WO2022121929A1 - Use of pyrido[1,2-a]pyrimidinone compound in treating gynaecological tumors - Google Patents
Use of pyrido[1,2-a]pyrimidinone compound in treating gynaecological tumors Download PDFInfo
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- WO2022121929A1 WO2022121929A1 PCT/CN2021/136363 CN2021136363W WO2022121929A1 WO 2022121929 A1 WO2022121929 A1 WO 2022121929A1 CN 2021136363 W CN2021136363 W CN 2021136363W WO 2022121929 A1 WO2022121929 A1 WO 2022121929A1
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- pharmaceutically acceptable
- treatment
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- acceptable salt
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present application belongs to the field of medicinal chemistry, and relates to the use of pyrido[1,2-a]pyrimidinone compounds for treating gynecological tumors.
- the PI3K pathway is the most frequently mutated place in human cancer cells, leading to cell proliferation, activation, and signal amplification.
- PI3K kinase (phosphatidylinositol-3-kinase, PI3Ks) belongs to the family of lipid kinases, which can phosphorylate the 3'-OH end of the inositol ring of phosphatidylinositol, which is a regulatory subunit of phosphatidylinositol.
- PIP2 phosphatidylinositol 4,5-bisphosphate
- PIP3 phosphatidylinositol 3,4,5-triphosphate
- the tumor suppressor gene PTEN (phosphatase and tension homolog deleted on chromosome ten) dephosphorylates PIP3 to generate PIP2, thereby realizing the negative regulation of PI3K/Akt signaling pathway, inhibiting cell proliferation and promoting cell apoptosis.
- PTEN phosphatase and tension homolog deleted on chromosome ten
- WO2015192760 discloses a series of compounds as PI3K inhibitors, and also specifically discloses the compound of formula I with the following structure:
- the application provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of gynecological tumors:
- the present application provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of gynecological tumors.
- the application provides a method of treating a gynecological tumor, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
- a compound of formula I of the application is used as the single active agent.
- the compound of formula I, or a pharmaceutically acceptable salt thereof, of the application may be in the form of a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition is a single dose pharmaceutical composition.
- the present application provides a pharmaceutical composition for treating gynecological tumors, the pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof.
- the application provides a method of treating gynecological tumors, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
- the application provides a kit for the treatment of gynecological tumors, the kit comprising the compound of formula I described in the application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, preferably in a single dose form; and instructions for use.
- the gynecological tumor is selected from recurrent or metastatic gynecological tumors. In some aspects, the gynecological tumor comprises Stage I, Stage II, Stage III, and/or Stage IV.
- the gynecological tumor is selected from locally advanced recurrent or metastatic gynecological tumors.
- the gynecological tumor is selected from gynecological tumors in which the PIK3CA, PIK3R1 or PIK3R2 genes are altered.
- the PIK3CA, PIK3R1 or PIK3R2 gene is altered to a mutation, deletion, splicing, fusion, insertion, duplication, or amplification of the PIK3CA, PIK3R1 or PIK3R2 gene.
- the PIK3CA gene alteration occurs in any exon of the gene. In some aspects of the application, the PIK3CA gene alteration comprises an alteration that occurs in exons 1, 2, 5, 7, 9 or 20. In some aspects of the application, the PIK3CA gene alteration comprises one or more of the following site mutations: Q60K, R88Q, E110K, K111N, R263Q, R277W, R278W, K331E, K333N, N345K, G353D, S405F, E418K, E453K , P539R, E542K/Q/V/G, Q546E/H/K/L/P/R, E545A/D/G/K/Q/V, F909L, Y1021C/H/H, T1025A/S, M1043I/V including one or more of the following sites or fragments; Deletion of: W11_P18, G106_N107,
- the PIK3R1 gene alteration comprises one or more of the following site mutations: A10T/V, S102L, E109K, A201V, I220F, Q221E, G376R/E, K379N/E, S429Y, D440G, I442S , Y452C/N, Q457P, D464N, R465T, R503Q, R514C, R557P, E558Q, I559T/V, D560H/G/Y, N564D/K, S565N/R, K567E, P568T, D569G, L570P, L573P, R574I/T /S, R577K, Y580D/C/N, L584F, W624C, E635K, F646S, R649W, N711S, or V718A; including one or more of the following site or fragment insertion
- the PIK3R2 gene alteration comprises one or more of the following site mutations: F15V, G28S, G103V, L127I, A298V, Y331C, D334Tfs*7, G373R, K376E, I378S, G385W, S390P, R406H , K435N, M476I, E499D, C501F, R531P, R539H, D557Y/N/H, N561D, K564E, P565S, R571H, R647C, or G722Afs*152; includes splice at any of the following: X431_splice, X473_splice, or X603_splice ; includes fusions of the form: PIK3R2-EEF1A2.
- the gynecological tumor is selected from recurrent or metastatic gynecological tumors in which the PIK3CA, PIK3R1 or PIK3R2 genes are altered. In some aspects of the application, the gynecologic tumor is selected from locally advanced recurrent or metastatic gynecologic tumors in which the PIK3CA, PIK3R1, or PIK3R2 genes are altered.
- the gynecological tumor patients are selected from patients with disease progression, recurrence or metastasis after previous treatment with platinum-containing regimens.
- the gynecological tumor patients are selected from patients with disease progression, locally advanced recurrence or metastasis after previous treatment with platinum-containing regimens.
- the gynecological tumor patient is selected from patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations, and patients with disease progression, locally advanced recurrence or metastasis after previous platinum-containing regimen treatment.
- the gynecological tumor may comprise platinum-sensitive or platinum-resistant.
- the gynecological tumor is selected from endometrial cancer, cervical cancer, or ovarian cancer.
- the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, or carcinosarcoma.
- the cervical cancer is selected from squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.
- the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, or endometrioid ovarian cancer >grade II (high-grade serous Type ovarian cancer or endometrioid ovarian cancer grade ⁇ II must have an endometrioid component >50%).
- the gynecological tumor is selected from the group consisting of endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, or grade ⁇ II endometrioid ovarian cancer (high-grade serous ovarian cancer or grade ⁇ II endometrioid ovarian cancer Endometrioid component must be >50%).
- the ovarian cancer is selected from platinum-sensitive or platinum-resistant advanced or metastatic ovarian cancer.
- the platinum-resistant form is a refractory form.
- the gynecological tumor patient is selected from unresectable, locally advanced recurrent and/or metastatic gynecological tumor patients.
- the gynecological tumor patient is selected from patients with recurrent or metastatic gynecological tumor who have a PIK3CA, PIK3R1 or PIK3R2 gene alteration, and who have previously received first-, second-, or third-line or above treatment with disease progression.
- the gynecological tumor patient is selected from locally advanced recurrent or metastatic gynecological tumors with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after previous first-line, second-line or third-line treatment or more patient.
- the gynecological tumor patient is selected from recurrent or metastatic endometrial cancer with a PIK3CA, PIK3R1 or PIK3R2 gene alteration and disease progression after previous first-line, second-line or third-line therapy or more patient.
- the gynecological tumor patient is selected from locally advanced recurrent or metastatic intrauterine disease with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after previous first-line, second-line or third-line treatment or more Membrane cancer patients.
- the gynecological tumor patient is selected from patients with recurrent or metastatic cervical cancer who have a PIK3CA, PIK3R1 or PIK3R2 gene alteration and have previously received first-line, second-line or third-line or above treatment with disease progression.
- the gynecological tumor patient is selected from locally advanced recurrent or metastatic cervical cancer with PIK3CA, PIK3R1 or PIK3R2 gene alteration and disease progression after previous first-line, second-line or third-line treatment and above patient.
- the gynecological tumor patient is selected from patients with recurrent or metastatic ovarian cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or third-line or above treatment in the past.
- the gynecological tumor patient is selected from locally advanced recurrent or metastatic ovarian cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or third-line or above treatment in the past.
- the gynecological tumor patient is selected from patients with recurrent or metastatic endometrial cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or more prior therapy.
- the gynecological tumor patient is selected from locally advanced recurrent or metastatic endometrial cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or more prior therapy.
- the gynecological tumor patient is selected from patients with recurrent or metastatic cervical cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or more prior therapy.
- the gynecological tumor patient is selected from locally advanced recurrent or metastatic cervical cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or above treatment in the past.
- the gynecological tumor patient is selected from patients with recurrent or metastatic ovarian cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving third-line or more prior therapy.
- the gynecological tumor patient is selected from locally advanced recurrent or metastatic ovarian cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving third-line or more prior therapy.
- At least one of the first-line, second-line, or third-line therapy the patient has previously received is selected from platinum-based regimen therapy.
- the first-line therapy is selected from platinum-based regimen therapy.
- the gynecological tumor patients are selected from patients who have received standard treatment in the past but have failed treatment or have no existing effective treatment plan for advanced stage.
- the standard of care treatment is a platinum-based regimen treatment.
- the treatment failure refers to disease progression, recurrence, or metastasis.
- the patients with gynecological tumors are selected from patients who have been previously treated with one or more prior treatment regimens. In some aspects of the present application, the patient with a gynecological tumor is selected from patients who have been previously treated with one, two, three, four, or five prior treatment regimens.
- the prior treatment regimen includes surgery, radiation therapy, or drug therapy.
- the drug therapy includes chemotherapy, targeted drug therapy, immunotherapy, or endocrine therapy.
- the prior treatment regimen includes at least one platinum-based regimen treatment.
- the prior treatment regimen includes at least one treatment with a platinum-based regimen and does not include treatment with a PI3K, AKT, or mTOR inhibitor.
- the patients with gynecological tumors are selected from patients who have received one or more prior treatment regimens, and the prior treatment regimens include at least one platinum-based regimen treatment .
- the drug used in the platinum-containing regimen treatment comprises cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, or lobaplatin.
- the drug used in the platinum-based regimen treatment includes cisplatin, carboplatin, nedaplatin, or oxaliplatin.
- the platinum-based regimen treatment includes the following regimens: cisplatin, carboplatin, nedaplatin, oxaliplatin, cisplatin in combination with 5-fluorouracil, cisplatin in combination with paclitaxel, cisplatin in combination with topology Tecan, cisplatin combined with gemcitabine, cisplatin combined with vinorelbine, cisplatin combined with irinotecan, cisplatin combined with ifosfamide, cisplatin combined with etoposide, bleomycin combined with etoposide combined with cisplatin, cisplatin combined with ifosfamide Platinum combined with paclitaxel combined with bevacizumab, cisplatin combined with topotecan combined with bevacizumab, cisplatin combined with vincristine combined with bleomycin, cisplatin combined with bleomycin combined with
- the drugs used in the chemotherapy include cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, lobaplatin, doxorubicin, liposome Mycin, paclitaxel, nab-paclitaxel, docetaxel, capecitabine, cyclophosphamide, melphalan, docetaxel, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, mitomycin , topotecan, pemetrexed, etoposide, bleomycin, leucovorin, vincristine, or vinorelbine.
- the drugs used in the targeted drug therapy include bevacizumab, cetuximab, nimotuzumab, pazopanib ), rucaparib, veliparib, niraparib, olaparib, gefitinib, erlotinib, entrectinib, Rotinib, or tramitinib.
- the drug used in the immunotherapy comprises pembrolizumab, ipilimumab, or PD-1 antibody.
- the drugs used for endocrine therapy include anastrozole, letrozole, exemestane, leuprolide acetate, tamoxifen, megestrol acetate, or fulvestrant group.
- the drugs used in the drug treatment include cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, lobaplatin, doxorubicin, liposome Doxorubicin, paclitaxel, nab-paclitaxel, docetaxel, capecitabine, cyclophosphamide, melphalan, docetaxel, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, mitosis Vincristine, topotecan, pemetrexed, etoposide, bleomycin, leucovorin, vincristine, vinorelbine, bevacizumab, cetuximab, nimotuzumab , pazopanib, lucaparib, veliparib, niraparib, olaparib, gefitini
- the radiation therapy comprises conventional radiation therapy, radioactive seed inter-tissue brachytherapy, or intraoperative radiation therapy.
- the patient with endometrial cancer is selected from patients who have failed standard therapy or who have no existing effective treatment options for advanced stage, and the patient with endometrial cancer is selected from patients who have received at least 1 standard therapy , and patients with stage I/II relapsed disease who have received ⁇ 1 line of platinum-containing regimens; or, selected from patients with advanced (III/IV) relapsed disease who have received ⁇ 1 line of platinum-containing regimens in the past or, selected from patients with imaging-proven disease progression or recurrence during or within 6 months of treatment; or, selected from patients who have previously received neoadjuvant or adjuvant platinum-based regimens during or 6 months after treatment Patients with imaging-proven disease progression or relapse within
- the standard of care treatment is a platinum-based regimen treatment.
- the patient with cervical cancer is selected from patients who have failed standard treatment or who have no existing effective treatment options for advanced stage, and the patient with cervical cancer is selected from patients who cannot undergo radical surgery, and/or radical surgery Patients with recurrence/metastasis after radiotherapy and who have received ⁇ 1 line of platinum-based chemotherapy after recurrence; or, selected from patients with imaging-confirmed disease progression or recurrence during treatment or within 6 months after treatment; or, selected from Patients with imaging-proven disease progression or relapse during or within 6 months of prior neoadjuvant or adjuvant platinum-containing regimens.
- the standard of care treatment is a platinum-based regimen treatment.
- the ovarian cancer patient is selected from patients who have failed standard therapy or who have no existing effective treatment options for advanced stage, and the ovarian cancer patient is selected from platinum-sensitive patients who have received ⁇ 2 lines of therapy in the past type or platinum-resistant advanced or metastatic disease.
- the platinum-resistant type is the refractory type, including disease progression or recurrence during the treatment of the previous platinum-containing chemotherapy regimen or within ⁇ 6 months after the end of the platinum-containing treatment.
- the platinum-sensitive type that is, disease progression or relapse after ⁇ 6 months after the end of the platinum-based chemotherapy regimen, includes ⁇ 2 different platinum-based regimens (including the initial platinum-based chemotherapy regimen) received in the past. disease progression or relapse after treatment.
- the standard of care treatment is a platinum-based regimen treatment.
- the dosing cycle for treating a patient's gynecological tumor is 2-6 weeks. In some aspects of the present application, the administration period for treating a patient's gynecological tumor is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or a range formed by any of the above values. In some aspects of the application, the dosing cycle for treating a patient's gynecological tumor is 4 weeks.
- the daily dose for treating a patient's gynecological tumor is selected from 1-100 mg. In some aspects of the application, the daily dose for treating a patient's gynecological tumor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg , 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg , 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg,
- the number of daily administrations for treating a patient's gynecological tumor is 1, 2, or 3 times.
- the treatment of the patient's gynecological tumor may be administered once a day.
- the dosing regimen for treating gynecological tumors in the patient includes: the dosing cycle is 2-6 weeks, the daily dose is 1-40 mg, and the daily administration frequency is 1-3 times.
- the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be administered by various routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous , intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular or intrathecal. In one specific regimen, it is administered orally.
- the method of administration can be comprehensively determined according to factors such as drug activity, toxicity, and patient tolerance.
- a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in spaced dosing.
- the pharmaceutical composition of the present application can be prepared by combining the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation , such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.
- the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
- Suitable pharmaceutically acceptable adjuvants include, but are not limited to, binders, diluents, wetting agents, disintegrating agents, lubricants, glidants, sweeteners or flavoring agents, and the like.
- the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, dropping pills, pastes, powders, etc., preferably tablets and capsules.
- the oral preparations can be prepared by conventional methods using pharmaceutically acceptable excipients/carriers known in the art.
- Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrating agents, lubricants and the like.
- Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin or mixtures thereof, etc.; binders include hypromellose, carboxymethylcellulose, sodium carboxymethylcellulose , ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, starch, sucrose, glucose, gelatin or mixtures thereof, etc.; wetting agents include stearic acid Magnesium, talc, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc or mixtures thereof, etc.; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl Cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropyl
- the pharmaceutical composition is a single-dose pharmaceutical composition.
- the pharmaceutical composition contains 1 mg to 50 mg of a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition contains 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg or 50 mg, or any of the foregoing values as endpoints constitute a range or any value therein of a compound of the present application, or a pharmaceutically acceptable salt thereof, for example 1 mg to 50 mg, 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5mg to 20mg, etc.
- the compound of formula I of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof produces a good curative effect in the treatment of gynecological tumors, has a certain objective remission rate, and provides a good disease control rate to the treated patient,
- the treated patients have a longer survival period and a longer duration of disease remission.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment suitable for use in contact with human and animal tissue without excessive of toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt includes salts of base ions with the free acid or salts of acid ions with the free base.
- the amount of a compound of formula I or a pharmaceutically acceptable salt thereof eg, the amount administered, dosage, content in a pharmaceutical composition, is calculated as its free base form.
- compounds in this application can form acid addition salts if they have, for example, at least one basic center.
- Corresponding acid addition salts with additionally present basic centers can also be formed, if desired.
- Compounds having at least one acidic group eg COOH
- Corresponding internal salts can also be formed if the compounds contain, for example, both carboxyl and amino groups.
- patient is a mammal. In some embodiments, the patient is a human.
- pharmaceutical composition refers to a mixture of one or more compounds of the present application, or a pharmaceutical combination thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
- the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application or a pharmaceutical combination thereof to a patient.
- treating generally refers to obtaining a desired pharmacological and/or physiological effect.
- the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
- Treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.
- the term "effective amount” means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the described herein
- the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound or a pharmaceutically acceptable salt thereof, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but may vary, for example. The feasibility is determined by those skilled in the art based on their own knowledge and the present disclosure.
- single-dose refers to the smallest packaged unit containing a certain amount of medicine, for example, each tablet is a single dose; a box of medicines contains seven capsules, each capsule is a single dose; or each injection bottle is a single dose.
- carboplatin combined with paclitaxel and bevacizumab refers to the combination of carboplatin, paclitaxel, and bevacizumab.
- Capecitabine with oxaliplatin with or without bevacizumab refers to the combination of capecitabine, oxaliplatin, and bevacizumab, or capecitabine with oxaliplatin without bevacizumab Monoclonal antibody use.
- the term "refractory” refers to a particular cancer that is resistant or unresponsive to therapy with a particular therapeutic agent. Cancers that are refractory to therapy with a specific therapeutic agent can begin when treatment with the specific therapeutic agent is initiated (ie, there is no response upon initial exposure to the therapeutic agent); or, when the therapeutic agent is used for the first time The development of resistance to the therapeutic agent results in the course of its treatment or during subsequent treatment with the therapeutic agent.
- platinum-refractory refers to cancers that do not respond to treatment with anticancer drugs containing metallic platinum, such as cisplatin and carboplatin.
- recurrence refers to the recurrence of cancer, usually after a period of undetectable cancer. Cancer may return to the same location as the original (primary) tumor, or to another location in the body, also known as a recurrence. In the present invention, recurrence includes local recurrence.
- the term “locally recurrent” refers to a recurrence in the same or near the same place as the primary tumor, usually after a period of undetectable cancer.
- the term “locally advanced” refers to the spread of the primary lesion to nearby tissues or lymph nodes.
- first-line therapy refers to the first treatment for the disease. It is usually part of a set of standard treatments, such as chemotherapy and radiation after surgery. First-line therapy, when used alone, is recognized as the best therapy. If it does not cure the disease or causes serious side effects, other treatments may be added or used.
- second-line therapy refers to treatment given when the initial treatment (first-line treatment) is ineffective or stops working.
- third-line treatment or multi-line treatment can be deduced by analogy.
- metastatic refers to the spread or metastases of cancer from a primary site to other areas of the body, forming cancerous lesions that behave biologically in new locations.
- standard therapy refers to an approach accepted by medical professionals as an appropriate treatment for a particular type of disease, and is widely used by medical professionals.
- adjuvant therapy refers to the administration of additional cancer treatment after the first treatment to reduce the risk of cancer recurrence.
- Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.
- neoadjuvant therapy refers to treatment given as a first step before primary treatment (eg, surgery) to shrink a tumor.
- primary treatment eg, surgery
- neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. This is an induction therapy.
- the drugs used in the prior treatment regimen may refer to the following contents, and may also refer to treatment guidelines or textbooks related to medicine and pharmacy:
- ICON-7&GOG-218 regimen Paclitaxel combined with carboplatin combined with bevacizumab, and then continued with bevacizumab maintenance therapy.
- the doxorubicin is the same as doxorubicin, and the two can be used interchangeably.
- the doxorubicin liposome, the liposomal doxorubicin and the liposomal doxorubicin are all the same, and the three can be used interchangeably.
- step 3 Transfer the premixed material in step 1) to a wet granulation pot and add the binder obtained in step 2) to start granulation.
- the prepared soft wet wood is granulated, dried, and mixed with magnesium stearate.
- the resulting tablet is coated.
- the compound of formula I is prepared according to the method disclosed in WO2015192760.
- Administration method oral administration once a day on an empty stomach (QD administration, 15 mg or 30 mg dose), continuous administration for 28 days as a treatment cycle.
- Medication Tablets of the compound of formula I, 5 mg or 20 mg.
- Endometrial cancer Endometrial cancer confirmed by histopathology, including endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, carcinosarcoma;
- Cervical cancer Histopathologically confirmed cervical cancer, including squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma;
- Ovarian cancer Histopathologically confirmed epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer and endometrioid ovarian cancer grade ⁇ II (high-grade serous ovarian cancer or ⁇ Grade II endometrioid ovarian cancer must have an endometrioid component >50%).
- Subjects must have a positive sample for PIK3CA, PIK3R1 or PIK3R2 gene alteration (mutation or amplification) to be enrolled: ⁇ 10 freshly cut unstained sections of tumor tissue obtained within 2 years are preferred for genetic testing ; If tumor tissue sections cannot be provided, 10 mL of peripheral blood should be provided for genetic testing.
- Endometrial cancer at least 1 standard treatment and ⁇ 1 line of platinum-containing regimen for stage I/II recurrent disease, or ⁇ 1 line of platinum-containing regimen for advanced stage system therapy (Stage III/IV) disease; imaging-proven disease progression or recurrence (according to RECIST 1.1 criteria) during or within 6 months of treatment; Imaging-proven disease progression or recurrence within one month is also counted as first-line systemic therapy for advanced or metastatic disease;
- Cervical cancer recurrent/metastatic disease for which curative surgery and/or curative radiotherapy cannot be performed, and ⁇ 1 line of platinum-based chemotherapy after recurrence; imaging findings during or within 6 months after treatment Confirmed disease progression or recurrence (according to RECIST 1.1 criteria); imaging-confirmed disease progression or recurrence during or within 6 months after neoadjuvant or adjuvant therapy with platinum-based regimens was also counted as first-line therapy Systemic therapy for advanced or metastatic disease;
- Ovarian cancer platinum-sensitive or platinum-resistant advanced or metastatic disease (at least 4 cycles of treatment, during or 6 months after previous neoadjuvant or adjuvant therapy with platinum-based regimens) who have received ⁇ 2 lines of therapy Imaging-proven disease progression or recurrence [according to RECIST 1.1 criteria], also counted as first-line treatment), and meet any of the following: (1) Platinum-resistant or refractory type, including previous platinum-containing chemotherapy regimens Disease progression or recurrence during or within ⁇ 6 months after the end of platinum-containing chemotherapy; (2) platinum-sensitive type (ie, disease progression or recurrence ⁇ 6 months after the end of platinum-containing chemotherapy regimen), who have received ⁇ 2 different chemotherapy regimens in the past. Disease progression or recurrence after treatment with platinum-based regimens (including those initially containing platinum-based regimens).
- contraceptive measures such as intrauterine device [IUD], contraceptives or condoms
- IUD intrauterine device
- serum or urine pregnancy test negative within 7 days before study enrollment and must be non-lactating subjects.
- the main efficacy evaluation index objective response rate (ORR), that is, the number of CR+PR cases/total number of cases, including complete remission (CR) and partial remission (PR) cases.
- ORR objective response rate
- PFS progression-free survival
- DCR disease control rate
- DOR disease response time
- OS survival time
- a 60-year-old female patient who underwent radical resection of ovarian cancer (full uterus with double appendages + rolled carpet rectal fossa peritonectomy - omentectomy + pelvic lymph node dissection + para-aortic lymph node dissection + tumor reduction surgery), postoperative pathological classification It is high-grade serous ovarian cancer with necrosis, showing vascular tumor thrombus, involving the serosal membrane of the left uterine wall, (part of the rectum and sigmoid colon) from the adventitia to the mucosal layer, and metastasizes or infiltrates to 23/60 lymph nodes.
- TC regimen paclitaxel 270 mg, carboplatin 550 mg
- 1 cycle of TC regimen paclitaxel 100 mg, carboplatin 300 mg
- TC regimen paclitaxel 100 mg, carboplatin 250 mg
- One cycle of chemotherapy oral Nirapari Capsule therapy after chemotherapy, targeted therapy with Oral Olapari Tablets after the end of treatment
- GP regimen 1.2g gemcitabine, 110mg cisplatin
- chemotherapy for 2 cycles after treatment
- GP regimen After the end of the GC regimen (docetaxel 120mg, carboplatin 500mg) chemotherapy for one cycle, the disease progressed after self-stop.
Abstract
The present application provides a use of pyrido[1,2-a]pyrimidinone compound in treating gynaecological tumors. Specifically, provided are a pyrido[1,2-a]pyrimidinone compound for treating gynaecological tumors or pharmaceutical compositions thereof, and a method or a use of the pyrido[1,2-a]pyrimidinone compound for treating gynaecological tumors.
Description
相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS
本申请要求于2020年12月08日向中国国家知识产权局提交的第202011444228.1号中国专利申请的优先权和权益,所述申请公开的内容通过引用整体并入本文中。This application claims priority to and the benefit of Chinese Patent Application No. 202011444228.1 filed with the State Intellectual Property Office of China on December 08, 2020, the disclosure of which is incorporated herein by reference in its entirety.
本申请属于医药化学领域,涉及吡啶并[1,2-a]嘧啶酮化合物的治疗妇科肿瘤的用途。The present application belongs to the field of medicinal chemistry, and relates to the use of pyrido[1,2-a]pyrimidinone compounds for treating gynecological tumors.
PI3K通路是人体癌细胞中最常发生变异的地方,可导致细胞的增殖、活化、放大信号。The PI3K pathway is the most frequently mutated place in human cancer cells, leading to cell proliferation, activation, and signal amplification.
PI3K激酶(磷脂酰肌醇3-激酶,phosphatidylinositol-3-kinase,PI3Ks)属于脂质激酶家族,能够磷酸化磷脂酰肌醇的肌醇环3’-OH端,其为一种由调节亚单位p85或p101和催化亚单位p110组成的脂激酶,通过催化磷脂酰肌醇4,5-二磷酸(phosphatidylinositol 4,5-bisphosphate,PIP2)磷酸化为磷脂酰肌醇3,4,5-三磷酸(phosphatidylinositol 3,4,5-trisphosphate,PIP3)而激活下游的Akt等从而对细胞的增殖、生存和代谢等起关键作用。因此,抑制磷酸酯酰肌醇3激酶,可以影响PI3K通路,从而抑制癌细胞的增殖与活化。PI3K kinase (phosphatidylinositol-3-kinase, PI3Ks) belongs to the family of lipid kinases, which can phosphorylate the 3'-OH end of the inositol ring of phosphatidylinositol, which is a regulatory subunit of phosphatidylinositol. A lipid kinase composed of p85 or p101 and the catalytic subunit p110, which catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (phosphatidylinositol 3,4,5-trisphosphate, PIP3) and activate the downstream Akt, etc., which play a key role in cell proliferation, survival and metabolism. Therefore, inhibition of phosphoinositide 3-kinase can affect the PI3K pathway, thereby inhibiting the proliferation and activation of cancer cells.
肿瘤抑制基因PTEN(phosphatase and tension homolog deleted on chromosome ten)使PIP3去磷酸化生成PIP2,从而实现PI3K/Akt信号通路的负性调节,抑制细胞增殖和促进细胞凋亡。PI3K基因突变和扩增在癌症中频繁发生以及PTEN在癌症中缺失等都提示PI3K与肿瘤发生的密切关系。The tumor suppressor gene PTEN (phosphatase and tension homolog deleted on chromosome ten) dephosphorylates PIP3 to generate PIP2, thereby realizing the negative regulation of PI3K/Akt signaling pathway, inhibiting cell proliferation and promoting cell apoptosis. The frequent occurrence of PI3K gene mutation and amplification in cancer and the loss of PTEN in cancer suggest the close relationship between PI3K and tumorigenesis.
WO2015192760公开了一系列作为PI3K抑制剂的化合物,还具体公开了如下结构的式I化合物:WO2015192760 discloses a series of compounds as PI3K inhibitors, and also specifically discloses the compound of formula I with the following structure:
发明内容SUMMARY OF THE INVENTION
本申请提供用于治疗妇科肿瘤的式I化合物、或其药学上可接受的盐:The application provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of gynecological tumors:
另一方面,本申请提供式I化合物、或其药学上可接受的盐在制备治疗妇科肿瘤的药物中的用途。In another aspect, the present application provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of gynecological tumors.
另一方面,本申请式I化合物、或其药学上可接受的盐在治疗妇科肿瘤中的用途。In another aspect, the use of the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, in the treatment of gynecological tumors.
另一方面,本申请提供一种治疗妇科肿瘤的方法,所述方法包括向患者给予治疗有效量的式I化合物、或其药学上可接受的盐。In another aspect, the application provides a method of treating a gynecological tumor, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
在本申请的一些方案中,本申请式I化合物、或其药学上可接受的盐是作为单一活性剂使用。In some aspects of the application, a compound of formula I of the application, or a pharmaceutically acceptable salt thereof, is used as the single active agent.
在本申请的一些方案中,本申请式I化合物、或其药学上可接受的盐可以处于包含式I化合物、或其药学上可接受的盐的药物组合物的形式。在一些方案中,所述药物组合物为单剂量药物组合物。In some aspects of the application, the compound of formula I, or a pharmaceutically acceptable salt thereof, of the application may be in the form of a pharmaceutical composition comprising the compound of formula I, or a pharmaceutically acceptable salt thereof. In some aspects, the pharmaceutical composition is a single dose pharmaceutical composition.
另一方面,本申请提供用于治疗妇科肿瘤的药物组合物,所述药物组合物包含式I化合物、或其药学上可接受的盐。In another aspect, the present application provides a pharmaceutical composition for treating gynecological tumors, the pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof.
另一方面,本申请提供一种治疗妇科肿瘤的方法,所述方法包括向患者给予治疗有效量的式I化合物、或其药学上可接受的盐、或其药物组合物。In another aspect, the application provides a method of treating gynecological tumors, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
另一方面,本申请提供用于治疗妇科肿瘤的试剂盒,所述试剂盒包含本申请所述的式I化合物、或其药学上可接受的盐、或其药物组合物,优选处于单剂量的形式;以及使用说明。In another aspect, the application provides a kit for the treatment of gynecological tumors, the kit comprising the compound of formula I described in the application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, preferably in a single dose form; and instructions for use.
发明详述Detailed description of the invention
在本申请的一些方案中,所述妇科肿瘤选自复发性或转移性妇科肿瘤。在一些方案中,所述妇科肿瘤包括I期、II期、III期和/或IV期。In some aspects of the present application, the gynecological tumor is selected from recurrent or metastatic gynecological tumors. In some aspects, the gynecological tumor comprises Stage I, Stage II, Stage III, and/or Stage IV.
在本申请的一些方案中,所述妇科肿瘤选自局部晚期复发性或转移性妇科肿瘤。In some aspects of the application, the gynecological tumor is selected from locally advanced recurrent or metastatic gynecological tumors.
在本申请的一些方案中,所述妇科肿瘤选自其中PIK3CA、PIK3R1或PIK3R2基因改变的妇科肿瘤。在本申请的一些方案中,所述PIK3CA、PIK3R1或PIK3R2基因改变为PIK3CA、PIK3R1或PIK3R2基因的突变、缺失、拼接、融合、插入、重复、或扩增。In some aspects of the application, the gynecological tumor is selected from gynecological tumors in which the PIK3CA, PIK3R1 or PIK3R2 genes are altered. In some aspects of the application, the PIK3CA, PIK3R1 or PIK3R2 gene is altered to a mutation, deletion, splicing, fusion, insertion, duplication, or amplification of the PIK3CA, PIK3R1 or PIK3R2 gene.
在本申请的一些方案中,所述PIK3CA基因改变发生在该基因的任一外显子中。在本申请的一些方案中,所述PIK3CA基因改变包括发生在外显子1、2、5、7、9或20中的改变。在本申请的一些方案中,所述PIK3CA基因改变包括一个或多个以下位点突变:Q60K、R88Q、E110K、K111N、R263Q、R277W、R278W、K331E、K333N、N345K、G353D、S405F、E418K、E453K、P539R、E542K/Q/V/G、Q546E/H/K/L/P/R、E545A/D/G/K/Q/V、F909L、Y1021C/H/H、T1025A/S、M1043I/V、H1047R/L/Y、G1049R/S、E1093K、C1258R、E1624K、E1633K、E1634G、Q1636K、H3140K、H3140R、H3140L、H3139Y、H1047R、C420R、H1047Q、或I143V;包括一个或多个以下位点或片段的缺失:W11_P18、G106_N107、R108_E109、L113、H419_C420、P449_L452、G463_N465delinsD、或E545_Q546delinsDK;包括以下任一位点处的拼接:X26_splice、X353_splice、或X555_splice;包括以下形式的融合:FNDC3B-PIK3CA。In some aspects of the application, the PIK3CA gene alteration occurs in any exon of the gene. In some aspects of the application, the PIK3CA gene alteration comprises an alteration that occurs in exons 1, 2, 5, 7, 9 or 20. In some aspects of the application, the PIK3CA gene alteration comprises one or more of the following site mutations: Q60K, R88Q, E110K, K111N, R263Q, R277W, R278W, K331E, K333N, N345K, G353D, S405F, E418K, E453K , P539R, E542K/Q/V/G, Q546E/H/K/L/P/R, E545A/D/G/K/Q/V, F909L, Y1021C/H/H, T1025A/S, M1043I/V including one or more of the following sites or fragments; Deletion of: W11_P18, G106_N107, R108_E109, L113, H419_C420, P449_L452, G463_N465delinsD, or E545_Q546delinsDK; includes splice at any of the following sites: X26_splice, X353_splice, or X555_splice; includes fusion of the form: FNDC3B-PI.
在本申请的一些方案中,所述PIK3R1基因改变包括一个或多个以下位点突变:A10T/V、S102L、E109K、A201V、I220F、Q221E、G376R/E、K379N/E、S429Y、D440G、I442S、Y452C/N、Q457P、D464N、R465T、R503Q、R514C、R557P、E558Q、I559T/V、D560H/G/Y、N564D/K、S565N/R、K567E、P568T、D569G、L570P、L573P、R574I/T/S、R577K、Y580D/C/N、L584F、W624C、E635K、F646S、R649W、N711S、或V718A;包括一个或多个以下位点或片段插入:E468_E469insGLYE、Q455_F456insL、H450_E451insD、或Y580_L581insF;包括一个或多个以下位点或片段缺失:L380、V401_N406、E403_L404、I405、E439、D440_E451、N441_T454、I442_E443delinsK、H450、G446_E451、L449_Y452delinsFH、E451_Y452、H450_T454、N453_Y463、K448_N453、L449_Q455、F456_Q457、Q457_E462、Q457_S460、E458、S460_D464、L449_K459、Q455_K459、R461_E462delinsQ、D464_Y467、R465_Y467、L466、L466_E469、L466_Y470delinsF、E558_K561、M563_L570delinsI、P568_L573、L570_D578、I571_L573、I571_R574、L573_R574、R574、K575_T576、K575_R577、K575_L581、T576、Q579_Y580、D578_M582delinsE、Q579_Y580delinsH、M563_L570delinsI、M563_N564delinsI、或R577_L581;包括一个或多个以下位点或片段重复或扩增:E468_Y470dup、Y452dup、E462dup、D569dup、H450_E451dup、或K575_R577dup;包括以下任一位点处的拼接:X340_splice、X373_splice、X433_splice、X434_splice、X475_splice、或X582_splice;包括以下任一形式的融合:MARVELD2-PIK3R1、PIK3R1-NDUFB7、或TMEM171-PIK3R1。In some aspects of the application, the PIK3R1 gene alteration comprises one or more of the following site mutations: A10T/V, S102L, E109K, A201V, I220F, Q221E, G376R/E, K379N/E, S429Y, D440G, I442S , Y452C/N, Q457P, D464N, R465T, R503Q, R514C, R557P, E558Q, I559T/V, D560H/G/Y, N564D/K, S565N/R, K567E, P568T, D569G, L570P, L573P, R574I/T /S, R577K, Y580D/C/N, L584F, W624C, E635K, F646S, R649W, N711S, or V718A; including one or more of the following site or fragment insertions: E468_E469insGLYE, Q455_F456insL, H450_E451insD, or Y580_L581insF; including one or more多个以下位点或片段缺失:L380、V401_N406、E403_L404、I405、E439、D440_E451、N441_T454、I442_E443delinsK、H450、G446_E451、L449_Y452delinsFH、E451_Y452、H450_T454、N453_Y463、K448_N453、L449_Q455、F456_Q457、Q457_E462、Q457_S460、E458、S460_D464 、L449_K459、Q455_K459、R461_E462delinsQ、D464_Y467、R465_Y467、L466、L466_E469、L466_Y470delinsF、E558_K561、M563_L570delinsI、P568_L573、L570_D578、I571_L573、I571_R574、L573_R574、R574、K575_T576、K575_R577、K575_L581、T576、Q579_Y580、D578_M582delinsE、Q579_Y580delinsH、M563_L570delinsI、M563_N564delinsI , or R577_L581; includes one or more of the following sites or fragment repeats or amplifications: E468_Y470dup, Y452dup, E462dup, D569dup, H450_E451dup, or K575_R577dup; includes splicing at any of the following sites: X340_splice, X373_splice , X433_splice, X434_splice, X475_splice, or X582_splice; including fusions of any of the following: MARVELD2-PIK3R1, PIK3R1-NDUFB7, or TMEM171-PIK3R1.
在本申请的一些方案中,所述PIK3R2基因改变包括一个或多个以下位点突变:F15V、G28S、G103V、L127I、A298V、Y331C、D334Tfs*7、G373R、K376E、I378S、G385W、S390P、R406H、K435N、M476I、E499D、C501F、R531P、R539H、D557Y/N/H、N561D、K564E、P565S、R571H、R647C、或G722Afs*152;包括以下任一位点处的拼接:X431_splice、X473_splice、或X603_splice;包括以下形式的融合:PIK3R2-EEF1A2。In some aspects of the application, the PIK3R2 gene alteration comprises one or more of the following site mutations: F15V, G28S, G103V, L127I, A298V, Y331C, D334Tfs*7, G373R, K376E, I378S, G385W, S390P, R406H , K435N, M476I, E499D, C501F, R531P, R539H, D557Y/N/H, N561D, K564E, P565S, R571H, R647C, or G722Afs*152; includes splice at any of the following: X431_splice, X473_splice, or X603_splice ; includes fusions of the form: PIK3R2-EEF1A2.
在本申请的一些方案中,所述妇科肿瘤选自其中PIK3CA、PIK3R1或PIK3R2基因改变的复发性或转移性妇科肿瘤。在本申请的一些方案中,所述妇科肿瘤选自其中PIK3CA、PIK3R1或PIK3R2基因改变的局部晚期复发性或转移性妇科肿瘤。In some aspects of the application, the gynecological tumor is selected from recurrent or metastatic gynecological tumors in which the PIK3CA, PIK3R1 or PIK3R2 genes are altered. In some aspects of the application, the gynecologic tumor is selected from locally advanced recurrent or metastatic gynecologic tumors in which the PIK3CA, PIK3R1, or PIK3R2 genes are altered.
在本申请的一些方案中,所述妇科肿瘤患者选自既往接受过含铂类方案治疗后疾病进展、复发或转移的患者。In some schemes of the present application, the gynecological tumor patients are selected from patients with disease progression, recurrence or metastasis after previous treatment with platinum-containing regimens.
在本申请的一些方案中,所述妇科肿瘤患者选自既往接受过含铂类方案治疗后疾病进展、局部晚期复发或转移的患者。In some schemes of the present application, the gynecological tumor patients are selected from patients with disease progression, locally advanced recurrence or metastasis after previous treatment with platinum-containing regimens.
在本申请的一些方案中,所述妇科肿瘤患者选自其中PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过含铂类方案治疗后疾病进展、局部晚期复发或转移的患者。In some aspects of the present application, the gynecological tumor patient is selected from patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations, and patients with disease progression, locally advanced recurrence or metastasis after previous platinum-containing regimen treatment.
在本申请的一些方案中,所述妇科肿瘤可包括铂类敏感型或铂类耐药型。In some aspects of the application, the gynecological tumor may comprise platinum-sensitive or platinum-resistant.
在本申请的一些方案中,所述妇科肿瘤选自子宫内膜癌、宫颈癌、或卵巢癌。In some aspects of the application, the gynecological tumor is selected from endometrial cancer, cervical cancer, or ovarian cancer.
在本申请的一些方案中,所述子宫内膜癌选自子宫内膜样腺癌、浆液性腺癌、透明细胞癌、未分化癌、或癌肉瘤。In some aspects of the application, the endometrial cancer is selected from endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, or carcinosarcoma.
在本申请的一些方案中,所述宫颈癌选自鳞癌、腺癌、或腺鳞癌。In some aspects of the application, the cervical cancer is selected from squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma.
在本申请的一些方案中,所述卵巢癌选自上皮性卵巢癌、输卵管癌、原发性腹膜癌、高级别浆液型卵巢癌、或≥II级的子宫内膜样卵巢癌(高级别浆液型卵巢癌或≥II级的子宫内膜样卵巢癌的子宫内膜样成分须>50%)。In some aspects of the application, the ovarian cancer is selected from epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, or endometrioid ovarian cancer >grade II (high-grade serous Type ovarian cancer or endometrioid ovarian cancer grade ≥ II must have an endometrioid component >50%).
在本申请的一些方案中,所述妇科肿瘤选自子宫内膜样腺癌、浆液性腺癌、透明细胞癌、未分化癌、癌肉瘤、宫颈鳞癌、宫颈腺癌、宫颈腺鳞癌、上皮性卵巢癌、输卵管癌、原发性腹膜癌、高级别浆液型卵巢癌、或≥II级的子宫内膜样卵巢癌(高级别浆液型卵巢癌或≥II级的子宫内膜样卵巢癌的子宫内膜样成分须>50%)。In some aspects of the application, the gynecological tumor is selected from the group consisting of endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, or grade ≥II endometrioid ovarian cancer (high-grade serous ovarian cancer or grade ≥II endometrioid ovarian cancer Endometrioid component must be >50%).
在本申请的一些方案中,所述卵巢癌选自铂类敏感型或铂类耐药型晚期或转移性卵巢癌。在本申请的一些方案中,所述铂类耐药型即难治型。In some aspects of the application, the ovarian cancer is selected from platinum-sensitive or platinum-resistant advanced or metastatic ovarian cancer. In some aspects of the present application, the platinum-resistant form is a refractory form.
在本申请的一些方案中,所述妇科肿瘤患者选自不可手术切除的、局部晚期复发性和/或转移性的妇科肿瘤患者。In some aspects of the present application, the gynecological tumor patient is selected from unresectable, locally advanced recurrent and/or metastatic gynecological tumor patients.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过一线、二线或三线及以上治疗后疾病进展的复发性或转移性妇科肿瘤患者。In some aspects of the present application, the gynecological tumor patient is selected from patients with recurrent or metastatic gynecological tumor who have a PIK3CA, PIK3R1 or PIK3R2 gene alteration, and who have previously received first-, second-, or third-line or above treatment with disease progression.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过一线、二线或三线及以上治疗后疾病进展的局部晚期复发性或转移性妇科肿瘤患者。In some aspects of the present application, the gynecological tumor patient is selected from locally advanced recurrent or metastatic gynecological tumors with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after previous first-line, second-line or third-line treatment or more patient.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过一线、二线或三线及以上治疗后疾病进展的复发性或转移性子宫内膜癌患者。In some aspects of the present application, the gynecological tumor patient is selected from recurrent or metastatic endometrial cancer with a PIK3CA, PIK3R1 or PIK3R2 gene alteration and disease progression after previous first-line, second-line or third-line therapy or more patient.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过一线、二线或三线及以上治疗后疾病进展的局部晚期复发性或转移性子宫内膜癌患者。In some aspects of the present application, the gynecological tumor patient is selected from locally advanced recurrent or metastatic intrauterine disease with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after previous first-line, second-line or third-line treatment or more Membrane cancer patients.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过一线、二线或三线及以上治疗后疾病进展的复发性或转移性宫颈癌患者。In some schemes of the present application, the gynecological tumor patient is selected from patients with recurrent or metastatic cervical cancer who have a PIK3CA, PIK3R1 or PIK3R2 gene alteration and have previously received first-line, second-line or third-line or above treatment with disease progression.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过一线、二线或三线及以上治疗后疾病进展的局部晚期复发性或转移性宫颈癌患者。In some schemes of the present application, the gynecological tumor patient is selected from locally advanced recurrent or metastatic cervical cancer with PIK3CA, PIK3R1 or PIK3R2 gene alteration and disease progression after previous first-line, second-line or third-line treatment and above patient.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过二线或三线及以上治疗后疾病进展的复发性或转移性卵巢癌患者。In some aspects of the present application, the gynecological tumor patient is selected from patients with recurrent or metastatic ovarian cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or third-line or above treatment in the past.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过二线或三线及以上治疗后疾病进展的局部晚期复发性或转移性卵巢癌患者。In some schemes of the present application, the gynecological tumor patient is selected from locally advanced recurrent or metastatic ovarian cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or third-line or above treatment in the past.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过二线及以上治疗后疾病进展的复发性或转移性子宫内膜癌患者。In some aspects of the present application, the gynecological tumor patient is selected from patients with recurrent or metastatic endometrial cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or more prior therapy.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过二线及以上治疗后疾病进展的局部晚期复发性或转移性子宫内膜癌患者。In some schemes of the present application, the gynecological tumor patient is selected from locally advanced recurrent or metastatic endometrial cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or more prior therapy.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过二线及以上治疗后疾病进展的复发性或转移性宫颈癌患者。In some aspects of the present application, the gynecological tumor patient is selected from patients with recurrent or metastatic cervical cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving second-line or more prior therapy.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过二线及以上治疗后疾病进展的局部晚期复发性或转移性宫颈癌患者。In some schemes of the present application, the gynecological tumor patient is selected from locally advanced recurrent or metastatic cervical cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving second-line or above treatment in the past.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过三线及以上治疗后疾病进展的复发性或转移性卵巢癌患者。In some aspects of the present application, the gynecological tumor patient is selected from patients with recurrent or metastatic ovarian cancer who have PIK3CA, PIK3R1 or PIK3R2 gene alterations and whose disease has progressed after receiving third-line or more prior therapy.
在本申请的一些方案中,所述妇科肿瘤患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、并且既往接受过三线及以上治疗后疾病进展的局部晚期复发性或转移性卵巢癌患者。In some schemes of the present application, the gynecological tumor patient is selected from locally advanced recurrent or metastatic ovarian cancer patients with PIK3CA, PIK3R1 or PIK3R2 gene alterations and disease progression after receiving third-line or more prior therapy.
在本申请的一些方案中,所述患者既往接受过的一线、二线或三线治疗中的至少一个选自含铂类方案治疗。在本申请的一些方案中,所述一线治疗选自含铂类方案治疗。In some regimens of the present application, at least one of the first-line, second-line, or third-line therapy the patient has previously received is selected from platinum-based regimen therapy. In some regimens of the present application, the first-line therapy is selected from platinum-based regimen therapy.
在本申请的一些方案中,所述妇科肿瘤患者选自既往接受过标准治疗但治疗失败或者晚期无现有有效治疗方案的患者。在本申请的一些方案中,所述标准治疗为含铂类方案治疗。In some schemes of the present application, the gynecological tumor patients are selected from patients who have received standard treatment in the past but have failed treatment or have no existing effective treatment plan for advanced stage. In some regimens of the present application, the standard of care treatment is a platinum-based regimen treatment.
在本申请的一些方案中,所述治疗失败指疾病进展、复发或转移。In some aspects of the application, the treatment failure refers to disease progression, recurrence, or metastasis.
在本申请的一些方案中,所述妇科肿瘤的患者选自既往接受过一种或两种以上在先治疗方案的治疗的患者。在本申请的一些方案中,所述妇科肿瘤的患者选自既往接受过一种、两种、三种、四种、或五种在先治疗方案的治疗的患者。In some aspects of the present application, the patients with gynecological tumors are selected from patients who have been previously treated with one or more prior treatment regimens. In some aspects of the present application, the patient with a gynecological tumor is selected from patients who have been previously treated with one, two, three, four, or five prior treatment regimens.
在本申请的一些方案中,所述在先治疗方案包括手术治疗、放疗、或药物治疗。In some aspects of the application, the prior treatment regimen includes surgery, radiation therapy, or drug therapy.
在本申请的一些方案中,所述药物治疗包括化疗、靶向药物治疗、免疫治疗、或内分泌治疗。In some aspects of the application, the drug therapy includes chemotherapy, targeted drug therapy, immunotherapy, or endocrine therapy.
在本申请的一些方案中,所述在先治疗方案至少包括一种含铂类方案治疗。In some regimens of the present application, the prior treatment regimen includes at least one platinum-based regimen treatment.
在本申请的一些方案中,所述在先治疗方案至少包括一种含铂类方案治疗,且不包含PI3K、AKT或mTOR抑制剂的治疗。In some regimens of the present application, the prior treatment regimen includes at least one treatment with a platinum-based regimen and does not include treatment with a PI3K, AKT, or mTOR inhibitor.
在本申请的一些方案中,所述妇科肿瘤的患者选自既往接受过一种或两种以上在先治疗方案的治疗的患者,并且所述在先治疗方案至少包括一种含铂类方案治疗。In some aspects of the present application, the patients with gynecological tumors are selected from patients who have received one or more prior treatment regimens, and the prior treatment regimens include at least one platinum-based regimen treatment .
在本申请的一些方案中,所述含铂类方案治疗所用的药物包括顺铂、卡铂、奈达铂、奥沙利铂、双环铂、吡铂、米铂、或洛铂。在本申请的一些方案中,所述含铂类方案治疗所用的药物包括顺铂、卡铂、奈达铂、或奥沙利铂。In some regimens of the present application, the drug used in the platinum-containing regimen treatment comprises cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, or lobaplatin. In some regimens of the present application, the drug used in the platinum-based regimen treatment includes cisplatin, carboplatin, nedaplatin, or oxaliplatin.
在本申请的一些方案中,所述含铂类方案治疗包括以下方案:顺铂、卡铂、奈达铂、奥沙利铂、顺铂联合5-氟尿嘧啶、顺铂联合紫杉醇、顺铂联合拓扑替康、顺铂联合吉西他滨、顺铂联合长春瑞滨、顺铂联合伊立替康、顺铂联合异环磷酰胺、顺铂联合依托泊苷、博来霉素联合依托泊苷联合顺铂、顺铂联合紫杉醇联合贝伐单抗、顺铂联合拓扑替康联合贝伐单抗、顺铂联合长春新碱联合博来霉素、顺铂联合博来霉素联合异环磷酰胺、紫杉醇联合异环磷酰胺联合顺铂、长春新碱联合异环磷酰胺联合顺铂、顺铂联合依托泊苷联合丝裂霉素、顺铂联合异环磷酰胺联合5-氟尿嘧啶联合长春新碱、卡铂联合紫杉醇、卡铂联合脂质体阿霉素、卡铂联合多烯紫杉醇、卡铂联合异环磷酰胺、卡铂联合多西他赛、卡铂联合白蛋白紫杉醇、卡铂联合多柔比星脂质体、卡铂联合贝伐单抗、卡铂联合紫杉醇联合贝伐单抗、卡铂联合吉西他滨联合或不联合贝伐单抗、卡铂联合脂质体多柔比星联合或不联合贝伐单抗、5-氟尿嘧啶联合甲酰四氢叶酸联合奥沙利铂联合或不联合贝伐单抗、卡培他滨联合奥沙利铂联合或不联合贝伐单抗、ICON-7&GOG-218方案、或紫杉醇联合奈达铂。In some regimens of the present application, the platinum-based regimen treatment includes the following regimens: cisplatin, carboplatin, nedaplatin, oxaliplatin, cisplatin in combination with 5-fluorouracil, cisplatin in combination with paclitaxel, cisplatin in combination with topology Tecan, cisplatin combined with gemcitabine, cisplatin combined with vinorelbine, cisplatin combined with irinotecan, cisplatin combined with ifosfamide, cisplatin combined with etoposide, bleomycin combined with etoposide combined with cisplatin, cisplatin combined with ifosfamide Platinum combined with paclitaxel combined with bevacizumab, cisplatin combined with topotecan combined with bevacizumab, cisplatin combined with vincristine combined with bleomycin, cisplatin combined with bleomycin combined with ifosfamide, paclitaxel combined with isocycline Phosphoramide combined with cisplatin, vincristine combined with ifosfamide combined with cisplatin, cisplatin combined with etoposide combined with mitomycin, cisplatin combined with ifosfamide combined with 5-fluorouracil combined with vincristine, carboplatin combined with paclitaxel , carboplatin combined with liposomal doxorubicin, carboplatin combined with docetaxel, carboplatin combined with ifosfamide, carboplatin combined with docetaxel, carboplatin combined with nab-paclitaxel, carboplatin combined with doxorubicin lipid body, carboplatin with bevacizumab, carboplatin with paclitaxel with bevacizumab, carboplatin with gemcitabine with or without bevacizumab, carboplatin with liposomal doxorubicin with or without bevacizumab Antibiotics, 5-fluorouracil combined with leucovorin combined with oxaliplatin with or without bevacizumab, capecitabine combined with oxaliplatin with or without bevacizumab, ICON-7&GOG-218 regimen, Or paclitaxel combined with nedaplatin.
在本申请的一些方案中,所述化疗所用的药物包括顺铂、卡铂、奈达铂、奥沙利铂、双环铂、吡铂、米铂、洛铂、阿霉素、脂质体阿霉素、紫杉醇、白蛋白紫杉醇、多烯紫杉醇、卡培他滨、环磷酰胺、美法仑、多西他赛、5-氟尿嘧啶、吉西他滨、异环磷酰胺、伊立替康、丝裂霉素、拓扑替康、培美曲塞、依托泊苷、博来霉素、甲酰四氢叶酸、长春新碱、或长春瑞滨。In some schemes of the present application, the drugs used in the chemotherapy include cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, lobaplatin, doxorubicin, liposome Mycin, paclitaxel, nab-paclitaxel, docetaxel, capecitabine, cyclophosphamide, melphalan, docetaxel, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, mitomycin , topotecan, pemetrexed, etoposide, bleomycin, leucovorin, vincristine, or vinorelbine.
在本申请的一些方案中,所述靶向药物治疗所用的药物包括贝伐单抗(bevacizumab)、西妥昔单抗(cetuximab)、尼妥珠单抗(nimotuzumab)、帕唑帕尼(pazopanib)、卢卡帕尼(rucaparib)、维利帕尼(veliparib)、尼拉帕利(niraparib)、奥拉帕利(olaparib)、吉非替尼、厄洛替尼、恩曲替尼、拉罗替尼、或曲米替尼。In some schemes of the present application, the drugs used in the targeted drug therapy include bevacizumab, cetuximab, nimotuzumab, pazopanib ), rucaparib, veliparib, niraparib, olaparib, gefitinib, erlotinib, entrectinib, Rotinib, or tramitinib.
在本申请的一些方案中,所述免疫治疗所用的药物包括帕姆单抗(pembrolizumab)、伊匹单抗(ipilimumab)、或PD-1抗体。In some aspects of the present application, the drug used in the immunotherapy comprises pembrolizumab, ipilimumab, or PD-1 antibody.
在本申请的一些方案中,所述内分泌治疗所用的药物包括阿那曲唑、来曲唑、依西美坦、醋酸亮丙瑞林、他莫昔芬、醋酸甲地孕酮、或氟维司群。In some aspects of the application, the drugs used for endocrine therapy include anastrozole, letrozole, exemestane, leuprolide acetate, tamoxifen, megestrol acetate, or fulvestrant group.
在本申请的一些方案中,所述药物治疗所用的药物包括顺铂、卡铂、奈达铂、奥沙利铂、双环铂、吡铂、米铂、洛铂、阿霉素、脂质体阿霉素、紫杉醇、白蛋白紫杉醇、多烯紫杉醇、卡培他滨、环磷酰胺、美法仑、多西他赛、5-氟尿嘧啶、吉西他滨、异环磷酰胺、伊立替康、丝裂霉素、拓扑替康、培美曲塞、依托泊苷、博来霉素、甲酰四氢叶酸、长春新碱、长春瑞滨、贝伐单抗、西妥昔单抗、尼妥珠单抗、帕唑帕尼、卢卡帕尼、维利帕尼、尼拉帕利、奥拉帕利、吉非替尼、厄洛替尼、恩曲替尼、拉罗替尼、曲米替尼、帕姆单抗、伊匹单抗、PD-1抗体、阿那曲唑、来曲唑、依西美坦、醋酸亮丙瑞林、他莫昔芬、醋酸甲地孕酮、或氟维司群。In some schemes of the present application, the drugs used in the drug treatment include cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, lobaplatin, doxorubicin, liposome Doxorubicin, paclitaxel, nab-paclitaxel, docetaxel, capecitabine, cyclophosphamide, melphalan, docetaxel, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, mitosis Vincristine, topotecan, pemetrexed, etoposide, bleomycin, leucovorin, vincristine, vinorelbine, bevacizumab, cetuximab, nimotuzumab , pazopanib, lucaparib, veliparib, niraparib, olaparib, gefitinib, erlotinib, entrectinib, larottinib, tramitinib , pembrolizumab, ipilimumab, PD-1 antibody, anastrozole, letrozole, exemestane, leuprolide acetate, tamoxifen, megestrol acetate, or fulvestrant group.
在本申请的一些方案中,所述放疗包括常规放疗、放射性粒子组织间近距离放疗、或术中放疗。In some aspects of the application, the radiation therapy comprises conventional radiation therapy, radioactive seed inter-tissue brachytherapy, or intraoperative radiation therapy.
在本申请的一些方案中,所述子宫内膜癌的患者选自标准治疗失败或晚期无现有有效治疗方案的患者,并且所述子宫内膜癌的患者选自至少接受过1次标准治疗,且接受过≥1线含铂类方案治疗的I/II期复发性疾病患者;或者,选自既往接受过≥1线含铂类方案系统治疗的晚期(III/IV期)复发性疾病患者;或者,选自治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发的患者;或者,选自既往接受过含铂类方案的新辅助或辅助治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发的患者。在本申请的一些方案中,所述标准治疗为含铂类方案治疗。In some aspects of the present application, the patient with endometrial cancer is selected from patients who have failed standard therapy or who have no existing effective treatment options for advanced stage, and the patient with endometrial cancer is selected from patients who have received at least 1 standard therapy , and patients with stage I/II relapsed disease who have received ≥1 line of platinum-containing regimens; or, selected from patients with advanced (III/IV) relapsed disease who have received ≥1 line of platinum-containing regimens in the past or, selected from patients with imaging-proven disease progression or recurrence during or within 6 months of treatment; or, selected from patients who have previously received neoadjuvant or adjuvant platinum-based regimens during or 6 months after treatment Patients with imaging-proven disease progression or relapse within In some regimens of the present application, the standard of care treatment is a platinum-based regimen treatment.
在本申请的一些方案中,所述宫颈癌的患者选自标准治疗失败或晚期无现有有效治疗方案的患者,并且所述宫颈癌的患者选自无法进行根治性手术、和/或根治性放疗后复发/转移且复发后接受过≥1线含铂类方案化疗的患者;或者,选自治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发的患者;或者,选自既往接受过含铂类方案的新辅助或辅助治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发的患者。在本申请的一些方案中,所述标准治疗为含铂类方案治疗。In some aspects of the present application, the patient with cervical cancer is selected from patients who have failed standard treatment or who have no existing effective treatment options for advanced stage, and the patient with cervical cancer is selected from patients who cannot undergo radical surgery, and/or radical surgery Patients with recurrence/metastasis after radiotherapy and who have received ≥1 line of platinum-based chemotherapy after recurrence; or, selected from patients with imaging-confirmed disease progression or recurrence during treatment or within 6 months after treatment; or, selected from Patients with imaging-proven disease progression or relapse during or within 6 months of prior neoadjuvant or adjuvant platinum-containing regimens. In some regimens of the present application, the standard of care treatment is a platinum-based regimen treatment.
在本申请的一些方案中,所述卵巢癌的患者选自标准治疗失败或晚期无现有有效治疗方案的患者,并且所述卵巢癌的患者选自既往接受过≥2线治疗的铂类敏感型或铂类耐药型晚期或转移性疾病患者。在本申请的一些方案中,所述铂类耐药型即难治型,包括既往含铂类化疗方案治疗期间或者含铂类治疗结束后≤6个月内疾病进展或复发。在本申请的一些方案中,所述铂类敏感型即含铂类化疗方案结束≥6个月后疾病进展或复发,包括既往接受过≥2种不同含铂类方案(其中包含最初含铂类方案在内)治疗后疾病进展或复发。在本申请的一些方案中,所述标准治疗为含铂类方案治疗。In some aspects of the present application, the ovarian cancer patient is selected from patients who have failed standard therapy or who have no existing effective treatment options for advanced stage, and the ovarian cancer patient is selected from platinum-sensitive patients who have received ≥ 2 lines of therapy in the past type or platinum-resistant advanced or metastatic disease. In some schemes of the present application, the platinum-resistant type is the refractory type, including disease progression or recurrence during the treatment of the previous platinum-containing chemotherapy regimen or within ≤6 months after the end of the platinum-containing treatment. In some regimens of the present application, the platinum-sensitive type, that is, disease progression or relapse after ≥6 months after the end of the platinum-based chemotherapy regimen, includes ≥2 different platinum-based regimens (including the initial platinum-based chemotherapy regimen) received in the past. disease progression or relapse after treatment. In some regimens of the present application, the standard of care treatment is a platinum-based regimen treatment.
给药方案dosing regimen
在本申请的一些方案中,所述治疗患者的妇科肿瘤的给药周期是2-6周。在本申请的一些方案中,所述治疗患者的妇科肿瘤的给药周期是2周、3周、4周、5周、6周或上述任意值形成的范围。在本申请的一些方案中,所述治疗患者的妇科肿瘤的给药周期是4周。In some aspects of the application, the dosing cycle for treating a patient's gynecological tumor is 2-6 weeks. In some aspects of the present application, the administration period for treating a patient's gynecological tumor is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or a range formed by any of the above values. In some aspects of the application, the dosing cycle for treating a patient's gynecological tumor is 4 weeks.
在本申请的一些方案中,所述治疗患者的妇科肿瘤的每日剂量选自1-100mg。在本申请的一些方案中,所述治疗患者的妇科肿瘤的每日剂量选自1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、21mg、22mg、23mg、24mg、25mg、26mg、27mg、28mg、29mg、30mg、31mg、32mg、33mg、34mg、35mg、36mg、37mg、38mg、39mg、40mg、41mg、42mg、43mg、44mg、45mg、46mg、47mg、48mg、49mg、50mg、51mg、52mg、53mg、54mg、55mg、56mg、57mg、58mg、59mg、60mg、61mg、62mg、63mg、64mg、65mg、66mg、67mg、68mg、69mg、70mg、71mg、72mg、73mg、74mg、75mg、76mg、77mg、78mg、79mg、80mg、81mg、82mg、83mg、84mg、85mg、86mg、87mg、88mg、89mg、90mg、91mg、92mg、93mg、94mg、 95mg、96mg、97mg、98mg、99mg、100mg、或上述任意值形成的范围。在本申请的一些方案中,所述治疗患者的妇科肿瘤的每日剂量选自1-50mg、5-50mg、10-50mg、10-40mg、15-30mg、或20-30mg。In some aspects of the application, the daily dose for treating a patient's gynecological tumor is selected from 1-100 mg. In some aspects of the application, the daily dose for treating a patient's gynecological tumor is selected from 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg , 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg , 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49mg, 50mg, 51mg, 52mg, 53mg, 54mg, 55mg, 56mg, 57mg, 58mg, 59mg, 60mg, 61mg, 62mg, 63mg, 64mg, 65mg , 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72mg, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88mg, 89mg, 90mg , 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, or a range formed by any of the above values. In some aspects of the application, the daily dose for treating a patient's gynecological tumor is selected from 1-50 mg, 5-50 mg, 10-50 mg, 10-40 mg, 15-30 mg, or 20-30 mg.
在本申请的一些方案中,所述治疗患者的妇科肿瘤的每日给药次数是1次、2次或3次。In some aspects of the present application, the number of daily administrations for treating a patient's gynecological tumor is 1, 2, or 3 times.
在本申请的一些方案中,所述治疗患者的妇科肿瘤的每日给药可为1次。In some aspects of the present application, the treatment of the patient's gynecological tumor may be administered once a day.
在本申请的一些方案中,所述治疗患者的妇科肿瘤的给药方案包括:给药周期是2-6周,每日剂量是1-40mg,每日给药次数是1-3次。In some aspects of the present application, the dosing regimen for treating gynecological tumors in the patient includes: the dosing cycle is 2-6 weeks, the daily dose is 1-40 mg, and the daily administration frequency is 1-3 times.
本申请的式I化合物、或其药学上可接受的盐、或其药物组合物可通过多种途径给药,所述途径包括但不限于以下途径:口服、胃肠外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内或鞘内。在一个特定的方案中,通过口服给药。The compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof can be administered by various routes, including but not limited to the following routes: oral, parenteral, intraperitoneal, intravenous , intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intraadipose, intraarticular or intrathecal. In one specific regimen, it is administered orally.
给药的方法可根据药物的活性、毒性以及患者的耐受性等因素综合确定。在部分实施方案中,以间隔给药的方式给予本申请的化合物、或其药学上可接受的盐、或其药物组合物。The method of administration can be comprehensively determined according to factors such as drug activity, toxicity, and patient tolerance. In some embodiments, a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered in spaced dosing.
药物组合物pharmaceutical composition
本申请的药物组合物可通过将本申请的式I化合物、或其药学上可接受的盐与适宜的药学上可接受的辅料组合而制备,例如可配制成固态、半固态、液态或气态制剂,如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。本申请的药物组合物可以采用本领域众所周知的方法制造,如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。适合的药学上可接受的辅料包括但不限于:黏合剂、稀释剂、润湿剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。The pharmaceutical composition of the present application can be prepared by combining the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, with suitable pharmaceutically acceptable excipients, for example, it can be formulated into a solid, semi-solid, liquid or gaseous preparation , such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols. The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like. Suitable pharmaceutically acceptable adjuvants include, but are not limited to, binders, diluents, wetting agents, disintegrating agents, lubricants, glidants, sweeteners or flavoring agents, and the like.
在本申请的部分方案中,所述的药物组合物是适于口服的制剂,包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等,优选片剂和胶囊剂。所述的口服制剂可使用本领域公知的药学上可接受的辅料/载体通过常规方法制得。药学上可接受的载体包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂等。稀释剂包括微晶纤维素、甘露醇、乳糖、蔗糖、淀粉、预胶化淀粉、糊精或其混合物等;黏合剂包括羟丙甲纤维素、羧甲基纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙基纤维素、低取代羟丙基纤维素、明胶、聚乙烯吡咯烷酮、淀粉、蔗糖、葡萄糖、明胶或其混合物等;润湿剂包括硬脂酸镁、滑石粉、聚乙二醇、十二烷基硫酸钠、微粉硅胶、滑石粉或其混合物等;崩解剂包括羧甲基淀粉钠、干淀粉、微晶纤维素、羟乙基甲基纤维素、羧甲基纤维素钠、羧甲基纤维素钙、交联羧甲基纤维素钠、低取代羟丙甲基纤维素或交联聚维酮或其混合物等;润滑剂包括硬脂酸镁、胶体二氧化硅、滑石粉、聚乙二醇、硬脂酸、硬脂富马酸钠或其混合物等。其中,药学上可接受的辅料还包括着色剂、甜味剂、包衣剂等。In some schemes of the present application, the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, dropping pills, pastes, powders, etc., preferably tablets and capsules. The oral preparations can be prepared by conventional methods using pharmaceutically acceptable excipients/carriers known in the art. Pharmaceutically acceptable carriers include diluents, binders, wetting agents, disintegrating agents, lubricants and the like. Diluents include microcrystalline cellulose, mannitol, lactose, sucrose, starch, pregelatinized starch, dextrin or mixtures thereof, etc.; binders include hypromellose, carboxymethylcellulose, sodium carboxymethylcellulose , ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, gelatin, polyvinylpyrrolidone, starch, sucrose, glucose, gelatin or mixtures thereof, etc.; wetting agents include stearic acid Magnesium, talc, polyethylene glycol, sodium lauryl sulfate, micronized silica gel, talc or mixtures thereof, etc.; disintegrants include sodium carboxymethyl starch, dry starch, microcrystalline cellulose, hydroxyethyl methyl Cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, low-substituted hydroxypropylmethyl cellulose or crospovidone or mixtures thereof; lubricants include stearin Magnesium acid, colloidal silicon dioxide, talc, polyethylene glycol, stearic acid, sodium stearyl fumarate or mixtures thereof, and the like. Wherein, the pharmaceutically acceptable adjuvants also include colorants, sweeteners, coating agents and the like.
在本申请的部分方案中,所述的药物组合物为单剂量药物组合物。在部分实施方案中,所述药物组合物含有1mg至50mg的本申请的式I化合物、或其药学上可接受的盐。在部分实施方案中,所述药物组合物含有1mg、2mg、5mg、8mg、10mg、12mg、15mg、18mg、20mg、22mg、25mg、28mg、30mg、32mg、35mg、38mg、40mg、42mg、45mg、48mg或50mg、或者任意前述值作为端点构成的范围或其中的任意值的本申请的化合物、或其药学上可接受的盐,例如1mg至50mg、2mg至50mg、10mg至40mg、5mg至30mg、5mg至20mg等。In some schemes of the present application, the pharmaceutical composition is a single-dose pharmaceutical composition. In some embodiments, the pharmaceutical composition contains 1 mg to 50 mg of a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition contains 1 mg, 2 mg, 5 mg, 8 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 22 mg, 25 mg, 28 mg, 30 mg, 32 mg, 35 mg, 38 mg, 40 mg, 42 mg, 45 mg, 48 mg or 50 mg, or any of the foregoing values as endpoints constitute a range or any value therein of a compound of the present application, or a pharmaceutically acceptable salt thereof, for example 1 mg to 50 mg, 2 mg to 50 mg, 10 mg to 40 mg, 5 mg to 30 mg, 5mg to 20mg, etc.
技术效果technical effect
本申请的式I化合物、或其药学上可接受的盐、或其药物组合物在治疗妇科肿瘤方面产生良好的疗效,具有一定的客观缓解率,并提供给所治疗患者良好的疾病控制率,使得所治疗患者具有更长的生存期,更长的疾病缓解持续时间。The compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof produces a good curative effect in the treatment of gynecological tumors, has a certain objective remission rate, and provides a good disease control rate to the treated patient, The treated patients have a longer survival period and a longer duration of disease remission.
定义和说明Definition and Explanation
除非另有说明,本申请中所用的术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照本领域普通的含义去理解。当本申请中出现商品名时,意在指代其对应的商品或其活性成分。Unless otherwise specified, terms used in this application have the following meanings. A particular term should not be considered indeterminate or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to its corresponding trade or its active ingredient.
术语“药学上可接受的”是针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用于与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment suitable for use in contact with human and animal tissue without excessive of toxicity, irritation, allergic reactions or other problems or complications commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”包括碱根离子与游离酸形成的盐或酸根离子与游离碱形成的盐。The term "pharmaceutically acceptable salt" includes salts of base ions with the free acid or salts of acid ions with the free base.
如本申请所用,式I化合物或其药学上可接受的盐的量,例如给药量、剂量、药物组合物中的含量,以其游离碱形式计算。As used herein, the amount of a compound of formula I or a pharmaceutically acceptable salt thereof, eg, the amount administered, dosage, content in a pharmaceutical composition, is calculated as its free base form.
如本申请所用,本申请中的化合物如果具有例如至少一个碱性中心,则其可以形成酸加成盐。如果需要的话,还可以形成具有另外存在的碱性中心的相应的酸加成盐。具有至少一个酸性基团(例如COOH)的化合物还可以与碱形成盐。如果化合物例如既包含羧基又包含氨基,则还可以形成相应的内盐。As used herein, compounds in this application can form acid addition salts if they have, for example, at least one basic center. Corresponding acid addition salts with additionally present basic centers can also be formed, if desired. Compounds having at least one acidic group (eg COOH) can also form salts with bases. Corresponding internal salts can also be formed if the compounds contain, for example, both carboxyl and amino groups.
术语“患者”是哺乳动物。在部分实施方案中,所述患者是人。The term "patient" is a mammal. In some embodiments, the patient is a human.
术语“药物组合物”是指一种或多种本申请的化合物或其药物组合或其药学上可接受的盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对患者给予本申请的化合物或其药物组合。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application, or a pharmaceutical combination thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application or a pharmaceutical combination thereof to a patient.
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用,可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗,包括:(a)抑制疾病的症状,即阻止其发展;或(b)缓解疾病的症状,即,导致疾病或症状退化。The term "treating" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. "Treatment" as used herein encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie, preventing its progression; or (b) alleviating the symptoms of the disease, ie, causing regression of the disease or symptoms.
术语“有效量”意指(i)治疗特定疾病、病况或障碍,(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状,或(iii)延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物或其药学上可接受的盐的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物或其药学上可接受的盐、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变,但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "effective amount" means (i) treating a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) delaying the described herein The amount of a compound of the present application, or a pharmaceutically acceptable salt thereof, for the onset of one or more symptoms of a particular disease, condition or disorder. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound or a pharmaceutically acceptable salt thereof, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but may vary, for example. The feasibility is determined by those skilled in the art based on their own knowledge and the present disclosure.
术语“单剂量”是指含有一定量药品的最小包装单元,例如每片药物为单剂量;一盒药有七粒胶囊,则每个胶囊为单剂量;或者每瓶注射液为单剂量。The term "single-dose" refers to the smallest packaged unit containing a certain amount of medicine, for example, each tablet is a single dose; a box of medicines contains seven capsules, each capsule is a single dose; or each injection bottle is a single dose.
术语“联合”指所述药物联合使用。例如,卡铂联合紫杉醇联合贝伐单抗指卡铂、紫杉醇和贝伐单抗三种药物联合使用。卡培他滨联合奥沙利铂联合或不联合贝伐单抗指卡培他滨、奥沙利铂和贝伐单抗联合使用,或者卡培他滨联合奥沙利铂但不联合贝伐单抗使用。The term "combination" refers to the combined use of the drugs. For example, carboplatin combined with paclitaxel and bevacizumab refers to the combination of carboplatin, paclitaxel, and bevacizumab. Capecitabine with oxaliplatin with or without bevacizumab refers to the combination of capecitabine, oxaliplatin, and bevacizumab, or capecitabine with oxaliplatin without bevacizumab Monoclonal antibody use.
在癌症背景下,术语“难治性”(refractory)指特定的癌症对于使用一种特定治疗剂的疗法有抗性或无反应。难以使用一种特定治疗剂的疗法治疗的癌症可以始于当用该特定治疗剂开始治疗的时候(即一开始暴露在该治疗剂的时候就无反应);或者,是在使用该治疗剂首次治疗其的过程中或是使用该治疗剂进行后续治疗的期间,对该治疗剂发展出抗性的结果。例如,铂难治指使用含金属铂的抗癌药物(例如顺铂和卡铂)对治疗无反应的癌症。In the context of cancer, the term "refractory" refers to a particular cancer that is resistant or unresponsive to therapy with a particular therapeutic agent. Cancers that are refractory to therapy with a specific therapeutic agent can begin when treatment with the specific therapeutic agent is initiated (ie, there is no response upon initial exposure to the therapeutic agent); or, when the therapeutic agent is used for the first time The development of resistance to the therapeutic agent results in the course of its treatment or during subsequent treatment with the therapeutic agent. For example, platinum-refractory refers to cancers that do not respond to treatment with anticancer drugs containing metallic platinum, such as cisplatin and carboplatin.
在癌症背景下,术语“复发性”(recurrent)指通常在一段时间内无法检测到癌症之后癌症再次发生。癌症可能会回到与原始(原发性)肿瘤相同的位置,或者回到体内的另一个位置,也称为复发。在本发明中,复发包括局部复发。In the context of cancer, the term "recurrent" refers to the recurrence of cancer, usually after a period of undetectable cancer. Cancer may return to the same location as the original (primary) tumor, or to another location in the body, also known as a recurrence. In the present invention, recurrence includes local recurrence.
在癌症背景下,术语“局部复发”(locally recurrent)指通常在一段时间内无法检测到癌症后,在与原发病灶相同或附近的地方复发。In the context of cancer, the term "locally recurrent" refers to a recurrence in the same or near the same place as the primary tumor, usually after a period of undetectable cancer.
在癌症背景下,术语“局部晚期”(locally advanced)指原发病灶扩散到附近的组织或淋巴结。In the context of cancer, the term "locally advanced" refers to the spread of the primary lesion to nearby tissues or lymph nodes.
在癌症背景下,术语“一线治疗”(first-line therapy)指针对疾病的第一次治疗。它通常是一组标准治疗方法的一部分,例如手术后进行化疗和放疗。一线疗法单独使用时,是公认的最佳疗法。如果它不能治愈疾病或引起严重的副作用,则可以添加或使用其他治疗方法。In the context of cancer, the term "first-line therapy" refers to the first treatment for the disease. It is usually part of a set of standard treatments, such as chemotherapy and radiation after surgery. First-line therapy, when used alone, is recognized as the best therapy. If it does not cure the disease or causes serious side effects, other treatments may be added or used.
在癌症背景下,术语“二线治疗”(second-line therapy)指当初始治疗(一线治疗)无效或停止发挥作用时所给予的治疗。三线治疗或多线治疗的意思可以此类推。In the context of cancer, the term "second-line therapy" refers to treatment given when the initial treatment (first-line treatment) is ineffective or stops working. The meaning of third-line treatment or multi-line treatment can be deduced by analogy.
在癌症背景下,术语“转移性”(metastatic)指癌症由原发病灶扩散或转移到身体其他区域,并在新位置上形成生物学行为类似的癌性病变。In the context of cancer, the term "metastatic" refers to the spread or metastases of cancer from a primary site to other areas of the body, forming cancerous lesions that behave biologically in new locations.
在癌症背景下,术语“标准治疗”(standard therapy)指被医学专家接受为特定类型疾病的适当治疗方法,并且被医疗专业人员广泛使用。In the context of cancer, the term "standard therapy" refers to an approach accepted by medical professionals as an appropriate treatment for a particular type of disease, and is widely used by medical professionals.
在癌症背景下,术语“辅助治疗”(adjuvant therapy)指在首次治疗后给予额外的癌症治疗以降低癌症复发的风险。辅助治疗可包括化疗、放疗、激素疗法、靶向疗法或生物疗法。In the context of cancer, the term "adjuvant therapy" refers to the administration of additional cancer treatment after the first treatment to reduce the risk of cancer recurrence. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy.
在癌症背景下,术语“新辅助治疗”(neoadjuvant therapy)指在主要治疗前(例如手术)用于缩小肿瘤的作为第一步给予的治疗。新辅助疗法的例子包括化疗、放疗和激素疗法。这是一种诱导疗法。In the context of cancer, the term "neoadjuvant therapy" refers to treatment given as a first step before primary treatment (eg, surgery) to shrink a tumor. Examples of neoadjuvant therapy include chemotherapy, radiation therapy, and hormone therapy. This is an induction therapy.
如本申请所用,所述在先治疗方案所用药物可参考以下内容,也可参考治疗指南或涉及医学、药学的教科书:As used in this application, the drugs used in the prior treatment regimen may refer to the following contents, and may also refer to treatment guidelines or textbooks related to medicine and pharmacy:
ICON-7&GOG-218方案:紫杉醇联合卡铂联合贝伐单抗治疗,再继续用贝伐单抗维持治疗。ICON-7&GOG-218 regimen: Paclitaxel combined with carboplatin combined with bevacizumab, and then continued with bevacizumab maintenance therapy.
如本申请所用,所述阿霉素与多柔比星相同,二者可以替换使用。As used in this application, the doxorubicin is the same as doxorubicin, and the two can be used interchangeably.
如本申请所用,所述多柔比星脂质体、脂质体多柔比星以及脂质体阿霉素均相同,三者之间可以替换使用。As used in this application, the doxorubicin liposome, the liposomal doxorubicin and the liposomal doxorubicin are all the same, and the three can be used interchangeably.
在本文中,除非另有说明,否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述,意味着除所列出的要素、组分和步骤外,还可涵盖其它未指明的要素、组分和步骤。As used herein, unless stated otherwise, the terms "comprise, comprises and comprising" or equivalents are open-ended expressions meaning that in addition to the listed elements, components and steps, there may be Other unspecified elements, components and steps are encompassed.
为了描述和公开的目的,以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。在本文中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。All patents, patent applications, and other identified publications are expressly incorporated herein by reference for the purposes of description and disclosure. Any citation of these publications herein does not constitute an admission that the publications form part of the common general knowledge in the field.
通过具体的实施例更详细地说明本发明。为说明目的提供以下实施例,它们不应以任何方式限制本发明。The present invention is explained in more detail by means of specific examples. The following examples are provided for illustrative purposes and should not limit the invention in any way.
实施例1 式I化合物的片剂Example 1 Tablets of the compound of formula I
表1式I化合物的片剂的处方组成Table 1 Formulation Composition of Tablets of Compounds of Formula I
制备方法:Preparation:
1)将式I化合物、微晶纤维素、甘露醇、交联羧甲基纤维素钠依次过粉碎整粒机,过筛后收集物料,然后进行预混,得到预混物料。1) The compound of formula I, microcrystalline cellulose, mannitol, and croscarmellose sodium are successively passed through a pulverizing and granulating machine, and the materials are collected after sieving, and then premixed to obtain a premixed material.
2)将羟丙甲基纤维素配置为水溶液作为粘合剂。2) The hypromellose was formulated into an aqueous solution as a binder.
3)将步骤1)中的预混物料转至湿法制粒锅中加入步骤2)获得的粘合剂开始制粒。3) Transfer the premixed material in step 1) to a wet granulation pot and add the binder obtained in step 2) to start granulation.
4)制备得到的软湿材整粒,干燥,加入硬脂酸镁总混。4) The prepared soft wet wood is granulated, dried, and mixed with magnesium stearate.
5)压片。5) Tablet.
任选地,对所得片剂进行包衣。Optionally, the resulting tablet is coated.
其中,式I化合物根据WO2015192760中公开的方法进行制备。Wherein, the compound of formula I is prepared according to the method disclosed in WO2015192760.
实施例2 妇科肿瘤Example 2 Gynecological tumor
2.1给药方案2.1 Dosing schedule
给药方法:每天空腹口服一次(QD给药,15mg或30mg剂量),连续给药28天为一个治疗周期。Administration method: oral administration once a day on an empty stomach (QD administration, 15 mg or 30 mg dose), continuous administration for 28 days as a treatment cycle.
药物:式I化合物的片剂,5mg或20mg。Medication: Tablets of the compound of formula I, 5 mg or 20 mg.
2.2入组标准2.2 Inclusion criteria
1)病理学证实的恶性妇科肿瘤,包括:1) Pathologically confirmed malignant gynecological tumors, including:
a)子宫内膜癌:组织病理学证实的子宫内膜癌,包括子宫内膜样腺癌、浆液性腺癌、透明细胞癌、未分化癌、癌肉瘤;a) Endometrial cancer: Endometrial cancer confirmed by histopathology, including endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, undifferentiated carcinoma, carcinosarcoma;
b)宫颈癌:组织病理学证实的宫颈癌,包括鳞癌、腺癌以及腺鳞癌;b) Cervical cancer: Histopathologically confirmed cervical cancer, including squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma;
c)卵巢癌:组织病理学证实的上皮性卵巢癌、输卵管癌、原发性腹膜癌、高级别浆液型卵巢癌和≥II级的子宫内膜样卵巢癌(高级别浆液型卵巢癌或≥II级的子宫内膜样卵巢癌的子宫内膜样成分须>50%)。c) Ovarian cancer: Histopathologically confirmed epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer and endometrioid ovarian cancer grade ≥II (high-grade serous ovarian cancer or ≥ Grade II endometrioid ovarian cancer must have an endometrioid component >50%).
2)受试者必须有一个PIK3CA、PIK3R1或PIK3R2基因改变(突变或扩增)呈阳性的样本方可入组:首选2年内获取的肿瘤组织≥10张新切的未染色切片用于基因检测;若不能提供肿瘤组织切片的,需提供10mL外周血用于基因检测。2) Subjects must have a positive sample for PIK3CA, PIK3R1 or PIK3R2 gene alteration (mutation or amplification) to be enrolled: ≥10 freshly cut unstained sections of tumor tissue obtained within 2 years are preferred for genetic testing ; If tumor tissue sections cannot be provided, 10 mL of peripheral blood should be provided for genetic testing.
3)不可手术切除的、局部晚期复发和/或转移性的肿瘤患者,具有至少1个可测量病灶(根据RECIST1.1标准,可测量病灶的螺旋CT扫描长径≥10mm或肿大淋巴结短径≥15mm)。3) Patients with unresectable, locally advanced recurrent and/or metastatic tumors with at least 1 measurable lesion (according to RECIST1.1 criteria, the long diameter of the spiral CT scan of the measurable lesion is ≥10mm or the short diameter of enlarged lymph nodes) ≥15mm).
4)标准治疗失败或晚期无现有有效治疗方案的受试者,此外还需须满足以下任意一项:4) Subjects who have failed standard treatment or who have no existing effective treatment options in the late stage, in addition to any of the following:
a)子宫内膜癌:至少接受过1次标准治疗,且接受过≥1线含铂类方案系统治疗的I/II期复发性疾病,或既往接受≥1线含铂类方案系统治疗的晚期(III/IV期)疾病;治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发(根据RECIST 1.1标准);既往接受含铂类方案的新辅助或辅助治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发的,亦算作1线针对晚期或转移性疾病的系统治疗;a) Endometrial cancer: at least 1 standard treatment and ≥ 1 line of platinum-containing regimen for stage I/II recurrent disease, or ≥ 1 line of platinum-containing regimen for advanced stage system therapy (Stage III/IV) disease; imaging-proven disease progression or recurrence (according to RECIST 1.1 criteria) during or within 6 months of treatment; Imaging-proven disease progression or recurrence within one month is also counted as first-line systemic therapy for advanced or metastatic disease;
b)宫颈癌:无法进行根治性手术和/或根治性放疗的复发性/转移性疾病,且复发后接受过≥1线含铂类方案化疗;治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发(根据RECIST 1.1标准);既往接受含铂类方案的新辅助或辅助治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发的,亦算作1线针对晚期或转移性疾病的系统治疗;b) Cervical cancer: recurrent/metastatic disease for which curative surgery and/or curative radiotherapy cannot be performed, and ≥1 line of platinum-based chemotherapy after recurrence; imaging findings during or within 6 months after treatment Confirmed disease progression or recurrence (according to RECIST 1.1 criteria); imaging-confirmed disease progression or recurrence during or within 6 months after neoadjuvant or adjuvant therapy with platinum-based regimens was also counted as first-line therapy Systemic therapy for advanced or metastatic disease;
c)卵巢癌:既往接受过≥2线治疗的铂敏感或铂耐药晚期或转移性疾病(治疗至少4个周期,既往接受含铂类方案的新辅助或辅助治疗期间或治疗后6个月内出现影像学证实的疾病进展或复发[根据RECIST 1.1标准]的,亦算作1线治疗),同时满足以下任何一条:①铂类耐药或难治型,包括既往含铂类化疗方案治疗期间或者含铂类治疗结束后≤6个月内疾病进展或复发;②铂类敏感型(即含铂类化疗方案结束≥6个月后疾病进展或复发),既往接受过≥2种不同含铂类方案(其中包含最初含类铂方案在内)治疗后疾病进展或复发。c) Ovarian cancer: platinum-sensitive or platinum-resistant advanced or metastatic disease (at least 4 cycles of treatment, during or 6 months after previous neoadjuvant or adjuvant therapy with platinum-based regimens) who have received ≥2 lines of therapy Imaging-proven disease progression or recurrence [according to RECIST 1.1 criteria], also counted as first-line treatment), and meet any of the following: (1) Platinum-resistant or refractory type, including previous platinum-containing chemotherapy regimens Disease progression or recurrence during or within ≤6 months after the end of platinum-containing chemotherapy; (2) platinum-sensitive type (ie, disease progression or recurrence ≥6 months after the end of platinum-containing chemotherapy regimen), who have received ≥2 different chemotherapy regimens in the past. Disease progression or recurrence after treatment with platinum-based regimens (including those initially containing platinum-based regimens).
5)年龄≥18岁(以签署知情同意当日计算);女性;ECOG体能状态0-1;预计生存期≥3个月。5) Age ≥18 years old (calculated on the day of signing informed consent); female; ECOG performance status 0-1; expected survival period ≥3 months.
6)应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器[IUD],避孕药或避孕套);在研究入组前的7天内血清或尿妊娠试验阴性,且必须为非哺乳期受试者。6) It should be agreed that contraceptive measures (such as intrauterine device [IUD], contraceptives or condoms) must be used during the study period and within 6 months after the end of the study; serum or urine pregnancy test negative within 7 days before study enrollment , and must be non-lactating subjects.
7)受试者自愿加入本研究,签署知情同意书,依从性好。7) The subjects voluntarily joined the study, signed the informed consent, and had good compliance.
2.3评价方法及指标2.3 Evaluation methods and indicators
根据RECIST 1.1标准评价疗效。Efficacy was evaluated according to RECIST 1.1 criteria.
主要疗效评价指标:客观缓解率(ORR),即CR+PR例数/总例数,包含完全缓解(CR)和部分缓解(PR)的病例。The main efficacy evaluation index: objective response rate (ORR), that is, the number of CR+PR cases/total number of cases, including complete remission (CR) and partial remission (PR) cases.
次要疗效评价指标:无进展生存期(PFS)、6个月无进展生存率、疾病控制率(DCR)、疾病缓解时间(DOR)、和生存期(OS)。Secondary efficacy evaluation indicators: progression-free survival (PFS), 6-month progression-free survival rate, disease control rate (DCR), disease response time (DOR), and survival time (OS).
2.4病例12.4 Case 1
患者,女,60岁,卵巢癌根治术(全子宫双附件+卷地毯直肠窝腹膜切除-大网膜切除+盆腔淋巴结清扫+腹主动脉旁淋巴结清扫+减瘤术),术后病理分型为高级别浆液型卵巢癌伴坏死,可见脉管瘤栓,累犯子宫体左侧壁浆膜、(部分直肠及乙状结肠)外膜外至粘膜层,并转移或浸润至23/60枚淋巴结。A 60-year-old female patient who underwent radical resection of ovarian cancer (full uterus with double appendages + rolled carpet rectal fossa peritonectomy - omentectomy + pelvic lymph node dissection + para-aortic lymph node dissection + tumor reduction surgery), postoperative pathological classification It is high-grade serous ovarian cancer with necrosis, showing vascular tumor thrombus, involving the serosal membrane of the left uterine wall, (part of the rectum and sigmoid colon) from the adventitia to the mucosal layer, and metastasizes or infiltrates to 23/60 lymph nodes.
临床诊断后行TC方案(紫杉醇270mg、卡铂550mg)化疗6周期,后调整剂量行TC方案(紫杉醇100mg、卡铂300mg)化疗1周期,后调整剂量行TC方案(紫杉醇100mg、卡铂250mg)化疗1周期,化疗结束后口服尼拉帕利胶囊治疗,治疗结束后开始口服奥拉帕利片靶向治疗,治疗结束后行GP方案(吉西他滨1.2g、顺铂110mg)化疗2周期,GP方案结束后行GC方案(多西他赛120mg、卡铂500mg)化疗1周期,自行停止后疾病进展。After clinical diagnosis, 6 cycles of TC regimen (paclitaxel 270 mg, carboplatin 550 mg) were performed, followed by 1 cycle of TC regimen (paclitaxel 100 mg, carboplatin 300 mg) after dose adjustment, and TC regimen (paclitaxel 100 mg, carboplatin 250 mg) after dose adjustment. One cycle of chemotherapy, oral Nirapari Capsule therapy after chemotherapy, targeted therapy with Oral Olapari Tablets after the end of treatment, GP regimen (1.2g gemcitabine, 110mg cisplatin) chemotherapy for 2 cycles after treatment, GP regimen After the end of the GC regimen (docetaxel 120mg, carboplatin 500mg) chemotherapy for one cycle, the disease progressed after self-stop.
入组后,开始实施式I化合物15mg QD治疗,在给予治疗前CT扫描显示,可测量靶病灶(右侧肝肾间隙处)总径57mm,给药后定期进行CT扫描,治疗2周期后,靶病灶总径降至53mm,疗效评估为疾病稳定SD,降低达到7%,未出现新发病灶。After being enrolled in the group, 15mg QD treatment of the compound of formula I was started. Before the treatment, the CT scan showed that the total diameter of the measurable target lesion (the space between the right liver and kidney) was 57 mm. After the administration, CT scans were performed regularly. The total diameter of the target lesions was reduced to 53 mm, and the curative effect was evaluated as stable disease SD, with a reduction of 7%, and no new lesions appeared.
2.5病例22.5 Case 2
患者,女,52岁,因卵巢囊肿破裂行右附件切除术,术后病理提示:右附件腺癌。免疫组化:CK7(+),CK20(-),PAX8(+),ER(-),PR(灶+),CDX2(-),SATB2(-),SMAD4(+),P16(+),P53(+),Wt1(-),Ki67(部分+)。临床诊断:卵巢原发粘液性癌。A 52-year-old female patient underwent right adnexectomy due to ovarian cyst rupture. The postoperative pathological findings were right adnexal adenocarcinoma. Immunohistochemistry: CK7(+), CK20(-), PAX8(+), ER(-), PR(Focus+), CDX2(-), SATB2(-), SMAD4(+), P16(+), P53(+), Wt1(-), Ki67 (partially +). Clinical diagnosis: primary mucinous carcinoma of the ovary.
临床诊断后行卵巢癌根治术+全子宫左附件切除+大网膜切除+阑尾切除+复杂肠粘连松解。术后MR提示盆底腹膜转移可能,行紫杉醇+卡铂化疗4疗程。化疗后B超显示下腹部及盆腔内囊性实性占位,行盆腔包块切除术+复杂肠粘连松解术,术后病理显示:盆腔肿块符合高级别浆液型卵巢癌复发。After clinical diagnosis, radical ovarian cancer surgery + total left hysterectomy + omentectomy + appendectomy + complex intestinal adhesion release was performed. Postoperative MR showed the possibility of pelvic floor peritoneal metastasis. Paclitaxel + carboplatin chemotherapy was given for 4 courses. After chemotherapy, B-ultrasound showed cystic solid mass in the lower abdomen and pelvis, and pelvic mass resection + complex intestinal adhesion release was performed. Postoperative pathology showed that the pelvic mass was consistent with the recurrence of high-grade serous ovarian cancer.
入组后,开始实施式I化合物15mg QD治疗,在给予治疗前CT扫描显示,可测量靶病灶(盆腔占位肿块)总径95mm,给药后定期进行CT扫描,治疗2周期后,靶病灶总径降至74mm,疗效评估为疾病稳定SD,降低达到22.1%。未出现新发病灶。After the group was enrolled, 15mg QD treatment of the compound of formula I was started. Before the treatment, the CT scan showed that the total diameter of the target lesion (pelvic mass) was 95mm. After the administration, CT scan was performed regularly. The overall diameter was reduced to 74 mm, and the efficacy assessment was stable disease SD, with a reduction of 22.1%. No new lesions appeared.
Claims (23)
- 如权利要求1所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤选自复发性或转移性妇科肿瘤。The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the gynecological tumor is selected from recurrent or metastatic gynecological tumors.
- 如权利要求1或2所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤选自局部晚期复发性或转移性妇科肿瘤。The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the gynecological tumor is selected from locally advanced recurrent or metastatic gynecological tumor.
- 如权利要求1-3任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤选自其中PIK3CA、PIK3R1或PIK3R2基因改变的妇科肿瘤;优选地,所述PIK3CA、PIK3R1或PIK3R2基因改变包括PIK3CA、PIK3R1或PIK3R2基因的突变、缺失、拼接、融合、插入、重复、或扩增。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein the gynecological tumor is selected from gynecological tumors in which the PIK3CA, PIK3R1 or PIK3R2 gene is altered; preferably, the PIK3CA , PIK3R1 or PIK3R2 gene alterations include mutations, deletions, splices, fusions, insertions, duplications, or amplifications of the PIK3CA, PIK3R1 or PIK3R2 genes.
- 如权利要求1-4任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤选自其中PIK3CA、PIK3R1或PIK3R2基因改变的局部晚期复发性或转移性妇科肿瘤。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the gynecological tumor is selected from locally advanced recurrent or metastatic gynecological tumors in which the PIK3CA, PIK3R1 or PIK3R2 gene is altered .
- 如权利要求1-5任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤选自子宫内膜癌、宫颈癌、或卵巢癌。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, wherein the gynecological tumor is selected from endometrial cancer, cervical cancer, or ovarian cancer.
- 如权利要求1-6任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤选自子宫内膜样腺癌、浆液性腺癌、透明细胞癌、未分化癌、癌肉瘤、宫颈鳞癌、宫颈腺癌、宫颈腺鳞癌、上皮性卵巢癌、输卵管癌、原发性腹膜癌、高级别浆液型卵巢癌、或≥II级的子宫内膜样卵巢癌;优选地,所述高级别浆液型卵巢癌或≥II级的子宫内膜样卵巢癌的子宫内膜样成分>50%。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, wherein the gynecological tumor is selected from endometrioid adenocarcinoma, serous adenocarcinoma, clear cell carcinoma, and undifferentiated carcinoma , carcinosarcoma, cervical squamous cell carcinoma, cervical adenocarcinoma, cervical adenosquamous carcinoma, epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, high-grade serous ovarian cancer, or ≥ grade II endometrioid ovarian cancer; Preferably, the high-grade serous ovarian cancer or endometrioid ovarian cancer >50% has an endometrioid component.
- 如权利要求1-7任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤的患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、既往接受过一线、二线或三线及以上治疗后疾病进展的复发性或转移性妇科肿瘤患者、优选局部晚期复发性或转移性妇科肿瘤患者。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein the patient with gynecological tumor is selected from the group consisting of PIK3CA, PIK3R1 or PIK3R2 gene alterations, who have previously received first-line, second-line Or patients with recurrent or metastatic gynecological tumors whose disease has progressed after third-line or above treatment, preferably patients with locally advanced recurrent or metastatic gynecological tumors.
- 如权利要求1-8任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤的患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、既往接受过一线、二线或三线及以上治疗后疾病进展的复发性或转移性子宫内膜癌患者、优选局部晚期复发性或转移性子宫内膜癌患者。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein the patient with gynecological tumor is selected from the group consisting of PIK3CA, PIK3R1 or PIK3R2 gene alterations, who have previously received first-line, second-line Or patients with recurrent or metastatic endometrial cancer whose disease has progressed after third-line or above treatment, preferably patients with locally advanced recurrent or metastatic endometrial cancer.
- 如权利要求1-9任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤的患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、既往接受过一线、二线或三线及以上治疗后疾病进展的复发性或转移性宫颈癌患者、优选局部晚期复发性或转移性宫颈癌患者。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein the patient with gynecological tumor is selected from the group consisting of PIK3CA, PIK3R1 or PIK3R2 gene alterations, who have previously received first-line, second-line Or patients with recurrent or metastatic cervical cancer whose disease has progressed after third-line or above treatment, preferably patients with locally advanced recurrent or metastatic cervical cancer.
- 如权利要求1-10任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤的患者选自其中具有PIK3CA、PIK3R1或PIK3R2基因改变、既往接受过二线或三线及以上治疗后疾病进展的复发性或转移性卵巢癌患者、优选局部晚期复发性或转移性卵巢癌患者。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the patient with gynecological tumor is selected from the group consisting of PIK3CA, PIK3R1 or PIK3R2 gene alterations, who have received second-line or third-line previously Patients with recurrent or metastatic ovarian cancer whose disease has progressed after the above treatment, preferably patients with locally advanced recurrent or metastatic ovarian cancer.
- 如权利要求1-11任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤的患者选自既往接受过标准治疗但治疗失败或晚期无现有有效治疗方案的患者;优选地,所述标准治疗包含含铂类方案治疗;优选地,所述含铂类方案治疗所用的药物包括顺铂、卡铂、奈达铂、奥沙利铂、双环铂、吡铂、米铂、或洛铂。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein the patient with gynecological tumor is selected from the group that has received standard treatment in the past but failed treatment or has no existing effective treatment plan for advanced stage Preferably, the standard treatment includes platinum-based regimen treatment; preferably, the drugs used in the platinum-based regimen treatment include cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, pyridoxine Platinum, Miplatin, or Loboplatin.
- 如权利要求1-12任一项所述的式I化合物或其药学上可接受的盐,其中,所述妇科肿瘤的患者选自既往接受过一种或两种以上在先治疗方案的治疗的患者;优选地,所述妇科肿瘤的患者选自既往接受过一种、 两种、三种、四种或五种在先治疗方案的治疗的患者。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein the patient with gynecological tumor is selected from those who have received one or more than two prior treatment regimens in the past Patients; preferably, the patients with gynecological tumors are selected from patients who have been previously treated with one, two, three, four or five prior treatment regimens.
- 如权利要求13所述的式I化合物或其药学上可接受的盐,其中,所述在先治疗方案包括手术治疗、放疗、或药物治疗。The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 13, wherein the prior treatment regimen comprises surgical treatment, radiotherapy, or drug treatment.
- 如权利要求13所述的式I化合物或其药学上可接受的盐,其中,所述在先治疗方案至少包括一种含铂类方案治疗;优选地,所述含铂类方案治疗所用的药物包括顺铂、卡铂、奈达铂、奥沙利铂、双环铂、吡铂、米铂、或洛铂。The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 13, wherein the prior treatment regimen includes at least one platinum-based regimen treatment; preferably, the drug used for the platinum-based regimen treatment These include cisplatin, carboplatin, nedaplatin, oxaliplatin, bicycloplatin, picoplatin, meplatin, or lobaplatin.
- 如权利要求1-15任一项所述的式I化合物或其药学上可接受的盐,其中,所述治疗患者的妇科肿瘤的给药周期是2-6周。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein the administration period for treating a patient's gynecological tumor is 2-6 weeks.
- 如权利要求1-16任一项所述的式I化合物或其药学上可接受的盐,其中,所述治疗患者的妇科肿瘤的每日剂量为1-100mg。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein the daily dose for treating a patient's gynecological tumor is 1-100 mg.
- 如权利要求1-17任一项所述的式I化合物或其药学上可接受的盐,其中,所述治疗患者的妇科肿瘤的每日给药次数是1次、2次或3次。The compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein the number of daily administrations for treating a patient's gynecological tumor is 1, 2 or 3 times.
- 用于治疗妇科肿瘤的药物组合物,所述药物组合物包含如权利要求1-18任一项所述的式I化合物或其药学上可接受的盐,以及药学上可接受的辅料。A pharmaceutical composition for treating gynecological tumors, the pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1-18, and a pharmaceutically acceptable excipient.
- 一种用于治疗妇科肿瘤的试剂盒,所述试剂盒包含式I化合物或其药学上可接受的盐、或其药物组合物,优选处于单剂量的形式;以及使用说明,A kit for treating gynecological tumors, the kit comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, preferably in the form of a single dose; and instructions for use,
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