JPWO2019191279A5 - - Google Patents
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- JPWO2019191279A5 JPWO2019191279A5 JP2020551912A JP2020551912A JPWO2019191279A5 JP WO2019191279 A5 JPWO2019191279 A5 JP WO2019191279A5 JP 2020551912 A JP2020551912 A JP 2020551912A JP 2020551912 A JP2020551912 A JP 2020551912A JP WO2019191279 A5 JPWO2019191279 A5 JP WO2019191279A5
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Description
[本発明1001]
対象においてがんを治療する方法であって、有効量のポジオチニブを該対象に投与する工程を含み、該対象が1つ以上のＨＥＲ2エクソン19変異を有すると判定されている、前記方法。
[本発明1002]
前記1つ以上のＨＥＲ2エクソン19変異が、ＨＥＲ2のアミノ酸668～769における、点変異、挿入、および／または1～18個のヌクレオチドの欠失を含む、本発明1001の方法。
[本発明1003]
前記1つ以上のＨＥＲ2エクソン19変異が、ＨＥＲ2点変異としてさらに定義される、本発明1001の方法。
[本発明1004]
前記対象が、2つ、3つ、または4つのＨＥＲ2エクソン19変異を有すると判定されている、本発明1001の方法。
[本発明1005]
前記1つ以上のＨＥＲ2エクソン19変異が、Ｒ668、Ｒ678、Ｖ754、Ｌ755、Ｉ767、およびＤ769からなる群より選択される1つ以上の残基にある、本発明1002の方法。
[本発明1006]
前記1つ以上のＨＥＲ2エクソン19変異が、Ｒ668Ｑ、Ｒ678Ｑ、Ｖ754Ｍ、Ｌ755Ｐ、Ｌ755Ｓ、Ｌ755Ｗ、Ｄ769Ｈ、Ｄ769Ｎ、Ｉ767Ｍ、およびＤ769Ｙからなる群より選択される、本発明1001～1005のいずれかの方法。
[本発明1007]
前記エクソン19変異がＬ755Ｐである、本発明1001の方法。
[本発明1008]
患者由来のゲノム試料を分析することにより、前記対象がＨＥＲ2エクソン19変異を有すると判定されている、本発明1001～1007のいずれかの方法。
[本発明1009]
前記ゲノム試料が、唾液、血液、尿、正常組織、または腫瘍組織から単離される、本発明1009の方法。
[本発明1010]
ＨＥＲ2エクソン19変異の存在が、核酸配列決定またはＰＣＲ分析によって判定される、本発明1001～1007のいずれかの方法。
[本発明1011]
さらなる抗がん療法を施す工程をさらに含む、本発明1001の方法。
[本発明1012]
前記さらなる抗がん療法が、化学療法、放射線療法、遺伝子療法、手術、ホルモン療法、抗血管新生療法、または免疫療法である、本発明1011の方法。
[本発明1013]
ポジオチニブおよび／または前記抗がん療法が、静脈内、皮下、骨内、経口、経皮、持続型放出にて、制御型放出にて、遅延型放出にて、坐剤として、または舌下に、投与される、本発明1011の方法。
[本発明1014]
ポジオチニブおよび／または前記抗がん療法の投与が、局所投与、局部投与、または全身投与を含む、本発明1011の方法。
[本発明1015]
ポジオチニブおよび／または前記抗がん療法が2回以上施される、本発明1011の方法。
[本発明1016]
ポジオチニブが経口投与される、本発明1001の方法。
[本発明1017]
ポジオチニブが5～25ｍｇの用量で投与される、本発明1001の方法。
[本発明1018]
ポジオチニブが、8ｍｇ、12ｍｇ、または16ｍｇの用量で投与される、本発明1001の方法。
[本発明1019]
ポジオチニブが毎日投与される、本発明1001の方法。
[本発明1020]
ポジオチニブが継続的に投与される、本発明1019の方法。
[本発明1021]
ポジオチニブが28日サイクルで投与される、本発明1019の方法。
[本発明1022]
前記がんが、口腔がん、中咽頭がん、上咽頭がん、呼吸器がん、泌尿生殖器がん、消化器がん、中枢もしくは末梢神経系組織のがん、内分泌もしくは神経内分泌がんまたは造血系のがん、神経膠腫、肉腫、がん腫、リンパ腫、黒色腫、線維腫、髄膜腫、脳がん、中咽頭がん、上咽頭がん、腎臓がん、胆道がん、褐色細胞腫、膵島細胞がん、リー・フラウメニ腫瘍、甲状腺がん、副甲状腺がん、下垂体腫瘍、副腎腫瘍、骨肉腫、多発性神経内分泌腫瘍Ｉ型およびＩＩ型、乳がん、肺がん、頭頸部がん、前立腺がん、食道がん、気管がん、肝臓がん、膀胱がん、胃がん、膵臓がん、卵巣がん、子宮がん、子宮頸がん、精巣がん、結腸がん、直腸がん、または皮膚がんである、本発明1001～1015のいずれかの方法。
[本発明1023]
前記がんが非小細胞肺がん（ＮＳＣＬＣ）である、本発明1001～1015のいずれかの方法。
[本発明1024]
前記がんが結腸直腸がんである、本発明1001～1015のいずれかの方法。
[本発明1025]
前記対象がヒトである、本発明1001～1015のいずれかの方法。
[本発明1026]
1つ以上のＨＥＲ2エクソン19変異を有すると判定された対象において使用するための、ポジオチニブを含む薬学的組成物。
[本発明1027]
前記1つ以上のＨＥＲ2エクソン19変異が、アミノ酸668～769における、点変異、挿入、および／または1～18個のヌクレオチドの欠失を含む、本発明1026の組成物。
[本発明1028]
前記1つ以上のＨＥＲ2エクソン19変異が、ＨＥＲ2点変異としてさらに定義される、本発明1026の組成物。
[本発明1029]
前記対象が、2つ、3つ、または4つのＨＥＲ2エクソン19変異を有すると判定されている、本発明1026の組成物。
[本発明1030]
前記1つ以上のＨＥＲ2エクソン19変異が、Ｒ668、Ｒ678、Ｖ754、Ｌ755、Ｉ767、およびＤ769からなる群より選択される1つ以上の残基にある、本発明1028の組成物。
[本発明1031]
前記1つ以上のＨＥＲ2エクソン19変異が、Ｒ668Ｑ、Ｒ678Ｑ、Ｖ754Ｍ、Ｌ755Ｐ、Ｌ755Ｓ、Ｌ755Ｗ、Ｄ769Ｈ、Ｄ769Ｎ、Ｉ767Ｍ、およびＤ769Ｙからなる群より選択される、本発明1026の組成物。
[本発明1032]
前記対象が抗がん療法によって治療されている、本発明1026の組成物。
[本発明1033]
がんを有する対象におけるポジオチニブ単独または第2の抗がん療法との組み合わせに対する応答性を予測する方法であって、患者から得られたゲノム試料におけるＨＥＲ2エクソン19変異を検出する工程を含み、該試料がＨＥＲ2エクソン19変異の存在について陽性である場合に、該患者がポジオチニブ単独または抗がん療法との組み合わせに対して好ましい応答性を有すると予測される、前記方法。
[本発明1034]
前記ＨＥＲ2エクソン19変異が、ＨＥＲ2エクソン19点変異としてさらに定義される、本発明1033の方法。
[本発明1035]
前記ゲノム試料が、唾液、血液、尿、正常組織、または腫瘍組織から単離される、本発明1033の方法。
[本発明1036]
前記ＨＥＲ2エクソン19変異の存在が、核酸配列決定またはＰＣＲ分析によって判定される、本発明1033の方法。
[本発明1037]
前記ＨＥＲ2エクソン19変異が、アミノ酸668～769における、点変異、挿入、および／または1～18個のヌクレオチドの欠失を含む、本発明1036の方法。
[本発明1038]
前記1つ以上のＨＥＲ2エクソン19変異が、Ｒ668、Ｒ678、Ｖ754、Ｌ755、Ｉ767、およびＤ769からなる群より選択される1つ以上の残基にある、本発明1037の方法。
[本発明1039]
前記1つ以上のＨＥＲ2エクソン19変異が、Ｒ668Ｑ、Ｒ678Ｑ、Ｖ754Ｍ、Ｌ755Ｐ、Ｌ755Ｓ、Ｌ755Ｗ、Ｄ769Ｈ、Ｄ769Ｎ、Ｉ767Ｍ、およびＤ769Ｙからなる群より選択される、本発明1033～1038のいずれかの方法。
[本発明1040]
ポジオチニブ単独または抗がん療法との組み合わせに対する好ましい応答性が、腫瘍の大きさもしくは腫瘍量の減少、腫瘍成長の阻害、腫瘍関連疼痛の軽減、がん関連病態の軽減、がん関連症状の軽減、がんの非進行、無病期間の延長、進行までの期間の延長、寛解の誘導、転移の減少、または患者の生存性の向上を含む、本発明1033の方法。
[本発明1041]
好ましい応答性を有すると予測された前記患者に、ポジオチニブを単独でまたは第2の抗がん療法と組み合わせて投与する工程をさらに含む、本発明1033～1041のいずれかの方法。
[本発明1042]
（ａ）ヒトがん細胞から単離された核酸；および
（ｂ）ヒトＨＥＲ2コード配列の変異を有するエクソン19の少なくとも第1の部分を増幅できるプライマー対
を含む、組成物。
[本発明1043]
前記配列中に変異が存在する場合に、前記ヒトＨＥＲコード配列のエクソン19の第1の部分に特異的にハイブリダイズすることができる、標識されたプローブ分子をさらに含む、本発明1042の組成物。
[本発明1044]
熱安定性ＤＮＡポリメラーゼをさらに含む、本発明1042の組成物。
[本発明1045]
ｄＮＴＰをさらに含む、本発明1042の組成物。
[本発明1046]
Ｒ668Ｑ、Ｒ678Ｑ、Ｖ754Ｍ、Ｌ755Ｐ、Ｌ755Ｓ、Ｌ755Ｗ、Ｄ769Ｈ、Ｄ769Ｎ、Ｉ767Ｍ、およびＤ769Ｙからなる群より選択される変異が存在する場合に、前記標識されたプローブが、前記ヒトＨＥＲ2コード配列のエクソン19の第1の部分にハイブリダイズする、本発明1043～1045のいずれかの組成物。
[本発明1047]
変異ＨＥＲ2タンパク質をコードする単離された核酸であって、該変異タンパク質が、アミノ酸668～769における、1つ以上の点変異、挿入、および／または1～18個のヌクレオチドの欠失を含む1つ以上のＨＥＲ2エクソン19変異だけ、野生型ヒトＨＥＲ2と異なる、前記単離された核酸。
[本発明1048]
前記1つ以上のＨＥＲ2エクソン19変異が、残基Ｒ668、Ｒ678、Ｖ754、Ｌ755、Ｉ767、および／またはＤ769にある、本発明1047の単離された核酸。
[本発明1049]
前記1つ以上のＨＥＲ2エクソン19変異が、Ｒ668Ｑ、Ｒ678Ｑ、Ｖ754Ｍ、Ｌ755Ｐ、Ｌ755Ｓ、Ｌ755Ｗ、Ｄ769Ｈ、Ｄ769Ｎ、Ｉ767Ｍ、およびＤ769Ｙからなる群より選択される、本発明1047または1048の単離された核酸。
本発明の他の目的、特徴、および利点は、以下の詳細な説明から明らかとなるだろう。しかしながら、本明細書の詳細な説明から、本発明の精神および範囲の範囲内でのさまざまな変更および修飾が当業者には明らかとなることから、詳細な説明および特定の実施例は、本発明の好ましい実施形態を示すものではあるが、例示のみを目的としていることが理解されるべきである。
[Invention 1001]
A method of treating cancer in a subject comprising administering to the subject an effective amount of positiveotinib, wherein the subject has been determined to have one or more HER2 exon 19 mutations.
[Invention 1002]
The method of the invention 1001 wherein the one or more HER2 exon 19 mutations comprise a point mutation, insertion, and / or deletion of 1-18 nucleotides at amino acids 668-769 of HER2.
[Invention 1003]
The method of the present invention 1001 wherein the one or more HER2 exon 19 mutations are further defined as HER2 point mutations.
[Invention 1004]
The method of the invention 1001 wherein the subject has been determined to have two, three, or four HER2 exon 19 mutations.
[Invention 1005]
The method of the invention 1002, wherein the one or more HER2 exon 19 mutations are in one or more residues selected from the group consisting of R668, R678, V754, L755, I767, and D769.
[Invention 1006]
The method of any of 1001-1005 of the present invention, wherein the one or more HER2 exon 19 mutations are selected from the group consisting of R668Q, R678Q, V754M, L755P, L755S, L755W, D769H, D769N, I767M, and D769Y.
[Invention 1007]
The method of the present invention 1001 wherein the exon 19 mutation is L755P.
[Invention 1008]
The method of any of 1001-1007 of the present invention, wherein the subject has been determined to have the HER2 exon 19 mutation by analyzing a genomic sample derived from a patient.
[Invention 1009]
The method of the present invention 1009, wherein the genomic sample is isolated from saliva, blood, urine, normal tissue, or tumor tissue.
[Invention 1010]
The method of any of 1001-1007 of the present invention, wherein the presence of the HER2 exon 19 mutation is determined by nucleic acid sequencing or PCR analysis.
[Invention 1011]
The method of the present invention 1001 further comprising the step of applying further anti-cancer therapy.
[Invention 1012]
The method of the invention 1011, wherein the further anti-cancer therapy is chemotherapy, radiation therapy, gene therapy, surgery, hormone therapy, anti-angiogenic therapy, or immunotherapy.
[Invention 1013]
Podiotinib and / or said anti-cancer therapy can be given intravenously, subcutaneously, intraosseously, orally, transdermally, with sustained release, with controlled release, with delayed release, as a suppository, or sublingually. , Administered, the method of the present invention 1011.
[Invention 1014]
The method of the present invention 1011, wherein administration of pogiotinib and / or said anti-cancer therapy comprises local administration, local administration, or systemic administration.
[Invention 1015]
The method of the present invention 1011, wherein the pogiotinib and / or the anti-cancer therapy is given more than once.
[Invention 1016]
The method of the present invention 1001 in which pogiotinib is orally administered.
[Invention 1017]
The method of the present invention 1001 in which pogiotinib is administered at a dose of 5-25 mg.
[Invention 1018]
The method of the present invention 1001 in which pogiotinib is administered at a dose of 8 mg, 12 mg, or 16 mg.
[Invention 1019]
The method of the present invention 1001 in which pogiotinib is administered daily.
[Invention 1020]
The method of the present invention 1019, wherein pogiotinib is continuously administered.
[Invention 1021]
The method of the present invention 1019, wherein pogiotinib is administered in a 28-day cycle.
[Invention 1022]
The cancers are oral cancer, mesopharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, gastrointestinal cancer, cancer of central or peripheral nervous system tissue, endocrine or neuroendocrine cancer. Or hematopoietic cancer, glioma, sarcoma, cancer, lymphoma, melanoma, fibroma, meningitis, brain cancer, mesopharyngeal cancer, nasopharyngeal cancer, kidney cancer, biliary tract cancer , Brown cell tumor, pancreatic islet cell cancer, Lee Fraumeni tumor, thyroid cancer, parathyroid cancer, pituitary tumor, adrenal tumor, osteosarcoma, multiple neuroendocrine tumor types I and II, breast cancer, lung cancer, head and neck Partial cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testis cancer, colon cancer , Rectal cancer, or skin cancer, any of the methods 1001-1015 of the present invention.
[Invention 1023]
The method of any of 1001-1015 of the present invention, wherein the cancer is non-small cell lung cancer (NSCLC).
[Invention 1024]
The method of any of 1001 to 1015 of the present invention, wherein the cancer is colorectal cancer.
[Invention 1025]
The method of any of 1001 to 1015 of the present invention, wherein the subject is a human.
[Invention 1026]
A pharmaceutical composition comprising a positive otinib for use in a subject determined to have one or more HER2 exon 19 mutations.
[Invention 1027]
The composition of the invention 1026, wherein the one or more HER2 exon 19 mutations comprise a point mutation, insertion, and / or deletion of 1-18 nucleotides at amino acids 668-769.
[Invention 1028]
The composition of the invention 1026, wherein the one or more HER2 exon 19 mutations are further defined as HER2 point mutations.
[Invention 1029]
The composition of the invention 1026, wherein the subject has been determined to have two, three, or four HER2 exon 19 mutations.
[Invention 1030]
The composition of the invention 1028, wherein the one or more HER2 exon 19 mutations are in one or more residues selected from the group consisting of R668, R678, V754, L755, I767, and D769.
[Invention 1031]
The composition of the invention 1026, wherein the one or more HER2 exon 19 mutations are selected from the group consisting of R668Q, R678Q, V754M, L755P, L755S, L755W, D769H, D769N, I767M, and D769Y.
[Invention 1032]
The composition of the invention 1026, wherein the subject is being treated with anti-cancer therapy.
[Invention 1033]
A method of predicting responsiveness to positiveotinib alone or in combination with a second anticancer therapy in a subject with cancer, comprising detecting a HER2 exon 19 mutation in a genomic sample obtained from a patient. The method described above, wherein the patient is expected to have a favorable response to positiveotinib alone or in combination with anti-cancer therapy if the sample is positive for the presence of the HER2 exon 19 mutation.
[Invention 1034]
The method of the present invention 1033, wherein the HER2 exon 19 mutation is further defined as a HER2 exon 19 point mutation.
[Invention 1035]
The method of the present invention 1033, wherein the genomic sample is isolated from saliva, blood, urine, normal tissue, or tumor tissue.
[Invention 1036]
The method of the present invention 1033, wherein the presence of the HER2 exon 19 mutation is determined by nucleic acid sequencing or PCR analysis.
[Invention 1037]
The method of the invention 1036, wherein the HER2 exon 19 mutation comprises a point mutation, insertion, and / or deletion of 1-18 nucleotides at amino acids 668-769.
[Invention 1038]
The method of the invention 1037, wherein the one or more HER2 exon 19 mutations are in one or more residues selected from the group consisting of R668, R678, V754, L755, I767, and D769.
[Invention 1039]
The method of any of the present inventions 1033-1038, wherein the one or more HER2 exon 19 mutations are selected from the group consisting of R668Q, R678Q, V754M, L755P, L755S, L755W, D769H, D769N, I767M, and D769Y.
[Invention 1040]
Preferred responsiveness to pogiotinib alone or in combination with anticancer therapy is reduced tumor size or volume, inhibition of tumor growth, reduction of tumor-related pain, reduction of cancer-related conditions, reduction of cancer-related symptoms. The method of the present invention 1033, comprising non-progression of cancer, prolongation of disease-free period, prolongation of time to progression, induction of remission, reduction of metastasis, or improvement of patient viability.
[Invention 1041]
The method of any of 1033-1041 of the present invention, further comprising the step of administering positiveotinib alone or in combination with a second anti-cancer therapy to said patient predicted to have favorable responsiveness.
[Invention 1042]
(A) Nucleic acid isolated from human cancer cells; and
(B) A primer pair capable of amplifying at least the first portion of exon 19 having a mutation in the human HER2 coding sequence.
A composition comprising.
[Invention 1043]
The composition of 1042 of the invention further comprising a labeled probe molecule capable of specifically hybridizing to the first portion of exon 19 of the human HER coding sequence when a mutation is present in the sequence. ..
[Invention 1044]
The composition of the invention 1042 further comprising a thermostable DNA polymerase.
[Invention 1045]
The composition of 1042 of the present invention further comprising dNTP.
[Invention 1046]
In the presence of mutations selected from the group consisting of R668Q, R678Q, V754M, L755P, L755S, L755W, D769H, D769N, I767M, and D769Y, the labeled probe is the exon 19 of the human HER2 coding sequence. The composition of any of 1043-1045 of the present invention, which hybridizes to the first moiety.
[Invention 1047]
An isolated nucleic acid encoding a mutant HER2 protein, wherein the mutant protein comprises one or more point mutations, insertions, and / or deletions of 1-18 nucleotides at amino acids 668-769 1 The isolated nucleic acid that differs from wild-type human HER2 by only one or more HER2 exon 19 mutations.
[Invention 1048]
The isolated nucleic acid of the invention 1047, wherein the one or more HER2 exon 19 mutations are in residues R668, R678, V754, L755, I767, and / or D769.
[Invention 1049]
The isolated nucleic acid of the invention 1047 or 1048, wherein the one or more HER2 exon 19 mutations are selected from the group consisting of R668Q, R678Q, V754M, L755P, L755S, L755W, D769H, D769N, I767M, and D769Y. ..
Other objects, features, and advantages of the invention will become apparent from the detailed description below. However, since the detailed description of the present specification reveals to those skilled in the art various changes and modifications within the spirit and scope of the invention, detailed description and specific examples are provided in the present invention. Although presenting a preferred embodiment of the above, it should be understood that it is intended for illustration purposes only.
Claims (13)
Applications Claiming Priority (5)
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| US62/688,049 | 2018-06-21 | ||
| PCT/US2019/024353 WO2019191279A2 (en) | 2018-03-27 | 2019-03-27 | Compounds with anti-tumor activity against cancer cells bearing her2 exon 19 mutations |
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| JPWO2019191279A5 true JPWO2019191279A5 (en) | 2022-04-01 |
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| EP (1) | EP3773551A4 (en) |
| JP (1) | JP7386174B2 (en) |
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| WO2020132633A1 (en) * | 2018-12-21 | 2020-06-25 | Board Of Regents, The University Of Texas System | Combination therapy for the treatment of cancer |
| JP2022527788A (en) * | 2019-03-29 | 2022-06-06 | ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム | Compounds with antitumor activity against cancer cells with EGFR or HER2 exon 20 insertion |
| MX2021012705A (en) * | 2019-04-17 | 2021-11-12 | Univ Texas | Compounds against cancer bearing tyrosine kinase inhibitor resistant egfr mutations. |
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