WO2019109938A1 - Parp抑制剂用于治疗化疗耐药的卵巢癌或乳腺癌的用途 - Google Patents

Parp抑制剂用于治疗化疗耐药的卵巢癌或乳腺癌的用途 Download PDF

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WO2019109938A1
WO2019109938A1 PCT/CN2018/119318 CN2018119318W WO2019109938A1 WO 2019109938 A1 WO2019109938 A1 WO 2019109938A1 CN 2018119318 W CN2018119318 W CN 2018119318W WO 2019109938 A1 WO2019109938 A1 WO 2019109938A1
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use according
inhibitor
cancer
vegfr
polymerase inhibitor
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PCT/CN2018/119318
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English (en)
French (fr)
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王泉人
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江苏恒瑞医药股份有限公司
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Priority to CN201880059076.8A priority Critical patent/CN111093706B/zh
Priority to CA3080644A priority patent/CA3080644A1/en
Priority to BR112020010435-3A priority patent/BR112020010435A2/pt
Priority to EP18885829.4A priority patent/EP3721906A4/en
Priority to AU2018380174A priority patent/AU2018380174A1/en
Priority to US16/767,385 priority patent/US20200281923A1/en
Priority to KR1020207018161A priority patent/KR20200096788A/ko
Priority to CN202111060793.2A priority patent/CN113768933B/zh
Priority to MX2020005659A priority patent/MX2020005659A/es
Priority to RU2020119898A priority patent/RU2777519C2/ru
Priority to JP2020529362A priority patent/JP2021505548A/ja
Publication of WO2019109938A1 publication Critical patent/WO2019109938A1/zh

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    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to the use of a PARP inhibitor for the preparation of a medicament for the treatment of chemotherapy-resistant ovarian or breast cancer.
  • Epithelial ovarian cancer is the highest mortality rate of gynecological malignant tumors. Nearly 75% of patients have advanced treatment at the time of treatment. Requires radical surgery and standard treatment with platinum-based chemotherapy. After standard treatment is completed. Although the complete response rate can reach 40% to 60%, more than 90% of patients will relapse on average 18 months, and then face the risk of death due to chemotherapy resistance and disease progression.
  • platinum-containing regimens such as platinum-containing chemotherapy
  • the drug from the last chemotherapy to the tumor recurrence / progression time ⁇ 6 months
  • the follow-up will use single-agent chemotherapy, chemotherapy regimen including docetaxel, paclitaxel weekly treatment, liposomal doxorubicin, gemcitabine, etc., these treatments
  • the effectiveness is limited.
  • the tumor remission rate is generally 15-20% during the treatment period, and the disease-free survival period is about 3 to 4 months.
  • TNBC triple negative breast cancer
  • ER estrogen receptor
  • progesterone receptor progesterone
  • HER2 human epidermal growth factor receptor 2
  • Drug resistance is a difficult problem in the treatment of ovarian cancer and breast cancer. It can usually be divided into congenital resistance (or primary resistance) and secondary resistance (or recurrent resistance). After recurrence of ovarian cancer, it is important to determine whether the patient is platinum-sensitive or platinum-resistant.
  • Poly ADP-ribose polymerase or poly ADP-ribose polymerase plays an important role in repairing DNA single-strand breaks (SSBs) induced by different causes. Since the PARP inhibitor Olaparib was marketed in 2014 for the treatment of ovarian cancer with BRCA1/2 mutation, the development of anti-tumor PARP inhibitors has developed rapidly. Preclinical studies have confirmed that in addition to single-agent applications, PARP inhibitors can also be used as a radiosensitizing agent, combined with radiotherapy and chemotherapy, to enhance anti-tumor efficacy and reduce radiopharmaceutical or radiation doses, reducing side effects.
  • PARP inhibitors can also be used as a radiosensitizing agent, combined with radiotherapy and chemotherapy, to enhance anti-tumor efficacy and reduce radiopharmaceutical or radiation doses, reducing side effects.
  • WO2012019427A1 discloses a PARP inhibitor capable of inhibiting the growth of various tumors, and the structure is as shown in formula (B)
  • VEGF Vascular endothelial growth factor
  • Bevacizumab is a recombinant human anti-VEGF monoclonal antibody and is the first drug approved for anti-tumor angiogenesis.
  • the small molecule tyrosine kinase inhibitor Apatinib disclosed in WO2005000232A2 (publication 2005-01-06) has a highly selective competition for the ATP binding site of VEGFR-2 in cells, blocking downstream signal transduction and inhibiting The formation of tumor neovascularization ultimately achieves the purpose of treating tumors.
  • the structure of Apatinib is as shown in formula (I)
  • the combination of more than one anti-tumor drug with different target and interrelated effects can improve the anti-tumor activity of single drug and reduce the toxicity of the drug, and is a generally accepted anti-tumor therapy.
  • a phase II clinical trial combining the PARP inhibitor Olaparib with Cediranib, a drug that inhibits VEGFR activity by inhibiting VEGFR activity initially confirmed that the combination regimen was used in the treatment of ovarian cancer sensitive to recurrent platinum compounds. The efficacy was more significant in patients, indicating that the combination of the two types of targets for drug therapy has good feasibility.
  • VEGFR and PARP inhibitors are disclosed in the patent applications WO2010096627A1 (Publication 2010-08-26), WO2014004376A2 (Publication 2014-01-03), WO2016116602A1 (Publication 2016-07-28), WO2016179123A1 (Publication 2016-11-10) It is used to treat malignant tumors (such as breast cancer or ovarian cancer), but the existing joint program is aimed at the treatment of sensitive ovarian cancer with platinum. It is not known whether the combined effect of ovarian cancer or breast cancer resistant to relapse chemotherapy is effective. Synergy.
  • the technical problem to be solved by the present invention provides a poly ADP-ribose polymerase (PARP) inhibitor for the preparation of a medicament for treating chemotherapy-resistant ovarian cancer or breast cancer
  • PARP poly ADP-ribose polymerase
  • the present invention provides the use of a PARP inhibitor for the preparation of a medicament for the treatment of chemotherapy-resistant ovarian cancer or chemotherapy-resistant breast cancer.
  • the PARP inhibitor is selected from the group consisting of olaparib, Talazoparib, Veliparib, Rucaparib, CEP-8983 or BGB-290.
  • the PARP inhibitor structure is as shown in formula (B) or a pharmaceutically acceptable salt thereof,
  • the poly(ADP-ribose) polymerase inhibitor has a synergistic effect when used in combination with a VEGFR inhibitor, the VEGFR-2 being selected from the group consisting of a VEGFR-2 inhibitor, the VEGFR-2 being selected from, but not limited to, PAN-90806, Foretinib, Tafetinib, Kanitinib, Apatinib, Tanibirumab, Anlotinib, Lucitanib, Vatalanib, West Cediranib, Chiauranib, Dovitinib, Donafenib, Famitinib, Sitravatinib, Telatinib, L -21649, TAS-115, Cabozintinib, Thiophenib, Fruquintinib, Brivanib, Sulfatinib, Ramucirumab, Glesatinib , Nintedanib, Puquitinib, Axitinib, EDP317, Sorafen
  • VEGFR-2 inhibitor structure is as shown in formula (I) or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salts of the above schemes are selected from, but not limited to, hydrochlorides, methanesulfonates, maleates, malates or besylates, preferably mesylate.
  • the combination of the present invention has a synergistic pharmacodynamic effect.
  • the poly ADP-ribose polymerase inhibitor is administered at a dose of 0.1 to 1000 mg, and may be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 0 mg, 5 mg, 10 mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 305mg, 310mg,
  • the VEGFR inhibitor is administered in an amount of 0.1 to 1000 mg, and may be 0.1 mg, 0.3 mg, 0.5 mg, 0.7 mg, 0.9 mg, 0 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg.
  • the ratio of the VEGFR inhibitor to the poly ADP-ribose polymerase inhibitor is from 0.001 to 1000.
  • the daily dose ratio of the VEGFR inhibitor to the adenosine ribose polymerase inhibitor is 0.5:1 to 2:1, which may be 0.50:1, 0.51:1, 0.52:1. 0.53:1, 0.54:1, 0.55:1, 0.56:1, 0.57:1, 0.58:1, 0.59:1, 0.60:1, 0.61:1, 0.62:1, 0.63:1, 0.64:1, 0.65: 1, 0.66: 1, 0.67: 1, 0.68: 1, 0.69: 1, 0.70: 1, 0.71:1, 0.72: 1, 0.73: 1, 0.74: 1, 0.75: 1, 0.76: 1, 0.77: 1, 0.78:1, 0.79:1, 0.80:1, 0.81:1, 0.82:1, 0.83:1, 0.84:1, 0.85:1, 0.86:1, 0.87:1, 0.88:1, 0.89:1, 0.90: 1, 0.91:1, 0.92: 1, 0.93: 1, 0.94: 1, 0.95: 1, 0.96: 1, 0.97: 1, 0.98: 1, 0.99: 1, 1.00: 1, 1.01:1, 1.02: 1,
  • the polyA diphosphate ribose polymerase inhibitor is administered at a dose of 1-500 mg, preferably 2.5 mg, 3 mg, 5 mg, 6 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 50mg, 55
  • the polyA diphosphate ribose polymerase inhibitor inhibitor is administered at a dose of 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg (twice a day), or 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225
  • the VEGFR inhibitor is recommended once a day, and the poly ADP-ribose polymerase inhibitor is recommended to be administered twice daily at intervals of ⁇ 12 hours.
  • the chemotherapy resistance of the present invention includes primary drug resistance and relapse chemotherapy resistance, and preferably relapse chemotherapy resistance.
  • the recurrent chemotherapy-resistant ovarian cancer or the relapsed chemotherapy-resistant breast cancer of the present invention refers to a cancer cell group which is sensitive to drugs, which is produced during repeated treatment and repeated contact with ovarian cancer or breast cancer drugs. Drug resistance.
  • the medicament for treating ovarian cancer is selected from, but not limited to, gemcitabine, paclitaxel, bevacizumab, sorafenib, sunitinib, pazopanib, levabinib mesylate, carboplatin, docetaxel , pemetrexed disodium, everolimus, erlotinib, nervatinib, gefitinib, Nintedanib, dasatinib, Trametinib, avelumab, ribociclib, Ipilimumab, lobaplatin, Enzalutamide, mifi Ketone, Olaparib, alkylating agent, camphorsulfonic acid, Clovis, imatin
  • the medicament for treating breast cancer is selected from, but not limited to, trastuzumab, atezolizumab, gemcitabine, paclitaxel, pembrolizumab, ramucirumab, durvalumab, bevacizumab, oxaliplatin, capecitabine, nivolumab, losopro Nim, tamoxifen, levabinib mesylate, paclitaxel, everolimus, nervatinib, gefitinib, avelumab, ribociclib, Enzalutamide, pabotini, alkylating agent, aza Glycoside, trastuzumab, abiraterone, doxorubicin, abemaciclib, anastrozole, zoledronic acid, Eribulin methanesulfonic acid, pertuzumab, docetaxel, epirubicin, rapa Dini, letrozole, cabazitax
  • the present invention provides a use of a VEGFR inhibitor in combination with a poly ADP-ribose polymerase inhibitor for the preparation of a medicament for treating platinum-resistant ovarian or breast cancer.
  • the invention provides the use of a VEGFR inhibitor in combination with a poly ADP-ribose polymerase inhibitor for the preparation of a medicament for the treatment of recurrent platinum-resistant ovarian cancer.
  • the invention provides the use of a VEGFR inhibitor in combination with a poly ADP-ribose polymerase inhibitor for the manufacture of a medicament for the treatment of recurrent platinum-resistant breast cancer.
  • the ovarian cancer of the present invention is selected from the group consisting of high-grade serous ovarian cancer, fallopian tube or primary peritoneal cancer, ovarian epithelial cancer, and ovarian tumor.
  • the breast cancer of the present invention is preferably triple negative breast cancer.
  • the present invention also provides a use of a compound of the formula (B) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of ovarian cancer which is sensitive to platinum compounds or to chemotherapy or chemotherapy-resistant breast cancer.
  • the poly(ADP-ribose) polymerase inhibitor of the formula (B) or a pharmaceutically acceptable salt thereof is used in combination with a VEGFR inhibitor, and the synergistic effect is combined, and the VEGFR inhibitor is preferably It is a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a use of the formula (B) or a pharmaceutically acceptable salt thereof, in combination with the formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating ovarian cancer or breast cancer .
  • the ovarian cancer is selected from the group consisting of high grade serous ovarian cancer, fallopian tube or primary peritoneal cancer, ovarian epithelial cancer, ovarian tumor.
  • the ovarian cancer is chemoresistant, preferably relapsed chemotherapy.
  • the ovarian cancer is resistant to a platinum compound, more preferably to a relapsed platinum compound.
  • the ovarian cancer is sensitive to a platinum compound, preferably an ovarian cancer that is sensitive to previous platinum compounds.
  • the breast cancer is selected from the group consisting of triple negative breast cancer.
  • adenosine diphosphate ribose polymerase inhibitor represented by the formula (B) or a pharmaceutically acceptable salt thereof is used in combination with a VEGFR inhibitor, and has a synergistic effect.
  • the poly(ADP-ribose) polymerase inhibitor is administered alone, ie, without the use of other drugs having anti-tumor effects, but does not exclude the use of some ancillary agents that do not have an anti-tumor effect.
  • the invention also provides a pharmaceutical composition of a poly ADP-ribose polymerase inhibitor and a VEGFR inhibitor, comprising optionally one or more pharmaceutically acceptable carriers, excipients and/or diluents.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms.
  • a pharmaceutical preparation of a poly Adiphosphate ribose polymerase inhibitor and a VEGFR inhibitor can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, Sterile powder for injection and concentrated solution for injection), suppository, inhalation or spray.
  • the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like.
  • the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.
  • the poly ADP-ribose polymerase inhibitor of the present invention and the VEGFR inhibitor pharmaceutical composition may be administered alone or in combination with one or more therapeutic agents. Accordingly, in certain preferred embodiments, the pharmaceutical compositions further comprise one or more therapeutic agents.
  • the therapeutic agent is selected from the group consisting of: an antibody, an alkylating agent, an antimetabolite, an antibiotic, an alkaloid, or a hormone, and the alkylating agent is selected from the group consisting of bendamustine or temozolomide.
  • the anti-metabolism is selected from the group consisting of 5-fluorouracil or cytarabine, the antibody is selected from Herceptin, and the antibiotic is selected from the group consisting of doxorubicin or mitomycin C, and the alkaloid is selected from the group consisting of a base or a harringtonine, the hormone being selected from prednisone or thyroxine.
  • the components to be combined may be administered simultaneously or sequentially.
  • a second therapeutic agent can be administered prior to, concurrently with, or subsequent to the use of a VEGFR inhibitor of the invention in combination with a poly(ADP-ribose) polymerase inhibitor.
  • the ingredients to be combined may also be administered in combination in the form of the same preparation or in separate separate preparations.
  • the present invention also provides a method of treating recurrent chemoresistance-resistant ovarian cancer comprising administering to a cancer patient the aforementioned adenosine diphosphate ribose polymerase inhibitor and a VEGFR inhibitor.
  • the method comprises the step of determining whether the patient is a platinum-based compound or a platinum-based resistant type after the patient has relapsed ovarian cancer.
  • the present invention also provides a method for treating ovarian cancer comprising administering to a cancer patient a compound represented by the above formula (B) or a pharmaceutically acceptable salt thereof and a compound of the formula (I) or a pharmaceutically acceptable thereof salt.
  • the method comprises the step of determining whether the patient is a platinum-based compound or a platinum-based resistant type after the patient has relapsed ovarian cancer.
  • the present invention also provides a method of treating breast cancer comprising administering to a cancer patient the aforementioned polyadenosine diphosphate ribose polymerase inhibitor and a VEGFR inhibitor. If not explained to the contrary, the terms in the present invention have the following meanings:
  • the platinum-resistant type of the present invention refers to a recurrence within 6 months after the end of chemotherapy with a platinum-containing regimen; and the relapsed after 6 months of chemotherapy is a platinum-based sensitive type (or platinum-sensitive type).
  • the recurrent resistance of the present invention is also called secondary resistance.
  • the enrolled subject of the present invention is preferably a histologically or cytologically confirmed recurrent ovarian cancer patient (requires high-grade serous and/or ovarian epithelial cancer, fallopian tube cancer or original known to have BRCA1/2 loss-of-function mutation) Primary peritoneal cancer), while receiving 2 to 4 platinum-containing regimens at the same time, the last platinum-containing regimen was treated with non-PD, relapse/progress within 6 months after treatment, or toxicity was not tolerated during treatment And the patient's penultimate platinum-containing regimen relapses or progresses ⁇ 6 months after the end of treatment; or, patients with recurrent metastatic triple-negative breast cancer diagnosed by histology or cytology, after no more than two-line chemotherapy after recurrence and metastasis, Treatment failed.
  • Toxicity is not tolerated: Grade 4 hematologic toxicity or grade 3 and above non-hematologic toxicity occurs during treatment.
  • Definition of treatment failure disease progression or relapse after treatment, systemic chemotherapy must be ⁇ 2 cycles; triple negative breast cancer is defined as: cancer tissue immunohistochemical examination of progesterone receptor (PR), estrogen receptor The body (ER) was negative and human epidermal growth factor receptor 2 (HER2) was negative (IHC-/+ or IHC++ but FISH/CISH-).
  • the present invention relates to "combination" as a mode of administration, which means administering at least one dose of a VEGFR inhibitor and at least one dose of a poly(ADP-ribose) polymerase inhibitor over a certain period of time, two of which Substances all show pharmacological effects.
  • the time period may be within one administration period, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
  • the VEGFR inhibitor and the poly ADP-ribose polymerase inhibitor can be administered simultaneously or sequentially.
  • Such a term includes treatment in which apafitinib and a poly(ADP-ribose) polymerase inhibitor are administered by the same route of administration or by different routes of administration.
  • the combined modes of administration of the present invention are selected from the group consisting of simultaneous administration, independent formulation and co-administration or independently formulated and administered sequentially.
  • an "effective amount” as used herein includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate the diagnosis.
  • An effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health of the patient, the route and dosage of the method of administration, and the severity of the side effects.
  • An effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • Total survival refers to the period from random period to death from any cause. For subjects who survived at the last follow-up, their OS was censored as data at the last follow-up. In the subjects who were lost to follow-up, the OS was counted as data censored by the last confirmed survival time before the loss of follow-up.
  • the data censored OS is defined as the time from random grouping to censoring.
  • Objective response rate refers to the proportion of patients whose tumor shrinks to a certain extent and remains for a certain period of time, including cases of CR and PR.
  • Objective tumor remission assessment criteria (RECIST 1.1 criteria) were used to assess objective tumor remission. Subjects must be accompanied by measurable tumor lesions at baseline, and the efficacy criteria were divided into complete response (CR), partial response (PR), stable (SD), and progression (PD) according to RECIST 1.1 criteria.
  • DCR Disease Control Rate
  • CR Complete remission
  • Partial remission The sum of the target lesion diameters is at least 30% less than the baseline level.
  • PD Disease progression: reference to the minimum of the sum of all measured target lesion diameters throughout the experimental study, with a diameter and relative increase of at least 20% (referenced to baseline values if the baseline measurement is minimal); In addition, the absolute value of the diameter and the absolute value must be increased by at least 5 mm (one or more new lesions are also considered to be disease progression).
  • Stable disease The extent of target lesion reduction did not reach PR, and the degree of increase did not reach PD level. Between the two, the minimum value of the sum of diameters could be used as a reference.
  • PARP inhibitor 4-[[3-[[2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5- ⁇ ]pyrazin-7-yl]carbonyl]-4-fluorophenyl]methyl-1(2H)-pyridazinone can be prepared according to the method of patent application WO2012019427A1.
  • Compound B Apatinib mesylate can be prepared according to the method of patent application WO2010031266A1.
  • Example 1 Effectiveness of Compound A alone in the treatment of recurrent chemotherapy-resistant ovarian cancer
  • Compound A was administered at a dose level of 120 mg/d and above, and 23 patients with recurrent ovarian cancer who had failed to undergo standard treatment for histological or cytological diagnosis. These patients had at least 2 lines during the recurrence and metastasis of ovarian cancer.
  • Compound A starting doses of 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 150 mg, orally twice daily, or 120 mg, 160 mg once daily.
  • the objective response rate (ORR) of Compound A for single-use and daily dose of 120 mg for recurrent platinum-resistant ovarian cancer was 18.2%, and the disease control rate (DCR) was 81.8%.
  • Example 2 The efficacy of the combination of the compounds A and B of the present invention in the treatment of recurrent chemotherapy-resistant ovarian cancer
  • Toxicity is not tolerated: Grade 4 hematologic toxicity or grade 3 and above non-hematologic toxicity occurs during treatment.
  • Compound A starting dose of 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg twice daily, or 80 mg, 120 mg, 200 mg, 240 mg, 300 mg once daily; first evaluation of efficacy (including imaging and serological examination) The investigator assessed that there was no effective remission and no adverse events of grade 3 or above occurred during the medication, and the dose could be increased with the consent of the subject;
  • Compound B initial dose 250 mg, orally, once daily.
  • the objective response rate (ORR) of platinum-resistant ovarian cancer in the combined group of 120 mg (twice a day) was 100% (2/2), disease control Rate (DCR) is 100% (2/2);
  • the objective response rate (ORR) of platinum-resistant ovarian cancer in the combined group of 160 mg (twice a day) was 100% (3/3), and the disease control rate (DCR) was 100% (3/3);
  • the objective response rate (ORR) for platinum-sensitive ovarian cancer was 100% (1/1) and the disease control rate (DCR) was 100% (1/1) for the combined group of 160 mg (twice a day).
  • the objective response rate (ORR) of platinum-resistant ovarian cancer was 27.27% (3/11) and the disease control rate (DCR) was 63.6% (7/11).
  • the objective response rate (ORR) for platinum-sensitive ovarian cancer was 40% (6/15) and the disease control rate (DCR) was 93.33% (14/15) for the combined group of 200 mg (twice a day).
  • ORR objective response rate
  • DCR disease control rate
  • the objective response rate (ORR) was 43.75% (7/16) and the disease control rate (DCR) was 93.75% (15/15) in the combination group with daily dose of 120 mg or more. 16). It also shows excellent clinical results.

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Abstract

本发明提供了PARP抑制剂用于治疗化疗耐药的卵巢癌或乳腺癌的用途。具体而言，本发明提供一种PARP抑制剂在制备治疗化疗耐药的卵巢癌或乳腺癌的药物中的用途，所述PARP抑制剂选自如通式(B)所示的化合物或其可药用的盐。

Description

PARP抑制剂用于治疗化疗耐药的卵巢癌或乳腺癌的用途 技术领域
本发明涉及PARP抑制剂在制备治疗化疗耐药的卵巢癌或乳腺癌的药物中的用途。
背景技术
卵巢上皮癌(epithelial ovarian cancer，EOC)是致死率最高的妇科恶性肿瘤，近75％的患者就诊时已为中晚期，需要根治性手术与含铂类方案化疗的标准治疗方式，标准治疗完成后其完全缓解率虽可达40％～60％，但超过90％患者将于平均18个月复发，并随之面临因化疗抗拒和疾病进展的死亡风险。
针对复发性卵巢癌，如为含铂化疗方案治疗敏感者(自末次化疗至肿瘤复发/进展时间≥6个月)，则后续治疗将继续选取含铂类方案治疗，如为含铂化疗方案耐药(自末次化疗至肿瘤复发/进展时间<6个月)，则后续将选用单药化疗，化疗方案包括多西他赛、紫杉醇周疗、脂质体阿霉素、吉西他滨等，这些治疗的有效性有限，治疗期间肿瘤缓解率普遍在15～20％，无疾病进展生存期约3～4个月，针对复发性卵巢癌，亟待开发高效、低毒的治疗方案。
乳腺癌是一类在形态学、分子生物学、临床表现以及治疗反应性上具有高度异质性的疾病。三阴性乳腺癌(triple negative breast cancer，TNBC)是其中一种特殊亚型，占所有乳腺癌的12％～17％，表现为雌激素受体(estrogen receptor，ER)、孕激素受体(progesterone receptor，PR)及人表皮生长因子受体2(human epidermal growth factor receptor 2，HER2)均为阴性。此类型乳腺癌在非洲裔美国人、绝经前年轻女性及BRCA1基因突变的患者中发病率更高，且细胞分化差、有高度侵袭性，远处转移风险高，更倾向于内脏转移，有研究显示复发转移性TNBC中位生存期仅13个月，5年生存率不到30％。由于三阴性乳腺癌缺乏内分泌治疗及分子靶向治疗的靶点，因此化疗是三阴性乳腺癌患者主要的全身治疗手段。
耐药是治疗卵巢癌、乳腺癌的一个难题，通常可分为先天型耐药(或称为原发性耐药)和继发型耐药(或称复发性耐药)。在卵巢癌复发后，判断患者是铂类化合物敏感型还是铂类化合物耐药型，对治疗方案的制定很重要。
多聚二磷酸腺苷核糖聚合酶或聚ADP核糖聚合酶(PARP)在修复因不同原因诱发的DNA单链断裂(SSB)过程中发挥重要作用。自2014年PARP抑制剂Olaparib上市用于治疗BRCA1/2突变的卵巢癌以来，抗肿瘤治疗的PARP抑制剂研发得以迅速发展。临床前研究证实，除了单药应用，PARP抑制剂还可以作为放、化疗增敏剂与放、化疗联用，增强抗肿瘤疗效而减少放、化疗用药或放射剂量，降低 毒副作用。最近的一项II期临床试验结果则表明，Olaparib对于具有DNA修复基因突变的晚期前列腺癌患者表现出88％的应答，能够使其肿瘤生长被抑制甚至缩小，总生存期长于同类患者预期的存活时间。因此不断拓展PARP抑制剂的使用方式及适应症范围对于PARP抑制剂的研发及应用具有良好的推动作用。WO2012019427A1(公开2012-02-16)公开了PARP抑制剂，能够抑制多种肿瘤的生长，结构如式(B)所示
Figure PCTCN2018119318-appb-000001
血管内皮生长因子(VEGF)是迄今证实最为重要的正性调控蛋白。VEGF通过与其受体亚型VEGFR-2结合，诱导VEGFR-2磷酸化，并进而激活一系列级联反应，引起血管内皮细胞增殖，诱导血管生成。有研究表明，VEGF及其受体在胃癌组织中均呈高表达，其表达量与胃癌预后呈正相关。因此，靶向VEGF或其受体从而破坏新生血管生成的治疗无疑可为胃癌患者提供全新的治疗方向及分子靶点。贝伐单抗(Bevacizumab)为重组人源抗VEGF单克隆抗体，是首个被批准应用于抗肿瘤血管生成的药物。WO2005000232A2(公开2005-01-06)公开的小分子酪氨酸激酶抑制剂阿帕替尼(Apatinib)具备高度选择性竞争细胞内VEGFR-2的ATP结合位点，阻断下游信号转导，抑制肿瘤新生血管的生成，最终达到治疗肿瘤的目的。阿帕替尼(Apatinib)结构如式(I)所示
Figure PCTCN2018119318-appb-000002
联合使用一种以上靶点各异又相互关联的抗肿瘤药物，充分发挥各组分优势，既能提高单药的抗肿瘤活性又可降低药物毒性，是一种被普遍接受的抗肿瘤疗法。一项将PARP抑制剂Olaparib与通过抑制VEGFR活性抗新生血管生成的药物Cediranib联用的Ⅱ期临床试验初步证实该联用方案相较于两药单用在复发性铂类 化合物治疗敏感的卵巢癌患者中疗效更为显著，表明上述两类靶点的药物联用方案用于肿瘤治疗具有良好的可行性。
专利申请WO2010096627A1(公开2010-08-26)、WO2014004376A2(公开2014-01-03)、WO2016116602A1(公开2016-07-28)、WO2016179123A1(公开2016-11-10)中公开了VEGFR与PARP抑制剂联用在治疗恶性肿瘤(如乳腺癌或卵巢癌等)，但现有联合方案都是针对铂治疗敏感卵巢癌，不知晓联用对复发性化疗耐药的卵巢癌或乳腺癌的抑制效果是否具备协同作用。
发明内容
本发明要解决的技术问题提供一种多聚二磷酸腺苷核糖聚合酶(PARP)抑制剂在制备治疗化疗耐药的卵巢癌或乳腺癌的药物中的用途
本发明的技术方案如下：
本发明提供了提供一种PARP抑制剂在制备治疗化疗耐药的卵巢癌或化疗耐药的乳腺癌的药物中的用途。
优选地，所述PARP抑制剂选自奥拉帕尼、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
在优选实施方案中，所述PARP抑制剂结构如通式(B)所示的或其可药用的盐，
Figure PCTCN2018119318-appb-000003
进一步地，所述多聚二磷酸腺苷核糖聚合酶抑制剂与VEGFR抑制剂联合使用后具备协同作用，所述VEGFR抑制剂选自VEGFR-2抑制剂，所述VEGFR-2选自但不限于PAN-90806、Foretinib、他菲替尼(Tafetinib)、康尼替尼(Kanitinib)、阿帕替尼(Apatinib)、Tanibirumab、安罗替尼(Anlotinib)、德立替尼(Lucitanib)、Vatalanib、西地尼布(Cediranib)、西奥罗尼(Chiauranib)、多韦替尼(Dovitinib)、多纳非尼(Donafenib)、法米替尼(Famitinib)、Sitravatinib、特拉替尼(Telatinib)、L-21649、TAS-115、卡博替尼(Cabozantinib)、噻尔非尼(Thiophenib)、呋喹替尼(Fruquintinib)、布立尼布(Brivanib)、索凡替尼(Sulfatinib)、Ramucirumab、Glesatinib、尼达尼布(Nintedanib)、普喹替尼(Puquitinib)、阿西替尼(Axitinib)、EDP317、索拉非尼(Sorafenib)、麦他替尼(Metatinib)、Tivozanib、瑞戈非尼(Regorafenib)、Midostaurin、培唑帕尼(Pazopanib)、HLX-06、Altiratinib、宁格替尼 (Ningetinib)、舒尼替尼(Sunitinib)、AL-8326、Rebastinib或以上药物的可药用盐。
在优选实施方案中，所述VEGFR-2抑制剂结构如通式(I)所示的或其可药用的盐，
Figure PCTCN2018119318-appb-000004
上述方案所述可药用的盐选自但不限于盐酸盐、甲磺酸盐、马来酸盐、苹果酸盐或苯磺酸盐等，优选甲磺酸盐。
本发明所述联合具有协同药效作用。
在一些实施方案中，所述多聚二磷酸腺苷核糖聚合酶抑制剂给药剂量为0.1-1000mg，可以为0.1mg、0.3mg、0.5mg、0.7mg、0.9mg、0mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、525mg、550mg、575mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、825mg、850mg、875mg、900mg、925mg、950mg、975mg、1000mg。
在另一可选实施方案中，所述VEGFR抑制剂给药剂量为0.1-1000mg，可以为0.1mg、0.3mg、0.5mg、0.7mg、0.9mg、0mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、525mg、550mg、575mg、600mg、625mg、650mg、675mg、700mg、725mg、750mg、775mg、800mg、825mg、850mg、875mg、900mg、925mg、950mg、975mg、1000mg。
在优选实施方案中，所述VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂 的给药剂量比例为0.001～1000。
在可选实施方案中，所述VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂日服剂量比0.5:1～2:1，可为0.50:1、0.51:1、0.52:1、0.53:1、0.54:1、0.55:1、0.56:1、0.57:1、0.58:1、0.59:1、0.60:1、0.61:1、0.62:1、0.63:1、0.64:1、0.65:1、0.66:1、0.67:1、0.68:1、0.69:1、0.70:1、0.71:1、0.72:1、0.73:1、0.74:1、0.75:1、0.76:1、0.77:1、0.78:1、0.79:1、0.80:1、0.81:1、0.82:1、0.83:1、0.84:1、0.85:1、0.86:1、0.87:1、0.88:1、0.89:1、0.90:1、0.91:1、0.92:1、0.93:1、0.94:1、0.95:1、0.96:1、0.97:1、0.98:1、0.99:1、1.00:1、1.01:1、1.02:1、1.03:1、1.04:1、1.05:1、1.06:1、1.07:1、1.08:1、1.09:1、1.10:1、1.11:1、1.12:1、1.13:1、1.14:1、1.15:1、1.16:1、1.17:1、1.18:1、1.19:1、1.20:1、1.21:1、1.22:1、1.23:1、1.24:1、1.25:1、1.26:1、1.27:1、1.28:1、1.29:1、1.30:1、1.31:1、1.32:1、1.33:1、1.34:1、1.35:1、1.36:1、1.37:1、1.38:1、1.39:1、1.40:1、1.41:1、1.42:1、1.43:1、1.44:1、1.45:1、1.46:1、1.47:1、1.48:1、1.49:1、1.50:1、1.51:1、1.52:1、1.53:1、1.54:1、1.55:1、1.56:1、1.57:1、1.58:1、1.59:1、1.60:1、1.61:1、1.62:1、1.63:1、1.64:1、1.65:1、1.66:1、1.67:1、1.68:1、1.69:1、1.70:1、1.71:1、1.72:1、1.73:1、1.74:1、1.75:1、1.76:1、1.77:1、1.78:1、1.79:1、1.80:1、1.81:1、1.82:1、1.83:1、1.84:1、1.85:1、1.86:1、1.87:1、1.88:1、1.89:1、1.90:1、1.91:1、1.92:1、1.93:1、1.94:1、1.95:1、1.96:1、1.97:1、1.98:1、1.99:1、2.00:1，优选0.83:1、1.25:1、1.56:1、1.88:1。
进一步地，在可选实施方案中，所述多聚二磷酸腺苷核糖聚合酶抑制剂的给药剂量为1-500mg，优选2.5mg、3mg、5mg、6mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg或500mg，和VEGFR抑制剂的给药剂量为1-850mg，优选2.5mg、3mg、5mg、6mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、 300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg、500mg、505mg、510mg、515mg、520mg、525mg、530mg、535mg、540mg、545mg、550mg、555mg、560mg、565mg、570mg、575mg、580mg、585mg、590mg、595mg、600mg、605mg、610mg、615mg、620mg、625mg、630mg、635mg、640mg、645mg、650mg、655mg、660mg、665mg、670mg、675mg、680mg、685mg、690mg、695mg、700mg、705mg、710mg、715mg、720mg、725mg、730mg、735mg、740mg、745mg、750mg、755mg、760mg、765mg、770mg、775mg、780mg、785mg、790mg、795mg、800mg、805mg、810mg、815mg、820mg、825mg、830mg、835mg、840mg、845mg、850mg，更优选自50mg、100mg、150mg、200mg、250mg、375mg、425mg、500mg、600mg、700mg、750mg、800mg或850mg。
在优选实施方案中，所述多聚二磷酸腺苷核糖聚合酶抑制剂抑制剂的给药剂量为40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg(一日二次)，或80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg(一日一次)进行剂量递增，分别联合固定剂为250mg或375mg的VEGFR(一日一次)。
在可选实施方案中，所述VEGFR抑制剂推荐一日一次，多聚二磷酸腺苷核糖聚合酶抑制剂推荐一日两次、间隔～12小时。
本发明所述化疗耐药包括原发性耐药和复发性化疗耐药，优选复发性化疗耐药。
本发明所述复发性化疗耐药的卵巢癌或复发性化疗耐药的乳腺癌是指原来对药物敏感的癌细胞群，在反复治疗，与治疗卵巢癌或乳腺癌药物屡次接触的过程中产生耐药性。所述治疗卵巢癌的药物选自但不限于吉西他滨、紫杉醇、贝伐单抗、索拉非尼、舒尼替尼、帕唑帕尼、甲磺酸乐伐替尼、卡铂、多西紫杉醇、培美曲塞二钠、依维莫司、埃罗替尼、来那替尼、吉非替尼、Nintedanib、达沙替尼、Trametinib、avelumab、ribociclib、Ipilimumab、洛铂、Enzalutamide、米非司酮、Olaparib、烷化剂、樟脑磺酸、Clovis、伊马替尼、s-malate 184、阿扎胞苷、西妥昔单抗、Alza、阿那曲唑、依西美坦、copanlisib盐酸盐、伊立替康、来那度胺、帕妥株单抗、维莫德吉、阿柏西普、白介素、拓扑替康、多西他赛、左炔诺孕酮、 帕尼单抗、长春氟宁、非格司亭、来曲唑、卡巴他赛、多柔比星、六甲蜜胺、卫康醇、西罗莫司、氨基蝶呤、凡德他尼、干扰素α-2b后续的生物、pharmbiotek、重组人干扰素α-2b、苯达莫司汀、belinostat、immuncell LC、干扰素γ-1b、catumaxomab、glutoxim、Vorinostat、西曲瑞克、ponatinib、treosulfan、依托泊苷、贝沙罗汀、紫杉醇、洛铂、伊沙匹隆、多西紫杉醇、米托蒽醌、米非司酮、紫杉醇、盐酸多柔比星、贝洛替康、雷替曲塞、紫杉醇、阿利维A酸、盐酸多柔比星、沙妥莫单抗喷地肽、盐酸拓扑替康、奈达铂、多西他赛、顺铂、奥沙利铂/草酸铂等中至少一种，优选铂类化合物，例如卡铂、顺铂、奥沙利铂/草酸铂、环硫铂、奈达铂或洛铂。所述治疗乳腺癌的药物选自但不限于曲妥珠单抗、atezolizumab、吉西他滨、紫杉醇、Pembrolizumab、ramucirumab、durvalumab、贝伐单抗、奥沙利铂、卡培他滨、Nivolumab、卢索替尼、他莫昔芬、甲磺酸乐伐替尼、紫杉醇、依维莫司、来那替尼、吉非替尼、avelumab、ribociclib、Enzalutamide、帕博西尼、烷化剂、阿扎胞苷、曲妥珠单抗、阿比特龙、阿霉素、abemaciclib、阿那曲唑、唑来膦酸、Eribulin甲磺酸、帕妥株单抗、多西他赛、表柔比星、拉帕替尼、来曲唑、卡巴他赛、曲妥珠单抗、凡德他尼、阿西替尼、干扰素γ-1b、曲妥珠单抗生物仿制药、罗米地辛、比卡鲁胺、多西紫杉醇、尿多酸肽、氨柔比星、伊沙匹隆、米非司酮、紫杉醇、托瑞米芬、顺铂、紫杉醇等中的至少一种，优选自吉西他滨、多西他赛、表柔比星、紫杉醇、拉帕替尼或铂类化合物，例如卡铂、顺铂、奥沙利铂/草酸铂、环硫铂、奈达铂或洛铂。
本发明提供一种VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂联合在制备治疗铂类化合物耐药的卵巢癌或乳腺癌的药物中的用途。
优选地，本发明提供一种VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂联合在制备治疗复发性铂类化合物耐药的卵巢癌的药物中的用途。
优选地，本发明提供一种VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂联合在制备治疗复发性铂类化合物耐药的乳腺癌的药物中的用途。
本发明所述卵巢癌选自高级别浆液性卵巢癌、输卵管或原发性腹膜癌、卵巢上皮癌、卵巢肿瘤。
本发明所述的乳腺癌优选三阴性乳腺癌。
本发明还提供一种通式(B)所示的或其可药用的盐在制备治疗既往铂类化合物敏感的卵巢癌或既往化疗治疗失败或化疗耐药的乳腺癌的药物中的用途。
进一步地，所述多聚二磷酸腺苷核糖聚合酶抑制剂通式(B)所示的或其可药用的盐与VEGFR抑制剂联合使用，联合后具备协同作用，所述VEGFR抑制剂优选为通式(I)所示的或其可药用的盐。
本发明还提供一种通式(B)所示的或其可药用的盐联合通式(I)所示的或其可药用的盐在制备治疗卵巢癌或乳腺癌的药物中的用途。
在可选实施方案中，所述卵巢癌选自高级别浆液性卵巢癌、输卵管或原发性 腹膜癌、卵巢上皮癌、卵巢肿瘤。
在可选实施方案中，所述卵巢癌为化疗耐药的，优选复发性化疗耐药。
在优选实施方案中，所述卵巢癌为铂类化合物耐药的，更优选复发性铂类化合物耐药的。
在优选实施方案中，所述卵巢癌为铂类化合物敏感的，优选既往铂类化合物敏感的卵巢癌。在可选实施方案中，所述乳腺癌选自三阴性乳腺癌。
进一步地，所述多聚二磷酸腺苷核糖聚合酶抑制剂通式(B)所示的或其可药用的盐与VEGFR抑制剂联合使用，联合后具备协同作用。
在一些实施方案中，所述的多聚二磷酸腺苷核糖聚合酶抑制剂单独施用，即无需与其它具有抗肿瘤作用的药物联合使用，但是不排除使用一些不具有抗肿瘤作用的辅助用药。
本发明还提供一种多聚二磷酸腺苷核糖聚合酶抑制剂与VEGFR抑制剂的药物组合物，包含任选的一种或多种药用载体、赋形剂和/或稀释剂。所述药物组合物可以制成药学上可接受的任一剂型。例如，多聚二磷酸腺苷核糖聚合酶抑制剂与VEGFR抑制剂的药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
此外，本发明的所述药物组合物还可以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。
本发明所述多聚二磷酸腺苷核糖聚合酶抑制剂与VEGFR抑制剂药物组合物可以单独给药，或者与一种或多种治疗剂联合使用。因此，在某些优选的实施方案中，所述的药物组合物还含有一种或多种治疗剂。在某些优选的实施方案中，所述治疗剂选自：抗体、烷化剂、抗代谢类、抗生素类、生物碱类或激素类，所述烷化剂选自苯达莫司汀或替莫唑胺，所述抗代谢类选自5-氟尿嘧啶或阿糖胞苷，所述抗体选自赫赛汀，所述抗生素类选自阿霉素或丝裂霉素C，所述生物碱类选自长春碱类或三尖杉酯碱类，所述激素类选自泼尼松或甲状腺素。
待组合的各成分(例如，VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂及第二治疗剂)可同时给药或依次顺序地分开用药。例如，可以在将本发明VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂联用之前、同时或之后，施用第二治疗剂。此外，待组合的各成分还可以同一制剂形式或以分开的不同制剂的形式联合给药。
本发明还提供了一种治疗复发性化疗耐药的卵巢癌的方法，包括向癌症患者 给予前述的多聚二磷酸腺苷核糖聚合酶抑制剂与VEGFR抑制剂。
进一步地，该方法包括：在患者卵巢癌复发后，判断患者是铂类化合物敏感型还是铂类化合物耐药型的步骤。
本发明还提供了一种治疗卵巢癌的方法，包括向癌症患者给予前述的通式(B)所示的或其可药用的盐和通式(I)所示的或其可药用的盐。
进一步地，该方法包括：在患者卵巢癌复发后，判断患者是铂类化合物敏感型还是铂类化合物耐药型的步骤。
本发明还提供了一种治疗乳腺癌的方法，包括向癌症患者给予前述的多聚二磷酸腺苷核糖聚合酶抑制剂与VEGFR抑制剂。如无相反解释，本发明中术语具有如下含义：
本发明所述的铂耐药型是指含铂方案化疗结束6个月内复发的；而结束化疗6个月后复发者为铂类化合物敏感型(或称为铂治疗敏感型)。
本发明所述复发性耐药又称为继发型耐药。
本发明入组受试者优选为组织学或细胞学确诊的复发性卵巢癌患者(需是高级别浆液性和/或已知存在BRCA1/2功能缺失性突变的卵巢上皮癌、输卵管癌或原发性腹膜癌)，同时既往接受过2～4次含铂方案治疗，最后一次含铂方案治疗期间疗效为非PD，治疗结束后<6个月内复发/进展，或治疗期间毒性不能耐受，且患者倒数第二次含铂方案自治疗结束后≥6个月复发或进展；或者，组织学或细胞学确诊的复发转移性三阴性乳腺癌患者，复发转移后经过不超过两线化疗，治疗失败。
注：毒性不能耐受：治疗期间发生4级的血液学毒性或3级及以上的非血液学毒性。治疗失败的定义：治疗过程中疾病进展或治疗结束后复发，接受系统化疗必须≥2个周期；三阴性乳腺癌的定义为：癌组织免疫组化检查孕激素受体(PR)、雌激素受体(ER)均为阴性，人表皮生长因子受体2(HER2)阴性(IHC-/+或IHC++但FISH/CISH-)。
本发明关于“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量的VEGFR抑制剂和至少一种剂量的多聚二磷酸腺苷核糖聚合酶抑制剂，其中两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内，更优选12小时以内。可以同时或依次给予VEGFR抑制剂和多聚二磷酸腺苷核糖聚合酶抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予阿帕替尼和多聚二磷酸腺苷核糖聚合酶抑制剂。本发明所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
本发明所述的“有效量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂 量或给药方案。
总生存期(OS)指从随机期至任何原因导致死亡的期。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活时间计为数据删失。数据删失的OS定义为从随机分组到删失的时间。
客观缓解率(Objective response rate，ORR)指肿瘤缩小达到一定并且保持一定时间的病人的比例，包含了CR和PR的病例。采用实体瘤缓解评估标准(RECIST 1.1标准)来评定肿瘤客观缓解。受试者在基线时必须伴有可测量的肿瘤病灶，疗效评定标准根据RECIST 1.1标准分为完全缓解(CR)、部分缓解(PR)、稳定(SD)、进展(PD)。
疾病控制率(Disease Control Rate，DCR)指经确认的完全缓解、部分缓解和疾病稳定(≥8周)病例数在可评价疗效患者中的百分比。
完全缓解(CR)：所有靶病灶消失，全部病理淋巴结(包括靶结节和非靶结节)短直径必须减少至＜10mm。
部分缓解(PR)：靶病灶直径之和比基线水平减少至少30％。
疾病进展(PD)：以整个实验研究过程中所有测量的靶病灶直径之和的最小值为参照，直径和相对增加至少20％(如果基线测量值最小就以基线值为参照)；除此之外，必须满足直径和的绝对值增加至少5mm(出现一个或多个新病灶也视为疾病进展)。
疾病稳定(SD)：靶病灶减小的程度没达到PR，增加的程度也没达到PD水平，介于两者之间，研究时可以直径之和的最小值作为参考。
化合物A：PARP抑制剂，4-[[3-[[2-(三氟甲基)-5,6,7,8-四氢-[1,2,4]三唑并[1,5-α]吡嗪-7-基]羰基]-4-氟苯基]甲基-1(2H)-酞嗪酮，可按照专利申请WO2012019427A1中的方法制备。
化合物B：甲磺酸阿帕替尼，可按照专利申请WO2010031266A1中的方法制备。
具体实施方式
下述试验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。本领域技术人员在本说明书的教导下，能够对本发明的技术方案进行适当的修改或改变，而不背离本发明的精神和范围。
实施例1：化合物A单用治疗复发性化疗耐药的卵巢癌的有效性
I期临床中，化合物A在120mg/d及以上剂量水平，入组23位组织学或细胞学确诊的经标准治疗失败的复发性卵巢癌患者，这些患者在卵巢癌复发转移阶段至少经过2线系统化疗，化疗方案以含铂类化疗方案，均为含铂治疗耐药或治疗期间不 耐受化疗毒性。
给药方案：
化合物A：起始剂量10mg、20mg、40mg、60mg、80mg、100mg、150mg，每日两次口服，或者120mg、160mg，每日一次口服。
结论：
从23例中22例可评价的临床数据来看，单用、日服剂量120mg化合物A针对复发性铂耐药卵巢癌的疾病客观缓解率(ORR)为18.2％，疾病控制率(DCR)为81.8％。
从13例临床数据来看，单用、日服剂量120mg化合物A针对铂耐药BRCA未突变卵巢癌的疾病客观缓解率(ORR)为15.4％，疾病控制率(DCR)为84.6％。
实施例2：本发明化合物A和B联用治疗复发性化疗耐药的卵巢癌的有效性
I期临床入组32位组织学或细胞学确诊的复发性卵巢癌患者(需是高级别浆液性和/或已知存在BRCA1/2功能缺失性突变的卵巢上皮癌、输卵管癌或原发性腹膜癌)，同时既往接受过2～4次含铂方案治疗，最后一次含铂方案治疗期间疗效为非PD，治疗结束后<6个月内复发/进展，或治疗期间毒性不能耐受，且患者倒数第二次含铂方案自治疗结束后≥6个月复发或进展。
注：毒性不能耐受：治疗期间发生4级的血液学毒性或3级及以上的非血液学毒性。
给药方案：
化合物A：起始剂量40mg、60mg、80mg、100mg、120mg、150mg，每日两次，或者80mg、120mg、200mg、240mg、300mg，每日一次；首次疗效评价(包括影像学检查和血清学检查)经研究者评估未有效缓解且用药期间未出现3级及以上不良事件，经受试者本人同意，可以提高剂量；
化合物B：初始剂量250mg，口服，每日一次。
数据：
针对耐药或敏感复发性卵巢癌可评价病例中，日服120mg(一日两次)的联合组针对铂耐药卵巢癌的客观缓解率(ORR)为100％(2/2)，疾病控制率(DCR)为100％(2/2)；
日服160mg(一日两次)的联合组针对铂耐药卵巢癌的客观缓解率(ORR)为100％(3/3)，疾病控制率(DCR)为100％(3/3)；
日服160mg(一日两次)的联合组针对铂敏感卵巢癌的客观缓解率(ORR)为100％(1/1)，疾病控制率(DCR)为100％(1/1)；
日服200mg(一日两次)的联合组针对铂耐药卵巢癌的客观缓解率(ORR)为27.27％(3/11)，疾病控制率(DCR)为63.6％(7/11)；
日服200mg(一日两次)的联合组针对铂敏感卵巢癌的客观缓解率(ORR)为40％(6/15)，疾病控制率(DCR)为93.33％(14/15)。
数据分析：
16例铂耐药复发卵巢癌可评价病例中，日服剂量120mg以上化合物A的联合组的客观缓解率(ORR)为50％(8/16)，疾病控制率(DCR)为75％(12/16)。该数据明显优于现有针对铂耐药的复发性卵巢癌的治疗方案(ORR，10～30％)。
16例铂敏感复发卵巢癌可评价病例中，日服剂量120mg以上化合物A的联合组的客观缓解率(ORR)为43.75％(7/16)，疾病控制率(DCR)为93.75％(15/16)。也展现优异临床效果。

Claims (16)

  1. 多聚二磷酸腺苷核糖聚合酶抑制剂在制备治疗化疗耐药的卵巢癌或乳腺癌的药物中的用途。
  2. 根据权利要求1所述的用途，其特征在于，所述多聚二磷酸腺苷核糖聚合酶抑制剂选自奥拉帕尼、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
  3. 根据权利要求1所述的用途，其特征在于，所述多聚二磷酸腺苷核糖聚合酶抑制剂结构如通式(B)所示的化合物或其可药用的盐，
    Figure PCTCN2018119318-appb-100001
  4. 根据权利要求1-3任一项所述的用途，其特征在于，所述多聚二磷酸腺苷核糖聚合酶抑制剂与VEGFR抑制剂联合使用，所述VEGFR抑制剂优选VEGFR-2抑制剂。
  5. 根据权利要求4所述的用途，其特征在于，所述VEGFR-2抑制剂结构如通式(I)所示的或其可药用的盐，
    Figure PCTCN2018119318-appb-100002
  6. 如权利要求5所述的用途，其特征在于，所述可药用的盐选自盐酸盐、甲磺酸盐、马来酸盐、苹果酸盐或苯磺酸盐，优选甲磺酸盐。
  7. 根据权利要求1-6任一项所述的用途，其特征在于，所述联合具有协同药效作用。
  8. 根据权利要求1-7任一项所述的用途，其特征在于，所述化疗耐药选自复发性化疗耐药。
  9. 根据权利要求1-7任一项所述的用途，其特征在于，所述化疗耐药选自铂类化合物耐药，优选复发性铂类化合物耐药。
  10. 根据权利要求1-9任一项所述的用途，其特征在于，所述卵巢癌选自卵巢上皮癌、高级别浆液性卵巢癌、卵巢肿瘤。
  11. 根据权利要求1-10任一项所述的用途，其特征在于，所述乳腺癌选自三阴性乳腺癌。
  12. 根据权利要求1-11任一项所述的用途，其特征在于，所述VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂的日服剂量比例为0.001～1000，优选日服剂量比0.83:1、1.25:1、1.56:1、1.88:1。
  13. 根据权利要求1-12任一项所述的用途，其特征在于，所述多聚二磷酸腺苷核糖聚合酶抑制剂的给药剂量为1-500mg，优选80mg、100mg、120mg、160mg、200mg或300mg。
  14. 根据权利要求13所述的用途，其特征在于所述多聚二磷酸腺苷核糖聚合酶抑制剂的给药频率为一日两次，给药间隔12小时。
  15. 根据权利要求1-14任一项所述的用途，其特征在于，所述VEGFR抑制剂的给药剂量为1-850mg，优选50mg、100mg、150mg、200mg、250mg、375mg、425mg、500mg、600mg、700mg、750mg、800mg或850mg。
  16. 含有权利要求1-15任一项所述的多聚二磷酸腺苷核糖聚合酶抑制剂与VEGFR抑制剂的药物组合物，其特征在于，包含一种或多种可药用的赋形剂、稀释剂或载体。
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