NZ791442A - Dosage regimen for treatment of solid tumors - Google Patents
Dosage regimen for treatment of solid tumorsInfo
- Publication number
- NZ791442A NZ791442A NZ791442A NZ79144217A NZ791442A NZ 791442 A NZ791442 A NZ 791442A NZ 791442 A NZ791442 A NZ 791442A NZ 79144217 A NZ79144217 A NZ 79144217A NZ 791442 A NZ791442 A NZ 791442A
- Authority
- NZ
- New Zealand
- Prior art keywords
- dose
- cancer
- administered
- hydrate
- compound
- Prior art date
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 74
- 201000011510 cancer Diseases 0.000 claims abstract description 77
- 238000011068 load Methods 0.000 claims abstract description 75
- 239000011780 sodium chloride Substances 0.000 claims abstract description 62
- 150000003839 salts Chemical class 0.000 claims abstract description 61
- 239000003246 corticosteroid Substances 0.000 claims abstract description 33
- 150000001875 compounds Chemical class 0.000 claims description 62
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 54
- DNSISZSEWVHGLH-UHFFFAOYSA-N Butyramide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims description 53
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 49
- 239000003814 drug Substances 0.000 claims description 27
- 208000005017 Glioblastoma Diseases 0.000 claims description 15
- 206010024190 Leiomyosarcomas Diseases 0.000 claims description 15
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 15
- 201000005202 lung cancer Diseases 0.000 claims description 15
- 201000010536 head and neck cancer Diseases 0.000 claims description 14
- 201000007270 liver cancer Diseases 0.000 claims description 14
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 13
- 206010025650 Malignant melanoma Diseases 0.000 claims description 13
- 206010039491 Sarcoma Diseases 0.000 claims description 13
- 201000010881 cervical cancer Diseases 0.000 claims description 13
- 201000001441 melanoma Diseases 0.000 claims description 13
- 201000000849 skin cancer Diseases 0.000 claims description 13
- 206010006187 Breast cancer Diseases 0.000 claims description 12
- 206010059352 Desmoid tumour Diseases 0.000 claims description 12
- 201000006827 desmoid tumor Diseases 0.000 claims description 12
- 208000006990 Cholangiocarcinoma Diseases 0.000 claims description 11
- 208000000172 Medulloblastoma Diseases 0.000 claims description 11
- 208000002154 Non-Small-Cell Lung Carcinoma Diseases 0.000 claims description 11
- 108009000071 Non-small cell lung cancer Proteins 0.000 claims description 11
- 208000008443 Pancreatic Carcinoma Diseases 0.000 claims description 11
- 201000002740 oral squamous cell carcinoma Diseases 0.000 claims description 11
- 201000002528 pancreatic cancer Diseases 0.000 claims description 11
- 206010073071 Hepatocellular carcinoma Diseases 0.000 claims description 10
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N Prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 claims description 10
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 claims description 10
- 201000011231 colorectal cancer Diseases 0.000 claims description 10
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 10
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 229960004618 prednisone Drugs 0.000 claims description 9
- 208000002517 Adenoid Cystic Carcinoma Diseases 0.000 claims description 8
- 201000007416 salivary gland adenoid cystic carcinoma Diseases 0.000 claims description 8
- 201000009030 carcinoma Diseases 0.000 claims description 6
- 230000002611 ovarian Effects 0.000 claims description 5
- 210000000481 Breast Anatomy 0.000 claims description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims description 4
- 229960000890 hydrocortisone Drugs 0.000 claims description 4
- 101710034857 ATIC Proteins 0.000 claims description 3
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 claims description 3
- VHRSUDSXCMQTMA-PJHHCJLFSA-N Methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 claims description 3
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 3
- 210000003491 Skin Anatomy 0.000 claims description 3
- 229960003290 cortisone acetate Drugs 0.000 claims description 3
- 229960004584 methylprednisolone Drugs 0.000 claims description 3
- 229960005205 prednisolone Drugs 0.000 claims description 3
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 claims description 2
- 229960001067 hydrocortisone acetate Drugs 0.000 claims description 2
- 229960003114 tixocortol pivalate Drugs 0.000 claims 2
- BISFDZNIUZIKJD-XDANTLIUSA-N tixocortol pivalate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CSC(=O)C(C)(C)C)(O)[C@@]1(C)C[C@@H]2O BISFDZNIUZIKJD-XDANTLIUSA-N 0.000 claims 2
- YCBAQKQAINQRFW-UGSOOPFHSA-N 4,4,4-trifluoro-N-[(2S)-1-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-oxopropan-2-yl]butanamide Chemical compound OCCN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)CCC(F)(F)F)C)C2=CC=CC=C2C2=CC=CN=C21 YCBAQKQAINQRFW-UGSOOPFHSA-N 0.000 abstract 1
- 230000002354 daily Effects 0.000 description 34
- 241001465754 Metazoa Species 0.000 description 26
- 210000004027 cells Anatomy 0.000 description 19
- 231100000607 toxicokinetics Toxicity 0.000 description 19
- 230000002401 inhibitory effect Effects 0.000 description 15
- 230000004044 response Effects 0.000 description 15
- 210000004369 Blood Anatomy 0.000 description 13
- 239000008280 blood Substances 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 11
- 229940079593 drugs Drugs 0.000 description 11
- 230000003285 pharmacodynamic Effects 0.000 description 11
- 238000002600 positron emission tomography Methods 0.000 description 11
- 231100000419 toxicity Toxicity 0.000 description 11
- 230000001988 toxicity Effects 0.000 description 11
- 241000282472 Canis lupus familiaris Species 0.000 description 10
- 230000000275 pharmacokinetic Effects 0.000 description 10
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 9
- 206010033128 Ovarian cancer Diseases 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 108009000163 Notch Signaling Proteins 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 150000002500 ions Chemical class 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 102000014736 Notch Human genes 0.000 description 7
- 108050005080 Notch Proteins 0.000 description 7
- 235000012631 food intake Nutrition 0.000 description 7
- 238000003384 imaging method Methods 0.000 description 7
- 230000000968 intestinal Effects 0.000 description 7
- 230000001594 aberrant Effects 0.000 description 6
- 231100000682 maximum tolerated dose Toxicity 0.000 description 6
- 230000001225 therapeutic Effects 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 241000700159 Rattus Species 0.000 description 5
- 230000003247 decreasing Effects 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 230000003442 weekly Effects 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 4
- 210000003141 Lower Extremity Anatomy 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 210000002307 Prostate Anatomy 0.000 description 4
- 230000002411 adverse Effects 0.000 description 4
- 239000000090 biomarker Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 230000002496 gastric Effects 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 230000036210 malignancy Effects 0.000 description 4
- 108010082117 matrigel Proteins 0.000 description 4
- 230000000116 mitigating Effects 0.000 description 4
- 238000003305 oral gavage Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000010254 subcutaneous injection Methods 0.000 description 4
- 239000007929 subcutaneous injection Substances 0.000 description 4
- 210000001519 tissues Anatomy 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 230000035533 AUC Effects 0.000 description 3
- 210000000349 Chromosomes Anatomy 0.000 description 3
- 230000037242 Cmax Effects 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 210000003608 Feces Anatomy 0.000 description 3
- 206010061289 Metastatic neoplasm Diseases 0.000 description 3
- 210000001744 T-Lymphocytes Anatomy 0.000 description 3
- 230000035852 Tmax Effects 0.000 description 3
- 210000002700 Urine Anatomy 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000001154 acute Effects 0.000 description 3
- 230000002730 additional Effects 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 230000000259 anti-tumor Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003540 gamma secretase inhibitor Substances 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 230000001394 metastastic Effects 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing Effects 0.000 description 3
- 238000004450 types of analysis Methods 0.000 description 3
- 235000003197 Byrsonima crassifolia Nutrition 0.000 description 2
- 240000001546 Byrsonima crassifolia Species 0.000 description 2
- 229940063834 Carboxymethylcellulose Sodium Drugs 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 229940064701 Corticosteroid nasal preparations for topical use Drugs 0.000 description 2
- 229960001334 Corticosteroids Drugs 0.000 description 2
- 206010011906 Death Diseases 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 206010015281 Erythroleukaemia Diseases 0.000 description 2
- 210000002175 Goblet Cells Anatomy 0.000 description 2
- 208000009503 Leukemia, Erythroblastic, Acute Diseases 0.000 description 2
- 229940068968 Polysorbate 80 Drugs 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 206010041823 Squamous cell carcinoma Diseases 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 102000004965 antibodies Human genes 0.000 description 2
- 108090001123 antibodies Proteins 0.000 description 2
- 239000002518 antifoaming agent Substances 0.000 description 2
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000002759 chromosomal Effects 0.000 description 2
- 231100000005 chromosome aberration Toxicity 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 201000003963 colon carcinoma Diseases 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 201000008286 diarrhea Diseases 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 230000004049 epigenetic modification Effects 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 230000002068 genetic Effects 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 230000002503 metabolic Effects 0.000 description 2
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000003325 tomography Methods 0.000 description 2
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 2
- 230000036269 ulceration Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GDBQQVLCIARPGH-ULQDDVLXSA-N (2S)-2-acetamido-N-[(2S)-1-[[(2S)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- ZYZCGGRZINLQBL-JCGNTXOTSA-N (5R,8R,11R,12S,15S,18S,19S,22R)-15-[3-(diaminomethylideneamino)propyl]-18-[(1E,3E,5S,6S)-6-methoxy-3,5-dimethyl-7-phenylhepta-1,3-dienyl]-1,5,12,19-tetramethyl-2-methylidene-8-(2-methylpropyl)-3,6,9,13,16,20,25-heptaoxo-1,4,7,10,14,17,21-heptazacyclopenta Chemical compound C([C@H](OC)[C@@H](C)\C=C(/C)\C=C\[C@H]1[C@@H](C(=O)N[C@H](CCC(=O)N(C)C(=C)C(=O)N[C@H](C)C(=O)N[C@H](CC(C)C)C(=O)N[C@H]([C@H](C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1)C(O)=O)C(O)=O)C)C1=CC=CC=C1 ZYZCGGRZINLQBL-JCGNTXOTSA-N 0.000 description 1
- VHJLVAABSRFDPM-UHFFFAOYSA-N 1,4-dimercaptobutane-2,3-diol Chemical compound SCC(O)C(O)CS VHJLVAABSRFDPM-UHFFFAOYSA-N 0.000 description 1
- WRDABNWSWOHGMS-UHFFFAOYSA-N 2-(4-fluorosulfonylphenyl)ethylazanium;chloride Chemical compound Cl.NCCC1=CC=C(S(F)(=O)=O)C=C1 WRDABNWSWOHGMS-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl dihydrogen phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- 101700000782 ABL1 Proteins 0.000 description 1
- MGSKVZWGBWPBTF-UHFFFAOYSA-N AEBSF Chemical compound NCCC1=CC=C(S(F)(=O)=O)C=C1 MGSKVZWGBWPBTF-UHFFFAOYSA-N 0.000 description 1
- 230000036443 AUC0-24hr Effects 0.000 description 1
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 description 1
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 108010039627 Aprotinin Proteins 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 241000288575 Astomaea Species 0.000 description 1
- 101710022987 BBBI Proteins 0.000 description 1
- 238000000035 BCA protein assay Methods 0.000 description 1
- PXXJHWLDUBFPOL-UHFFFAOYSA-N Benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010009887 Colitis Diseases 0.000 description 1
- 230000007067 DNA methylation Effects 0.000 description 1
- 230000033616 DNA repair Effects 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 229940109526 Ery Drugs 0.000 description 1
- 206010015548 Euthanasia Diseases 0.000 description 1
- 230000036826 Excretion Effects 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 210000003736 Gastrointestinal Contents Anatomy 0.000 description 1
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 1
- 101700051067 ITC Proteins 0.000 description 1
- ZPNFWUPYTFPOJU-LPYSRVMUSA-N Iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 210000004347 Intestinal Mucosa Anatomy 0.000 description 1
- 206010073095 Invasive ductal breast carcinoma Diseases 0.000 description 1
- 102100005748 KRT18 Human genes 0.000 description 1
- 108010066327 Keratin-18 Proteins 0.000 description 1
- 206010024324 Leukaemias Diseases 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 230000036091 Metabolic activity Effects 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 206010027476 Metastasis Diseases 0.000 description 1
- 210000003097 Mucus Anatomy 0.000 description 1
- 206010028549 Myeloid leukaemia Diseases 0.000 description 1
- MQUQNUAYKLCRME-UHFFFAOYSA-N N-(4-chloro-3-oxo-1-phenylbutan-2-yl)-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-UHFFFAOYSA-N 0.000 description 1
- MQUQNUAYKLCRME-INIZCTEOSA-N N-tosyl-L-phenylalanyl chloromethyl ketone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-INIZCTEOSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 1
- 230000005913 Notch signaling pathway Effects 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N Okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 210000002381 Plasma Anatomy 0.000 description 1
- 208000009052 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 230000036045 Renal clearance Effects 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- 229940035295 Ting Drugs 0.000 description 1
- YWDBSCORAARPPF-VWUMJDOOSA-N Tixocortol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CS)[C@@H]4[C@@H]3CCC2=C1 YWDBSCORAARPPF-VWUMJDOOSA-N 0.000 description 1
- FPKOPBFLPLFWAD-UHFFFAOYSA-N Trinitrotoluene Chemical compound CC1=CC=C([N+]([O-])=O)C([N+]([O-])=O)=C1[N+]([O-])=O FPKOPBFLPLFWAD-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000010380 Tumor Lysis Syndrome Diseases 0.000 description 1
- 206010045170 Tumour lysis syndrome Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- XXAXKCWOTRABOW-UHFFFAOYSA-N [1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]azanium;(4-nitrophenyl) phosphate Chemical compound OCC(N)(CO)CO.OCC(N)(CO)CO.OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XXAXKCWOTRABOW-UHFFFAOYSA-N 0.000 description 1
- CEGXZKXILQSJHO-AKNDJLBFSA-N [18F]C(=O)C[C@@H](O)[C@H](O)[C@H](O)CO Chemical compound [18F]C(=O)C[C@@H](O)[C@H](O)[C@H](O)CO CEGXZKXILQSJHO-AKNDJLBFSA-N 0.000 description 1
- 230000035507 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 201000005510 acute lymphocytic leukemia Diseases 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229960004405 aprotinin Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000035572 chemosensitivity Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000002596 correlated Effects 0.000 description 1
- 230000002559 cytogenic Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 230000002074 deregulated Effects 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- JIQFFACVQXXHMY-UHFFFAOYSA-N diaminomethylidene-[5-methoxy-4-[(4-methylphenyl)sulfonylamino]-5-oxopentyl]azanium;chloride Chemical compound Cl.NC(N)=NCCCC(C(=O)OC)NS(=O)(=O)C1=CC=C(C)C=C1 JIQFFACVQXXHMY-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- GFEYTWVSRDLPLE-UHFFFAOYSA-L dihydrogenvanadate Chemical compound O[V](O)([O-])=O GFEYTWVSRDLPLE-UHFFFAOYSA-L 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 230000035510 distribution Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 230000029578 entry into host Effects 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 230000003628 erosive Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000010195 expression analysis Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 201000002146 gastrointestinal system disease Diseases 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 244000144993 groups of animals Species 0.000 description 1
- 239000001963 growth media Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000003116 impacting Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 230000003902 lesions Effects 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 201000009673 liver disease Diseases 0.000 description 1
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 1
- 230000002934 lysing Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000003990 molecular pathway Effects 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000001613 neoplastic Effects 0.000 description 1
- 230000003448 neutrophilic Effects 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000036231 pharmacokinetics Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000865 phosphorylative Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000092 prognostic biomarker Substances 0.000 description 1
- 239000003531 protein hydrolysate Substances 0.000 description 1
- 230000000268 renotropic Effects 0.000 description 1
- 230000003248 secreting Effects 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 230000037394 skin elasticity Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Inorganic materials [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 230000000707 stereoselective Effects 0.000 description 1
- 230000000576 supplementary Effects 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000004876 tela submucosa Anatomy 0.000 description 1
- 230000030968 tissue homeostasis Effects 0.000 description 1
- 229960004631 tixocortol Drugs 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 239000000700 tracer Substances 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 238000002562 urinalysis Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- DHCLVCXQIBBOPH-UHFFFAOYSA-N β-glycerophosphoric acid Chemical compound OCC(CO)OP(O)(O)=O DHCLVCXQIBBOPH-UHFFFAOYSA-N 0.000 description 1
Abstract
dosing regimen comprising administering 4,4,4-trifluoro-N-[(1S)-2-[[(7S)-5-(2-hydroxyethyl)-6-oxo-7H-pyrido[2,3-d][3]benzazepin-7-yl]amino]-1-methyl-2-oxo-ethyl]butanamide or a pharmaceutically acceptable salt or hydrate thereof for treating a solid tumor cancer at a specified loading dose for a defined period of doses followed by a maintenance dose and optionally administering a corticosteroid during administration of the loading dose is provided. efined period of doses followed by a maintenance dose and optionally administering a corticosteroid during administration of the loading dose is provided.
Description
DOSAGE REGIMEN FOR TREATMENT OF SOLID TUMORS
This ation is a divisional of New Zealand patent application 750561, which
is the national phase entry in New Zealand of PCT international ation
(published as
herein by reference.
Notch signaling plays an important role during development and tissue
homeostasis. Dysregulation of Notch signaling due to mutation, amplification, or
overexpression of ligands and/or receptors, is implicated in a number of malignancies.
Inhibition of Notch signaling through inhibition of gamma secretase cleavage of the
Notch signaling pathway is a potential target for the development of cancer therapeutics.
4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide, or a pharmaceutically
acceptable salt or hydrate thereof, and methods of making and using this compound,
including for the treatment of T-cell acute blastic leukemia, acute lymphoblastic
leukemia, acute myelogenous ia, chronic myelogenous ia, erythroleukemia,
breast cancer, ovarian cancer, melanoma, lung cancer, pancreatic cancer, glioblastoma,
colorectal cancer, head and neck cancer, cervical cancer, prostate , liver cancer,
squamous cell carcinoma (oral), skin cancer and oblastoma are disclosed in WO
2013/016081. 4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide, or a pharmaceutically
acceptable salt or hydrate thereof, is being investigated in a phase 1 clinical trial and
expansion cohorts having a d molecular pathway alteration, or a tissue based
malignant tumor, and in combination with other ically identified anticancer agents
against specified tumor types and in a clinical trial in patients with T-cell acute
lymphoblastic ia or T-cell lymphoblastic lymphoma (T-ALL/T-LBL).
The most serious toxicities associated with gamma secretase inhibitors ing
the Notch y for treating cancer are gastrointestinal toxicities such as diarrhea
including mucoid enteropathy or mucoid gastroenteropathy. Rapid differentiation of
progenitor cells into secretory goblet cells in the intestinal crypts occurs after
administration of gamma secretase inhibitors. Notch signaling is required to maintain the
normal architecture of the intestinal epithelium. In vivo models have been used to
evaluate methods of ameliorating the gastrointestinal toxicity by administration of gamma
secretase inhibitors with intermittent dosing and co-administration of corticosteroids
Bender et al., Cancer Res., 2013, 73(8) Supplement, Abstract 1131. While meeting with
some success, suitable efficacy against solid tumor cancers with acceptable
gastrointestinal toxicities remains e. (Takebe et al., Pharmacology & Therapeutics,
2014, 141: 140-149).
The skilled n will appreciate that a “loading dose” of a drug is an initial
higher dose of a drug given at the beginning of a course of treatment before dropping
down to a lower enance dose.” A loading dose is typically useful for drugs that
achieve their therapeutic old level relatively slowly. An initial loading dose or
doses are administered for the drug to reach the appropriate therapeutic level more y
than if administered only at a lower fixed dose.
The present invention balances a need for a therapeutic agent dose regimen that
exhibits activity (efficacy) in the treatment of solid tumor cancers while mitigating
gastrointestinal ty. There is also a need for a dose regimen in which 4,4,4-trifluoro-
N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]-
1-methyloxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate
f trates therapeutic efficacy and durable response in solid tumor cancer
patients without adversely impacting efficacy, or causing dose limiting, or dose schedule
limiting gastrointestinal toxicities.
One aspect of the present ion es a method of treating a solid tumor
cancer t comprising administering to a patient in need of treatment 4,4,4-trifluoro-
N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]-
1-methyloxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate
thereof, wherein
a) a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose are
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid.
Another aspect of the invention provides a nd 4,4,4-trifluoro-N-[(1S)
(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyl-
2-oxo-ethyl]butanamide or a pharmaceutically acceptable salt or hydrate thereof, for use
in the treatment of a solid tumor cancer, wherein said compound or a pharmaceutically
acceptable salt or hydrate thereof is administered:
a) at a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose are
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid.
A further aspect of the invention provides the use of trifluoro-N-[(1S)
[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyl-
2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof, for
preparation of a medicament for treating a solid tumor cancer wherein said medicament is
administered:
a) at a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose
stered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
c) administering, during stration of the loading dose, 1-50 mg/day of a
corticosteroid.
Another aspect of the invention es a method of treating a solid tumor cancer
comprising administering to a patient in need of treatment 4,4,4-trifluoro-N-[(1S)
[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyl-
2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof,
a) a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the g dose, 1-50 mg/day of a
corticosteroid;
wherein the solid tumor cancer is selected from the group ting of triple negative
breast cancer, breast cancer, ovarian cancer, melanoma, lung cancer, non-small cell lung
cancer, atic cancer, glioblastoma, colorectal cancer, head and neck cancer, cervical
cancer, prostate cancer, liver cancer, oral squamous cell carcinoma, skin cancer,
medulloblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and d
cystic carcinoma.
A further aspect of the present invention provides the compound 4,4,4-trifluoro-N-
[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]
methyloxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof,
for use in the treatment of a solid tumor cancer wherein said compound or a
pharmaceutically able salt or hydrate f is administered:
a) at a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid;
wherein the solid tumor cancer is selected from the group consisting of triple negative
breast cancer, breast cancer, ovarian cancer, melanoma, lung cancer, non-small cell
lung cancer, pancreatic cancer, glioblastoma, ctal cancer, head and neck cancer,
cervical cancer, prostate , liver cancer, oral squamous cell carcinoma, skin
cancer, oblastoma, cellular carcinoma, intrahepatic and extrahepatic
giocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and
adenoid cystic carcinoma.
Another aspect of the present provides the use of 4,4,4-trifluoro-N-[(1S)[[(7S)-
-(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxoethyl
amide, or a pharmaceutically able salt or e f, for
preparation of a medicament for treating a solid tumor cancer wherein said medicament is
administered:
a) at a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a nance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid; and
wherein said solid tumor cancer is selected from the group consisting of triple negative
breast cancer, breast cancer, ovarian cancer, melanoma, lung cancer, non-small cell lung
cancer, pancreatic cancer, glioblastoma, colorectal cancer, head and neck cancer, cervical
, prostate cancer, liver cancer, oral squamous cell carcinoma, skin cancer,
medulloblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and adenoid
cystic carcinoma.
Another aspect of the ion es a method of treating a solid tumor cancer
comprising administering to a patient in need of treatment 4,4,4-trifluoro-N-[(1S)
[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyl-
2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof, wherein
a) a loading dose of at least one dose and up to 6 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a nance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid;
wherein the solid tumor cancer is selected from the group consisting of triple negative
breast cancer, breast cancer, ovarian , melanoma, lung cancer, non-small cell lung
cancer, pancreatic cancer, glioblastoma, colorectal cancer, head and neck cancer, cervical
cancer, prostate cancer, liver cancer, oral squamous cell carcinoma, skin cancer,
oblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and d
cystic carcinoma.
A further aspect of the present ion provides a compound 4,4,4-trifluoro-N-
2-[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]
methyloxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof,
for use in the treatment of a solid tumor cancer wherein said compound or a
pharmaceutically able salt or hydrate thereof is administered:
a) at a g dose of at least one dose and up to 6 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose stered three times per week; and
optionally
c) administering, during stration of the loading dose, 1-50 mg/day of a
osteroid;
wherein the solid tumor cancer is selected from the group consisting of triple negative
breast cancer, breast cancer, n cancer, melanoma, lung cancer, non-small cell lung
cancer, atic cancer, glioblastoma, colorectal cancer, head and neck cancer, cervical
cancer, prostate cancer, liver cancer, oral squamous cell carcinoma, skin cancer,
medulloblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and adenoid
cystic carcinoma.
Another aspect of the present provides the use of 4,4,4-trifluoro-N-[(1S)[[(7S)-
-(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-
ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof, for
preparation of a medicament for treatment of a solid tumor cancer; wherein said
medicament is administered:
a) at a loading dose of at least one dose and up to 6 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during stration of the g dose, 1-50 mg/day of a
corticosteroid;
wherein the solid tumor cancer is selected from the group consisting of triple negative
breast cancer, breast , ovarian cancer, ma, lung cancer, non-small cell lung
cancer, pancreatic cancer, glioblastoma, ctal cancer, head and neck cancer, cervical
cancer, prostate cancer, liver cancer, oral squamous cell carcinoma, skin cancer,
medulloblastoma, hepatocellular oma, intrahepatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and d
cystic carcinoma.
Another aspect of the invention provides a method of treating a solid tumor cancer
comprising administering to a patient in need of treatment 4,4,4-trifluoro-N-[(1S)
(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyl-
2-oxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof,
a) a loading dose of at least one dose and up to 3 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid;
wherein the solid tumor cancer is selected from the group consisting of triple negative
breast cancer, breast cancer, ovarian cancer, melanoma, lung cancer, non-small cell lung
, pancreatic cancer, glioblastoma, colorectal cancer, head and neck cancer, cervical
cancer, prostate cancer, liver cancer, oral squamous cell carcinoma, skin cancer,
medulloblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, osarcoma, and adenoid
cystic carcinoma.
A further aspect of the t ion provides a compound 4,4,4-trifluoro-N-
[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]
methyloxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof,
for use in the treatment of a solid tumor cancer wherein said compound or a
pharmaceutically acceptable salt or hydrate thereof is administered:
a) at a loading dose of at least one dose and up to 3 doses at 75-150 mg/dose
stered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose stered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid;
n the solid tumor cancer is ed from the group consisting of triple negative
breast cancer, breast cancer, ovarian , melanoma, lung cancer, non-small cell lung
cancer, pancreatic cancer, glioblastoma, ctal cancer, head and neck cancer, cervical
cancer, prostate , liver cancer, oral squamous cell carcinoma, skin cancer,
medulloblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and adenoid
cystic carcinoma.
Another aspect of the present provides the use of 4,4,4-trifluoro-N-[(1S)[[(7S)-
5-(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxoethyl
]butanamide, or a pharmaceutically acceptable salt or hydrate thereof, for
preparation of a medicament for treatment of a solid tumor cancer; wherein said
ment is administered:
a) at a loading dose of at least one dose and up to 3 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid;
wherein the solid tumor cancer is selected from the group consisting of triple negative
breast cancer, breast cancer, ovarian cancer, melanoma, lung cancer, all cell lung
cancer, pancreatic cancer, glioblastoma, colorectal cancer, head and neck cancer, cervical
cancer, prostate , liver cancer, oral squamous cell carcinoma, skin cancer,
medulloblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and d
cystic carcinoma.
A still further aspect of the present ion provides a method of treating
leiomyosarcoma comprising administering to a patient in need of treatment 4,4,4-
trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepin
no]methyloxo-ethyl]butanamide, or a pharmaceutically acceptable salt or
hydrate thereof,
a) a loading dose of at least one dose and up to 3 doses at 75-150 e
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid.
A further aspect of the present invention provides the compound 4,4,4-trifluoro-N-
[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]
methyloxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof,
for use in the treatment of leiomyosarcoma wherein said compound or a pharmaceutically
acceptable salt or hydrate thereof is stered:
a) at a loading dose of at least one dose and up to 3 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) stering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid.
Another aspect of the t provides the use of 4,4,4-trifluoro-N-[(1S)[[(7S)-
-(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-
ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof, for
ation of a medicament for treatment of leiomyosarcoma wherein said medicament
is administered:
a) at a loading dose of at least one dose and up to 3 doses at 75-150 mg/dose
stered twice or three times per week; followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid.
The compound 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-
pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide (“Compound
1”), or a pharmaceutically acceptable salt or hydrate f , is taught to be a Notch
inhibitor in
An tive amount" means a dose of Compound 1, or pharmaceutically
acceptable salt or hydrate thereof, or pharmaceutical composition ning the
compound, or pharmaceutically acceptable salt or hydrate thereof, necessary to inhibit
Notch signaling in a solid tumor cancer patient, and either destroy the target cancer cells
or slow or arrest the progression of the cancer in a patient. An effective amount
encompasses both a loading or first dose and a maintenance or second dose of Compound
1, or pharmaceutically acceptable salt or hydrate thereof, or pharmaceutical composition
containing the compound, or a ceutically acceptable salt or hydrate thereof,
necessary to inhibit Notch signaling in a solid tumor cancer patient, and either destroy the
target cancer cells or slow or arrest the progression of the cancer in a patient. g
doses of Compound 1 or a pharmaceutically acceptable salt or hydrate thereof in an adult
t are in the range of 75 to 150 mg/dose administered twice (two days) in a seven
day week or three times (three days) in a seven day week (TIW). At least one loading
dose is administered and as many as 12 loading doses over one 28 day cycle are
administered. Preferably, 1 to 6 loading doses are administered over 14 days of a 28 day
cycle. Also ably, at least one loading dose and up to 3 loading doses are
administered over 7 days of a 28 day cycle. It will be appreciated the number of loading
doses is dependent on whether the administration regimen is twice per week or three
times per week. A maintenance or second dose of 50 mg per dose is administered TIW
following the loading dose or doses. Preferably, the maintenance dose is administered
over any remaining days of a first 28 day cycle to one or more additional 28 day cycles.
Optionally, during administration of the loading dose, 1-50 mg/day of a corticosteroid is
administered.
The terms ment," "treat," and "treating," are meant to e the full
um of intervention for the solid tumor cancer, such as administration of the active
compound to alleviate, to slow, or e one or more of the symptoms, and to delay
progression of the cancer even if the cancer is not actually eliminated.
The “gastrointestinal toxicities” the present dose regimen ng dose
administration followed by maintenance dose administration and the optional
administration of a corticosteroid) may ameliorate or mitigate include diarrhea, nausea,
vomiting, mucoid enteropathy and/or colitis. Higher doses, more frequent dosing, and
more weeks, or cycles of treatment tend to cause higher grades of gastrointestinal
toxicities in patients. Mitigating or ameliorating these ties may facilitate a patient
receiving additional doses, and/or weeks or cycles of treatment for their cancer.
“Corticosteroids” means hydrocortisone, hydrocortisone acetate, cortisone acetate,
tixocortol te, prednisolone, methylprednisolone, and sone, preferably
prednisone. Although a dose of 1-50 mg/day is contemplated, it is possible to increase
the dose up to 80 mg/day.
As used herein, the term “patient” means mammal; “mammal” means the
Mammalia class of higher vertebrates; and the term “mammal” includes, but is not limited
to, a human.
The solid tumor cancers against which the preset dosing regimen will be
cious while mitigating gastrointestinal toxicities include triple negative breast
, breast , ovarian cancer, ma, lung cancer, non-small cell lung cancer,
pancreatic cancer, glioblastoma, colorectal cancer, head and neck cancer, cervical cancer,
prostate cancer, liver cancer, oral squamous cell carcinoma, skin cancer,
medulloblastoma, hepatocellular carcinoma, epatic and extrahepatic
cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and adenoid
cystic carcinoma.
In the present ion a loading dose (first dose) administration of at least one
up to 12 doses of 75 to 150 mg/dose twice (two days) in a seven day week or three times
(three days) in a seven day week (TIW) during a 28 day cycle is used. The number of
doses a patient receives may be adjusted to provide a more optimal eutic benefit to
a patient and/or to mitigate or ameliorate observed toxicities or symptoms related to
tumor lysis syndrome. A maintenance dose (second dose) administration of 50 mg per
dose TIW is preferred for the remaining days, if any, of a first 28 day cycle and may be
extended to one or more additional 28-day cycles. The maintenance dose, or second
dose, is administered through one or more partial or full 28 day cycles at the discretion of
a physician. Optionally, and preferably, administration (pre-, concomitant, or postadministration
of Compound 1 or a pharmaceutically able salt or hydrate thereof)
of a osteroid, and most preferably prednisone, during the loading dose
administration of Compound 1 to mitigate or ameliorate intestinal toxicities is
contemplated.
The skilled artisan will appreciate the dose regimen of the present invention is
provided to afford a more optimal therapeutic efficacy, while ameliorating or mitigating
gastrointestinal toxicities. This regimen is in contrast to administering a fixed dose with
dose or administration adjustments by, and at the discretion of, a physician that are known
and routinely used such as for patients with renal or hepatic impairment or to mitigate
toxicities based on individual t variabilities and response to the active
pharmaceutical agent.
The compound of the present invention is preferably formulated as a
pharmaceutical composition using a pharmaceutically acceptable carrier and administered
by a variety of routes. Preferably, such compositions are for oral administration. Such
pharmaceutical compositions and processes for preparing them are well known in the art.
(See, e.g., Remington: The e and Practice of Pharmacy, L. V. Allen, Editor, 22nd
Edition, Pharmaceutical Press, 2012). In a particular embodiment, the pharmaceutical
composition comprises 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-
pyrido[2,3-d][3]benzoazepinyl]amino]methyloxo-ethyl]butanamide, or a
pharmaceutically acceptable salt or hydrate thereof, and a pharmaceutically acceptable
The compound of the present invention is capable of reaction with a number of
inorganic and organic acids to form ceutically acceptable acid addition salts. Such
pharmaceutically able salts and common methodology for preparing them are well
known in the art. See, e.g., P. Stahl, et al., OK OF PHARMACEUTICAL
SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2002); S.M.
Berge, et al., “Pharmaceutical Salts, “Journal of ceutical Sciences, Vol. 66, No. 1,
January 1977.
Compound 1, or a pharmaceutically acceptable salt or hydrate thereof, may be
prepared by a variety of ures known in the art, as well as those described in WO
2013/016081. The specific synthetic steps may be combined in different ways to prepare
Compound 1, or a pharmaceutically acceptable salt or hydrate thereof.
Compound 1 is named 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-
7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide; and may
also be named: )[[(7S)-6,7-dihydro(2-hydroxyethyl)oxo-5H-pyrido[3,2-
a][3]benzazepinyl]amino]methyloxoethyl]-4,4,4-trifluorobutanamide; other
names may be used to unambiguously identify Compound 1.
Compound 1 is named as a single stereoisomer. There are two chiral centers
giving rise to four stereoisomers. As used herein, nces to Compound 1 are meant to
also include stereoisomeric mixtures including nd 1. Herein, the Cahn-Ingold-
Prelog designations of (R)- and (S)- are used to refer to specific isomers. Specific
stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or
enriched starting materials. The specific stereoisomers of starting materials,
ediates, or racemic mixtures including Compound 1 can be resolved by techniques
well known in the art, such as those found in Stereochemistry of c Compounds, E.
I. Eliel and S. H. Wilen (Wiley 1994) and Enantiomers, Racemates, and Resolutions, J.,
Jacques, A. Collet, and S. H. Wilen (Wiley 1991), including chromatography on chiral
stationary phases, enzymatic resolutions, or fractional crystallization or chromatography
of diastereomers formed for that purpose, such as reomeric salts. While all
mixtures containing the compound of the t invention are contemplated within the
present invention, the red ment is Compound 1.
It has also been found that Compound 1 exists as atropisomers, or specific
conformers. In aqueous solutions, 8-9% of atropisomer 2 (minor atropisomer) is detected
by 1H NMR and LC-MS in equilibrium with atropisomer 1 (major atropisomer) at
ambient temperature after 24 hours. In organic solvents, at ambient temperature after 24
hours, approximately 1-2% of atropisomer 2 is ed by 1H NMR and LC-MS in
equilibrium with atropisomer 1. Although detectable by 1H NMR and LC-MS analysis,
atropisomer 2 is not isolable.
The nds employed as initial starting materials in the synthesis of the
compound of the present invention are well known and, to the extent not commercially
available, are readily sized using specific nces provided, by standard
procedures commonly employed by those of ordinary skill in the art or are found in
general reference texts.
Examples of known procedures and methods include those described in general
reference texts such as Comprehensive Organic Transformations, VCH Publishers Inc,
1989; Compendium of Organic Synthetic Methods, Volumes 1-10, 1974-2002, Wiley
Interscience; Advanced c Chemistry, Reactions Mechanisms, and Structure, 5th
Edition, Michael B. Smith and Jerry March, Wiley Interscience, 2001; Advanced Organic
Chemistry, 4th Edition, Part B, ons and Synthesis, Francis A. Carey and Richard J.
Sundberg, Kluwer Academic / Plenum Publishers, 2000, etc., and references cited therein.
Cancer is increasingly ized as a heterogeneous collection of diseases whose
initiation and progression are induced by the aberrant function of one or more genes that
regulate DNA repair, genome stability, cell proliferation, cell death, on,
angiogenesis, invasion, and metastasis in cell and tissue microenvironments. Variant or
aberrant function of the “cancer” genes may result from naturally ing DNA
polymorphism, changes in genome copy number (through amplification, deletion,
chromosome loss, or duplication), changes in gene and some structure gh
chromosomal translocation, inversion, or other rearrangement that leads to deregulated
gene expression), and point mutations. Cancerous neoplasms may be d by one
aberrant gene function, and maintained by the same aberrant gene function, or
maintenance and progression exacerbated by additional nt gene functions.
Beyond the genetic chromosomal aberrations mentioned above, each of the
cancers may also include epigenetic modifications of the genome including DNA
methylation, c imprinting, and histone cation by acetylation, methylation,
or phosphorylation. An epigenetic modification may play a role in the induction and/or
maintenance of the malignancy.
Diagnosis of cancerous malignancies by biopsy, immunophenotyping and other
tests are known and routinely used. In addition to high resolution chromosome banding
and advanced chromosomal imaging technologies, chromosome aberrations in suspected
cases of cancer can be determined through cytogenetic analysis such as fluorescence in
situ hybridization (FISH), karyotyping, spectral karyotyping (SKY), multiplex FISH (MFISH
), comparative genomic hybridization (CGH), single nucleotide rphism
arrays (SNP Chips) and other diagnostic and analysis tests known and used by those
d in the art.
PET/CT imaging of cancer with combined positron emission tomography (PET)
and X-ray computerized tomography (CT) scanners has become a standard component of
diagnosis and staging in oncology. The use of the radiolabeled tracer 2-deoxy
[18F]fluoro-D-glucose (FDG) is used for the majority of all PET/CT imaging procedures.
One of the advantages of PET/CT imaging is its ability to , very early during
ent, icant changes in glucose metabolism or even complete shutoff of the
neoplastic cell lism as a surrogate of tumor chemosensitivity assessment. In
addition to cancer detection and staging, PET/CT imaging is becoming increasingly
important as a quantitative monitor of individual response to therapy and an evaluation
tool for new drug therapies. Changes in FDG accumulation have been shown to be useful
as an imaging marker for assessing response to y. RECIST criteria, where response
of tumors to therapy has ionally assessed by measurement of changes in
size/dimension of the tumors in CT images may not evidence early response to the
therapy. Changes in size of tumors as a result of therapy may take a long period of time
to develop. The most widely used parameter is the standardized uptake value (SUV) is
defined as the maximal SUV value (SUVMAX) in the region of interest and reduction in
SUVMAX is generally considered the most reliable tor of the metabolic activity
shutdown.
Aberrant tutive Notch signaling is ated in a number of solid tumor
malignancies (cancers) including breast cancer, ovarian cancer (Park et al. Cancer
Research, 2006(66):6312-6318), melanoma (Gast et al. Genes, Chromosomes & Cancer,
2010(49):733-745), lung cancer, non-small cell lung cancer off et al. PNAS,
2009(106):22293-22298), pancreatic cancer, glioblastoma, colorectal cancer, head and
neck cancer, cervical cancer, te cancer, liver cancer, squamous cell carcinoma
(oral), skin cancer and medulloblastoma (Ranganathan et al., Nature Review Cancer,
2011(11):338-351 and Supplementary Information S1 (table)). Aberrant Notch signaling
may be activated in particular soft tissue sarcomas ro et al. Am J Pathol,
2013(182(6)):2015-2027.
Preclinical Evaluations
A study is carried out to assess the toxicity and toxicokinetics of 4,4,4-Trifluoro-
N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]-
1-methyloxo-ethyl]butanamide in rats given oral gavage doses of 0, 1.3, or 4.3 mg/kg
once daily for 2 weeks or 1, 3, 10, or 30 mg/kg 3 times/week for 2 weeks.
4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide is combined with a
vehicle comprising 1% carboxymethylcellulose sodium, 0.25% polysorbate 80 and 0.05%
Dow Corning® Antifoam 1510-US in purified water. Sprague Dawley CD®/IGS rats
(crl:CD(SD)), International Genetic Standardization (IGS) 7-9 week old rats, 3/sex/group,
Charles River Laboratories, Inc, are used for the study. Animals are fed ad libitum with
12 hours light, 12 hours dark cycle maintained in ventilated stainless-steel racks at an
ambient ature of 22.2 +/- 8° C and relative humidity of 30% to 70%. The test
compound is dosed according to Table 1. The test nd is administered by oral
gavage in a volume of 10 mL/kg body weight. The duration of the study for all groups is
14 days.
Table 1. Dosing Regimen
Animal
Frequency Dose (mg/kg)
Daily 0 01
Daily 1.3 06 & 12
Daily 4.3 07 & 13
3 times/week 1 02 & 08
3 times/week 3 03 & 09
3 times/week 10 04 & 10
3 times/week 30 05 & 11
Observations, at a minimum, for Groups 01, 06 and 07 are ed daily before
dosing, approximately one (1) hour postdose, and in the afternoon except afternoon
observations are not ed on weekends. Observations for Groups 02, 03, 04, and 05
are recorded beginning on Day 3. At a minimum, ations are recorded as described
on dosing days. On non-dosing days, observations are recorded at approximately the
same time as for groups receiving daily doses. Animals are weighed on Days 1, 3, 6, 10,
and 14. Terminal body s are collected at scheduled necropsy. Food consumption
weights are recorded on Days 1, 3, 6, 10, and 14.
Additional Groups of animals 3/sex/group (Groups 08, 09, and 12) and 3
s/group (Groups 10, 11, and 13) are dosed for kinetic evaluations. For
Groups 08, 09, and 10, blood is collected from each animal at the following times
relative to dosing on Days 3 and 14: 0 se; Day 14 only), 0.5, 1, 2, 4, 8, 24, 30, and
48 hours postdose. For Group 11, blood is ted from each animal at the ing
times relative to dosing on Day 3: 0.5, 1, 2, 4, 8, 24, 30, and 48 hours postdose. For
Group 12, blood is collected from each animal at the following times relative to dosing on
Days 1 and 14: 0 (predose; Day 14 only), 0.5, 1, 2, 4, 8, and 24 hours postdose. For
Group 13 blood is collected from each animal at the following times relative to dosing on
Day 1: 0.5, 1, 2, 4, 8, and 24 hours postdose. Groups 08 through 13 are used for
toxicokinetic evaluations. Among other evaluations, the blood samples are used for
pharmacokinetic parameters of absorption, distribution, metabolism, and excretion
analysis.
Exposure (AUC0-24hr) increased in a roughly linear and dose-proportional
manner following both single and le doses. No accumulation or major differences
between sexes are identified. Due to morbidity and/or mortality, exposure data following
multiple doses was only available for a limited number of animals at dose levels of
1.3 mg/kg daily and 10 mg/kg given 3 times/week and was not available at dose levels of
4.3 mg/kg daily or 30 mg/kg given 3 times/week. Changes in body weight and food
consumption parameters are observed at dose levels of 1.3 and 4.3 mg/kg administered
daily and at dose levels of 10 and 30 mg/kg administered 3 times/week. Substantial body
weight loss is observed at dose levels of 4.3 mg/kg given daily or 30 mg/kg given 3
times/week. At dose levels of 1.3 mg/kg given daily or 10 mg/kg given 3 times/week,
mean body weights are generally similar to or greater than atment but were slightly
to moderately decreased relative to the l group. Minimal to severe decreases in
food consumption are also noted and correlated with the decreased body weight gain
and/or body weight loss.
All non-toxicokinetic animals given 30 mg/kg 3 times/week are euthanized on
Day 10 due to poor condition. Two of three toxicokinetic (TK) animals given 10 mg/kg 3
times/week are ized on Day 10 due to poor condition and the remaining TK animal
was found dead prior to the 48 hr TK time point on Day 16. TK animals given daily
doses of 4.3 mg/kg are found dead on Days 7, 8, or 10, and s given daily doses of
4.3 mg/kg are euthanized on Day 10 due to poor condition. In addition, 2 of 3 female TK
animals given daily doses of 1.3 mg/kg are euthanized on Day 10 due to poor ion.
All non-TK animals, male TK animals, and 1 of 3 female TK animals given daily doses
of 1.3 mg/kg survived until the scheduled study termination. All non-TK animals given
≤10 mg/kg and TK animals given ≤3 mg/kg 3 times/week survived until the scheduled
study termination. The poor ion requiring euthanization is attributed to
intestinal toxicity, although inflammation, decreased food consumption, stress, and
dehydration are also observed. Compound related toxicities are seen in non-TK animals
of both sexes given 10 mg/kg administered 3 times/week, females given 3 mg/kg 3
times/week and are limited to mucoid pathy involving multiple levels of the
intestinal tract and minimal to slight renal tubular ration in males given 10 mg/kg 3
times/week.
Rats receiving the same total weekly dose (1.3 mg./kg daily or 3 mg/kg three
week; and 4.3 mg/kg daily or 10 mg/kg three time/week) had more severe
intestinal toxicity with daily dosing compared to three times/week dosing in this
study.
A study is carried out to assess the Toxicity and Toxicokinetics of 4,4,4-trifluoro-
N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]-
1-methyloxo-ethyl]butanamide in dogs given oral gavage doses of 0 or 1.3 mg/kg once
daily for 6 days or 0.3 or 3 mg/kg every other day for a total of 3 doses.
4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide is combined with a
vehicle comprising 1% carboxymethylcellulose sodium, 0.25% polysorbate 80 and 0.05%
Dow Corning® Antifoam 1510-US in purified water. Dogs (beagle), Covance Research
Products, 1 animal/sex/group are fed daily (soon after dosing) and are fasted overnight
prior to scheduled chemistry blood collections and necropsy. The test compound is
administered by oral gavage in a volume of 2 mL/kg body weight. The duration of the
study for all groups is 6 days.
Table 2 Dosing Regimen
Frequency Dose (mg/kg) Animal Group(s)
Daily 0 01
Daily 1.3 04
3 times/week; 0.3 02
Days 2, 4, and 6
3 times/week 3.0 03
Days 2, 4, and 6
Study Parameters
Toxicokinetics
Sample tion:
Groups 01 and 04, Blood is collected at the ing times relative to dosing on Day 1:
0.5, 1, 2, 4, 8, and 24 hours postdose.
Groups 02 and 04: Blood is collected at the following times relative to dosing on Days 2
and 6: 0 (predose; Day 6 only), 0.5, 1, 2, 4, 8, 24, 30, and 48 hours postdose.
Metabolite Analysis
Sample Collection: Blood is collected from one animal/sex in Group 03 at 2 hours
postdose on Day 6.
Observations
Groups 01 and 04: At a minimum, observations are recorded daily before ,
approximately 1 hour postdose, and in the afternoon, with the following exception:
afternoon clinical observations are not recorded on weekends.
Groups 02 and 03: At a minimum, ations are recorded before ,
approximately 1 hour postdose, and in the afternoon on Days 2 and 6; before dosing and
approximately 1 hour postdose on Day 4; and at approximately the same times as Groups
01 and/or 04 on Days 3, 5, and 7.
Body s:
Animals are weighed on Days 1 and 7.
Food Consumption:
A qualitative assessment of food consumption is made each day by visual estimation of
the amount of food remaining (recorded in increments of 25%).
Sample Collection:
Groups 01 and 04: Blood samples are collected before dosing on Day 1 and on Day 7
(not dosed on Day 7).
Groups 02 and 03: Blood samples are collected before dosing on Days 1 and 6.
Urine samples are collected from all animals by cystocentesis at the scheduled necropsy.
Animals given 1.3 mg/kg are euthanized following 6 daily doses due to poor
condition. Animals given 0.3 or 3 mg/kg 3 times/week (Days 2, 4, and 6) survived until
the scheduled termination. Compound-related signs limited to s given 6 daily
doses of 1.3 mg/kg included lateral recumbency and labored respiration for the female on
Day 7, sed activity for both animals on Days 6 and 7, and dehydration (decreased
skin elasticity) for both animals on Day 7. Other symptoms at this dose level ed
red, dark e only), mucoid, and watery (female only), feces. Compound-related
signs for animals given 3 mg/kg 3 times/week included red (male only), mucoid, and
watery (male only), feces. In animals given 0.3 mg/kg 3 times/week, signs are limited to
the female and included mucoid, and watery feces.
Body weight loss ed in all compound-treated groups and is considered
adverse in animals given 3 mg/kg 3 times/week or 1.3 mg/kg daily for 6 days. Decreased
food consumption also occurred in all compound-treated groups.
Adverse gastrointestinal (GI) changes occurred in s given 3 mg/kg 3 times
weekly and 1.3 mg/kg daily, and resulted in early euthanasia of both animals given 1.3
mg/kg. The male given 0.3 mg/kg 3 times weekly has adverse inflammatory changes in
the large intestine and evidence of systemic inflammation that are likely compound
related, but lacked the more characteristic mucoid enteropathy signs.
Gastrointestinal changes occurred at all levels of the GI tract and included mucoid
epithelial changes (mucoid pathy), erosion, ulceration, and inflammation involving
the submucosa and deeper layers of the intestinal wall. Intestinal changes are most
pronounced in animals given 1.3 mg/kg daily and included up to marked mucoid
enteropathy with red fluid intestinal contents, n, ulceration, and mostly neutrophilic
mixed inflammation. Mucoid enteropathy is characterized by increased s of
goblet cells at all levels of the mucosa, and when more pronounced, is associated with
disorganization, crypt dilation, and luminal ts composed of mucus and large
numbers of phils admixed with exfoliated enterocytes and cellular debris.
Table 3 Mean TK parameters in Beagle dogs (one male, one female, n = 2)
following a single oral dose or multiple TIW oral doses (3 doses/week) of 0.3 or 3
mg/kg.
Single oral dose
Parameter Units 0.3 mpk 3mpk
AUC ng*Hours/mL 1290 5860
Cmax ng/mL 309 2730
Tmax Hours 0.500 0.500
Multiple oral doses (3 doses/week)
Parameter Units 0.3 mpk 3 mpk
AUC ng*Hours/mL 3070 14400
Cmax ng/mL 2460 4530
Tmax Hours 0.750 0.750
Table 4. Mean TK parameters in Beagle dogs (one male, one female, n = 2)
following a single oral dose at 1.3 mg/kg
ter Units Subject Subject Mean n
0007_M 0008_F
AUC ng*Hours/mL 4030 4500 4270 2
Cmax ng/mL 1800 2070 1940 2
Tmax Hours 0.500 0.500 0.500 2
Beagle dogs receiving 1.3 mg/kg daily doses are euthanized following 6 doses.
Beagle dogs ing 0.3 or 3 mg/kg three times/week survived until the scheduled
necropsy. Dogs receiving daily dosing had more severe gastrointestinal toxicity
compared to three times/week dosing (where the daily dosing dogs and the three
times/week dogs received the same total weekly dose) in this study.
The preclinical rat and dog data shows that for the same total weekly dose, once
daily administration is not tolerated. In both regimens, 24 hour drug concentrations are
l, but with TIW dosing there is 24-48 hours between doses where there is no drug
in the system. These data suggest that some time off drug is required to minimize
toxicity.
In-vivo efficacy and target inhibition studies – Animal studies
To evaluate in vivo efficacy and effect of 4,4,4-Trifluoro-N-[(1S)[[(7S)(2-
hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxoethyl
]butanamide on inhibition of Notch processing pharmacodynamics (PD), several cell
lines- and patient-derived xenograft models are used. A2780 is a human ovarian cell line
(Sigma-Aldrich, No. 93112519); SW480 is a human colorectal cell line (ATCC No. CCL-
228); HCT 116 is a human colorectal cell line (ATCC No. CCL-247); U-87 MG is a
human glioblastoma cell line (ATCC No. HTB-14); A375 is a human malignant
melanoma cell line (ATCC No. CRL-1619); K-562 is a human c myelogenous
leukemia (CML) cell line characterized by the ce of a fusion transcript comprised
of the Bcr and Abl1 genes (ATCC No. CCL-243); Jurkat; HEL 92.1.7 is a human
erythroleukemia cell line (ATCC No. 0). Each of the cell lines are obtained from
the American Type e Collection (ATCC) at the ATCC number stated, except the
A2780 cell line which is ed from Sigma-Aldrich at the stated g number. The
cells are grown in their respective, recommended culture media at 37°C in 5% CO2 with
humidity in the atmosphere. A2780 (2 x 106), SW480 (6 x 106), HCT 116 (6 x 106), U-87
MG (6 x 106), and A-375 (10 x 106) cells in a 1:1 matrigel mix (0.2 mL volume) are
ted by subcutaneous injection in the hind leg of 6-8 weeks of age athymic nude
female mice (Harlan Laboratories). K-562 (6 x 106) cells in a 1:1 matrigel mix (0.2 mL
volume) are implanted by subcutaneous injection in the hind leg of 6-8 weeks of age CD1
nµ/nµ female mice (Charles River Laboratories). HEL 92.1.7 (7 x 106) in a 1:1 matrigel
mix (0.2 mL volume) are implanted by subcutaneous injection in the hind leg of 6-8
weeks of age CB17 severely ed immune deficient female mice (Taconic Farms).
Patient-derived tumors are minced into 1-2 mm pieces and mixed with matrigel (1:1) in
0.2 ml volume and implanted by subcutaneous injection in the hind leg of 6-8 weeks of
age c nude female mice n Laboratories). ts-derived tumor models
include: human colon carcinoma (EL2144), human triple negative invasive ductal breast
carcinoma (EL1997), human colon carcinoma (EL1989, EL 1986), and human
astoma (EL 2056) with samples obtained after patient consent and hospital approval
from IU Health, Methodist al, Indianapolis, Indiana, USA 46206. A total of 7 to
mice are used for each group. Just before implantation for A2780, SW480, HEL
, A-375, K-562, and patient-derived tumor models, animals are irradiated (450
Total Body Irradiation). Mice are fed ad libitum on normal chow. Treatment is initiated
with oral administration (gavage) of compound or vehicle (1% Na-CMC in 0.25%
Tween®-80) in 0.2 mL volume when tumor size reached to 150 ± 50 mm3. At designated
time points following treatment, animals are sacrificed by CO2 asphyxiation and cervical
dislocation. Tumors are removed and used for PD response analysis. Tumor growth and
body weight are monitored over time to evaluate efficacy and signs of toxicity.
Bidimensional measurements of tumors are performed twice a week and tumor volumes
are calculated based on the following formula: (Tumor Volume) = [(L) x (W2) x (Π/6)]
where L is is length and W is mid-axis width. Tumor volume data are transformed
to a log scale to equalize variance across time and treatment groups. The log volume data
are analyzed with a two-way repeated measures analysis of variance by time and
treatment using the MIXED™ procedures in SAS™ software (version 8.2). The
correlation model for the ed measures is spatial power. Treated groups are
compared to the control group at each time point. The MIXED™ procedure is also used
separately for each treatment group to calculate adjusted means and standard errors at
each time point. Both analyses account for the autocorrelation within each animal and the
loss of data that occurs when s with large tumors are removed from the study early.
The adjusted means and standard errors are d for each treatment group versus time.
Antitumor activity is expressed as tumor growth inhibition percentage (TGI %) and is
calculated by ing tumor volume in the treatment group with vehicle ent
group. Percentage Tumor Growth Inhibition (%TGI) and statistical significance value (p
value) for4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide is measured essentially
as described above and summarized in Table 5.
N1ICD Analysis
To evaluate N1ICD levels in tumors, approximately 75 mg is cut from the frozen
tumor and minced prior to nization (actual mass recorded). Frozen tumor samples
are transferred to Lysing Matrix-D™ tubes and re-suspended in ice-cold XY lysis buffer
(25 mM Tris pH 7.5, 10 µg/ml Trypsin/Chymotrypsin inhibitor, 10 µg/ml Aprotinin,
60 mM Beta-glycerol phosphate , 1% Triton® X-100, 10 mM NaF, 2.5 mM
pyrophosphate, 150 mM NaCl, 15 mM ne diamine tetra acetic acid (EDTA) pH 8.0,
5 mM ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetra acetic acid (EGTA) pH
8.0, 1 mM Na Vanadate, 10 µg/ml Leupeptin, 1 mM dithiothreitol, 1 µM microcystin LR,
µg/ml N-p-tosyl-L-phenylalanine chloromethyl ketone (TPCK), 2 mM Nα-p-tosyl-L-
arginine methyl ester hloride (TAME), 15 mM 4-nitrophenyl phosphate di(tris) salt
(PNPP), 0.1 mM 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF),
5 mM benzamidine, 1 µM Okadaic Acid) containing 1X Complete tablet (Roche
Complete™ No. 11697 498 001) and 1X Protease Inhibitor cocktail (Sigma-Aldrich
P8340) at a mass: volume ratio of 75 mg/ml buffer. Tissues are homogenized in a Fast
Prep FP120 homogenizer o Scientific, Rockford, IL) at a speed of 6.0 for 30
seconds at 4oC, followed by 15 minute incubation on ice. This is repeated for a total of 2-
3 cycles until homogenization is complete. Lysates are spun in a 4oC Eppendorf
centrifuge at 30,000 rpm for 15 s to remove debris. 400 µl of supernatant is
removed and transferred to a new Eppendorf tube and subjected to a freeze/thaw cycle.
Samples are re-spun in a 4oC Eppendorf centrifuge at 30,000 rpm for 30 minutes and 120
µl of supernatant is collected for analysis. Total protein concentration is ined using
Pierce BCA Protein Assay Kit™ o Scientific, Rockford, IL) using a
Thermomax™ plate reader (Molecular Devices, Sunnyvale, CA). N1ICD levels are
determined using a custom N1ICD ELISA. Analyte is captured with a cleaved
Notch1(Val1744)-specific custom rabbit monoclonal antibody and detected with a C-
terminal Notch1 SULFO-TAG™ (Meso Scale Discovery, rsburg, Maryland)
polyclonal sheep antibody (R&D Systems, Minneapolis, MN). Lysates are d to
2 µg/µl in ld ELISA tris lysis buffer (R6OTX) (Meso Scale Discovery,
Gaithersburg, Maryland) containing 1X Complete tablet (Roche te™ mini No. 11
836 153 001) and 1X Protease Inhibitor cocktail (Sigma-Aldrich P8340), and 25µl is
added to the ELISA plate. Incubation of 50 µg protein lysate is done at RT for one hour
each to capture analyte and with detection antibody. Plates are read on a Sector Imager
6000™ (Meso Scale ery, Gaithersburg, nd). Background subtracted N1ICD
is normalized to total protein and presented as % inhibition relative to the vehicle-treated
group. N1ICD % inhibition and tical significance (p value) as measured by ’s
method in tumors harvested 4 hours after last dose for 4,4,4-Trifluoro-N-[(1S)[[(7S)
(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-
ethyl]butanamide is analyzed essentially as described above and summarized in Table 5.
Table 5.
% N1ICD
Tumor Model Schedule % TGI (p Value) Inhibition (p
(mg/kg)
Value)
A2780 10 Q2Dx11 56.55 (< 0.0001) 68.5 (< 0.0001)
A2780 10 Q3Dx8 32.99 (< ) 55.3 (< 0.0001)
A2780 3 (BID)QDx7+(BID)Q2Dx7 72.35 (< 0.0001) 50.7 (0.0004)
A2780 3 QDx21 46.60 (< 0.0001) 62.8 (< 0.0001)
A2780 10 Q2Dx13 51.11 (< 0.0001) 74.8 (< 0.0001)
A2780 8 Q2Dx13 68.60 (< 0.0001) 71.7 (< 0.0001)
A2780 7 Q2Dx13 56.95 (< 0.0001) 65.9 (< 0.0001)
36.33 (< 0.05 to
A2780 6 Q2Dx13 60.7 (< 0.0001)
< 0.01)
36.65 (< 0.05 to
A2780 3 Q2Dx13 58.6 (< 0.0001)
< 0.01)
33.36 (< 0.05 to
A2780 1.5 QDx26 59.0 (< 0.0001)
< 0.01)
SW480 8 (Mon, Wed, Fri)x5 61.00 (< 0.0001) 72.5 (= 0.0002)
37.58 (< 0.05 to
HCT 116 8 (Mon, Wed, Fri)x4 73.0 (= 0.0005)
< 0.01)
U-87 MG 8 (Mon, Wed, Fri)x4 53.33 (< ) 87.8 (< 0.0001)
A-375 8 (Mon, Wed, Fri)x4 28.47 (NS) 77.5 (< 0.0001)
54.96 (< 0.01 to
K-562 8 (Mon, Wed, Fri)x4 47.6 (< 0.0001)
< 0.001)
HEL 92.1.7 8 Q2dx14 7.20 (NS) 56.7 (< 0.0001)
(Q2Dx7), 11-days OFF,
EL1997 80.28 (< 0.0001) 67.9 (< 0.0001)
8 (Mon, Wed, Fri)x4
(Q2Dx7), 11-days OFF,
EL1989 70.42 (< 0.0001) 79.2 (< 0.0001)
8 (Mon, Wed, Fri)x3
EL2144 10 Q2Dx8 53.37 (< ) ND*
EL2056 8 (Mon, Wed, Fri)x5 59.05 (< 0.0001) 83.5 (< 0.0001)
% N1ICD
Tumor Model le % TGI (p Value) Inhibition (p
Value)
EL1986 8 (Mon, Wed, Fri)x5 62.00 (< 0.0001) 84.9 (< 0.0001)
* Not Determined
The data in Table 5 show the tumor growth inhibition, and the inhibition of
N1ICD cleavage by 4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-
pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide in various
xenograft models of human tumors. The data in Table 5 also shows the effects of
alternative dosing regimens on tumor growth inhibition by Trifluoro-N-[(1S)
[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyl-
2-oxo-ethyl]butanamide. The data also shows that more frequent dosing affords greater
efficacy.
Using the preclinical data and pharmacokinetic/pharmacodynamic data from
patients in a phase 1 dose escalation study, PK/PD models are developed to te
s dosing regimens in patients, with a goal to maximize the time above 50%
inhibition of gene expression and time off drug based on average patient responses.
Clinical Evaluation
A study of 4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-
pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide hydrate in
patients with advanced or metastatic solid tumor cancer.
Study Design
This study is a enter, nonrandomized, open-label, dose-escalation study
ed by cohort expansion of oral dosed 4,4,4-trifluoro-N-[(1S)[[(7S)(2-
hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxoethyl
]butanamide hydrate in outpatients with advanced or metastatic solid tumor cancer.
Study Objectives
The primary objective of this study is to determine a recommended Phase 2 dose
of 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide hydrate that may be
safely administered to patients ing to 2 alternative dosing schedules with coadministration
of prednisone and to document antitumor activity..
The secondary objectives of the study are to terize the safety and toxicity
profile of 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide hydrate as assessed by
National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) v4.0; to te the pharmacokinetic (PK) parameters of 4,4,4-trifluoro-N-
2-[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]
methyloxo-ethyl]butanamide hydrate; and to document any antitumor activity
observed with 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide hydrate.
Exploratory objectives are to explore renal clearance and PK lites of 4,4,4-
trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepin
yl]amino]methyloxo-ethyl]butanamide e in plasma and urine; e
predictive biomarkers related to 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)
oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide
hydrate; explore pharmacodynamic (PD) effects of 4,4,4-trifluoro-N-[(1S)[[(7S)(2-
hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxoethyl
]butanamide hydrate on biomarkers indicative of Notch activity (Notch intracellular
domain by immunohistochemistry or an alternative validated ) including
cytokeratin 18 or Rules Based Medicine; explore the utility of positron emission
tomography (PET) scan or PET/CT to assess ent effect with 4,4,4-trifluoro-N-
[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]
methyloxo-ethyl]butanamide hydrate; explore the utility of dynamic contrast enhanced
magnetic resonance imaging (DCE-MRI) to assess treatment effect with 4,4,4-trifluoro-
N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]-
1-methyloxo-ethyl]butanamide hydrate; and explore the utility of Dynamic st-
Enhanced Ultrasonography DCE-US.
Trial Drug
4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide hydrate, given orally as
capsules 3 times per week for a 28-day cycle or twice per week for 14 days followed by
TIW dosing for weeks 3 and 4 of Cycle 1 and TIW for Cycle 2 and beyond for a 28-day
cycle.
4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide hydrate will be supplied
as 25 and 50 mg capsules in bottles for oral consumption. These capsules should be
stored at room temperature within the temperature range stated on the label.
Prednisone will either be provided or obtained locally as riate and required
and administered daily at a dose of 20 mg on days 1 through 14, and may be extended
h day 28 of Cycle 1.
Planned Duration of Treatment
Patients will e 1 cycle (28 days) of 4,4,4-trifluoro-N-[(1S)[[(7S)(2-
hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxoethyl
]butanamide e unless one or more of the criteria for discontinuation are
fulfilled. A patient may receive more than 1 cycle of treatment only if: 1) none of the
criteria for discontinuation have been fulfilled, and 2) the investigator determines that the
t is experiencing clinical benefit from the treatment.
The d duration is not fixed; patients will remain on study until they fulfill
one (1) of the criteria for study discontinuation. The post-discontinuation follow-up
period begins the day after the patient and the investigator agree that the patient will no
longer continue study treatment and is defined by the following periods: The short term
follow-up period begins 1 day after discontinuation of study treatment and lasts
approximately 30 days. The long-term follow-up period begins 1 day after the short-term
-up period is completed and continues until death or study closure to collect
survival data. After discontinuation, tumor measurements and other study procedures
will be performed.
This study will be considered closed approximately 12 months from the date that
the last t was enrolled. ts who are benefitting from treatment may continue to
receive study drug for long-term durations, even after the study has closed and final
database lock has occurred in the continued access period.
Dosing
4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide hydrate will be
administered orally following one of the following schedules (decision at investigator’s
discretion):
4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
enzazepinyl]amino]methyloxo-ethyl]butanamide hydrate will be
administered orally TIW following 1 of these schedules (decision at investigator’s
discretion):
Monday, day, Friday every week for a 28-day cycle
Tuesday, ay, Saturday every week for a 28-day cycle
day, Friday, Sunday every week for a 28-day cycle
Thursday, Saturday, Monday every week for a 28-day cycle
4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide e will be
administered orally twice a week for 2 weeks in Cycle 1, followed by TIW ,
following 1 of these schedules (decision at investigator’s discretion):
For Cycle 1: Monday and Friday for Weeks 1 and 2, followed by Monday,
Wednesday, Friday for Weeks 3 and 4. For Cycle 2 and beyond: Monday, Wednesday
and Friday every week for a 28-day cycle.
For Cycle 1: Tuesday and Saturday for Weeks 1 and 2, followed by Tuesday,
Thursday, Saturday for Weeks 3 and 4. For Cycle 2 and beyond: Tuesday, Thursday,
Saturday every week for a 28-day cycle.
For Cycle 1: Wednesday and Sunday for Weeks 1 and 2, followed by
day, Friday, Sunday for Weeks 3 and 4. For Cycle 2 and beyond: Wednesday,
Friday, Sunday every week for a 28-day cycle.
For Cycle 1: Thursday and Monday for Weeks 1 and 2, followed by Thursday,
Saturday, Monday for Weeks 3 and 4. For Cycle 2 and beyond: Thursday, Saturday,
Monday every week for a 28-day cycle.
Prednisone will be administered daily on Days 1 through 14 of Cycle 1 at the
dosage of 20 mg.
Dose Escalation Phase
Dose escalation will be driven by safety using the 3+3 method.
Table 6 Proposed Dose-Escalation Scheme
Dose Loading
Level Dose (mg)
1 75
2 100
3 125
4 150
By nature of being a dose-escalation study, data will be evaluated on an ongoing
basis until the maximum tolerated dose (MTD) is ined. If the MTD has not yet
been achieved at the highest pre-specified dose level, based on both safety and the
available PK data, following discussion with investigators, additional dose levels may be
investigated.
Once the MTD has been d, the cohort-expansion phase will be opened.
This study will explore 2 alternate dosing schedules and once an MTD has been
defined for each of these alternate schedules, a cohort expansion in approximately 15
leiomyosarcoma patients with histological ce of non-resectable or metastatic
osarcoma with prescreened, immunohistochemistry (IHC), alterations in the Notch
pathway such as mutations, amplification, or gene expressions d to the Notch
y will be opened for each dosing schedule.
Criteria for Evaluation
Safety: NCI CTCAE, version 4.0, adverse events (AE) and imiting
toxicities (DLT); collection of blood and urine samples for standard laboratory tests,
including chemistry, hematology, coagulation, and urinalysis.
Bioanalytical (including PK and PD): Plasma concentrations of 4,4,4-trifluoro-N-
[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]
methyloxo-ethyl]butanamide hydrate.
Efficacy:
Efficacy will be assessed using Response tion Criteria in Solid Tumors
(RECIST) v1.1 for solid tumors. Each patient will be assessed by 1 or more of the
ing radiologic tests for tumor measurement: X-ray computerized tomography (CT)
scan; magnetic resonance imaging (MRI); chest X-ray; positron emission tomography
(PET) scan; c contrast ed-magnetic resonance imaging (DCE-MRI);
PET/CT imaging Standardized Uptake Values (SUVMAX); Dynamic Contrast-Enhanced
Ultrasonography (DCE-US).
Each patient’s full extent of disease will also be assessed with: able tumor
measurement by RECIST 1.1 (Eisenhauer et al., Eur J Cancer. 2009, 45(2): 228-247);
and Choi et al., J Clin Oncol. 2007, 25(13): 1753-1759; and evaluation of performance
status by ECOG, Oken et al., Am J Clin Oncol. 1982, 5: 649-655.. To confirm objective
responses, all lesions should be radiologically assessed, and the same radiologic method
used for the initial response determination should be repeated at least 4 weeks following
the initial observation of an objective response, using the sample method that was used at
baseline. l metabolic response by PET scan is defined as a minimum of 15±25% in
tumor [18F]-FDG SUV after one cycle of therapy, and greater than 25% after more than
one treatment cycle and should be med at least 4 weeks later, according to PET
response criteria of the European Organization for Research and Treatment of Cancer
(Young et al., Eur J Cancer, 1999, Dec, 35(13): 1773-82.
Statistical Methods
Safety: Dose escalation will be driven by safety using the 3+3 method. Modelbased
analyses that incorporate prior expectations about the dose-toxicity curve will be
fitted to the data at the end of each cohort, which will be used by investigators and Lilly
clinical research physician to ine the next dose level. The maximum tolerated dose
is defined as the highest tested dose that has less than 33% probability of causing a DLT
during Cycle 1.
cy: Tumor response data will be ted and summarized by study part.
Pharmacokinetics: PK parameters for 4,4,4-trifluoro-N-[(1S)[[(7S)(2-
yethyl)oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-
ethyl]butanamide hydrate will be analyzed by standard non-compartmental methods of
analysis.
Pharmacodynamics: All PD data will be assessed. Exploratory PK/PD analyses
may be conducted to identify the exposure-biomarker se relationship.
Exploratory Samples: Blood s will be ted for exploratory analysis of
circulating Amyloid beta (Aβ) peptides before and after treatment. A mandatory tumor
tissue sample and a skin punch sample obtained previously, within two years of the date
of enrollment, or a fresh sample if no archival sample can be located for measuring
various biomarkers, potentially including gene-expression profiling as well as other
atory biomarkers. Pre- and post-dose tumor and skin es will also be collected
for analysis.
The following numbered paragraphs define particular aspects of the present
disclosure:
1. A method of treating a solid tumor cancer patient comprising administering to a
patient in need of treatment 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)
oxo-7H-pyrido[2,3-d][3]benzazepinyl]amino]methyloxoethyl
]butanamide or a pharmaceutically acceptable salt or hydrate thereof,
wherein
a. a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose
stered twice or three times per week during a 28 day cycle;
followed by
b. a maintenance dose of 50 mg/dose stered three times per week; and
optionally
c. administering, during administration of the loading dose, 1-50 mg/day of a
corticosteroid.
2. The method of paragraph 1 n a loading dose of at least one and up to 6
doses is administered.
3. The method of paragraph 1 wherein a loading dose of at least one and up to 3
doses is administered.
4. A compound 4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-
pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide, or a
pharmaceutically acceptable salt or hydrate f, for use in the treatment of a
solid tumor cancer , n said compound or a pharmaceutically acceptable salt
or hydrate thereof is administered:
a. at a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose
administered twice or three times per week during a 28 day cycle;
followed by
b. a maintenance dose of 50 e administered three times per week; and
optionally
c. administering, during stration of the loading dose, 1-50 mg/day of a
corticosteroid.
. The treatment of paragraph 4 wherein said loading dose is at least one dose and up
to 6 doses.
6. The treatment of paragraph 4 wherein said loading dose is at least one dose and up
to 3 doses.
7. Use of 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3-
d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide, or a
pharmaceutically acceptable salt or hydrate thereof, for preparation of a
medicament for treatment of a solid tumor cancer wherein said medicament is
administered:
a) at a loading dose of at least one dose and up to 12 doses at 75-150
mg/dose administered twice or three times per week during a 28 day cycle;
followed by
b) a maintenance dose of 50 mg/dose administered three times per week; and
optionally
c) administering, during administration of the loading dose, 1-50 mg/day of a
osteroid.
8. The use of paragraph 7 wherein said loading dose is at least one dose and up to 6
doses.
9. The use of paragraph 7 n said loading dose is at least one dose and up to 3
doses.
Claims (32)
1. A compound 4,4,4-Trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H- pyrido[2,3-d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide, or a 5 pharmaceutically acceptable salt or hydrate f, for use in the treatment of a solid tumor cancer, wherein said compound or the pharmaceutically acceptable salt or hydrate thereof is to be stered: a. at a g dose of at least one dose and up to 12 doses at 75-150 mg/dose twice or three times per week for at least one week during a 28 day cycle; 10 followed by b. a maintenance dose of 50 mg/dose three times per week.
2. The compound or the pharmaceutically acceptable salt or e f of claim 1, wherein, during the stration of the loading dose, 1-80 mg/day of a corticosteroid is to be administered for one or more days of the 28 day cycle. 15
3. The compound or the pharmaceutically acceptable salt or hydrate thereof of claim 2, wherein the corticosteroid is to be administered at a dose of 1-50 mg/day.
4. The compound or the pharmaceutically able salt or hydrate thereof of claim 2 or claim 3, wherein the corticosteroid is to be administered at a dose of 20 20
5. The compound or the pharmaceutically acceptable salt or hydrate thereof of claim 2 or claim 3, wherein the corticosteroid is to be administered at a dose of 20
6. The compound or the pharmaceutically acceptable salt or hydrate thereof of any one of claims 2-5, wherein the corticosteroid is selected from the group consisting 25 of hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone.
7. The compound or the pharmaceutically acceptable salt or hydrate thereof of claim 6, wherein the corticosteroid is prednisone.
8. The compound or the pharmaceutically acceptable salt or hydrate thereof of any 30 one of claims 1-7 wherein the loading dose is at least one dose and up to 6 doses.
9. The compound or the pharmaceutically acceptable salt or hydrate thereof of any one of claims 1-7 wherein the loading dose is at least one dose and up to 3 doses.
10. The compound or the pharmaceutically acceptable salt or e thereof of any one of claims 1-8, wherein the loading dose is to be administered for two weeks of 5 the 28 day cycle.
11. The compound or the pharmaceutically acceptable salt or hydrate thereof of any one of claims 1-10, wherein the loading dose is to be administered two times per week.
12. The compound or the pharmaceutically able salt or hydrate thereof of any 10 one of claims 1-10, wherein the loading dose is to be administered three times per week.
13. The compound or the pharmaceutically acceptable salt or hydrate thereof of any one of claims 1-12, wherein the loading dose is to be administered at 75 mg/dose.
14. The compound or the ceutically acceptable salt or e thereof of any 15 one of claims 1-12, wherein the loading dose is to be administered at 100 mg/dose.
15. The compound or the pharmaceutically acceptable salt or hydrate thereof of any one of claims 1-4, wherein the maintenance dose is to be administered over any remaining days of the 28 day cycle following administration of the loading dose 20 and, optionally, over one or more additional 28 day cycles.
16. The compound or the pharmaceutically acceptable salt or hydrate f of any one of claims 1-15, n said solid tumor cancer is selected from the group consisting of triple negative breast , breast cancer, ovarian , melanoma, lung cancer, non-small cell lung cancer, pancreatic cancer, 25 glioblastoma, ctal cancer, head and neck cancer, cervical cancer, prostate cancer, liver cancer, oral squamous cell carcinoma, skin , medulloblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic cholangiocarcinoma, desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and adenoid cystic carcinoma. 30
17. Use of 4,4,4-trifluoro-N-[(1S)[[(7S)(2-hydroxyethyl)oxo-7H-pyrido[2,3- d][3]benzazepinyl]amino]methyloxo-ethyl]butanamide, or a pharmaceutically acceptable salt or hydrate thereof, in the cture of a medicament for the treatment of a solid tumor cancer, wherein said medicament is to be administered: a) at a loading dose of at least one dose and up to 12 doses at 75-150 mg/dose 5 twice or three times per week for at least one week during a 28 day cycle; followed by b) a maintenance dose of 50 mg/dose three times per week.
18. The use of claim 17, wherein, during the administration of the loading dose, 1-80 mg/day of a corticosteroid is to be administered for one or more days of the 28 10 day cycle.
19. The use of claim 18, n the corticosteroid is to be administered at a dose of 1-50 mg/day.
20. The use of claim 18 or claim 19, wherein the corticosteroid is to be administered at a dose of 20 mg/day. 15
21. The use of any one of claims 18-20, wherein the osteroid is to be administered for at least 14 days of the 28 day cycle.
22. The use of any one of claims 18-21, wherein the corticosteroid is selected from the group consisting of hydrocortisone, hydrocortisone e, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, and prednisone. 20
23. The use of claim 22, wherein the corticosteroid is prednisone.
24. The use of any one of claims 17-23 wherein the loading dose is at least one dose and up to 6 doses.
25. The use of any one of claims 17-23 wherein the loading dose is at least one dose and up to 3 doses. 25
26. The use of any one of claims 17-24, wherein the loading dose is to be administered for two weeks of the 28 day cycle.
27. The use of any one of claims 17-26, n the g dose is to be administered two times per week.
28. The use of any one of claims 17-26, wherein the loading dose is to be 30 administered three times per week.
29. The use of any one of claims 17-28, wherein the loading dose is to be administered at 75 mg/dose.
30. The use of any one of claims 17-28, wherein the loading dose is to be administered at 100 mg/dose. 5
31. The use of any one of claims 17-30, wherein the maintenance dose is to be administered over any ing days of the 28 day cycle following administration of the loading dose and, optionally, over one or more additional 28 day cycles.
32. The use of any one of claims 17-31, wherein said solid tumor cancer is ed 10 from the group consisting of triple negative breast cancer, breast cancer, ovarian , melanoma, lung cancer, non-small cell lung cancer, atic cancer, glioblastoma, colorectal cancer, head and neck cancer, cervical cancer, prostate cancer, liver cancer, oral us cell carcinoma, skin cancer, medulloblastoma, hepatocellular carcinoma, intrahepatic and extrahepatic cholangiocarcinoma, 15 desmoid tumor, soft tissue sarcoma, leiomyosarcoma, and adenoid cystic carcinoma.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US62/381,911 | 2016-08-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ791442A true NZ791442A (en) | 2022-08-26 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017321011B2 (en) | Dosage regimen for treatment of solid tumors | |
JP6963146B1 (en) | Administration of KRAS inhibitors to treat cancer | |
TWI631950B (en) | Treatment of cancer with dihydropyrazino-pyrazines | |
WO2018107173A1 (en) | Glutamine transport inhibitors and methods for treating cancer | |
JP2023107801A (en) | combination therapy | |
EA029072B1 (en) | Combination therapy comprising a dihydropyrazino-pyrazine compound and an androgen receptor antagonist for treating prostate cancer | |
BR112021002963A2 (en) | Agnostic Methods of Platelet Counting of Myelofibrosis Treatment | |
WO2019165458A1 (en) | Methods of treatment of cancer comprising chk1 inhibitors | |
CN112955130A (en) | Solid dispersions and pharmaceutical compositions comprising substituted indanes and methods of making and using the same | |
JP2022500479A (en) | Treatment of Cancer Containing CDC7 Inhibitors | |
NZ791442A (en) | Dosage regimen for treatment of solid tumors | |
JP2021519285A (en) | Triple combination of pharmaceuticals containing dabrafenib, trametinib and ERK inhibitors | |
US20230233567A1 (en) | Belvarafenib for use in cancer treatment | |
US20230358726A1 (en) | Non-invasive functional companion assays for oncogene targeted therapy for brain cancer | |
ES2726401T3 (en) | Use of HDAC inhibitors for the treatment of bone destruction | |
WO2020232154A2 (en) | Methods of treating cancer using chk1 inhibitors | |
US20240165112A1 (en) | Therapy for the treatment of cancer | |
US20230095428A1 (en) | [6r]-mthf in 5-fu based chemotherapy of braf- or kras-mutated colorectal cancer | |
JP2010111582A (en) | Therapeutic agent for liver cancer comprising rifampicin as component |