘤活性提供了在曲妥珠单抗难治性受试者中测试用作单一试剂的奈拉替尼的基础。
在组A中，曲妥珠单抗暴露的中位持续时间为60周。受试者中的28个(28％)接受曲妥珠单抗作为辅助或新辅助治疗。大部分受试者(48％)在转移背景中接受一个基于曲妥珠单抗的方案，并且约43％接受第二或第三基于曲妥珠单抗的方案以治疗转移性疾病。组A受试者也进行了多方面的在先的细胞毒性治疗，53％的受试者接受了2-3个在先的方案，并且另外27％接受了超过3个在先的细胞毒性方案。合起来考虑，这些治疗特征描述了组A中被高强度预治疗的并且可能难治的研究群体。因此，难治性群体的26％的ORR表明，奈拉替尼可能是用于erbB-2阳性乳腺癌的高活性试剂。
与奈拉替尼相关的主要不利事件是腹泻，这通常可通过药物治疗、治疗中断或剂量改变来良好、轻易地控制。其他常见的不利事件是恶心、呕吐、疲劳和食欲减退。
实施例1
在随机化、双盲、以安慰剂为对照的3期试验中，在患有早期过表达/扩增HER-2/neu的乳腺癌的妇女中在曲妥珠单抗治疗之后，比较奈拉替尼与安慰剂。受试者必须已完成在先的辅助曲妥珠单抗治疗过程。如果已提供短于12个月的曲妥珠单抗，则必须已提供至少8次在先的剂量，并且必须指定，所述受试者没有资格或不能接受进一步的利用曲妥珠单抗的辅助治疗。在完成在先的辅助治疗过程(包括至少8次，优选12个月的曲妥珠单抗)后，受试者有资格用本文中描述的方案进行治疗。曲妥珠单抗的最后剂量必须在随机化开始前>2周并且<4年提供。随机化将通过下列因素分层：ER和/或PgR阳性对ER和PgR阴性；淋巴结状况(nodal status)(0、1-3、4或更多)；距离确诊<3年或>3年；与化学治疗顺次提供的曲妥珠单抗对与化学治疗同时提供的曲妥珠单抗。
以1:1的比例将有资格的受试者随机分配入下列两个组之一：每天奈拉替尼240mg，进行1年或每天安慰剂，进行1年。在中断研究治疗后，继续跟踪受试者的疾病复发和存活，直至获得无侵袭性疾病存活(IDFS)事件的计划数目，并且继续跟踪受试者之后的存活直至研究结束。可使用分层时序检验分析IDFS的主要功效终点(primary efficacyendpoint)和时间-对-事件第二终点。可利用分层Cox比例风险回归模型[DR Cox,1972,“Regression Models and Life Tables(withDiscussion)”,Journal of the Royal Statistical Society,Series B 34:187-220]产生危害比和相应的95％置信区间。可使用Kaplan-Meier法[Kaplan,E.L.和Meier,Paul."Nonparametric estimation from incomplete observations."J.Am.Stat.Assoc.53,457-481(1958)]评估事件的中位时间和相关的95％置信区间。为了治疗群体(定义为随机化的所有受试者)，进行主要功效分析。按治疗组概述了安全群体(定义为被剂量给予奈拉替尼或安慰剂的所有受试者)的不利事件和严重的不利事件。也概述了3级或更高级腹泻的发病率，并且使用Mantel-Haenszel检验测试了治疗组间的差异。[Mantel N&Haenszel W.Statistical aspects of the analysis of datafrom retrospective studies of disease.J.Nat.Cancer Inst.22:719-48,1959]。
本说明书中引用的所有出版物通过引用合并入本文。虽然已参考具体实施方案描述了本发明，但应当理解，可进行变动而不背离本发明的精神。此类变动意欲落在所述权利要求的范围内。
Claims (18)
1.治疗早期HER-2阳性乳腺癌的方案，包括在至少十二个周期的曲妥珠单抗辅助治疗完成后将奈拉替尼治疗递送至早期HER-2阳性乳腺癌患者；其中所述奈拉替尼治疗在手术和标准辅助治疗完成后约2周至约1年开始。
2.权利要求1的方案，其中奈拉替尼治疗过程在8个月至5年的范围内。
3.权利要求1的方案，其中所述癌症患者用奈拉替尼治疗至少约12个月。
4.权利要求1的方案，其中口服递送奈拉替尼。
5.权利要求4的方案，其中以片剂形式递送奈拉替尼。
6.权利要求1的方案，其中每天施用奈拉替尼。
7.权利要求1的方案，其中以每天120mg至300mg的剂量递送奈拉替尼。
8.权利要求的方案7,其中以240mg的剂量递送奈拉替尼。
9.用于改善早期HER-2阳性乳腺癌患者的无侵袭性疾病存活(IDFS)或无疾病存活(DFS)-HER2阳性原位导管癌(DCIS)和/或改善总存活、远处复发的时间和/或无远处疾病存活的方法，所述方法包括在至少十二个周期的曲妥珠单抗辅助治疗完成后将奈拉替尼递送至所述患者；其中所述奈拉替尼治疗在手术和标准辅助治疗完成后约2周至约1年开始。
10.权利要求9的方法，其中所述患者已接受了由曲妥珠单抗和一种或多种化学治疗组成的标准辅助治疗。
11.权利要求10的方法，其中所述化学治疗包括多柔比星、环磷酰胺、紫杉酚、多西他赛、卡铂、拉帕替尼、帕妥珠单抗、贝伐单抗、曲妥珠单抗-DM-1或基于蒽环类抗生素的治疗中的一种或多种。
12.用于改善无侵袭性疾病存活、无疾病存活-HER2阳性原位导管癌、总存活、远处复发的时间和/或无远处疾病存活的方案，包括用奈拉替尼治疗早期HER-2阳性乳腺癌患者至少十二个月，所述用奈拉替尼治疗在至少十二个周期的曲妥珠单抗辅助治疗完成后进行；其中所述奈拉替尼治疗在手术和标准辅助治疗完成后约2周至约1年开始。
13.权利要求12的方法，所述用奈拉替尼治疗在曲妥珠单抗治疗完成后约六个月至约十二个月开始。
14.权利要求12的方法，其中所述患者进一步经历选自用于骨质减少或骨质疏松症的双磷酸盐类和内分泌治疗的一种或多种的伴随治疗。
15.权利要求1的方案，其中所述早期HER-2阳性乳腺癌患者是激素受体阳性患者。
16.权利要求15的方案，其中所述激素受体阳性患者是雌激素受体或孕酮受体阳性患者。
17.权利要求9的方案，其中所述早期HER-2阳性乳腺癌患者是激素受体阳性患者。
18.权利要求17的方案，其中所述早期HER-2阳性乳腺癌是雌激素受体或孕酮受体阳性患者。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16679609P | 2009-04-06 | 2009-04-06 | |
| US61/166,796 | 2009-04-06 | ||
| CN2010800149162A CN102369010A (zh) | 2009-04-06 | 2010-03-24 | 用于乳腺癌的利用奈拉替尼的治疗方案 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010800149162A Division CN102369010A (zh) | 2009-04-06 | 2010-03-24 | 用于乳腺癌的利用奈拉替尼的治疗方案 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105999264A true CN105999264A (zh) | 2016-10-12 |
Family
ID=42313339
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410228902.0A Pending CN103989681A (zh) | 2009-04-06 | 2010-03-24 | 用于乳腺癌的利用奈拉替尼的治疗方案 |
| CN201610444390.0A Pending CN105999264A (zh) | 2009-04-06 | 2010-03-24 | 用于乳腺癌的利用奈拉替尼的治疗方案 |
| CN2010800149162A Pending CN102369010A (zh) | 2009-04-06 | 2010-03-24 | 用于乳腺癌的利用奈拉替尼的治疗方案 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410228902.0A Pending CN103989681A (zh) | 2009-04-06 | 2010-03-24 | 用于乳腺癌的利用奈拉替尼的治疗方案 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010800149162A Pending CN102369010A (zh) | 2009-04-06 | 2010-03-24 | 用于乳腺癌的利用奈拉替尼的治疗方案 |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US9211291B2 (zh) |
| EP (3) | EP2416774B1 (zh) |
| JP (7) | JP5992325B2 (zh) |
| KR (6) | KR20180056796A (zh) |
| CN (3) | CN103989681A (zh) |
| AR (1) | AR076197A1 (zh) |
| AU (1) | AU2010234968B2 (zh) |
| BR (1) | BRPI1012699A2 (zh) |
| CA (1) | CA2755789C (zh) |
| CY (2) | CY1125948T1 (zh) |
| DK (1) | DK3000467T3 (zh) |
| ES (2) | ES2561495T3 (zh) |
| FI (2) | FI3000467T3 (zh) |
| FR (1) | FR23C1027I2 (zh) |
| HK (2) | HK1167313A1 (zh) |
| HR (1) | HRP20230315T1 (zh) |
| HU (2) | HUE061640T2 (zh) |
| IL (4) | IL305394A (zh) |
| LT (2) | LT3000467T (zh) |
| MX (1) | MX356593B (zh) |
| NL (1) | NL301237I2 (zh) |
| NO (1) | NO2023028I1 (zh) |
| NZ (1) | NZ595143A (zh) |
| PL (1) | PL3000467T3 (zh) |
| PT (1) | PT3000467T (zh) |
| RU (2) | RU2011139363A (zh) |
| SG (1) | SG174382A1 (zh) |
| SI (1) | SI3000467T1 (zh) |
| TW (2) | TW201040143A (zh) |
| WO (1) | WO2010117633A1 (zh) |
| ZA (1) | ZA201108118B (zh) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101313702B1 (ko) | 2005-02-03 | 2013-10-04 | 와이어쓰 | 제피티니브 및/또는 에를로티니브 내성암 치료용 약제학적 조성물 |
| EP3488866A1 (en) | 2005-11-04 | 2019-05-29 | Wyeth LLC | Antineoplastic combinations with mtor inhibitor, herceptin, and/or hki-272 |
| US8022216B2 (en) | 2007-10-17 | 2011-09-20 | Wyeth Llc | Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof |
| EP3443961B1 (en) | 2008-06-17 | 2020-10-28 | Wyeth LLC | Antineoplastic combinations containing hki-272 and vinorelbine |
| BRPI0916694B1 (pt) | 2008-08-04 | 2021-06-08 | Wyeth Llc | uso de neratinibe em combinação com capecitabina para tratar câncer de mama metastático de erbb-2 positivo, kit e produto compreendendo os mesmos |
| CA2755789C (en) | 2009-04-06 | 2016-01-19 | Wyeth Llc | Treatment regimen utilizing neratinib for breast cancer |
| EP2498751B1 (en) | 2009-11-09 | 2019-04-03 | Wyeth LLC | Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea |
| KR20200022187A (ko) | 2018-08-22 | 2020-03-03 | 울산대학교 산학협력단 | Nono의 발현 또는 활성 억제제를 유효성분으로 포함하는 방사선 민감성 증진용 조성물 |
| CR20220241A (es) | 2019-11-04 | 2022-08-03 | Revolution Medicines Inc | Inhibidores de ras |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005028443A2 (en) * | 2003-09-15 | 2005-03-31 | Wyeth A Corporation Of The State Of Delaware, Usa | Protein tyrosine kinase enzyme inhibitors |
| US20070104721A1 (en) * | 2005-11-04 | 2007-05-10 | Wyeth | Antineoplastic combinations with mTOR inhibitor,herceptin, and/or hki-272 |
Family Cites Families (146)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1327358C (en) | 1987-11-17 | 1994-03-01 | Morio Fujiu | Fluoro cytidine derivatives |
| JP3040121B2 (ja) | 1988-01-12 | 2000-05-08 | ジェネンテク，インコーポレイテッド | 増殖因子レセプターの機能を阻害することにより腫瘍細胞を処置する方法 |
| CA2103059C (en) | 1991-06-14 | 2005-03-22 | Paul J. Carter | Method for making humanized antibodies |
| AU671491B2 (en) | 1992-12-18 | 1996-08-29 | F. Hoffmann-La Roche Ag | N-oxycarbonyl substituted 5'-deoxy-5-fluorcytidines |
| TW254946B (zh) | 1992-12-18 | 1995-08-21 | Hoffmann La Roche | |
| NZ272608A (en) | 1994-07-22 | 2000-05-26 | Lilly Co Eli | Inhibiting bone loss by administering a bisphosphonate and a second compound selected from various compounds, including 2-phenyl-3-aroylbenzothienes; bisphosphonate combination salts |
| US5476932A (en) | 1994-08-26 | 1995-12-19 | Hoffmann-La Roche Inc. | Process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives |
| GB9508565D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
| GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
| US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
| EP0860433B1 (en) | 1995-11-07 | 2002-07-03 | Kirin Beer Kabushiki Kaisha | Quinoline derivatives and quinazoline derivatives inhibiting autophosphorylation of growth factor receptor originating in platelet and pharmaceutical compositions containing the same |
| US5760041A (en) | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
| US6002008A (en) | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
| UA73073C2 (uk) | 1997-04-03 | 2005-06-15 | Уайт Холдінгз Корпорейшн | Заміщені 3-ціанохіноліни, спосіб їх одержання та фармацевтична композиція |
| US6251912B1 (en) | 1997-08-01 | 2001-06-26 | American Cyanamid Company | Substituted quinazoline derivatives |
| EA004436B1 (ru) | 1998-09-29 | 2004-04-29 | Уайт Холдингз Корпорейшн | Замещенные 3-цианохинолины в качестве ингибиторов протеинтирозинкиназ |
| US6297258B1 (en) | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| US6288082B1 (en) | 1998-09-29 | 2001-09-11 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| US6432979B1 (en) | 1999-08-12 | 2002-08-13 | American Cyanamid Company | Method of treating or inhibiting colonic polyps and colorectal cancer |
| EP1248869A2 (en) | 2000-01-07 | 2002-10-16 | Transform Pharmaceuticals, Inc. | High-throughput formation, identification, and analysis of diverse solid-forms |
| US6384051B1 (en) | 2000-03-13 | 2002-05-07 | American Cyanamid Company | Method of treating or inhibiting colonic polyps |
| US7306801B2 (en) | 2000-05-15 | 2007-12-11 | Health Research, Inc. | Methods of therapy for cancers characterized by overexpression of the HER2 receptor protein |
| DK1318837T3 (da) | 2000-08-11 | 2005-01-10 | Wyeth Corp | Fremgangsmåde til behandling af östrogenreceptorpositivt carcinom |
| TWI286074B (en) | 2000-11-15 | 2007-09-01 | Wyeth Corp | Pharmaceutical composition containing CCI-779 as an antineoplastic agent |
| TWI296196B (en) | 2001-04-06 | 2008-05-01 | Wyeth Corp | Antineoplastic combinations |
| MXPA03009092A (es) | 2001-04-06 | 2004-02-12 | Wyeth Corp | COMBINACIONES DE ANTINEOPLaSICOS COMO RAPAMICINA CON GEMCITABINA O FLUOROURACILO. |
| TWI233359B (en) | 2001-04-06 | 2005-06-01 | Wyeth Corp | Pharmaceutical composition for treating neoplasm |
| US20020198137A1 (en) | 2001-06-01 | 2002-12-26 | Wyeth | Antineoplastic combinations |
| WO2002098416A2 (en) | 2001-06-01 | 2002-12-12 | Wyeth | Antineoplastic combinations |
| UA77200C2 (en) | 2001-08-07 | 2006-11-15 | Wyeth Corp | Antineoplastic combination of cci-779 and bkb-569 |
| NZ533118A (en) | 2001-11-27 | 2006-07-28 | Wyeth Corp | 3-cyanoquinolines as inhibitors of EGF-R and HER2 kinases |
| TWI275390B (en) | 2002-04-30 | 2007-03-11 | Wyeth Corp | Process for the preparation of 7-substituted-3- quinolinecarbonitriles |
| BR0311814A (pt) | 2002-06-05 | 2005-03-15 | Cedars Sinai Medical Center | Método de tratar câncer empregando inibidores de cinase |
| AU2003248813A1 (en) | 2002-07-05 | 2004-01-23 | Beth Israel Deaconess Medical Center | Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms |
| US20040209930A1 (en) | 2002-10-02 | 2004-10-21 | Carboni Joan M. | Synergistic methods and compositions for treating cancer |
| CL2004000016A1 (es) | 2003-01-21 | 2005-04-15 | Wyeth Corp | Compuesto derivado de cloruro de 4-amino-2-butenoilo o una sal farmaceuticamente aceptable del mismo; procedimiento para preparar dicho compuesto, util como intermediario en la sintesis de compuestos inhibidores de proteina quinasa tirosina. |
| UA83484C2 (uk) | 2003-03-05 | 2008-07-25 | Уайт | Спосіб лікування раку грудей комбінацією похідного рапаміцину і інгібітора ароматази - летрозолу, фармацевтична композиція |
| UA80756C2 (en) | 2003-04-22 | 2007-10-25 | Wyeth Corp | Antineoplastic combinations of rapomicine and interferon alfa (?) in the treatment of neoplasms |
| US20050043233A1 (en) | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
| US8637553B2 (en) | 2003-07-23 | 2014-01-28 | Bayer Healthcare Llc | Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions |
| US20050025825A1 (en) | 2003-07-31 | 2005-02-03 | Xanodyne Pharmacal, Inc. | Tranexamic acid formulations with reduced adverse effects |
| RU2006106267A (ru) | 2003-08-01 | 2006-07-27 | Уайт Холдингз Корпорейшн (Us) | Применение комбинации ингибитора киназы рецептора эпидермального фактора роста и цитотоксических средств для лечения и ингибирования рака |
| MXPA06001590A (es) | 2003-08-19 | 2006-05-19 | Wyeth Corp | Proceso para la preparacion de 4-amino-3-quinolincarbonitrilos. |
| UA85394C2 (ru) | 2003-09-15 | 2009-01-26 | Вайет | Замещенные хинолины в качестве ингибиторов ферментов протеинтирозиновых киназ |
| TWI372066B (en) | 2003-10-01 | 2012-09-11 | Wyeth Corp | Pantoprazole multiparticulate formulations |
| US20050142192A1 (en) | 2003-10-15 | 2005-06-30 | Wyeth | Oral administration of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl] phosphonic acid and derivatives |
| EP1756137A4 (en) | 2003-11-05 | 2007-10-31 | Univ Texas | DIAGNOSTIC AND THERAPEUTIC PROCEDURES AND COMPOSITIONS CONCERNING PTEN AND BREAST CANCER |
| TW200526684A (en) | 2003-11-21 | 2005-08-16 | Schering Corp | Anti-IGFR1 antibody therapeutic combinations |
| AR047988A1 (es) | 2004-03-11 | 2006-03-15 | Wyeth Corp | Combinaciones antineoplásicas de cci-779 y rituximab |
| CA2556227C (en) | 2004-03-31 | 2013-03-19 | The General Hospital Corporation | Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments |
| CA2574311A1 (en) | 2004-07-23 | 2006-01-26 | Astrazeneca Ab | Method of predicting the responsiveness oa a tumor to erbb receptor drugs |
| US20060058311A1 (en) | 2004-08-14 | 2006-03-16 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation |
| TW200616612A (en) | 2004-10-08 | 2006-06-01 | Wyeth Corp | Method for the teatment of polycystic kidney disease field of invention |
| WO2006044453A1 (en) | 2004-10-13 | 2006-04-27 | Wyeth | Analogs of 17-hydroxywortmannin as pi3k inhibitors |
| WO2006044748A2 (en) | 2004-10-15 | 2006-04-27 | Monogram Biosciences, Inc. | RESPONSE PREDICTORS FOR ErbB PATHWAY-SPECIFIC DRUGS |
| GB0501999D0 (en) | 2005-02-01 | 2005-03-09 | Sentinel Oncology Ltd | Pharmaceutical compounds |
| KR101313702B1 (ko) | 2005-02-03 | 2013-10-04 | 와이어쓰 | 제피티니브 및/또는 에를로티니브 내성암 치료용 약제학적 조성물 |
| WO2006081985A1 (en) | 2005-02-04 | 2006-08-10 | F. Hoffmann-La Roche Ag | Combined treatment with an n4-(substituted-oxycarbonyl)-5’-deoxy-5-fluorocytidine derivative and an epidermal growth factor receptor kinase inhibitor |
| CA2599115A1 (en) | 2005-02-28 | 2006-08-31 | Eisai R & D Management Co., Ltd. | Novel combinational use of sulfonamide compound |
| CA2599445C (en) | 2005-03-09 | 2022-05-03 | Abbott Laboratories | Diagnostics method for identifying candidate patients for the treatment with trastuzumab |
| GB0504994D0 (en) | 2005-03-11 | 2005-04-20 | Biotica Tech Ltd | Novel compounds |
| RU2007134908A (ru) | 2005-04-14 | 2009-05-20 | Вайет (Us) | Применение ингибитора активности киназы рецептора эпидермального фактора роста для лечения пациентов, невосприимчивых к гефитинибу |
| US20110045459A1 (en) | 2005-04-21 | 2011-02-24 | Mischel Paul S | Molecular determinants of EGFR kinase inhibitor response in glioblastoma |
| JP5149159B2 (ja) | 2005-04-28 | 2013-02-20 | ワイス・エルエルシー | ミクロ化タナプロゲット、組成物およびその調製方法 |
| CA2603445A1 (en) | 2005-05-12 | 2006-11-16 | Pfizer Inc. | Anticancer combination therapy using sunitinib malate |
| CN101180269A (zh) | 2005-05-25 | 2008-05-14 | 惠氏公司 | 制备3-氰基-喹啉的方法和由其制得的中间体 |
| WO2006127207A1 (en) | 2005-05-25 | 2006-11-30 | Wyeth | Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof |
| DE102005053679A1 (de) | 2005-06-24 | 2006-12-28 | Bayer Healthcare Ag | Therapeutischer Einsatz von Moxifloxacin zur Rekonstruktion von Funktionsstörungen des Immunsystems |
| CN101247791A (zh) | 2005-07-15 | 2008-08-20 | 惠氏公司 | O-去甲基文拉法辛琥珀酸盐的高生物可利用的口服缓释剂型 |
| WO2007015569A1 (ja) | 2005-08-01 | 2007-02-08 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質の効果を予測する方法 |
| EP1925676A4 (en) | 2005-08-02 | 2010-11-10 | Eisai R&D Man Co Ltd | TEST METHOD FOR THE EFFECT OF A VASCULARIZATION INHIBITOR |
| ZA200802854B (en) | 2005-10-05 | 2009-06-24 | Astrazeneca Ltd | Method to predict or monitor the response of a patient to an ErbB receptor drug |
| WO2007050495A2 (en) | 2005-10-26 | 2007-05-03 | Children's Medical Center Corporation | Method to prognose response to anti-egfr therapeutics |
| TW200803842A (en) | 2005-11-04 | 2008-01-16 | Wyeth Corp | Antineoplastic combinations of temsirolimus and sunitinib malate |
| PT1948180E (pt) | 2005-11-11 | 2013-05-10 | Boehringer Ingelheim Int | Tratamento de combinação de cancro compreendendo inibidores de egfr/her2 |
| PL1951274T3 (pl) | 2005-11-24 | 2010-05-31 | Aicuris Gmbh & Co Kg | Parapoksywirusy w kombinacji z klasycznymi cytotoksycznymi środkami chemioterapeutycznymi jako biochemioterapia do leczenia raka |
| RU2008120672A (ru) | 2005-12-22 | 2010-01-27 | Вайет (Us) | Композиции для перорального введения, содержащие тайгециклин |
| WO2007095038A2 (en) | 2006-02-09 | 2007-08-23 | Novartis Ag | Mutations and polymorphisms of erbb2 |
| TW200806282A (en) | 2006-05-05 | 2008-02-01 | Wyeth Corp | Solid dosage formulations |
| EP2032980A4 (en) | 2006-05-18 | 2012-01-04 | Molecular Profiling Inst Inc | SYSTEM AND METHOD FOR DETERMINING AN INDIVIDUALIZED MEDICAL INTERVENTION FOR A PATHOLOGY |
| TW200808728A (en) | 2006-05-23 | 2008-02-16 | Wyeth Corp | Method of preparing 4-halogenated quinoline intermediates |
| CA2655997A1 (en) | 2006-06-30 | 2008-01-10 | Schering Corporation | Igfbp2 biomarker |
| PL2068880T3 (pl) | 2006-09-18 | 2012-09-28 | Boehringer Ingelheim Int | Sposób leczenia raka z mutacjami EGFR |
| JP2010504974A (ja) | 2006-09-28 | 2010-02-18 | フォリカ，インコーポレーテッド | 新しい毛嚢を生成させ毛髪を成長させる方法、キット、及び組成物 |
| WO2008043576A1 (en) | 2006-10-13 | 2008-04-17 | Medigene Ag | Use of oncolytic viruses and antiangiogenic agents in the treatment of cancer |
| NZ578329A (en) | 2006-12-13 | 2012-05-25 | Schering Corp | Igf1r inhibitors for treating cancer |
| EP2121018A2 (en) | 2006-12-13 | 2009-11-25 | Schering Corporation | Treating cancer with anti-igf1r antibody 19d12=sch 717454 |
| WO2008079346A1 (en) | 2006-12-21 | 2008-07-03 | Vertex Pharmaceuticals Incorporated | 5-cyan0-4- (pyrrolo [2, 3b] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors |
| RU2009125413A (ru) | 2007-01-12 | 2011-02-20 | Вайет (Us) | Композиции таблетка-в-таблетке |
| JP5276017B2 (ja) | 2007-01-25 | 2013-08-28 | デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド | Ｅｇｆｒ変異体仲介性疾患の治療における抗ｅｇｆｒ抗体の使用 |
| WO2008093878A1 (en) | 2007-02-01 | 2008-08-07 | Takeda Pharmaceutical Company Limited | Tablet preparation without causing a tableting trouble |
| WO2008121467A2 (en) | 2007-02-28 | 2008-10-09 | Dana-Farber Cancer Institute, Inc. | Combination therapy for treating cancer |
| GB0706633D0 (en) | 2007-04-04 | 2007-05-16 | Cyclacel Ltd | Combination |
| AU2008239594B2 (en) | 2007-04-13 | 2013-10-24 | Beth Israel Deaconess Medical Center | Methods for treating cancer resistant to ErbB therapeutics |
| US20100120072A1 (en) | 2007-04-19 | 2010-05-13 | Wellstat Biologics Corporation | Detection of elevated levels of her-2/neu protein from non-isolated circulating cancer cells and treatment |
| WO2008136838A1 (en) | 2007-05-04 | 2008-11-13 | Trustees Of Dartmouth College | Novel amide derivatives of cddo and methods of use thereof |
| WO2009005673A1 (en) | 2007-06-28 | 2009-01-08 | Schering Corporation | Anti-igf1r |
| EP2200431B1 (en) | 2007-09-10 | 2016-07-20 | Boston Biomedical, Inc. | Novel compositions and methods for cancer treatment |
| US20110306572A1 (en) | 2007-09-24 | 2011-12-15 | Tragara Pharmaceuticals, Inc | COMBINATION THERAPY FOR THE TREATMENT OF CANCER USING COX-2 INHIBITORS AND DUAL InHIBITORS OF EGFR [ErbB1] AND HER-2 [ErbB2] |
| US8022216B2 (en) | 2007-10-17 | 2011-09-20 | Wyeth Llc | Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof |
| CA2702637A1 (en) | 2007-10-22 | 2009-04-30 | Schering Corporation | Fully human anti-vegf antibodies and methods of using |
| JP2011502571A (ja) | 2007-11-05 | 2011-01-27 | ピュアテック ベンチャーズ | 医薬化合物を投与するための方法、キット、および組成物 |
| US20110091524A1 (en) | 2007-12-18 | 2011-04-21 | Yan Wang | Biomarkers for sensitivity to anti-igf1r therapy |
| US20100297118A1 (en) | 2007-12-27 | 2010-11-25 | Macdougall John | Therapeutic Cancer Treatments |
| WO2009105234A2 (en) | 2008-02-19 | 2009-08-27 | Combinatorx, Incorporated | Methods and compositions for the treatment of disorders associated with defects of the cystic fibrosis transmembrane conductance regulator gene or protein |
| ES2545760T3 (es) | 2008-02-25 | 2015-09-15 | Nestec S.A. | Selección de fármacos para terapia del cáncer de mama utilizando matrices de anticuerpos |
| US20100081632A1 (en) | 2008-03-06 | 2010-04-01 | Odyssey Thera, Inc. | High-content and high throughput assays for identification of lipid-regulating pathways, and novel therapeutic agents for lipid disorders |
| JP2011515478A (ja) | 2008-03-25 | 2011-05-19 | シェーリング コーポレイション | 結腸直腸がんを処置または予防するための方法 |
| WO2009121031A1 (en) | 2008-03-27 | 2009-10-01 | Vascular Biosciences, Inc. | Methods of novel therapeutic candidate identification through gene expression analysis in vascular-related diseases |
| US20090246198A1 (en) | 2008-03-31 | 2009-10-01 | Takeda Pharmaceutical Company Limited | Mapk/erk kinase inhibitors and methods of use thereof |
| WO2009126662A1 (en) | 2008-04-08 | 2009-10-15 | Syndax Pharmaceuticals, Inc. | Administration of an inhibitor of hdac, an inhibitor of her-2, and a selective estrogen receptor modulator |
| MX339476B (es) | 2008-04-18 | 2016-05-27 | Reata Pharmaceuticals Inc | Compuestos que incluyen un nucleo farmaceutico antiinflamatorio y sus metodos de uso. |
| WO2009146216A2 (en) | 2008-04-18 | 2009-12-03 | Reata Pharmaceuticals. Inc. | Antioxidant inflammation modulators: novel derivatives of oleanolic acid |
| KR101713140B1 (ko) | 2008-04-18 | 2017-03-08 | 리타 파마슈티컬스 잉크. | Ｃ-환에서 포화된 산화방지성 염증 조절제 올레아놀산 유도체 |
| TWI584808B (zh) | 2008-04-18 | 2017-06-01 | 瑞塔醫藥有限責任公司 | 抗氧化發炎調節劑：ｃ－１７同系齊墩果酸衍生物 |
| CN102083442B (zh) | 2008-04-18 | 2014-08-13 | 里亚塔医药公司 | 抗氧化剂炎症调节剂：在c-17具有氨基和其它修饰的齐墩果酸衍生物 |
| MX2010012064A (es) | 2008-05-05 | 2010-12-06 | Schering Corp | Uso secuencial de agentes quimioterapeuticos citotoxicos para el tratamiento de cancer. |
| WO2009151910A2 (en) | 2008-05-25 | 2009-12-17 | Wyeth | Combination product of receptor tyrosine kinase inhibitor and fatty acid synthase inhibitor for treating cancer |
| EP3443961B1 (en) | 2008-06-17 | 2020-10-28 | Wyeth LLC | Antineoplastic combinations containing hki-272 and vinorelbine |
| CA2731650A1 (en) | 2008-07-22 | 2010-01-28 | Tadashi Honda | Monocyclic cyanoenones and methods of use thereof |
| BRPI0916694B1 (pt) | 2008-08-04 | 2021-06-08 | Wyeth Llc | uso de neratinibe em combinação com capecitabina para tratar câncer de mama metastático de erbb-2 positivo, kit e produto compreendendo os mesmos |
| US20100069340A1 (en) | 2008-09-11 | 2010-03-18 | Wyeth | Pharmaceutical compositions of an src kinase inhibitor and an aromatase inhibitor |
| EP3075864A1 (en) | 2008-10-14 | 2016-10-05 | Caris MPI, Inc. | Gene and gene expressed protein targets depicting biomarker patterns and signature sets by tumor type |
| WO2010048477A2 (en) | 2008-10-24 | 2010-04-29 | Wyeth Llc | Improved process for preparation of coupled products from 4-amino-3-cyanoquinolines using stabilized intermediates |
| CA2741050A1 (en) | 2008-11-07 | 2010-05-14 | Santaris Pharma A/S | Erbb-3 (her3)-selective combination therapy |
| WO2010085845A1 (en) | 2009-01-28 | 2010-08-05 | The University Of Queensland | Cancer therapy and/or diagnosis |
| MX2011008221A (es) | 2009-02-04 | 2011-08-17 | Bipar Sciences Inc | Tratamiento de cancer de pulmon con un compuesto de nitrobenzamida en combinacion con un inhibidor de un factor de crecimieno. |
| WO2010098627A2 (ko) | 2009-02-27 | 2010-09-02 | 한올바이오파마주식회사 | 약제학적 제제 |
| AU2010221818A1 (en) | 2009-03-11 | 2011-10-06 | Auckland Uniservices Limited | Prodrug forms of kinase inhibitors and their use in therapy |
| CA2755789C (en) | 2009-04-06 | 2016-01-19 | Wyeth Llc | Treatment regimen utilizing neratinib for breast cancer |
| AR076053A1 (es) | 2009-04-14 | 2011-05-18 | Schering Corp | Derivados de pirazolo[1,5-a]pirimidina como inhibidores de mtor |
| WO2010124009A2 (en) | 2009-04-21 | 2010-10-28 | Schering Corporation | Fully human anti-vegf antibodies and methods of using |
| WO2010129053A2 (en) | 2009-05-05 | 2010-11-11 | Dana Farber Cancer Institute | Egfr inhibitors and methods of treating disorders |
| AU2010266342A1 (en) | 2009-07-02 | 2012-01-19 | Wyeth Llc | 3-cyanoquinoline tablet formulations and uses thereof |
| KR20110007985A (ko) | 2009-07-17 | 2011-01-25 | 한올바이오파마주식회사 | Ｎ,ｎ―디메틸 이미도디카르본이미딕 디아미드의 부틸산염, 이의 제조방법, 이를 포함하는 약제학적 조성물 및 이를 포함하는 복합제제 |
| KR20110007984A (ko) | 2009-07-17 | 2011-01-25 | 한올바이오파마주식회사 | Ｎ,ｎ―디메틸 이미도디카르본이미딕 디아미드의 프로피온산염, 이의 제조방법, 이를 포함하는 약제학적 조성물 및 이를 포함하는 복합제제 |
| KR20110021691A (ko) | 2009-08-25 | 2011-03-04 | 한올바이오파마주식회사 | 메트포르민 메탄설폰산염, 그의 제조방법, 그를 포함하는 약학 조성물 및 그를 포함하는 복합제제 |
| WO2011025271A2 (ko) | 2009-08-25 | 2011-03-03 | 한올바이오파마주식회사 | 메트포르민 아스코르브산염, 그의 제조방법, 그를 포함하는 약학 조성물 및 그를 포함하는 복합제제 |
| WO2011025269A2 (ko) | 2009-08-25 | 2011-03-03 | 한올바이오파마주식회사 | 메트포르민 타우린염, 그의 제조방법, 그를 포함하는 약학 조성물 및 그를 포함하는 복합제제 |
| CA2775155A1 (en) | 2009-10-01 | 2011-04-07 | Csl Limited | Method of treatment of philadelphia chromosome positive leukemia |
| PT2498756T (pt) | 2009-11-09 | 2019-11-26 | Wyeth Llc | Formulações de comprimidos de maleato de neratinib |
| EP2498751B1 (en) | 2009-11-09 | 2019-04-03 | Wyeth LLC | Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea |
| AU2010319483B2 (en) | 2009-11-13 | 2015-03-12 | Amgen Inc. | Material and methods for treating or preventing HER-3 associated diseases |
| US20130012465A1 (en) | 2009-12-07 | 2013-01-10 | Boehringer Ingelheim International Gmbh | Bibw 2992 for use in the treatment of triple negative breast cancer |
| EP2510121A1 (en) | 2009-12-11 | 2012-10-17 | Wyeth LLC | Phosphatidylinositol-3-kinase pathway biomarkers |
| CA2787048C (en) | 2010-01-13 | 2021-06-22 | Wyeth Llc | A cut-point in pten protein expression that accurately identifies tumors and is predictive of drug response to a pan-erbb inhibitor |
-
2010
- 2010-03-24 CA CA2755789A patent/CA2755789C/en active Active
- 2010-03-24 KR KR1020187014053A patent/KR20180056796A/ko active Application Filing
- 2010-03-24 CN CN201410228902.0A patent/CN103989681A/zh active Pending
- 2010-03-24 EP EP10722215.0A patent/EP2416774B1/en not_active Revoked
- 2010-03-24 EP EP15188350.1A patent/EP3000467B1/en active Active
- 2010-03-24 ES ES10722215.0T patent/ES2561495T3/es active Active
- 2010-03-24 NZ NZ595143A patent/NZ595143A/en unknown
- 2010-03-24 DK DK15188350.1T patent/DK3000467T3/da active
- 2010-03-24 AU AU2010234968A patent/AU2010234968B2/en active Active
- 2010-03-24 CN CN201610444390.0A patent/CN105999264A/zh active Pending
- 2010-03-24 US US13/256,910 patent/US9211291B2/en active Active
- 2010-03-24 IL IL305394A patent/IL305394A/en unknown
- 2010-03-24 RU RU2011139363/14A patent/RU2011139363A/ru unknown
- 2010-03-24 SI SI201032128T patent/SI3000467T1/sl unknown
- 2010-03-24 ES ES15188350T patent/ES2941894T3/es active Active
- 2010-03-24 KR KR1020227035333A patent/KR20220143154A/ko not_active Application Discontinuation
- 2010-03-24 KR KR1020147005926A patent/KR20140036332A/ko active Search and Examination
- 2010-03-24 IL IL264349A patent/IL264349B2/en unknown
- 2010-03-24 HU HUE15188350A patent/HUE061640T2/hu unknown
- 2010-03-24 EP EP23157078.9A patent/EP4218760A3/en active Pending
- 2010-03-24 KR KR1020197032944A patent/KR20190128004A/ko active Application Filing
- 2010-03-24 SG SG2011066180A patent/SG174382A1/en unknown
- 2010-03-24 HR HRP20230315TT patent/HRP20230315T1/hr unknown
- 2010-03-24 LT LTEP15188350.1T patent/LT3000467T/lt unknown
- 2010-03-24 KR KR1020117026353A patent/KR20120016085A/ko active Application Filing
- 2010-03-24 JP JP2012504700A patent/JP5992325B2/ja active Active
- 2010-03-24 BR BRPI1012699A patent/BRPI1012699A2/pt not_active Application Discontinuation
- 2010-03-24 PL PL15188350.1T patent/PL3000467T3/pl unknown
- 2010-03-24 FI FIEP15188350.1T patent/FI3000467T3/fi active
- 2010-03-24 PT PT151883501T patent/PT3000467T/pt unknown
- 2010-03-24 MX MX2011010511A patent/MX356593B/es active IP Right Grant
- 2010-03-24 CN CN2010800149162A patent/CN102369010A/zh active Pending
- 2010-03-24 KR KR1020167024069A patent/KR20160106211A/ko not_active Application Discontinuation
- 2010-03-24 WO PCT/US2010/028448 patent/WO2010117633A1/en active Application Filing
- 2010-04-02 TW TW099110424A patent/TW201040143A/zh unknown
- 2010-04-02 TW TW103110561A patent/TWI557108B/zh active
- 2010-04-05 AR ARP100101127A patent/AR076197A1/es unknown
-
2011
- 2011-09-15 IL IL215166A patent/IL215166A/en active IP Right Grant
- 2011-11-04 ZA ZA2011/08118A patent/ZA201108118B/en unknown
-
2012
- 2012-08-03 HK HK12107642.3A patent/HK1167313A1/zh not_active IP Right Cessation
-
2014
- 2014-07-25 RU RU2014130874A patent/RU2685715C2/ru active
- 2014-12-08 JP JP2014247707A patent/JP2015044871A/ja active Pending
-
2016
- 2016-05-24 JP JP2016103000A patent/JP2016147912A/ja not_active Withdrawn
- 2016-09-04 IL IL247609A patent/IL247609B/en active IP Right Grant
- 2016-09-27 HK HK16111293.3A patent/HK1223027A1/zh unknown
-
2017
- 2017-12-01 JP JP2017231667A patent/JP2018030891A/ja not_active Withdrawn
-
2019
- 2019-06-20 JP JP2019114554A patent/JP2019151671A/ja not_active Withdrawn
-
2021
- 2021-04-08 JP JP2021065698A patent/JP2021100985A/ja not_active Withdrawn
-
2023
- 2023-03-28 CY CY20231100167T patent/CY1125948T1/el unknown
- 2023-04-04 JP JP2023060682A patent/JP2023076588A/ja active Pending
- 2023-07-10 NL NL301237C patent/NL301237I2/nl unknown
- 2023-07-11 HU HUS2300023C patent/HUS2300023I1/hu unknown
- 2023-07-13 NO NO2023028C patent/NO2023028I1/no unknown
- 2023-07-19 FI FIC20230025C patent/FIC20230025I1/fi unknown
- 2023-07-20 LT LTPA2023520C patent/LTPA2023520I1/lt unknown
- 2023-07-20 CY CY2023015C patent/CY2023015I1/el unknown
- 2023-07-24 FR FR23C1027C patent/FR23C1027I2/fr active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005028443A2 (en) * | 2003-09-15 | 2005-03-31 | Wyeth A Corporation Of The State Of Delaware, Usa | Protein tyrosine kinase enzyme inhibitors |
| US20070104721A1 (en) * | 2005-11-04 | 2007-05-10 | Wyeth | Antineoplastic combinations with mTOR inhibitor,herceptin, and/or hki-272 |
Non-Patent Citations (1)
| Title |
|---|
| BURSTEIN H等: "HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: preliminary phase 2 results in patients with advanced breast cancer", 《BREAST CANCER RESEARCH AND TREATMENT》 * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105999264A (zh) | 用于乳腺癌的利用奈拉替尼的治疗方案 | |
| Safran et al. | Cetuximab with concurrent chemoradiation for esophagogastric cancer: assessment of toxicity | |
| CN105214086B (zh) | 抗-vegf抗体与化学治疗联合用于治疗乳腺癌的应用 | |
| CN109310754A (zh) | 使用包含抗erbb3抗体的联合疗法治疗er+、her2-、hrg+乳腺癌的方法 | |
| CN109939236A (zh) | 用于治疗癌症的磷酸肌醇3激酶抑制剂化合物和化疗剂的突变选择性及组合 | |
| CN103237810A (zh) | 用于治疗卵巢癌的抗血管发生疗法 | |
| CN107233343A (zh) | Akt抑制剂化合物和化疗剂的组合以及使用方法 | |
| CA3204489A1 (en) | Combination therapies for treatment of her2 cancer | |
| CN107750165A (zh) | 借助塞里班土单抗的组合治疗 | |
| RU2804713C2 (ru) | Схема лечения рака молочной железы с использованием нератиниба | |
| CN105916515A (zh) | 药物组合 | |
| Haokun | Oxaliplatin and Checkpoint Inhibitor Induces Immunogenic Cells Death and Promotes Therapeutic Efficacy in the Model of Murine Triple Positive Breast Cancer | |
| Vincenzo et al. | IMPACT OF INTEGRATED TREATMENTS ON PATIENT MANAGEMENT IN SOLID TUMORS: FROM DIAGNOSIS TO PALLIATIVE CARE |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1230078 Country of ref document: HK |
|
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20161012 Assignee: Beihai Kangcheng Pharmaceutical Co., Ltd Assignor: Lion biopharmaceutical company Contract record no.: X2020990000295 Denomination of invention: Treatment regimen utilizing neratinib for breast cancer License type: Common License Record date: 20200611 |
|
| EC01 | Cancellation of recordation of patent licensing contract | ||
| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: Beihai Kangcheng Pharmaceutical Co., Ltd Assignor: Lion biopharmaceutical company Contract record no.: X2020990000295 Date of cancellation: 20211015 |