OA19291A - Crenolanib for treating FLT3 mutated proliferative disorders associated mutations. - Google Patents
Crenolanib for treating FLT3 mutated proliferative disorders associated mutations. Download PDFInfo
- Publication number
- OA19291A OA19291A OA1201900173 OA19291A OA 19291 A OA19291 A OA 19291A OA 1201900173 OA1201900173 OA 1201900173 OA 19291 A OA19291 A OA 19291A
- Authority
- OA
- OAPI
- Prior art keywords
- crenolanib
- patient
- cancer
- flt3
- chromosomal
- Prior art date
Links
- DYNHJHQFHQTFTP-UHFFFAOYSA-N Crenolanib Chemical compound C=1C=C2N(C=3N=C4C(N5CCC(N)CC5)=CC=CC4=CC=3)C=NC2=CC=1OCC1(C)COC1 DYNHJHQFHQTFTP-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 229950009240 Crenolanib Drugs 0.000 title claims abstract description 79
- 201000010099 disease Diseases 0.000 title claims abstract description 65
- 101710009074 FLT3 Proteins 0.000 title claims abstract 26
- 102100004573 FLT3 Human genes 0.000 title claims abstract 15
- 230000035772 mutation Effects 0.000 title claims description 112
- 230000002062 proliferating Effects 0.000 title abstract 2
- 230000002068 genetic Effects 0.000 claims abstract description 39
- 230000004083 survival Effects 0.000 claims abstract description 30
- 238000010837 poor prognosis Methods 0.000 claims abstract description 18
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 9
- 206010000880 Acute myeloid leukaemia Diseases 0.000 claims description 80
- 208000007046 Leukemia, Myeloid, Acute Diseases 0.000 claims description 80
- 210000001185 Bone Marrow Anatomy 0.000 claims description 61
- ARQUTWAXTHJROR-UHFFFAOYSA-N benzenesulfonic acid;1-[2-[5-[(3-methyloxetan-3-yl)methoxy]benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine Chemical compound OS(=O)(=O)C1=CC=CC=C1.C=1C=C2N(C=3N=C4C(N5CCC(N)CC5)=CC=CC4=CC=3)C=NC2=CC=1OCC1(C)COC1 ARQUTWAXTHJROR-UHFFFAOYSA-N 0.000 claims description 40
- 206010024324 Leukaemias Diseases 0.000 claims description 37
- 238000002560 therapeutic procedure Methods 0.000 claims description 34
- 238000002512 chemotherapy Methods 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 28
- 230000002759 chromosomal Effects 0.000 claims description 26
- 201000011510 cancer Diseases 0.000 claims description 25
- 102100008060 WT1 Human genes 0.000 claims description 22
- 101700062995 WT1 Proteins 0.000 claims description 22
- 230000000694 effects Effects 0.000 claims description 19
- 101710038368 DNMT3A Proteins 0.000 claims description 16
- 102100006402 DNMT3A Human genes 0.000 claims description 16
- 102100013038 RUNX1 Human genes 0.000 claims description 14
- 101700025439 RUNX1 Proteins 0.000 claims description 14
- 201000003793 myelodysplastic syndrome Diseases 0.000 claims description 14
- 206010053871 Trisomy 8 Diseases 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 102000008037 Myeloid-Lymphoid Leukemia Protein Human genes 0.000 claims description 10
- 108010075393 Myeloid-Lymphoid Leukemia Protein Proteins 0.000 claims description 10
- 102100020079 NPM1 Human genes 0.000 claims description 10
- 101710026364 NPM1 Proteins 0.000 claims description 10
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 10
- -1 RUNXl Proteins 0.000 claims description 10
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 10
- 201000009928 Patau syndrome Diseases 0.000 claims description 9
- 206010044686 Trisomy 13 Diseases 0.000 claims description 9
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 claims description 9
- 206010028576 Myeloproliferative disease Diseases 0.000 claims description 8
- 108091007921 receptor tyrosine kinases Proteins 0.000 claims description 8
- 102000027656 receptor tyrosine kinases Human genes 0.000 claims description 8
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 7
- 239000008177 pharmaceutical agent Substances 0.000 claims description 7
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 7
- 102100004555 BCOR Human genes 0.000 claims description 6
- 108060000889 BCOR Proteins 0.000 claims description 6
- 108010045374 CD36 Antigens Proteins 0.000 claims description 6
- 102100019348 CEBPA Human genes 0.000 claims description 6
- 101700058775 CEBPA Proteins 0.000 claims description 6
- 102100002089 ETV6 Human genes 0.000 claims description 6
- 101700053672 ETV6 Proteins 0.000 claims description 6
- 102100006631 GRB7 Human genes 0.000 claims description 6
- 108010022046 GRB7 Adaptor Protein Proteins 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 210000000661 Isochromosomes Anatomy 0.000 claims description 6
- 101700016050 JAK2 Proteins 0.000 claims description 6
- 102100019516 JAK2 Human genes 0.000 claims description 6
- 102100009279 KRAS Human genes 0.000 claims description 6
- 101710033922 KRAS Proteins 0.000 claims description 6
- 101700053678 MUTYH Proteins 0.000 claims description 6
- 102100003827 MUTYH Human genes 0.000 claims description 6
- 102100001119 NRAS Human genes 0.000 claims description 6
- 101710033916 NRAS Proteins 0.000 claims description 6
- 102100003677 NUP98 Human genes 0.000 claims description 6
- 102000035266 SCARB3 Human genes 0.000 claims description 6
- 108060007427 SF3B1 Proteins 0.000 claims description 6
- 102100014711 SF3B1 Human genes 0.000 claims description 6
- 102100005108 SRSF2 Human genes 0.000 claims description 6
- 101700039960 SRSF2 Proteins 0.000 claims description 6
- 102100015334 STAG2 Human genes 0.000 claims description 6
- 101700002785 STAG2 Proteins 0.000 claims description 6
- 102100003998 TET2 Human genes 0.000 claims description 6
- 101700048164 TET2 Proteins 0.000 claims description 6
- 102100011276 TUSC3 Human genes 0.000 claims description 6
- 101700008695 TUSC3 Proteins 0.000 claims description 6
- 102100016864 TYK2 Human genes 0.000 claims description 6
- 101700057652 TYK2 Proteins 0.000 claims description 6
- 101700055602 U2AF1 Proteins 0.000 claims description 6
- 102100011052 U2AF1 Human genes 0.000 claims description 6
- 102100020461 ZRSR2 Human genes 0.000 claims description 6
- 101710011915 ZRSR2 Proteins 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 6
- 231100001075 aneuploidy Toxicity 0.000 claims description 6
- 238000003780 insertion Methods 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 6
- 108010054452 nuclear pore complex protein 98 Proteins 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- 102100016224 ASXL1 Human genes 0.000 claims description 5
- 101700021058 ASXL1 Proteins 0.000 claims description 5
- 206010001019 Acute promyelocytic leukaemia Diseases 0.000 claims description 5
- 101700032846 BRP1 Proteins 0.000 claims description 5
- 102100004121 IDH1 Human genes 0.000 claims description 5
- 101700024037 IDH1 Proteins 0.000 claims description 5
- 101700030371 IDH2 Proteins 0.000 claims description 5
- 102100002772 IDH2 Human genes 0.000 claims description 5
- 101700066748 IDH3B Proteins 0.000 claims description 5
- 208000005749 Leukemia, Promyelocytic, Acute Diseases 0.000 claims description 5
- 102100017818 PTPN11 Human genes 0.000 claims description 5
- 101710018405 PTPN11 Proteins 0.000 claims description 5
- 108091000081 Phosphotransferases Proteins 0.000 claims description 5
- 102000001253 Protein Kinases Human genes 0.000 claims description 5
- 102100000939 SETBP1 Human genes 0.000 claims description 5
- 101710024482 SETBP1 Proteins 0.000 claims description 5
- 102100004275 TCL1A Human genes 0.000 claims description 5
- 239000002246 antineoplastic agent Substances 0.000 claims description 5
- 231100000005 chromosome aberration Toxicity 0.000 claims description 5
- 230000036210 malignancy Effects 0.000 claims description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- 206010073479 Acute undifferentiated leukaemia Diseases 0.000 claims description 4
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 206010017758 Gastric cancer Diseases 0.000 claims description 4
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 claims description 4
- 208000008968 Lymphoma, Large-Cell, Anaplastic Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 208000008443 Pancreatic Carcinoma Diseases 0.000 claims description 4
- 208000006781 Prolymphocytic Leukemia Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 230000001154 acute Effects 0.000 claims description 4
- 230000001058 adult Effects 0.000 claims description 4
- 230000001684 chronic Effects 0.000 claims description 4
- 201000006934 chronic myeloid leukemia Diseases 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 201000002528 pancreatic cancer Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061934 Salivary gland cancer Diseases 0.000 claims description 3
- 208000000587 Small Cell Lung Carcinoma Diseases 0.000 claims description 3
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 3
- 206010057644 Testis cancer Diseases 0.000 claims description 3
- 206010046766 Uterine cancer Diseases 0.000 claims description 3
- 230000004075 alteration Effects 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 201000009251 multiple myeloma Diseases 0.000 claims description 3
- 230000000955 neuroendocrine Effects 0.000 claims description 3
- 102000005962 receptors Human genes 0.000 claims description 3
- 108020003175 receptors Proteins 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 229940086735 succinate Drugs 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- 201000010874 syndrome Diseases 0.000 claims description 3
- 201000003120 testicular cancer Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims description 2
- 206010020243 Hodgkin's disease Diseases 0.000 claims description 2
- 206010029379 Neutrophilia Diseases 0.000 claims description 2
- 210000001744 T-Lymphocytes Anatomy 0.000 claims description 2
- 101700039223 TCL1A Proteins 0.000 claims description 2
- 239000011886 peripheral blood Substances 0.000 claims description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 2
- 230000002074 deregulated Effects 0.000 claims 10
- 108060008100 TCL1 Proteins 0.000 claims 3
- 206010008958 Chronic lymphocytic leukaemia Diseases 0.000 claims 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims 2
- 208000000429 Leukemia, Lymphocytic, Chronic, B-Cell Diseases 0.000 claims 2
- 208000010125 Myocardial Infarction Diseases 0.000 claims 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims 2
- 230000036451 QT interval Effects 0.000 claims 2
- 238000000543 QT interval Methods 0.000 claims 2
- 238000009093 first-line therapy Methods 0.000 claims 2
- 201000010536 head and neck cancer Diseases 0.000 claims 2
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 claims 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N (2S)-7-fluoro-2-methyl-6-(4-methylpiperazin-1-yl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.0^{5,13}]trideca-5(13),6,8,11-tetraene-11-carboxylic acid Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims 1
- SUBDBMMJDZJVOS-XMMPIXPASA-N (R)-omeprazole Chemical compound C([S@@](=O)C=1NC2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-XMMPIXPASA-N 0.000 claims 1
- VHVPQPYKVGDNFY-TUJWMRSMSA-N 2-[(2S)-butan-2-yl]-4-[4-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-TUJWMRSMSA-N 0.000 claims 1
- 229960005260 Amiodarone Drugs 0.000 claims 1
- IYIKLHRQXLHMJQ-UHFFFAOYSA-N Amiodarone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(OCCN(CC)CC)C(I)=C1 IYIKLHRQXLHMJQ-UHFFFAOYSA-N 0.000 claims 1
- 206010002383 Angina pectoris Diseases 0.000 claims 1
- 206010003119 Arrhythmia Diseases 0.000 claims 1
- MQTOSJVFKKJCRP-BICOPXKESA-N Azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N Benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 1
- 206010007521 Cardiac arrhythmias Diseases 0.000 claims 1
- MYSWGUAQZAJSOK-UHFFFAOYSA-N Ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims 1
- CGHRJBLSXVCYQF-YXSUXZIUSA-N Dolasetron Chemical compound C1=CC=C[C]2C(C(O[C@@H]3C[C@@H]4C[C@@H]5C[C@@H](N4CC5=O)C3)=O)=CN=C21 CGHRJBLSXVCYQF-YXSUXZIUSA-N 0.000 claims 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N Esomeprazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N Fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N Granisetron Chemical group C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 claims 1
- 229960003727 Granisetron Drugs 0.000 claims 1
- LNEPOXFFQSENCJ-UHFFFAOYSA-N Haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 claims 1
- 206010020772 Hypertension Diseases 0.000 claims 1
- 229960000282 Metronidazole Drugs 0.000 claims 1
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 claims 1
- FABPRXSRWADJSP-MEDUHNTESA-N Moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims 1
- FELGMEQIXOGIFQ-UHFFFAOYSA-N Ondansetron Chemical compound CC1=NC=CN1CC1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-UHFFFAOYSA-N 0.000 claims 1
- GRHYHJAAOJVRSZ-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2N=C3[CH]C(OC(F)F)=CC=C3N=2)=C1OC GRHYHJAAOJVRSZ-UHFFFAOYSA-N 0.000 claims 1
- 229960004448 Pentamidine Drugs 0.000 claims 1
- XDRYMKDFEDOLFX-UHFFFAOYSA-N Pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims 1
- 229960001967 Tacrolimus Drugs 0.000 claims 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 claims 1
- 229960004099 azithromycin Drugs 0.000 claims 1
- 229960003405 ciprofloxacin Drugs 0.000 claims 1
- 229960003413 dolasetron Drugs 0.000 claims 1
- 229960004770 esomeprazole Drugs 0.000 claims 1
- 229960004884 fluconazole Drugs 0.000 claims 1
- 229960003878 haloperidol Drugs 0.000 claims 1
- 229960004130 itraconazole Drugs 0.000 claims 1
- 229960003376 levofloxacin Drugs 0.000 claims 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims 1
- 229960002509 miconazole Drugs 0.000 claims 1
- 229960003702 moxifloxacin Drugs 0.000 claims 1
- 229960000381 omeprazole Drugs 0.000 claims 1
- 229960005019 pantoprazole Drugs 0.000 claims 1
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 claims 1
- 229960001589 posaconazole Drugs 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 4
- 239000011780 sodium chloride Substances 0.000 abstract description 4
- 102000004632 fms-Like Tyrosine Kinase 3 Human genes 0.000 description 67
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 67
- 150000001875 compounds Chemical class 0.000 description 26
- 210000004369 Blood Anatomy 0.000 description 21
- 239000008280 blood Substances 0.000 description 21
- 238000003745 diagnosis Methods 0.000 description 16
- 230000001939 inductive effect Effects 0.000 description 14
- 210000004027 cells Anatomy 0.000 description 13
- 238000001574 biopsy Methods 0.000 description 11
- 230000004044 response Effects 0.000 description 11
- 230000003211 malignant Effects 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 9
- 230000001965 increased Effects 0.000 description 9
- 238000004393 prognosis Methods 0.000 description 9
- 230000002159 abnormal effect Effects 0.000 description 8
- 230000001186 cumulative Effects 0.000 description 7
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 230000002829 reduced Effects 0.000 description 7
- 208000003476 Primary Myelofibrosis Diseases 0.000 description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 6
- 238000009096 combination chemotherapy Methods 0.000 description 6
- 230000003247 decreasing Effects 0.000 description 6
- 238000001959 radiotherapy Methods 0.000 description 6
- RTAQQCXQSZGOHL-UHFFFAOYSA-N titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 6
- 230000037250 Clearance Effects 0.000 description 5
- 229960000684 Cytarabine Drugs 0.000 description 5
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytosar Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 210000004185 Liver Anatomy 0.000 description 5
- 230000035512 clearance Effects 0.000 description 5
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 206010064571 Gene mutation Diseases 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- 201000005510 acute lymphocytic leukemia Diseases 0.000 description 4
- 230000000735 allogeneic Effects 0.000 description 4
- 230000002559 cytogenic Effects 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- 230000000869 mutational Effects 0.000 description 4
- 230000001613 neoplastic Effects 0.000 description 4
- 238000009097 single-agent therapy Methods 0.000 description 4
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 3
- 206010008805 Chromosomal abnormality Diseases 0.000 description 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 3
- 229960000975 Daunorubicin Drugs 0.000 description 3
- 206010028537 Myelofibrosis Diseases 0.000 description 3
- CVWXJKQAOSCOAB-UHFFFAOYSA-N Quizartinib Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(=CC=2)C=2N=C3N(C4=CC=C(OCCN5CCOCC5)C=C4S3)C=2)=N1 CVWXJKQAOSCOAB-UHFFFAOYSA-N 0.000 description 3
- 229950001626 Quizartinib Drugs 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 231100000494 adverse effect Toxicity 0.000 description 3
- 230000003389 potentiating Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 210000001519 tissues Anatomy 0.000 description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 208000002047 Essential Thrombocythemia Diseases 0.000 description 2
- 230000035693 Fab Effects 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 2
- 229960000908 Idarubicin Drugs 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin hydrochloride Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- UIARLYUEJFELEN-LROUJFHJSA-N Lestaurtinib Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 2
- 229950001845 Lestaurtinib Drugs 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 206010028549 Myeloid leukaemia Diseases 0.000 description 2
- 208000008696 Polycythemia Vera Diseases 0.000 description 2
- 208000008383 Wilms Tumor Diseases 0.000 description 2
- 230000003213 activating Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000011132 hemopoiesis Effects 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 201000008026 nephroblastoma Diseases 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- UXXQOJXBIDBUAC-UHFFFAOYSA-N 4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 244000105975 Antidesma platyphyllum Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 210000002230 Centromere Anatomy 0.000 description 1
- 210000000349 Chromosomes Anatomy 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N Docetaxel 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 description 1
- 201000010374 Down syndrome Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010024379 Leukocytosis Diseases 0.000 description 1
- 206010024378 Leukocytosis Diseases 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 101710005117 M142.8 Proteins 0.000 description 1
- 101700049761 ML1 Proteins 0.000 description 1
- 206010027476 Metastasis Diseases 0.000 description 1
- 108020004388 MicroRNAs Proteins 0.000 description 1
- 229950010895 Midostaurin Drugs 0.000 description 1
- 229960001156 Mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N Mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 206010071972 N-ras gene mutation Diseases 0.000 description 1
- 108010055723 PDGF receptor tyrosine kinase Proteins 0.000 description 1
- 102100013577 POU2F2 Human genes 0.000 description 1
- 101710006193 POU2F2 Proteins 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 235000002343 Primula veris Nutrition 0.000 description 1
- 240000003122 Primula vulgaris Species 0.000 description 1
- 235000016311 Primula vulgaris Nutrition 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 230000036865 QTc prolongation Effects 0.000 description 1
- 101710008352 RPS5B Proteins 0.000 description 1
- 208000007660 Residual Neoplasm Diseases 0.000 description 1
- 210000002427 Ring Chromosomes Anatomy 0.000 description 1
- 210000001324 Spliceosomes Anatomy 0.000 description 1
- 206010043554 Thrombocytopenia Diseases 0.000 description 1
- 206010066901 Treatment failure Diseases 0.000 description 1
- 206010044685 Trisomy 11 Diseases 0.000 description 1
- 206010044688 Trisomy 21 Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000001594 aberrant Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 101700005476 ail Proteins 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000001413 cellular Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 201000011231 colorectal cancer Diseases 0.000 description 1
- 230000001472 cytotoxic Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000000779 depleting Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 231100000371 dose-limiting toxicity Toxicity 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 108091004535 flt3 ligand protein Proteins 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 235000009424 haa Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000527 lymphocytic Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229920001239 microRNA Polymers 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000007481 next generation sequencing Methods 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- 230000002246 oncogenic Effects 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100000730 tolerability Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Abstract
The present invention includes methods for treating a FLT3 mutated proliferative disorder comprising: measuring expression of a mutated FLT3 and one or more genetic abnormalities in a sample obtained from a tumor sample obtained from the patient, wherein the presence of the one or more genetic abnormalities indicates that the patient has a poor prognosis; and administering to the patient a therapeutically effective amount of crenolanib or a pharmaceutically acceptable salt thereof, wherein the crenolanib increases a chance of survival of the patient having both the mutated FLT3 and the one or more genetic abnormalities, wherein the crenolanib, as shown below, is administered to a subject suffering from said disorder.
Description
DETAILED DESCRIPTION OF THE INVENTION
While the making and using of various embodiments of the présent invention are discussed in detail below, it should be appreciated that the présent invention provides many applicable inventive concepts 1 · that can be embodied in a wide variety of spécifie contexts. The spécifie embodiments discussed herein arc mcrcly illustrative of spécifie ways to makc and use the invention and do not delimit the scopc ofthe invention.
To facilitate the understanding of this invention, a number of terms are defined below. Terms defîned herein hâve meanings as commonly understood by a person of ordinary skill in the areas relevant 15 to the présent invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a spécifie example may be used for illustration. The terminology herein is used to describe spécifie embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.
The présent invention comprises the use of the compounds of the présent invention to treat 2· disorders related to FLT3 kinase activity or expression in a subject.
Crenolanib (4-Piperidinaminc, l-[2-[5-[(3-mctliyl-3-oxctanyl) methoxy]-lH-benzimidazol-l-yl]-8quinolinyl]) and its pharmaceutically acceptable salts, are protein tyrosine kinase inhibitors sélective for constitutively active FLT3 mutations, including FLT3 ITD and FLT3 TKD mutations. Unlike prior FLT3 inhibitors in the art, the besylate sait form of crenolanib has been shown to be remarkably effective 25 in depleting circulating peripheral blood blast percentages and bone marrow blast percentages in heavily pretreated FLT3 mutant AML patients without significantly increasing patient QT prolongation. Crenolanib is currcntly being investigated for use in the treatment of patients with relapscd or rcfractory constitutively activated FLT3 mutated primary AML or AML secondary to myelodysplastic syndrome.
An analysis of Crenolanib’s efficacy in patients presenting with concomitant FLT3 mutations, as 3i well as other cytogenetic or molecular abnormalities, are also presently being developed through ongoing clinical trials.
Crenolanib safety and tolerability was evaluated between November 2M3 and September 2··6 in a phase I first-in-human dose-escalation single agent sludy in heavily pretreated patients with advanced solid tumors (Protocol Α53·1··1; See N Lewis et al., J Clin Oncol. 2M9; 27: p5262-5269). Fifty-nine 35 patients were enrolled and completed tire study. Most treatment related adverse events were of grade 1 or 2 severity. There was no evidence of cumulative toxicity. In patients treated with lower drug dosages ranging from 6·-2·· mg once daily, the most common adverse évents observed were grade 1 nausea and vomiting, which usually occurred approximately 45 minutes after dosing. There were no grade 3 or 4 toxicities in these patients. At higher doses 28· mg and 34· mg once daily, liver enzyme élévations were the most severe side effects. Liver enzyme levels returned to normal following the discontinuation of 5 crenolanib. The présent invention has demonstrated that the administration of 1·· mg three times daily of crenolanib besylate to human patients diagnoscd with constitutivcly activated FLT3 mutant relapsed or refractory AML does not always resuit in an élévation of liver enzymes. See Example two in Examples section of this patient application. It also demonstrates that when liver enzymes are elevated that liver enzyme levels can be decreased by discontinuing tire drug for approximately 1 week and re-starting 1 · crenolanib at a reducing dosage of 8· mg three times daily.
No grade 2/3/4 QT prolongation was observed in any of the 59 patients treated in the phase I dose escalation safety study, despite crenolanib dose received. Similarly, there hâve been no signifïcant différences in baseline QT prolongation and on-treatment QT prolongation in a currently ongoing pédiatrie glioma trial with twenty-four children being treated with the besylate form of crenolanib. 15 Likewise, the présent invention has shown no cases of QT prolongation following the administration of 1 ·· mg of crenolanib besylate three times daily to human patients diagnosed with constitutively activated FLT3 mutant relapsed or refractory AML. Other FLT3 inhibitors known in the art hâve caused signifïcant QTc prolongation leading to strict clinical study inclusion and exclusion criteria to prevent severe adverse events. For example, two separate quizartinib AML studies hâve revealed that the 2· compound causes signifïcant Q prolongation. In a 76 patient phase I single agent study evaluating the compound in both FLT3 wildtype and FLT ITD mutated relapsed and refractory AML identified QT prolongation as the dose limiting toxicity. Sec J Cortès et al. AC22·, a potent sélective, second génération FLT3 receptor tyrosine kinase (RTK) inhibitor, in a first-in-human (FIH) phase I AML study. Blood (ASH Annual Meeting Abstracts) 2··9 Nov. Additionally, intérim data from a phase II trial of 25 quizartinib monotherapy in 62 patients with relapsed or refractory AML with FLT3 ITD activating mutations asymptomatic QT prolongation was one of the most common (>19%) drug related adverse events. QT prolongation of ail grades occurred in 21 (34%) patients. More than half of the QT prolongation events recorded were grade 3 (18%). Reducing the starting dose of quizartinib by greater than 3·% did not alleviate ail cases of QT prolongation. See J Cortès et al. A phase II open-label, AC22· 3· monotherapy efficacy study in patients with refractory/relapsed FLT3-ITD positive acute myeloid leukemia: updated intérim results. Blood (ASH Annual Meeting Abstracts) 2·11 Dec.
As used herein, the term “poor prognosis” refers to a decreased chance of survival (for example, decreased overall survival, relapse-free survival, or metastasis-free survival). For example, a poor prognosis has a decreased chance of survival includes a survival time of equal to or less than 6· months, 35 such as 5· months, 4· months, 3· months, 2· months, 12 months, 6 months, or 3 months from time of diagnosis or first treatment or remission.
By contrast, a “good prognosis” refers to an incrcascd chance of survival, for cxamplc increascd overall survival, relapse-free survival, or metastasis-free survival. For example, a good prognosis has an increased chance of survival includes a survival time of at least 6· months from time of diagnosis, such as 6· months, 89 months, 199 months, 121 months, 159 months, or more from time of diagnosis or first treatment.
Détection of the mutated FLT3 and/or one or more genetic abnormalities can be performed using 5 any suitable means known in the art. For example, détection of gene mutations can be accomplished by dctccting nucleic acid molécules (such as DNA) using nucleic acid amplification methods (such as RTPCR) or high-throughput sequencing (i.e. “next-generation sequencing”). Détection of chromosomal abnormalities can also be accomplished using karyotyping or in situ hybridization tirât detect structural and numerical alterations.
In mutated FLT3 tumors, the alteration in expression or presence of one or more genetic abnormalities, such as, e.g., chromosomal translocations, délétions, alternative gene splicing, mutations or délétions within coding or intron-exon boundary régions, can be lead to a measurable decrease in prognosis. In addition to a pre-existing FLT3 mutation, the additional genetic abnormalities disclosed herein significantly decrease the prognosis of the patient. A poor prognosis can refer to any négative 15 clinical outcome, such as, but not limited to, a decrease in likelihood of survival (such as overall survival, relapse-free survival, or metastasis-free survival), a decrease in the time of survival (e.g., less than 5 years, or less than one year), presence of a malignant tumor, an increase in the severity of disease, a decrease in response to therapy, an increase in tumor récurrence, an increase in metastasis, or the like. In particular examples, a poor prognosis is a decreased chance of survival (for example, a survival time of 29 equal to or less than 69 months, such as 59 months, 49 months, 39 months, 29 months, 12 months, 6 months or 3 months from time of diagnosis or first treatment).
In other embodiments of the method, the presence of the one or more genetic abnormalities (in addition to the FLT3 mutation) in the tumor sample relative to a control indicates a poor prognosis for the patient with the tumor. The method includes detecting the presence of one or more genetic abnormalities 25 that lead to a poor prognosis that include, e.g., aneuploidy (e.g., monosomy, trisomy, or polysomy), a chromosomal aberration (e.g., a délétion, duplication, translocation, inversion, insertion, ring, or isochromosome), or the presence of a driver mutation, e.g., NPM1, DNMT3A, NRAS, KRAS, JAK2, PTPN11, TET2, IDH1, IDH2, WT1, RUNX1, CEBPA, ASXL1, BCOR, SF3B1, U2AF1, STAG2, SETBP1, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCL1A, TUSC3, BRP1, CD36, TYK2, or 39 MUTYH.
As used herein, the phrases mutations responsible for cancer and driver mutations are used intcrchangcably to refer to mutations that are présent in cancer tissues and which arc capable of inducing carcinogenesis of cells. Generally, if a mutation is found in a cancer tissue in which no other known oncogene mutations exists (in other words, if a mutation exists in a mutually exclusive manner with 35 known oncogene mutations), then the mutation can be determined to be a responsible mutation for cancer, and thus, a “driver mutation”.
In one embodiment to this aspect, the présent invention provides a method for reducing or inhibiting the kinase activity of FLT3 in a subject comprising the step of administering a compound of the présent invention to the subject.
As used herein, tire terni subject or “patient” are used interchangeable to refer to an animal, such as a mammal or a human, who has been the object of medical treatment, observation or experiment.
In one embodùnent to this aspect, the présent invention provides a method for reducing or 5 inhibiting the kinase activity of FLT3 in a subject comprising the step of administering a compound of the présent invention to the subject.
The tcrm subject refers to an animal, such as a mammal or a human, who has been the object of treatment, observation or experiment.
In other embodiments to this aspeck the présent invention provides therapeutic methods for treating 1· a subject with a cell proliférative disorder driven by aberrant kinase activity of mutant FLT3. In one example, the invention provides methods for treating a cell proliférative disorder related to mutant FLT3, comprising administration of a therapeutically effective amount of a pharmaceutical composition comprising a compound of the présent invention in a subject. Administration of said therapeutic agent can occur upon manifestation of symptoms characteristic of the FLT3 driven cell proliférative disorder, 15 such tirât a disease or disorder treated.
The tenu therapeutically effective amount as used herein, refers to an amount of active compound or pharmaceutical sait that elicits the biological or médicinal response in a subject that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
2· Methods for determining therapeutically effective doses for pharmaceutical compositions comprising a compound of dre présent invention are known in the art.
As used herein, the term composition is intended to encompass a product comprising the specified ingrédients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of tire specified ingrédients in the specified amounts.
As used herein, the terms “disorder related to FLT3,” or “disorders related to FLT3 receptor,” or “disorders related to FLT3 receptor tyrosine kinase,” or “FLT3 driven cell proliférative disorder” includes diseases associated with or implicating FLT3 activity, for example, mutations leading to constitutive activation of FLT3. Examples of “disorders related to FLT3” include disorders resulting from over stimulation of FLT3 due to mutations in FLT3, or disorders resulting from abnormally high 3· amount of FLT3 activity due to abnormally high amount of mutations in FLT3. It is known that overactivity of FLT3 has been implicated in the pathogenesis of many diseases, including the following listed cell proliférative disorders, neoplastic disorders and cancers.
The term “cell proliférative disorders” refers to excess cell prolifération of one or more subset of cells in a multicellular organism resulting in harm (i.e. discomfort or decreased life expectancy) to tire 35 multicellular organism. Cell proliférative disorders can occur in different types of animais and humans. As used herein, “cell proliférative disorders” include neoplastic disorders.
The term “neoplastic disorder’ as used herein, refers to a tumor resulting from abnormal or uncontrolled cellular growtli. Examples of neoplastic disorders include, but are not limited to tire following disorders, for instance: the myeloproliferative disorders, such as thrombocytopenia, essential thrombocytosis (ET), agnogenic myeloid metaplasia, myelofibrosis (MF), myelofibrosis with myeloid metaplasia (MMM), chronic idiopathic myelofibrosis (UIMF), and polycythemia vera (PV), tlie cytopenias, and pre-malignant myelodysplastic syndromes; cancerse such as glioma cancers, lung 5 cancers, breast cancers, colorectal cancers, prostate cancers, gastric cancers, esophageal cancers, colon cancers, pancreatic cancers, ovarian cances, and hematological malignancies, including myelodysplasia, multiple myeloma, leukemias, and lymphomas. Examples of hematological malignancies include, for instance, leukemias, lymphomas, Hodgkin’s disease, and myeloma. Also, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic 1· leukemia (CLL), chronic myeloid leukemia (CML), chronic neutrophilie leukemia (CNL), acute undifferentiated leukemia (AUL), anaplastic large-cell lymphoma (ALCL), prolymphocytic leukemia (PML), juvénile myelomonocytic leukemia (JMML), adult T-cell ALL, AML, with trilineage myelodysplasia (AMLITMDS), mixed lineage leukemia (MLL), myelodysplastic syndoromes (MDSs), myeloproliferative disorders (MPD), and multiple myeloma (MM).
The expression of mutated FLT3, constitutively active FLT3 mutant, and tire one or more genetic abnormalities, can be determined using standard molecular biology techniques, including sequencing at die RNA or DNA level, protein expression, protein function, the presence or absence of die RNA, DNA, and/or protein, as will be known to those of skill in the art following the teachings of, e.g., standard techniques for sequencing (including Next Génération Sequencing (NGS)), cloning, RNA and DNA 2· isolation, amplification and purification, détection and identification of chromosomal abnormalities, and various séparation techniques arc those known and commonly employcd by those skilled in the art. A number of standard techniques are described in Sambrook et al. (1989) Molecular Cloning, Second Edition, Cold Spring Harbor Laboratory, Plainview, N.Y.; Maniatis et al. (1982) Molecular Cloning, Cold Spring Harbor Laboratory, Plainview, N.Y.; Wu (ed.) (1993) Meth. Enzymol. 218, Part I; Wu (ed.) (1979) Metii. Enzymol. 68; Wu et al. (eds.) (1983) Medt. Enzymol. 1·· and 1·1; Grossman and Moldave (eds.) Meth. Enzymol. 65; Miller (ed.) (1972) Experiments in Molecular Genetics, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.; Old and Primrose (1981) Principles of Gene Manipulation, University of California Press, Berkeley; Schleif and Wensink (1982) Practical Methods in Molecular Biology; Glover (ed.) (1985) DNA Cloning Vol. I and II, IRL Press, Oxford, UK; Hames and Higgins
3· (eds.) (1985) Nucleic Acid Hybridization, IRL Press, Oxford, UK; Setlow and Hollaender (1979) Genetic Engineering: Principles and Methods, Vols. 1-4, Plénum Press, New York; Fitchen, et al. (1993) Annu Rev. Microbiol. 47:739-764; Tolstoshev, et al. (1993) in Genomic Research in Molecular Medicine and Virology, Academie Press; and Ausubel et al. (1992) Current Protocole in Molecular Biology, Greene/Wiley, New York, N.Y. Abbreviations and nomenclature, where employed, are deemed standard in the field and commonly used in professional joumals such as those cited herein. The above techniques can be used to detect genetic abnormalities such as aneuploidy, monosomy, trisomy, or polysomy; chromosomal aberrations such as one or more délétions, duplications, translocations, inversions, insertions, rings, or isochromosomes. Additional genetic abnormalities include driver mutations such as those selected from at least one of NPM1, DNMT3A, NRAS, KRAS, JAK2, PTPNH, TET2, IDH1, IDH2, WT1, RUNXl, CEBPA, ASXLl, BCOR, SF3B1, U2AF1, STAG2, SETBPl, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCLlA, TUSC3, BRPl, CD36, TYK2, or MUTYH, ail of them human or animal, with the names available from Genecards.com, with current accession numbers, sequences, and 5 probes to the same incorporated herein by reference.
In a further embodiment, the présent invention can be combined with another therapy as a combination therapy for treâting or inhibiting the onset of a cell proliférative disorder related to FLT3 in a subject. The combination therapy comprises the administration of a therapeutically effective amount of a compound of the présent invention and one or more other anti-cell prolifération thérapies including, but 1 · not limited to, chemotherapy and radiation therapy.
In an embodiment of the présent invention, a compound of the présent invention may be administered in combination with chemotherapy. Used herein, chemotherapy refers to a therapy involving a chemotherapeutic agent. A variety of chemotherapeutic agents may be used in combination with the présent invention. By way of example only, taxane compounds, specifically docetaxel, is safely 15 administered in combination with a compound of the présent invention in a dosage of 75 mg per square mctcr (mg/m2) of body surface area.
Chemotherapy is known to those skilled in the art. The appropriate dosage and scheme for chemotherapy will be similar to those already employed in clinical thérapies wherein the chemotherapy is delivered in combination with other thérapies or used alone.
2· In another embodiment of the présent invention, compounds of the présent invention may be administered in combination with radiation therapy. Used herein, “radiation therapy” refers to a therapy that comprises the exposure of a subject in need to radiation. Radiation therapy is known to those skilled in die art. The appropriate dosage and scheme for radiation therapy will be similar to those already employed in clinical thérapies wherein the radiation therapy is delivered in combination with other 25 thérapies or used alone.
In another embodiment of the présent invention, the compounds of the présent invention may be administered in combination with a targeted therapy. As used herein, “targeted therapy” refers to a therapy targeting a particular class of proteins involved in tumor development or oncogenic signaling. For example, tyrosine kinase inhibitors against vascular endothélial growth factor hâve been used in 3· treâting cancers.
The présent invention also includes methods that include die use of a second pharmaceutical agent in addition to compounds of the présent invention, the two may bc administered simultancously or scquentially (in cithcr order).
In one embodiment, the présent invention therapeutically effective amounts of the compound 35 having formula I :
or a pharmaceutically acceptable sait or solvaté thereof, in a therapeutically or prophylactically effective amount against a proliférative disease is selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), 5 bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and ncck cancer, liver cancer, lung cancer, nasopharyngcal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy. Pharmaceutically acceptable salts including hydrochloride, phosphate and lactate are prepared in a 1· manner similar to the benzenesulfonate sait and are well known to those of moderate skill in the art.
Compounds of the présent invention may be administered to a subject systemically, for example, orally, intravcnously, subcutancously, intramuscular, intradcrmal or parcntcrally. Tire compounds of the présent invention can also be administered to a subject locally.
Compounds of the présent invention may be formulated for slow-release or fast-release with the 15 objective of maintaining contact of compounds of the présent invention with targeted tissues for a desired range of time.
Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules, granules, and powders, liquid forms, such as solutions, émulsions, and suspensions. Forms useful for parentéral administration include stérile solutions, émulsions and suspensions.
2· The daily dosage of the compounds of the présent invention may be varied over a wide range from 5· to 5·· mg per adult human per day. For oral administration, the compositions arc prefcrably provided in the form of tablets containing 2· and 1·· milligrams. The compounds of the présent invention may be administered on a regimen up to three times or more per day. Preferably three times per day. Optimal doses to be administered may be determined by those skilled in the art, and will vary with the compound 25 of the présent invention used, the mode of administration, tire time of administration, the strength of the préparation, the details of dre disease condition. Factors associated with patient characteristics, such as âge, weight, and diet will call for dosage adjustments.
Préparation of the compounds of the présent invention. General synthetic methods which may be referred to for preparing the compounds of formula I are provided in U.S. Patent No. 5,99·,146 (issued 3· Nov. 23, 1999) (Warner-Lambert Co.) and PCT publishcd application numbers WO 99/16755 (publishcd Apr. 8, 1999) (Merck & Co.) WO ·1/4·217 (publishcd Jul. 7, 2··1) (Pfizer, Inc.), US Patent Application
CHU
No. US 2··5/·124599 (Pfizer, Inc.) and U.S. Patent No. 7,183,414 (Pfizer, Inc.), relevant portions incorporated herein by reference.
Pharmaceutically acceptable salts such as hydrochloride, phosphate and lactate are prepared in a manncr similar to the bcnzcnesulfonatc sait and are well known to those of moderato skill in the art.
The following représentative compounds of the présent invention are for exemplary purposes only and are in no way meant to limit the invention, including Crenolanib as Crenolanib Besylate, Crenolanib Phosphate, Crenolanib Lactate, Crenolanib Hydrochloride, Crenolanib Citrate, Crenolanib Acetate, Crenolanib Toluenesulphonate and Crenolanib Succinate.
SUMMARY OF EXAMPLES
1· Example A: The leukemic blasts from a newly diagnoscd patient harbored in addition to a FLT3ITD mutation, mutations in the NPM1 and DNMT3A genes. The patient achieved réduction in bone marrow blasts to less than 5% following induction combination chemotherapy followed by sequential administration of crenolanib besylate.
Example B: The leukemic blasts from a newly diagnosed patient harbored in addition to a FLT315 ITD mutation, a mutation in the RUNX1 gene. The patient achieved réduction in bone marrow blasts to less than 5% following induction combination chemotherapy followed by sequential administration of crenolanib besylate and was bridged to an allogeneic hematopoietic stem cell transplantation (HSCT).
Example C: The leukemic blasts from a newly diagnosed patient harbored in addition to a FLT3ITD mutation, a mutation in the RUNX1 gene and an abnormal karyotype containing trisomy 8 and 2· trisomy 13. The patient achieved réduction in bone marrow blasts to less than 5% following induction combination chemotherapy followed by sequential administration of crenolanib besylate and was bridged to an allogeneic hematopoietic stem cell transplantation (HSCT).
Example D: The leukemic blasts from a relapsed/refractory patient harbored in addition to a FLT3ITD mutation, an abnormal karyotype containing trisomy 8 and a (6;9) translocation. The patient 25 achieved réduction in bone marrow blasts to less than 5% following salvage combination chemotherapy followed by sequential administration of crenolanib besylate.
Example E: The leukemic blasts from a newly diagnosed patient harbored in addition to a FLT3ITD mutation, a mutation in the WT1 gene. The patient achieved réduction in bone marrow blasts to less titan 5% following induction combination chemotherapy followed by sequential administration of 3· crenolanib besylate and was bridged to an allogeneic hematopoietic stem cell transplantation (HSCT).
Fvnmnle F: The leukemic blasts from a relapsed/refractory patient with prior TKI failure harbored, in addition to a FLT3-ITD mutation, a mutation in the WT1 gene. The patient achieved réduction in bone marrow blasts to less than 5% following crenolanib besylate monothempv
Examplc G: The leukemic blasts from a relapsed/refractory patient with prior TKI failure harbored, 35 ;n <, m ττ-ττη y abnormal complex karyotype. The patient achieved réduction in bone marrow blasts to less than 5% following induction combination chemotherapy followed by sequential administration of crenolanib besylate and was bridg^1 an homntnnn.otin ctom <-Pn transplantation (HSCT).
Example H: The leukemic blasts from a relapsed/refractory patient with prior TKI failure harbored in addition to a FLT3-ITD mutation, mutations in the NPMl, DNMT3A, and WTl genes and an abnormal complex karyotype. The patient achieved réduction in bone marrow blasts to less than 1·% following crenolanib besylate monotherapy.
Example A: Effect of Crenolanib Besylate Therapy in a Newly Diagnosed AML Patient with FLT3-
ITD, NPMl, and DNMT3A Mutations with Normal Karyotype: Achievement of réduction in bone marrow blasts to less titan 5% with hématologie recovery.
A 54-year-old female was diagnosed with AML positive for both FLT3-ITD and FLT3-TKD mutations. The patient’s leukemic blasts also had mutations in the NPMl and DNMT3A genes. As the 1· FLT3-ITD, NPMl, and DNMT3A mutations are characterized as independent driver mutations, and are together associated with a particularly poor prognosis, the patient’s présentation of these triple mutations placed her in a significantly high-risk group for AML patients, associated with poor response rates, increased cumulative incidence of relapse, and shortened survival. Half of patients with these mutations are expected to die within 1 year of diagnosis. See Papaemmanuil, E., “Genomic Classification and
Prognosis in Acute Myeloid Leukemia,” New England J. Med. Vol. 374, No. 23, pp. 2209-2221 (9 June 2· 16).
At diagnosis, the patient was found to hâve 63% bone marrow blasts. Following diagnosis, the patient was provided with oral crenolanib besylate on a clinical trial newly diagnosed AML patients (NCT02283177). The patient was initially treated with induction chemotherapy, comprised of seven days 2· of cytarabine and three days of daunorubicin; the patient began therapy with 1·· mg of crenolanib besylate three times daily on day 1·.
A bone marrow biopsy taken on day 35 of the clinical trial revealed the patient’s bone marrow blasts had reduced to less than 5%, classified as a complété remission. The patient remains alive and free of disease more titan one year after start of therapy.
Table A below illustrâtes the ability of crenolanib to clear and maintain clearance of malignant leukemia in the bone marrow of Example A, a newly diagnosed AML patient with FLT3-ITD, NPMl, and DNMT3A mutations with normal karyotype after treatment with chemotherapy and crenolanib besylate.
Days on CÏinicaî Triai Bone Marrow BÏast (°7o)
...............0..............................................................................................................63%.........................................................................................
.............................. ........................... < 5%
------..................... <5%'..........................................
294 < 5%
...............__ <5%
3·
Example B: Effect of Crenolanib Besylate Therapy in a Newly Diagnosed AML Patient with FLT3ITD and RUNX1 Mutations with Normal Karyotype: Achievement of réduction in bone marrow blasts to
2· less than 5% with hématologie recovery.
A 23-year-old female was diagnosed with AML positive for FLT3-ITD, RUNXl, and DNMT3A mutations. FLT3-ITD and RUNXl mutations both independently categorize her as a high-risk AML patient, which is associated with poor response rate, increased cumulative incidence of relapse, and 5 shortened survival.
At diagnosis, the patient was found to hâve 7·% bone marrow blasts. Following diagnosis, the patient was provided with oral crcnolanib besylate on a clinical trial ncwly diagnosed AML patients (NCT*2283177). The patient was initially treated with induction chemotherapy, comprised of seven days of cytarabine and three days of daunorubicin; the patient began therapy with 1·· mg of crenolanib 1 · besylate three times daily on day 9.
A bone marrow biopsy taken on day 36 of the clinical trial revealed the patient’s bone marrow blasts had redueed to less titan 5%, classified as a complété remission. The patient remains alive and free of disease more titan 6·· days after start of therapy. Less than 15% of patients with RUNXl mutations treated with standard therapy would bc cxpectcd to survive without discase for rnorc than 6·· days. Scc 15 Mendier, RUNXl Mutations Are Associated With Poor Outcome in Younger and Older Patients With Cytogenetically Normal Acute Myeloid Leukemia and With Distinct Gene and MicroRNA Expression Signatures. J Clin. Oncol. 2·12;3·:31·9-3118.
Table B below illustrâtes the ability of crenolanib to clear and maintain clearance of malignant leukemia in the bone marrow of Examplc B, a ncwly diagnosed AML patient with FLT3-ITD and 2· RUNX1 mutations with normal karyotype after treatment with chemotherapy and crenolanib besylate.
Days on CÏinicaî Trial Bone Marrow Blast (%) —θ - .......... ........................
..............36........................................................................................... <5%
......................................................................... <5%
...............120.........................................................................................................<5% * No additional bone marrow biopsies were performed on study after day 12·, as the patient remained in remission.
Example C: Effect of Crenolanib Besylate Therapy in a Newly Diagnosed AML Patient with FLT325 ITD and RUNXl Mutations, Trisomy 8, and Trisomy 13: Achicvcmcnt of réduction in bone marrow blasts to less than 5% with hématologie recovery.
A 34-year-old female was diagnosed with AML positive for FLT3-ITD and RUNXl mutations. These mutations independently categorize her as a high-risk AML patient, which is associated with poor response rate, increased cumulative incidence of relapse, and shortened survival.
3· The patient was further shown to exhibit an abnormal karyotype, characterized by the appearance of trisomy 8 and trisomy 13. Trisomy 8 has been characterized as an independent driver mutation separate and apart from other driver mutations charactcristic of AML (such as the patient’s FLT3 mutational status) and has itself been independently associated with a poor prognosis. Trisomy 13 is also an independent, poor prognostic factor and has been strongly associated with RUNX1 mutations. See Dicker, F., et al. Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. Blood. 2··7;11·:13·8-1316. The patient’s présentation of these combined mutational and cytogenetic characteristics placed her in a higher risk group than tlie FLT3-ITD 5 mutation alone.
At diagnosis, the patient was found to hâve 81% bone marrow blasts. Following diagnosis, the patient was provided with oral crenolanib besylate on a clinical trial newly diagnosed AML patients (NCT82283177). The patient was initially treated with induction chemotherapy, comprised of seven days of cytarabinc and three days of daunorubicin; the patient began therapy with 1·· mg of crenolanib 1· besylate three times daily on day 9.
A bone marrow biopsy taken on day 36 of the clinical trial revealed the patient’s bone marrow blasts had reduced to less than 5%, classified as a complété remission, and the presence of FLT3-ITD and RUNX1 mutations were no longer détectable. A karyotype analysis further revealed that tire patient now exhibited a normal karyotype, with no clonal abnormalities detected including neither trisomy 8 nor 15 trisomy 13, as had been detected at baseline. The patient remains alive and free of disease for more than 5·· days after start of therapy. Less than 1·% of patients with these mutations treated with standard therapy would be expected to survive without disease for more than 5·· days. See Herold, T., Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis. Blood. 2·14;124:13·4-1311.
2· Table C below illustrâtes the abilily of crenolanib to clear and mainlain clearance of malignant leukemia in the bone marrow of Example C, a newly diagnosed AML patient with FLT3-ITD and RUNX1 mutations and trisomy 8 and trisomy 13 after treatment with chemotherapy and crenolanib besylate.
Days on Clinical Trial Bone Marrow BÎast (%)
...............0..............................................................................................................8Ï%......................................................................................... ...............36.............................................................................................................<5% __ -....... ..........................—....................... .................................................
— — .................
* No additional bone marrow biopsies were performed on study after day 144, as the patient remained in remission.
Example D: Effect of Crenolanib Besylate Therapy in a Relapsed/Refractory AML Patient with a FLT3-ITD Mutation, Trisomy 8, and (6;9) Translocation: Achievement of réduction in bone marrow blasts to less than 5% with hématologie rccovcry.
3t A 75-year-old male was diagnosed with AML positive for a FLT3-ITD mutation and harbored a (6;9) translocation, both of which indcpcndcntly catcgorized him as a high-risk AML patient, which is associated with poor response rate, increased cumulative incidence of relapse, and shortened survival. See Papaemmanuil, E., et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N Engl
J Med. 2·16;374:22·9-2221.
Following his diagnosis, the patient was initially treated with induction chemotherapy. Approximately seven months later the patient had relapsed with a bone marrow blast percentage of 39%.
Further genetic analysis showed that the patient had acquired a trisomy 8 chromosomal abnormality 5 in addition to the FLT3-ITD and (6;9) translocation that were présent upon initial diagnosis. As trisomy 8 has been also been characterized as an independent driver mutation separate and apart from other driver mutations characteristic of AML (such as the patient’s FLT3 mutational status and (6;9) translocation) and has itself been associated with a poor prognosis, the patient’s présentation of these three characteristics placed him in a significantly higher risk group.
· At the time of relapse, the patient was provided with oral crenolanib besylate on a clinical trial for relapsed or refractory AML patients (NCTH2626338). The patient was initially treated with salvage chemotherapy, comprised of six days of cytarabine and three days of mitoxantrone; the patient began therapy with 1 ·· mg of crenolanib besylate three times daily on day 8.
A bone marrow biopsy taken on day 34 of the clinical trial revealed the patient’s bone marrow 15 blasts had reduced to less than 5%, classified as a complété remission. Further analysis revealed that the patient now exhibited a normal male karyotype. Tire patient remained in remission for more than 4·· days. Less than 1·% of relapsed patients with these mutations treated with standard therapy would be expected to survive for more titan 4·· days. See Levis, M., et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse.
2· Blood. 2·11;117:3294-33·1.
Table D below illustrâtes the ability of crenolanib to clear and maintain clearance malignant leukemia in the bone marrow of Example D, a relapsed/refractory AML patient with a FLT3-ITD mutation, trisomy 8, and (6;9) translocation after treatment with salvage chemotherapy and crenolanib besylate.
Days on Clinical Trial | Bone Marrow Blast (%) |
0 | 39% |
34 | <5% |
115 | <5% |
* No additional bone marrow biopsies were performed on study after day 115, as tire patient remained in rémission.
Example E: Effect of Crenolanib Besylate Therapy in a Newly Diagnosed AML Patient with FLT3ITD and WT1 Mutations with Normal Karyotype: Achievement of réduction in bone marrow blasts to 3· less than 5% with hématologie recovery.
A 22-year-old female was diagnosed with AML positive for FLT3-ITD, WT1 and NPM1 mutations. FLT3-ITD and WT1 mutations botli independcntly categorizc hcr as a high-risk AML patient, which is associated with poor response rate, increased cumulative incidence of relapse, and shortened survival.
At diagnosis, the patient was found to hâve 65% bone marrow blasts. Following diagnosis, the patient was provided with oral crenolanib besylate on a clinical trial newly diagnosed AML patients 5 (NCT#2283177). The patient was initially treated with induction chemotherapy, comprised of seven day s of cytarabine and three days of idarubicin; the patient began therapy with 1·· mg of crenolanib besylate three times daily on day 12.
A bone marrow biopsy taken on day 34 of the clinical trial revealed the patient’s bone marrow blasts had reduced to less than 5%, classified as a complété remission. The patient remains alive and free 1· of disease more than 7·· days after start of therapy. Less than 15% of patients with WT1 mutations treated with standard therapy would be expected to survive without disease for more than 7·· days. See Paschka, P., et al. Wilms’ Turnor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol. 2··8;26:4595-46·2.
Table E below illustrâtes the ability of crenolanib to clear and maintain clearance of malignant leukemia in the bone marrow of Examplc E, a newly diagnosed AML patient with FLT3-ITD and WT1 mutations with normal kaiyotype after treatment with chemotherapy and crenolanib besylate.
Days on CÎinicaï Triai Bone Marrow Blast (%)
...............0............................................................................................................65%........................................................................................ ...............34...........................................................................................................<5% ........................................................................... ..............82.......................................................................................... .......<5% ................................................................
..............._................. ................................
Ëxampie F: Effect of Crenolanib Besylate Therapy in a Reïapsed/Refractory ÂML Patient with 2· FLT3-ITD and WT1 Mutations with Normal Kaiyotype: Achievement of réduction in bone marrow blasts to less than 5% with hématologie recovery.
A 72-year-old female was diagnosed with AML and initially treated with induction chemotherapy. Approximately four months later, the patient relapsed and was treated with multiple salvage thérapies, including the multikinase inhibitor midostaurin due to the presence of a FLT3-ITD mutation. Six weeks 25 following an allogenic stem cell transplant, the patient relapsed again. The patient’s history of multiple relapses and prior kinase inhibitor treatment placed this patient in a high-risk group.
Further analysis showed that the patient had mutations in the FLT3-ITD gene as well as the WT1 gene. As WT1 mutations hâve been associated with poor prognosis and treatment failure, the cooccurrence of FLT3-ITD and WT1 mutations placed the patient in an even higher risk group. See 3· Paschka, P., et al. Wilms’ Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol. 2··8;26:4595-46·2.
At the time of relapse following allogeneic stem cell transplant, the patient was provided with oral crenolanib besylate on a clinical trial for relapsed or refractory AML patients (NCT*1657682). The patient began therapy with 2·· mg/m2 per day of crenolanib besylate.
A bone marrow biopsy taken on day 54 of the clinical trial revealed the patient’s bone marrow 5 blasts had reduced to less than 5%, classified as a complété remission.
Table F below illustrâtes the ability of crenolanib to clear malignant leukemia in the bone marrow of Example F, a relapsed/refractory AML patient with FLT3-ITD and WT1 mutations with prior TKI failure.
Days on Clinical Trial Bone Marrow Blast (%)
...............Ô...............................................................................................................Ï5%........................................................................................
......29........... 12%...........
...............54............................................................................................................<5%....................................................................................... i· ..................................................................................................................................................................................................................................
Example G: Effect of Crenolanib Besylate Therapy in a Relapsed/Refractory AML Patient with a FLT3-ITD Mutation and Complex Karyotype: Achievement of réduction in bone marrow blasts to less than 5% with hématologie recovery.
A 43-year-old female was diagnosed with AML positive for a FLT3-ITD mutation. The patient did 15 not respond to initial therapy, which included induction chemotherapy and sorafenib (a tyrosine kinase inhibitor). The patient had 19% bone marrow blasts at the end of initial therapy, which indicated she was still positive for a FLT3-ITD mutation and also exhibited an abnormal karyotype consisting of monosomy 15, trisomy 21, trisomy 11, dicentric centromeres, and dérivative chromosomes. A FLT3-ITD mutation and a complex karyotype both independently categorized her as a high-risk AML patient, which 2· is associated with poor response rate, increased cumulative incidence of relapse, and shortened survival.
See Papaemmanuil, E., “Genomic Classification and Prognosis in Acute Myeloid Leukemia,” New England J. Med. Vol. 374, No. 23, pp. 22*9-2221 (9 June 2*16).
The patient was then provided with oral crenolanib besylate on a clinical trial for relapsed or refractory AML patients (NCT*24**281). Tire patient was initially treated with salvage chemotherapy, 25 comprised of four days of cytarabine and three days of idarubicin; the patient began therapy with 1·· mg of crenolanib besylate three times daily on day 5.
A bone marrow biopsy taken on day 2· of the clinical trial revealed die patient’s bone marrow blasts had reduced to less than 5%, classified as a complété remission. The patient remained in remission for over 2·· days. Less than 2·% of relapsed/refractory patients with these mutations treated with 3· standard therapy would be expected to achieve a complété remission. See Levis, M., et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood. 2*11;117:3294-33*1.
Table G below illustrâtes tire ability of crenolanib to clear malignant leukemia in tire bone marrow of Example G, a relapsed/refractory AML patient with FLT3-ITD mutation and complex karyotype with prior TKI failure after treatment with salvage chemotherapy and crenolanib besylate.
Days on Clinical Trial | Bone Marrow Blast (%) |
0 | 19% |
20 | <5% |
Example H: Effect of Crenolanib Besylate Therapy in a Relapsed/Refractory AML Patient with a FLT3-ITD mutation and Complex Karyotype: Achievement of réduction in bone marrow blasts to less than 1·% with hématologie recovery.
A 48-year-old female was diagnosed with AML positive for a FLT3-ITD mutation and normal 1· female karyotype and initially treated with induction chemotherapy. Approximately seven months later, tlie patient relapsed and received multiple salvage thérapies including chemotherapy and the tyrosine kinase inhibitor, sorafanib. The patient did not respond to these thérapies and had 46% bone marrow blasts following treatment, which blasts were positive for FLT3-ITD, FLT3-TKD, NPM1, DNMT3A, and WT1 mutations. Presence of concurrent FLT3-ITD, NPM1, and DNMT3A mutations and a WT1 mutation both placed the patient in a high-risk group. The patient was further shown to exhibit an abnormal complex karyotype characterized by translocations (1;6), (4:,19), and (1·;15). As complex karyotype has been characterized as an independent driver mutation separate and apart from other driver mutations characteristic of AML (such as the patient’s FLT3 mutational status) and has itself been associated with a poor prognosis, the patient’s présentation of thèse three sets of charactcristics placed 2· her in a significantly higher risk group.
The patient was then provided with oral crenolanib besylate of single-agent crenolanib in relapsed or refractory AML patients (NCT#1657682). The patient began therapy with 2·· mg/m2 per day of crenolanib besylate.
A bone marrow biopsy taken on day 29 of the clinical trial revealed the patient’s bone marrow 25 blasts had reduced to 7%, classified as a partial remission.
Table H below illustrâtes the ability of crenolanib to significantly reduce malignant leukemia in the bone marrow of Example H, a relapsed/refractory AML patient with FLT3-ITD and WT1 mutations and complex karyotype with prior TKI failure.
Days on Clinical Trial | Bone Marrow Blast (%) |
~........................................................ _____ .......................... | ........................................................ _______................. ............... |
3·
It is contemplated that any embodiment discussed in this spécification can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.
It will be understood that particular embodiments described herein are shown by way of illustration 5 and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine expérimentation, numerous équivalents to the spécifie procedures described herein. Such équivalents are considered to be within the scope of this invention and are covered by the claims.
1· Ail publications and patent applications mentioned in the spécification are indicative of the level of skill of those skilled in the art to which this invention pertains. Ail publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was spccifically and individually indicatcd to be incorporated by reference.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims 15 and/or the spécification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a définition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the inhérent variation of error for 2· the device, the method being employed to déterminé the value, or the variation that exists among the study subjects.
As used in this spécification and claims, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “hâve” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form 25 of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited éléments or method steps. In embodiments of any of the compositions and methods provided herein, “comprising” may be replaced with “consisting essentially of’ or “consisting of’. As used herein, the phrase “consisting essentially of’ requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention. As used herein, the 3· term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), propertie(s), method/process steps or limitation(s)) only.
The term “or combinations thereof’ as used herein refers to ail permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof’ is intended to 35 include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC,
AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.
As used herein, words of approximation such as, without limitation, “about”, substantial or 5 substantially refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating die condition as being présent The extent to which the description may vary will dépend on how great a change can be instituted and still hâve one of ordinary skilled in the art recognize the modified feature as still having the rcquired charactcristics and capabilities of flic unmodificd feature. In general, but subject 1· to the preceding discussion, a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ±1, 2, 3, 4, 5, 6, 7, 1·, 12 or 15%.
Ail of the compositions and/or methods disclosed and claimed herein can be made and executed without undue expérimentation in light of the présent disclosure. While the compositions and methods of this invention hâve been described in terms of preferred embodiments, it will be apparent to those of skill 15 in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. Ail such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended daims.
For each of the daims, each dépendent claim can dépend both from the independent claim and from 2· each ofthe prior dépendent daims for each and every claim so long as the prior claim provides a proper antécédent basis for a claim term or element.
REFERENCES
DREXLER, et al. Expression of FLT3 receptor and response to FLT3 ligand by leukemic cells Leukemia. April 1·, 1996; 1·:588-599 (ABSTRACT ONLY)
GILLILAND, et al. The rôles of FLT3 in hematopoiesis and leukemia. Blood. Sept. 1, 2M2;
1··: 1532-1542
STIREWALT, et al. The rôle of FLT3 in hacmatopoictic malignancies Nature Rcvicws Cancer. 2··3; 3:65·-665
NAKAO, et al. ABSTRACT ONLY : Internai tandem duplication of tire FLT3 gene found in acute 3· myeloid leukemia. Leukemia. 1996; 1 ·: 1911-1918
KIYOI, et al. Internai tandem duplication of the FLT3 gene is a novel modality of élongation mutation which causes constitutive activation of the product Leukemia. 1998; 12:1333-1337
KOTTARIDIS, et al. The présence of a FLT3 internai tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response 35 to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Counsel AML 1· and 12 trials Blood. Sept. 15, 2··!; 98: 1742-1759
YAMAMOTO, et al. Activating mutation of D835 within the activation loop of FLT3 in human hématologie malignancies Blood. 2M1; 972434-2439
THIEDE, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis Blood.
2M2; 99:4326-4335
BAINS, et al. FLT3 and NPMl mutations in myelodysplastic syndromes: Frequency and potential value for predicting progression to acute myeloid leukemia American Journal of Clinical Pathology. Januaiy 2·11; 135: 62-69
BHAMIDPAT1, et al. FLT3 mutations in myelodysplastic syndromes (MDS) and chronic 1· myelomonocytic leukemia (CMML). 2·12. Journal of Clinical Oncology. Suppl; abstract 6597
ΚΓΥΟΙ, et al. Internai tandem duplication of FLT3 associated with leukocytosis in acute promyelocytic leukemia Leukemia Study Group of the Ministry of Health and Welfare (Kohseisho). Leukemia. 1997;11:1447-1452
SCHN1T1GER, et al. Analysis of FLT3 length mutations in 1M3 patients with acute myeloid 15 leukemia: corrélation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the détection of minimal residual disease Blood. 2··2; 1··: 59-66
ABU-DUHIER, et al. FLT3 internai tandem duplication mutations in adult acute myeloid leukemia defme a higli-risk group” British Journal of Hematology. June 7, 2···; 111: 191-195
KIYOI et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid 2· leukemia Blood. May 1,1999; 93:3·74-3·8·
BACHER, et al. Prognostic relevance of FLT3-TKD mutations in AML: the combination matters - an analysis of 3·82 patients Blood. March 1, 2··8; 111:2527-2537
KINDLER, et al. FLT3 as a therapeutic target in AML: still challenging after ail these years Blood. Dec. 9, 2·1·; 116:5·89-1·2
LEVIS, et al. A FLT3 tyrosine kinase inhibitor is selectively cytotoxic to acute myeloid leukemia blasts harboring FLT3 internai tandem duplication mutations Blood. August 1, 2M1; 98(3): 885-887
SMITH, et al. Single agent CEP-7·!, a novel FLT3 inhibitor, shows biologie and clinical activity in patients with relapsed or refractory acute myeloid leukemia Blood, May 2··4; 1·3: 3669-3676
GRISWOLD, et al. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant 3· hematopoiesis Blood. Nov. 2··4; 1·4 (9): 2912-2918
YEE, et al., SU5416 and SU5614 inhibit kinase activity of wild-type and mutant FLT3 receptor tyrosine kinase. Blood, Oct 2··2; 1··(8): 2941-2949
O’Farrell et al., SU 11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood, May 2··3; 1·1(9): 3597-36·5
Murata, K. et al., Sélective cytotoxic mechanism of GTP-14564, a novel tyrosine kinase inhibitor in leukemia cells expressing a constitutively active Fms-like tyrosine kinase 3 (FLT3). J Biol Chem. Aug. 29, 2··3; 278 (35): 32892-32898 [Epub 2··3 Jun 18]
Stone, R. M et al., PKC-412 FLT3 inhibitor therapy in AML: results of a phase II trials. Ann.
Hematol. 2M4; 83 Suppl 1 :S89-9·
CHESON, et al. Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia J Clin Oncol. Dec. 15,2··3; 21: 4642-4649
LEVIS, et al. Small Molcucle FLT3 Tyrosine Kinase Inhibitors Current Pharmaceutical Design. 1· 2··4, 1·, 1183-1193
BORTHAKUR, et aL Phase I study of sorafenib in patients with refractory or relapsed acute leukemias. Hacmatologica. Jan. 2·11; 96: 62-8. EpubOct. 15, 2·1·
Small D. FLT3 mutations: biology and treatment. Hematology Am Soc Hematol Educ Program. 2M6: 178-84
AMIN, et al. Having a higher blast percentage in circulation than bone marrow; clinical implications in myelodysplastic syndrome and acute lymphoid and myeloid leukemias Leukemia. July 28, 2··5: 19: 1567-72
VANDERWALDE, A., “Genetics of Acute Myeloid Leukemia,” available at http://emedicinc.medscape.com/articlc/1936e33-ovcrview (lastupdated 1 Apr. 2·16)
2· PAPAEMMANUIL, E., “Genomic Classification and Prognosis in Acute Myeloid Leukemia,” New England J. Med. Vol. 374, No. 23, pp. 22·9-2221 (9 June 2·16)
DOHNER, H., et al. “Diagnosis and management of AML in adults: 2·17 ELN recommendations from an international expert panel,” Blood. Vol. 129, No. 3, pp. 424-447 (28 Nov. 2·16).
BAKSHI, S., et al. “Trisomy 8 in leukemia: A GCRI expérience,” Indian J Hum Genet. 25 2·12;18:1·6-1·8.
LEWIS, et al. Phase I study of the safety, tolcrability, and pharmacokinctics of oral CP-868-596, a highly spécifie platelet-derived growth factor receptor tyrosine kinase inhibitor in patients with advanced cancers J Clin Oncol. Nov. 1, 2··9; 27(31), 5262-5269
CORTES, et al. AC22·, a potent, sélective, second génération FLT3 receptor tyrosine kinase 3· (RTK) inhibitor, in a first-in-human (F1H) phase 1 AML study Blood (ASH Annual Meeting Abstracts) 2M9 Nov.
CORTES, et al. A phase II open-label, AC22· monotherapy efFicacy study in patients with refractoiy/relapsed FLT3-ITD positive acute myeloid leukemia: updated intérim results Blood (ASH Annual Meeting Abstracts) 2·11 Dec
3·
MENDLER, J., “RUNX1 Mutations Are Associated With Poor Outcome in Younger and Older Patients With Cytogenetically Normal Acute Myeloid Leukemia and With Distinct Gene and MicroRNA Expression Signatures,” J. Clin. Oncol. Vol. 3·, No. 25, pp. 31*9-3118 (2 July 2*12)
DICKER, F., et al. “Trisomy 13 is strongly associated with AMLI/RUNXI mutations and 5 increased FLT3 expression in acute myeloid leukemia,” Blood. 2··7;11·: 13*8-1316.
HEROLD, T., et al. “Isolated trisomy 13 defines a homogeneous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis,” Blood. 2*14; 124:13*4-1311.
LEVIS, M., et al. “Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse,” Blood. 2*11;117:3294-33*1.
1* PASCHKA, P., et al. “Wilms’ Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study,” J Clin Oncol. 2**8;26:4595-46*2.
Claims (5)
1. A method for treating a FLT3 mutated proliférative disorder comprising:
measuring expression of a mutated FLT3 or a constitutively active FLT3 mutant, and one or more genctic abnormalitics in a sample obtained from a tumor sample obtained from tire patient, wherein 5 the presence of the one or more genetic abnormalities indicates that the patient has a poor prognosis; and administering to the patient a tlierapeutically effective amount of crenolanib or a phannaceutically acceptable sait thereof, wherein the crenolanib increases a chance of survival of the patient having both the mutated FLT3 or the constitutively active FLT3 mutant and the one or more genetic abnormalities.
1· 2. The method of claim 1, wherein tire one or more genetic abnormalities are selected from at least one of a mutation in the RUNX1 or WT1 genes.
3. The method of claims 1 or 2, wherein the one or more genetic abnormalities is comprised of mutations in the FLT3-ITD, DNMT3A, andNPMl genes.
4. The method of claims 1 to 3, wherein the one or more genetic abnormalities is at least one of 15 trisomy 8 or trisomy 13.
5. The method of claims 1 to 4, wherein the proliférative disorder is selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, nasopharyngeal cancer, neuroendocrine cancer, 2· ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy.
6. The method of claims 1 to 5, wherein the additional genetic abnormality is an aneuploidy, monosomy, trisomy, or polysomy.
25 7. The method of claims 1 to 6, wherein the one or more genetic abnormalities is a chromosomal aberration, a chromosomal délétion, a chromosomal duplication, a chromosomal translocation, a chromosomal inversion, a chromosomal insertion, a chromosomal ring, or an isochromosome.
8. The method of claüns 1 to 7, wherein the one or more genetic abnormalities is a driver mutation in addition to the mutated FLT3.
3# 9. The method of claim 8, wherein the driver mutation is selected from at least one of NPM1,
DNMT3A, NRAS, KRAS, JAK2, PTPN11, TET2, IDH1, IDH2, WT1, RUNX1, CEBPA, ASXL1, BCOR, SF3B1, U2AF1, STAG2, SETBP1, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCL1A, TUSC3, BRP1, CD36, TYK2, or MUTYH.
1·. The method of claims 1 to 9, wherein the tlierapeutically effective amount of crenolanib or the 35 phannaceutically acceptable sait thereof are from about 5· to 5·· mg per day, 1·· to 45· mg per day, 2·· to 4·· mg per day, 3·· to 5·· mg per day, 35· to 5·· mg per day, or 4·· to 5·· mg per day; or
the therapeutically effective amount of crenolanib or the pharmaceutically acceptable sait thereof is administered at least one of continuously, intermittently, systemically, or locally; or the therapeutically effective amount of crenolanib or the pharmaceutically acceptable sait thereof is administered orally, intravenously, or intraperitoneally.
5 11. The method of claims 1 to 1·, wherein the crenolanib or the pharmaceutically acceptable sait thereof is crenolanib besylate, crenolanib phosphate, crenolanib lactate, crenolanib hydrochloride, crenolanib citrate, crenolanib acetate, crenolanib toluenesulphonate, and crenolanib succinate.
12. The method of claims 1 to 11, wherein the therapeutically effective amount of crenolanib or the pharmaceutically acceptable sait thereof is:
1· administered up to three times or more a day for as long as the subject is in need of treatment for the proliférative disorder; or provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed proliférative disorder patient, to maintain remission of an existing patient, or in a relapsed/refractory proliférative disorder patient; or
15 provided as a single agent or in combination with another pharmaceutical agent in a patient with a newly diagnosed proliférative disorder, to maintain remission, or in a relapsed/refractory proliférative disorder patient; or provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disorder pédiatrie patient, to maintain remission, or in a relapsed/refractory 2· proliférative disorder pédiatrie patient.
13. The method of claims 1 to 12, wherein the patient is relapsed/refractory to another tyrosine kinase inhibitor or chemotherapy.
14. A method for treating a patient suffering from a proliférative disease comprising:
identifying the patient in need of therapy for the proliférative disease and administering to the 25 patient a therapeutically effective amount of Crenolanib or a sait thereof, wherein the proliférative disease is characterized by deregulated FLT3 receptor tyrosine kinase activity; wherein the proliférative disease is selected from at least one of a leukemia, myeloma, myeloproliferative disease, myelodysplastic syndrome, idiopathic hyperéosinophilie syndrome (HES), bladder cancer, breast cancer, cervical cancer, CNS cancer, colon cancer, esophageal cancer, head and neck cancer, liver cancer, lung cancer, 3· nasopharyngeal cancer, neuroendocrine cancer, ovarian cancer, pancreatic cancer, prostate cancer, rénal cancer, salivary gland cancer, small cell lung cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, uterine cancer, and hématologie malignancy; and wherein the patient comprises both a deregulated FLT3 receptor tyrosine kinase and one or more genetic abnormalities, wherein the présence of the one or more genetic abnormalities indicates that tire
35 patient has a poor prognosis and the Crenolanib or a sait thereof increases a chance of survival of the patient having both the mutated FLT3 and the one or more genetic abnormalities.
15. The method of claim 14, wherein the FLT3 mutation is selected from at least one of FLT3-ITD or FLT3-TKD.
16. The method of claims 14 or 15, wherein the one or more genetic abnormalities is an aneuploidy, monosomy, trisomy, or polysomy.
17. The method of claims 14 to 16, wherein the one or more genetic abnormalities is a chromosomal aberration, a chromosomal délétion, a chromosomal duplication, a chromosomal translocation, a 5 chromosomal inversion, a chromosomal insertion, a chromosomal ring, or an isochromosome.
18. The method of claims 14 to 17, wherein the one or more genetic abnormalities include a driver mutation that is selected from at least one of NPM1, DNMT3A, NRAS, KRAS, JAK2, PTPN11, TET2, IDH1, IDH2, WT1, RUNXl, CEBPA, ASXL1, BCOR, SF3B1, U2AF1, STAG2, SETBP1, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCL1 A, TUSC3, BRP1, CD36, TYK2, or MUTYH.
1· 19. The method of claims 14 to 18, wherein the therapeutically effective amount of crenolanib or the pharmaceutically acceptable sait thereof is administered orally, intravenously, or intraperitoneally.
2·. The method of claims 14 to 19, wherein the therapeutically effective amount of crenolanib or the pharmaceutically acceptable sait thereof is:
at least one of Crenolanib Besylate, Crenolanib Phosphate, Crenolanib Lactate, Crenolanib 15 Hydrochloride, Crenolanib Citrate, Crenolanib Acetate, Crenolanib Touluenesulphonate and Crenolanib Succinatc; or is provided at least one of sequentially or concomitantly, with a chemotherapeutic agent in a newly diagnosed proliférative disease, to maintain remission, or a relapsed/refractory proliférative disease; or
2· is provided as a single agent or in combination with a chemotherapeutic agent for treatment of pédiatrie patient with the proliférative disease; or is provided at least one of sequentially or concomitantly to at least one of post standard induction therapy, or high dose induction therapy, in newly diagnosed proliférative disease; or is provided as a single agent in treatment of patients with the proliférative disease that is either 25 refractory to, or has relapsed after prior treatment with a chemotherapeutic agent.
21. Tire method of claims 14 to 2·, wherein the patient is refractory to at least one other tyrosine kinase inhibitor or a chemotherapy.
22. A method for treating a patient suffering from leukemia comprising:
obtaining a sample from tire patient suspected of having leukemia;
3· determining from the patient sample tirât the patient has a deregulated FLT3 receptor or a constitutively active FLT3 receptor;
further determining if the patient’s leukemia is also characterized by an additional genetic abnonnality; and administering to the patient in need of such treatment a therapeutically effective amount of 35 crenolanib or a sait thereof, wherein the leukemia is characterized by the deregulated FLT3 receptor or tire constitutively active FLT3 receptor and one or more genetic abnormalities causing a poor prognosis, wherein the crenolanib increases a chance of survival of the patient having both the deregulated FLT3 receptor or tire constitutively active FLT3 receptor and the one or more genetic abnormalities.
23. The method of claim 22, wherein the leukemia is selected from: Hodgkin’s disease; a myeloma; acute promyelocytic leukemia (APL); chronic lymphocytic leukemia (CLL); chronic myeloid leukemia (CML); chronic neutrophilie leukemia (CNL); acute undifferentiated leukemia (AUL); anaplastic largecell lymphoma (ALCL); prolymphocytic leukemia (PML): juvénile myelomonocytic leukemia (JMML):
5 adult T-cell ALL; acute myelogenous leukemia (AML), with trilineage myelodysplasia (AMLITMDS); mixed lineage leukemia (MLL); myelodysplastic syndromes (MDSs); myeloproliferative disorders (MPD); and multiple myeloma (MM).
24. The method of daims 22 or 23, wherein the FLT3 mutation is selected from at least one of FLT3-
ITD or FLT3-TKD.
I· 25. The method of daims 22 to 24, wherein the one or more gcnetic abnormalities is an aneuploidy, monosomy, trisomy, or polysomy.
26. The method of daims 22 to 25, wherein the one or more genetic abnormalities is a chromosomal aberration, a chromosomal délétion, a chromosomal duplication, a chromosomal translocation, a chromosomal inversion, a chromosomal insertion, a chromosomal ring, or an isochromosome.
15 27. The method of daims 22 to 26, wherein the one or more genetic abnormalities include a driver mutation that is selected from at least one of NPM1, DNMT3A, NRAS, KRAS, JAK2, PTPN11, TET2, 1DH1, 1DH2, WT1, RUNX1, CEBPA, ASXL1, BCOR, SF3B1, U2AF1, STAG2, SETBP1, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCL1 A, TUSC3, BRP1, CD36, TYK2, or MUTYH.
28. A method for specifically inhibiting a deregulated or constitutively active receptor tyrosine 2· kinase, comprising:
obtaining a sample;
determining which receptor tyrosine kinases are deregulated or constitutively active;
determining which of one or more genetic abnormalities are présent;
determining that dre deregulated or constitutively active receptor tyrosine kinase and the one or 25 more genetic abnormalities cause a poor prognosis; and administering to a mammal in need of such treatment a therapeutically effective amount of crenolanib or a sait thereof, wherein the crenolanib increases a chance of survival of the mammal having both tire deregulated FLT3 receptor or the constitutively active FLT3 receptor and the one or more genetic abnormalities.
3· 29. The method of claim 28, wherein the deregulated FLT3 receptor is selected from at least one of
FLT3-ITD or FLT3-TKD.
3·. The method of daims 28 or 29, wherein the one or more genetic abnormalities is an aneuploidy, monosomy, trisomy, or polysomy.
31. The method of daims 28 to 3·, wherein the one or more genetic abnormalities is a chromosomal
35 aberration, a chromosomal délétion, a chromosomal duplication, a chromosomal translocation, a chromosomal inversion, a chromosomal insertion, a chromosomal ring, or an isochromosome.
32. The method of claims 28 to 31, wherein the one or more genetic abnormalities include a driver mutation that is selected from at least one of NPM1, DNMT3A, NRAS, KRAS, JAK2, PTPN11, TET2, IDH1, IDH2, WT1, RUNX1, CEBPA, ASXL1, BCOR, SF3B1, U2AF1, STAG2, SETBP1, ZRSR2, GRB7, SRSF2, MLL, NUP98, ETV6, TCL1 A, TUSC3, BRP1, CD36, TYK2, or MUTYH.
5 33. The method of claim 28, wherein the therapeutically effective amount of crenolanib or the sait thereof is provided:
in an amount that decreases a patient’s circulating peripheral blood blast count; or in an amount that decreases a patient’s bone marrow blast count; or in an amount from about 5· to 5·· mg per day, 1·· to 45· mg per day, 2·· to 4·· mg per day, 1· 3·· to 5·· mg per day, 35· to 5Wmg per day, or 4·· to 5·· mg perday; or in an amount that is delivered at least one of continuously, intermittently, systemically, or locally.
34. The method of claims 28 to 33, wherein the therapeutically effective amount of crenolanib or the sait thereof is administered orally, intravenously, or intraperitoneally.
35. The method of claim 28, wherein tire Crenolanib or the sait thereof is at least one of Crenolanib 15 Besylate, Crenolanib Phosphate, Crenolanib Lactate, Crenolanib Hydrochloride, Crenolanib Citrate, Crenolanib Acetate, Crenolanib Touluenesulphonate and Crenolanib Succinate.
36. The method of claims 28 to 34, wherein the therapeutically effective amount of crenolanib or the sait thereof is at least one of:
administered up to three times or more a day for as long as the subject is in need of treatment; or 2· is provided at least one of sequentially or concomitantly, with another pharmaceutical agent in a newly diagnosed proliférative disease patient, to maintain remission, or in a relapsed/refractory proliférative disease patient; or the crenolanib or the sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disease patient, to maintain remission, or in a 25 relapsed/refractory proliférative disease patient; or the therapeutically effective amount of crenolanib or the sait thereof is provided as a single agent or in combination with another pharmaceutical agent in a newly diagnosed proliférative disease pédiatrie patient, to maintain remission, or in a relapsed/refractory proliférative disease pédiatrie patient.
37. The method of claims 28 to 36, wherein tire patient is relapsed/refractory to a prior tyrosine 3· kinase inhibitor.
38. A metiiod for treating a FLT3 mutated proliférative disorder in a patient, which comprises administering to the patient a therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof, wherein the patient has a QT interval (QTcF) > 45· msec.
39. The method of claim 38, wherein tire crenolanib is administered sequentially or concomitantly 35 with another agentknown to prolong the patient’s QT interval.
4·. Tire method of claims 38 to 39, wherein die agent is a 5-HT3 antagonist.
41. The method of claim 4·, wherein the 5-HT3 antagonist is granisetron, odansetron, or dolasetron.
42. The method of claim 38, wherein the agent is one of itraconazole, kétoconazole, fluconazole, miconazole, posaconazole, omeprazole, esomeprazole, pantoprazole, voriconaprazole, metronidazole, haloperidol, pentamidine, amiodarone, ciprofloxacin, levofloxacin, moxifloxacin, azithromycin, and tacrolimus.
5 43. A method for treâting a FLT3 mutated proliférative disorder in a patient, which comprises administering to the patient a therapeutically effective amount of crenolanib or a pharmaceutically acceptable sait thereof, wherein the patient also has a heart condition and the crenolanib does not negatively impact the heart condition.
44. The method of claim 43, wherein the heart condition is one of hypertension, angina, acute 1 · myocardial infarction, subacute myocardial infarction, or arrhythmia.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62/416,475 | 2016-11-02 | ||
US15/799,684 | 2017-10-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA19291A true OA19291A (en) | 2020-06-05 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11078541B2 (en) | Crenolanib for treating FLT3 mutated proliferative disorders associated mutations | |
US20220175752A1 (en) | Methods of Treating Ovarian Cancer | |
US20200338083A1 (en) | Combination therapies | |
US11007188B2 (en) | Crenolanib for treating FLT3 mutated proliferative disorders | |
Liu et al. | Small molecule inhibitors targeting the cancers | |
CA2824480A1 (en) | Anticancer therapy with dual aurora kinase / mek inhibitors | |
US8937095B2 (en) | Anticancer compounds | |
US20230000856A1 (en) | Novel uses of crenolanib | |
Park et al. | Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation | |
OA19291A (en) | Crenolanib for treating FLT3 mutated proliferative disorders associated mutations. | |
US20210251980A1 (en) | Crenolanib for treating flt3 mutated proliferative disorders associated mutations | |
US20210145823A1 (en) | Crenolanib for treating flt3 mutated proliferative disorders associated mutations | |
WO2019039390A1 (en) | Juvenile myelomonocytic leukemia therapeutic agent | |
US20220218694A1 (en) | Crenolanib for treating flt3 mutated proliferative disorders associated mutations | |
WO2021255518A1 (en) | Compositions and methods for treating acute myeloid leukemia | |
OA18036A (en) | Crenolanib for treating FLT3 mutated proliferative disorders. |