WO2018099423A1 - 一种vegfr抑制剂与parp抑制剂联合在制备治疗胃癌的药物中的用途 - Google Patents

一种vegfr抑制剂与parp抑制剂联合在制备治疗胃癌的药物中的用途 Download PDF

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WO2018099423A1
WO2018099423A1 PCT/CN2017/113899 CN2017113899W WO2018099423A1 WO 2018099423 A1 WO2018099423 A1 WO 2018099423A1 CN 2017113899 W CN2017113899 W CN 2017113899W WO 2018099423 A1 WO2018099423 A1 WO 2018099423A1
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inhibitor
use according
vegfr
gastric cancer
group
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PCT/CN2017/113899
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English (en)
French (fr)
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蒋家骅
曹国庆
杨昌永
张连山
邹建军
孙飘扬
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江苏恒瑞医药股份有限公司
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Priority to US16/463,445 priority Critical patent/US11000518B2/en
Priority to CN201780016819.9A priority patent/CN108778336A/zh
Priority to EP17876679.6A priority patent/EP3549608A4/en
Publication of WO2018099423A1 publication Critical patent/WO2018099423A1/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
    • A61K31/435—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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A61K31/495—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
    • 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
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to a VEGFR inhibitor in combination with a poly ADP-ribose polymerase inhibitor and its use in the manufacture of a medicament for the treatment of gastric cancer.
  • Gastric cancer is one of the most common malignant tumors of the digestive tract that poses a serious threat to human health. According to statistics, among all malignant tumors, the incidence of gastric cancer ranks fourth, while the mortality rate ranks third, and more than 700,000 people die of gastric cancer every year. Because the early symptoms are not typical, most patients with gastric cancer have reached the advanced stage of treatment. The lack of effective treatment means that their 5-year survival rate is no more than 20%, and the prognosis is very poor.
  • VEGF Vascular endothelial growth factor
  • Bevacizumab is a recombinant human anti-VEGF monoclonal antibody and is the first drug approved for anti-tumor angiogenesis.
  • a phase III clinical trial demonstrated that bevacizumab combined with chemotherapy as a first-line regimen is effective in the treatment of advanced gastric cancer, laying the foundation for anti-cancer therapy targeting neovascularization.
  • WO2005000232A2 Publication Date 2005-01-06
  • the small molecule tyrosine kinase inhibitor Apatinib methanesulfonate has a highly selective competition for intracellular VEGFR-2 ATP binding sites, blocking downstream signals Transduction, inhibit the formation of tumor neovascularization, and ultimately achieve the purpose of treating tumors.
  • Apatinib can significantly prolong the overall survival and progression-free survival of patients with advanced gastric cancer after second-line treatment failure, and improve the disease control rate. It is the only oral preparation approved for gastric cancer targeted drugs, filling the advanced gastric cancer. A blank in the field of three-line therapy, the structure of Apatinib is shown in formula (I)
  • Poly ADP-ribose polymerase or poly ADP-ribose polymerase plays an important role in repairing DNA single-strand breaks (SSBs) induced by different causes.
  • a number of PARP inhibitors including Niraparib, Veliparib, and Rucaparib are currently in Phase III clinical trials.
  • 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.
  • a recent phase II clinical trial showed that Olaparib showed an 88% response to advanced prostate cancer patients with DNA repair gene mutations, which allowed tumor growth to be inhibited or even reduced, and overall survival was longer than expected survival in similar patients. time. Therefore, the continuous expansion of the use of PARP inhibitors and the range of indications have a good impetus for the development and application of PARP inhibitors.
  • the occurrence and development of gastric cancer has been confirmed to be closely related to abnormal DNA repair function.
  • WO2012019427A1 Publication Date 2012-02-16 discloses a PARP inhibitor capable of inhibiting the growth of various tumors, and the structure is as shown in the formula (B)
  • 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 I clinical trial combining the PARP inhibitor Olaparib with Cediranib, a drug that inhibits VEGFR activity by inhibiting VEGFR activity initially confirmed that the combination was more effective than the two drugs in patients with ovarian cancer, indicating The drug combination scheme of the above two types of targets has good feasibility for tumor treatment.
  • VEGFR and VEGFR are disclosed in the patent applications WO2010096627A1 (Publication Day 2010-08-26), WO2014004376A2 (Publication Day 2014-01-03), WO2016116602A1 (Publication Day 2016-07-28), WO2016179123A1 (Publication Day 2016-11-10)
  • PARP inhibitors are used in the treatment of malignant tumors (such as breast cancer or ovarian cancer), but it is not known whether the combined inhibitory effect on gastric cancer has a synergistic effect.
  • the technical problem to be solved by the present invention is to provide a synergistic effect of a VEGFR inhibitor combined with a PARP inhibitor in the preparation of a medicament for treating gastric cancer.
  • 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 gastric cancer.
  • the VEGFR inhibitor is selected from the group consisting of a VEGFR-2 inhibitor.
  • VEGFR-2 inhibitor structure is represented by the formula (I) or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt of the above scheme is selected from the group consisting of hydrochloride, methanesulfonate, maleate, malate or benzenesulfonate.
  • the adenosine diphosphate ribose polymerase inhibitor of the above scheme is selected from the group consisting of olaparib, Niraparib, Talazoparib, Veliparib, Rucaparib, CEP-8983 or BGB-290.
  • the adenosine diphosphate ribose polymerase inhibitor structure of the above scheme is represented by the formula (B) or a pharmaceutically acceptable salt thereof,
  • the gastric cancer is selected from the group consisting of adenocarcinoma, adenosquamous carcinoma or squamous cell carcinoma.
  • the gastric cancer is selected from the group consisting of advanced gastric cancer.
  • the VEGFR inhibitor of the present invention is further combined with a polyadenosine diphosphate ribose polymerase for a third component, which may be selected from a platinum anticancer drug or a paclitaxel anticancer drug.
  • the platinum anticancer drug is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin or letroplatin.
  • the paclitaxel anticancer drug is selected from paclitaxel or docetaxel, and the administration form of paclitaxel is not limited, for example, an injection of paclitaxel, paclitaxel liposome or albumin-bound paclitaxel.
  • the combination of the present invention has a synergistic pharmacodynamic effect.
  • the combined mode of administration of the present invention is selected from the group consisting of simultaneous administration or sequential administration.
  • VEGFR inhibitor is from 0.1 to 1000 mg.
  • poly ADP-ribose polymerase inhibitor is 0.1-1000 mg.
  • the invention further relates to 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 gastric cancer, wherein the VEGFR inhibitor and the poly ADP-ribose polymerase inhibitor
  • the ratio is from 0.001 to 1000, preferably 1:1, 5:3 or 2:1.
  • the present invention further relates to the use of a VEGFR inhibitor in combination with a poly ADP-ribose polymerase inhibitor for the preparation of a medicament for treating gastric cancer, wherein the VEGFR inhibitor is administered at a dose of 1-850 mg, preferably 2.5 mg, 3mg, 5mg, 6mg, 10mg, 15mg, 20mg, 25mg, 30mg, 40mg, 50mg, 80mg, 100mg, 150mg, 200mg, 250mg, 350mg, 400mg, 450mg 500mg, 550mg, 600mg, 650mg, 700mg, 750mg, 800mg or 850mg
  • the polyadenosine diphosphate ribose polymerase inhibitor is administered at a dose of 1-500 mg, preferably 3 mg, 6 mg, 9 mg, 10 mg, 12 mg, 15 mg, 18 mg, 20 mg, 21 mg, 24 mg, 25 mg, 27 mg, 30 mg, 33 mg, 36 mg
  • the invention further relates to 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 gastric cancer, wherein the VEGFR inhibitor is recommended once a day, adenosine diphosphate ribose polymerase Inhibitors are recommended twice a day, 12 hours apart.
  • a VEGFR inhibitor in combination with a poly ADP-ribose polymerase inhibitor for the preparation of a medicament for the treatment of gastric cancer, wherein the poly ADP-ribose polymerase inhibitor inhibitor inhibitor
  • Dosage doses of 10 mg, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, and 100 mg were administered in combination with a fixative of 250 mg of VEGFR.
  • cisplatin is recommended for intravenous infusion, continuous administration, on the first day, the eighth day, and the 15th day of each cycle, and a fixed dose of 20 mg/m 2 is inhibited by using adenosine diphosphate ribose polymerase.
  • the intravenous infusion time should be greater than 3 hours.
  • paclitaxel injection is recommended for intravenous infusion, continuous administration, on the first day, the eighth day, and the 15th day of each cycle, a fixed dose of 60 mg/m 2 , in the use of poly ADP-ribose polymerase Inhibitors and VEGFR inhibitors should be administered 1 h later, and the intravenous infusion time should be greater than 3 hours.
  • VEGFR inhibitors of the invention have synergistic pharmacological effects in combination with poly ADP-ribose polymerase inhibitors.
  • the invention further relates to a pharmaceutical composition of a VEGFR inhibitor and a poly ADP-ribose polymerase inhibitor comprising 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 VEGFR inhibitor and a poly ADP-ribose polymerase 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, Capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral suspensions, syrups and the like.
  • the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.
  • the VEGFR inhibitor of the present invention and the poly ADP-ribose polymerase 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 formulation or in separate separate formulations.
  • the term “combination” or “combination” is a mode of administration, which includes various conditions in which two drugs are administered sequentially or simultaneously, and the term “simultaneously” as used herein refers to the same administration cycle.
  • the VEGFR inhibitor is administered with a poly ADP-ribose polymerase inhibitor, for example, within 2 days, or within 1 day.
  • the so-called “sequential or sequential” administration includes the administration of a VEGFR inhibitor and a poly ADP-ribose polymerase inhibitor, respectively, in different administration cycles. These modes of administration all belong to the combination administration described in the present invention.
  • the present invention also provides a method of treating gastric cancer comprising administering to a gastric cancer patient the aforementioned VEGFR inhibitor and a poly ADP-ribose polymerase inhibitor.
  • 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.
  • the gastric cancer patient of the present invention preferably fails or is intolerant by first-line chemotherapy, and the first-line chemotherapy regimen needs to include a platinum-based and/or fluorouracil-based regimen, and the histological or cytological diagnosis of the patient is preferably Recurrent or metastatic gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma).
  • Total survival refers to the date from a random date to any cause of death. For subjects who survived at the last follow-up, their OS was censored as data at the last follow-up. Subjects lost to follow-up, their OS lost The last confirmed survival time before the interview was counted as data censoring.
  • 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
  • Quality of Life score QoL reference EORTC QLQ-C30 version 3, Chinese version. Evaluation method: Observing the changes of clinical symptoms and objective examination results of tumor patients before and after treatment, and scoring the scores of each field of the scale in the eCRF table according to the requirements of the quality of life scale.
  • 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.
  • VEGFR inhibitor of the present invention a VEGFR inhibitor of the present invention and a poly ADP-ribose polymerase inhibitor can effectively solve the problem of drug resistance and improve the efficacy of the drug.
  • test protocols for the use of the compositions of the invention in a medicament for the treatment of gastric cancer are provided below to demonstrate the beneficial or beneficial technical effects of the compositions of the invention.
  • the following experimental schemes are merely illustrative of the present invention and are not intended to limit the scope of the invention.
  • a person skilled in the art can make appropriate modifications or changes to the technical solutions of the present invention without departing from the spirit and scope of the present invention.
  • Example 1 Effect of the composition of the present invention on subcutaneous transplantation of human gastric cancer PDX model STO#069 tumor-bearing nude mice
  • Test product Compound A (apartinib mesylate, which can be prepared according to the method in patent application WO2010031266A1), Compound B (which can be prepared according to the method in patent application WO2012019427A1), cisplatin (purchased from Sigma), paclitaxel (purchased from Taizhou Kerui Biotechnology Co., Ltd.).
  • mice BALB/c nude mice, 6-7 weeks old, female, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., experimental animal use license number: SCXK (Shanghai) 2015-0022; animal certificate number : 11400700166108, breeding environment: SPF level.
  • Control group solvent group.
  • Compound A Weighed Compound A (100 mg), added 0.5% carboxymethylcellulose solution (10 mL), vortexed or sonicated to dissolve the solution, and stored at 4 ° C, the dosage volume was 5 mL / kg;
  • Compound B Compound B (540 mg) was weighed and dissolved in pure water (31 mL), then 0.2% Tween 80 (0.18 mL) and 10% PEG 400 (9.0 mL) were added, vortexed to dissolve, and pure water was added. To the volume of the solution is 90mL, stored at 4 ° C, the dosage volume is 5mL / kg;
  • Cisplatin Weigh cisplatin (3mg) in physiological saline (6.0mL), the concentration of the solution is 0.5mg/mL, prepare the solution to a total of 6.0mL, store at 4 ° C, use 0.22 ⁇ m Millipore before each use Membrane filtration
  • Paclitaxel Take 6 mg/mL paclitaxel (1.5 mL) and prepare a 1.5 mg/mL solution with physiological saline (6.0 mL), store at 4 ° C, and prepare freshly before each use.
  • the STO # 069 gastric cancer patients tumor tissues (pathological diagnosis of gastric poorly differentiated adenocarcinoma) cut into small pieces ( ⁇ 30mm 3), subcutaneously implanted into nude mice right after the tumor grew to 600-700mm 3 in nude mice
  • the body was passaged and defined as 0 generation (P0). After implantation of 0 generation (P0) tumor, it was defined as 1 generation (P1). It was continuously implanted in nude mice in this order, and the next generation from FP5. Defined as FP6, and so on, FP6 tumor tissue was used for this study.
  • Tumor implantation STO#069FP6 tumor tissue (pathological diagnosis of poorly differentiated adenocarcinoma of the stomach) was cut into small pieces ( ⁇ 30 mm 3 ) and implanted into the right side of the nude mouse. The tumor size was close to 150- After 250mm 3 , grouping and treatment were started. There were 7 groups and 6 tumor-bearing mice in each group. The experimental methods for the mice were carried out according to the predetermined scheme in the experimental design of Table 1:
  • p.o. is oral, i.p. is intraperitoneal injection, BID is twice daily, QD is once daily, and QW is once a week.
  • the tumor volume was measured twice a week with a caliper and measured in two dimensions, in mm 3 ;
  • the tumor volume (V) is calculated as:
  • V 1/2 ⁇ a ⁇ b 2 , where a and b represent length and width, respectively.
  • T/C(%) (T-T0)/(C-C0) ⁇ 100%, where T and C are the tumor volumes of the drug-administered group and the solvent group at the end of the experiment; T0 and C0 are respectively at the beginning of the experiment. Tumor volume of the drug-administered group and the solvent group.
  • the end point of the efficacy study was set to 21 days. If the tumor volume was >2000 mm 3 or if the weight of the nude mice was reduced by more than 20% or the disease was very serious and sufficient food or water could not be obtained, the nude mice were removed from the experimental group. And euthanasia.
  • Compound A alone (50 mg/kg) can inhibit the growth of subcutaneous xenografts of human gastric cancer STO#069 nude mice.
  • the tumor inhibition rate was 55.32%
  • Compound B (30 mg/kg, The tumor inhibition rate of BID ⁇ 21) combined with cisplatin (5 mg/kg, QW ⁇ 3), paclitaxel (15 mg/kg, QW ⁇ 3), and compound A (50 mg/kg, QD ⁇ 21) was 61.40%, respectively.
  • the combination of the VEGFR inhibitor compound A and the PARP inhibitor compound B of the present invention has a remarkable synergistic effect, and the inhibitory effect on the proliferation of gastric cancer cells is significantly better than that of the single component VEGFR inhibitor compound A. Therefore, the combination of the VEGFR inhibitor of the present invention and the PARP inhibitor has a significant inhibitory effect on gastric cancer cells. Further combination with cisplatin or paclitaxel is superior to single drug or two-component combination.
  • Example 2 Effectiveness and safety of the composition of the invention for treating gastric cancer
  • Phase I clinical (NCT03026881) enrolled 10 subjects who failed or were intolerant with first-line chemotherapy.
  • the first-line chemotherapy regimen included a platinum-based and/or fluorouracil-based regimen and histology.
  • cytology confirmed as recurrent or metastatic gastric adenocarcinoma (including gastroesophageal junction adenocarcinoma).
  • Compound A initial dose 250 mg, orally, once a day;
  • Compound B starting dose 20 mg, 30 mg, 40 mg twice daily; first evaluation of efficacy (including imaging and serological examination) was evaluated by the investigator and no adverse events of grade 3 and above occurred during the treatment. I agree that the dose can be increased.
  • the subject's partial response rate (PR) was 50%, 2 cycles, the subject's disease stability rate (SD) was 37.5%, and the disease control rate (DCR) was as high as 87.5%.

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Abstract

本发明涉及一种VEGFR抑制剂与PARP抑制剂联合在制备治疗胃癌的药物中的用途。

Description

一种VEGFR抑制剂与PARP抑制剂联合在制备治疗胃癌的药物中的用途 技术领域
本发明涉及一种VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂联合，以及其在制备治疗胃癌的药物中的用途。
背景技术
胃癌是严重威胁人类健康的最常见消化道恶性肿瘤之一。据统计，在所有恶性肿瘤中，胃癌发病率位居第4，而死亡率位居第3，每年有超过70万人死于胃癌。由于早期症状不典型，大部分胃癌患者就诊时已至晚期，有效治疗手段的缺乏则使其5年生存率多不超过20％，预后很差。
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。一项III期临床试验证实贝伐单抗联合化疗作为一线方案治疗进展期胃癌疗效显著，为以新生血管生成为靶点的抗胃癌治疗奠定基础。WO2005000232A2(公开日2005-01-06)公开的小分子酪氨酸激酶抑制剂甲磺酸阿帕替尼(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。阿帕替尼能够显著延长二线治疗失败后的晚期胃癌患者的总生存期和无进展生存期，提高疾病的控制率，是目前获批的胃癌靶向药物中唯一的口服制剂，填补了晚期胃癌三线治疗领域的空白，阿帕替尼(Apatinib)结构如式(I)所示
Figure PCTCN2017113899-appb-000001
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年底FDA批准阿斯利康公司 研发的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。目前已有包括Niraparib、Veliparib、Rucaparib在内的多个PARP抑制剂处于III期临床试验中。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。胃癌的发生发展被证实与DNA损伤修复功能异常密切相关。WO2012019427A1(公开日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 PCTCN2017113899-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I期临床试验初步证实该联用方案相较于两药单用在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(公开日2010-08-26)、WO2014004376A2(公开日2014-01-03)、WO2016116602A1(公开日2016-07-28)、WO2016179123A1(公开日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)，但不知晓联用对胃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是提供一种VEGFR抑制剂与PARP抑制剂联合后具备协同作用在制备治疗胃癌的药物中的用途
本发明的技术方案如下：
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胃癌的药物中的用途。
优选的，所述VEGFR抑制剂选自VEGFR-2抑制剂。
进一步优选的，所述VEGFR-2抑制剂结构如通式(I)所示或其可药用的盐，
Figure PCTCN2017113899-appb-000003
上述方案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等。
上述方案所述多聚二磷酸腺苷核糖聚合酶抑制剂选自奥拉帕尼、Niraparib、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
上述方案所述多聚二磷酸腺苷核糖聚合酶抑制剂结构如通式(B)所示或其可药用的盐，
Figure PCTCN2017113899-appb-000004
在本发明一个优选的方案中，所述胃癌选自腺癌、腺鳞癌或鳞状细胞癌。
在本发明一个优选的方案中，所述胃癌选自晚期胃癌。
特别优选地，本发明中VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶还进一步联合第三组分，所述第三组分可以选自铂类抗癌药或紫杉醇类抗癌药。
在本发明一个优选的方案中，所述铂类抗癌药选自顺铂、卡铂、奥沙利铂、奈达铂或乐铂。
在本发明一个优选的方案中，所述紫杉醇类抗癌药选自紫杉醇或多西他赛，紫杉醇的给药形式没有限制，例如紫杉醇的注射液、紫杉醇脂质体或白蛋白结合型紫杉醇。
本发明所述联合具有协同药效作用。
本发明所述联合的给药方式选自：同时给药、或先后给药。
本发明所述的用途，其中，所述VEGFR抑制剂为0.1-1000mg。
本发明所述的用途，其中，所述多聚二磷酸腺苷核糖聚合酶抑制剂为0.1-1000mg。
本发明进一步涉及一种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胃癌的药物中的用途，其中，VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂的比例为0.001～1000，优选1∶1、5∶3或2∶1。
本发明进一步涉及一种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胃癌的药物中的用途，其中，VEGFR抑制剂的给药剂量为1-850mg，优选2.5mg、3mg、5mg、6mg、10mg、15mg、20mg、25mg、30mg、40mg、50mg、80mg、100mg、150mg、200mg、250mg、350mg、400mg、450mg 500mg、550mg、600mg、650mg、700mg、750mg、800mg或850mg，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3mg、6mg、9mg、10mg、12mg、15mg、18mg、20mg、21mg、24mg、25mg、27mg、30mg、33mg、36mg、40mg、45mg、60mg、80mg、100mg、120mg、150mg、160mg、200mg、250mg、270mg、300mg、350mg、400mg或450mg。
本发明进一步涉及一种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胃癌的药物中的用途，其中，VEGFR抑制剂推荐一天一次，多聚二磷酸腺苷核糖聚合酶抑制剂推荐一天两次、间隔12小时。
本发明优选实施方案中，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胃癌的药物中的用途，其中，多聚二磷酸腺苷核糖聚合酶抑制剂抑制剂的给药剂量为10mg、20mg，30mg，40mg、60mg、80mg及100mg进行剂量递增，分别联合固定剂为250mg的VEGFR。
上述方案中，顺铂推荐静脉滴注、连续给药期间每周期第1天、第8天、第15天给药，固定剂量20mg/m2，在使用多聚二磷酸腺苷核糖聚合酶抑制剂和VEGFR抑制剂1h后给药，静脉滴注时间应大于3小时。
上述方案中，紫杉醇注射液推荐静脉滴注、连续给药期间每周期第1天、第8天、第15天给药，固定剂量60mg/m2，在使用多聚二磷酸腺苷核糖聚合酶抑制剂和VEGFR抑制剂1h后给药，静脉滴注时间应大于3小时。
显著的，本发明的VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂联合应用具有协同药效作用。
本发明的还涉及一种VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶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，VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶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。
本发明的VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶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。
本发明中，所谓“联合用药”或“联用”是一种给药方式，其包括两种药物先后，或同时给药的各种情况，此处所谓“同时”是指在同一给药周期给予VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂，例如在2天内，或1天内给予两种药物。所谓“先后或相继”给药，则包括在不同给药周期内分别给予VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂的情况。这些给药方式，均属于本发明所述的联合给药。
本发明还提供了一种治疗胃癌的方法，包括向胃癌患者给予前述的VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂。
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。
本发明所述的胃癌患者优选为经一线化疗治疗失败或不耐受的，一线化疗方案需包含以铂类和/或氟尿嘧啶类药物为基础的方案，且患者的组织学或细胞学确诊优选为复发或转移性胃腺癌(包括胃食管结合部腺癌)。
注：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≥1个周期。
如无相反解释，本发明中术语具有如下含义：
总生存期(OS)指从随机日期至任何原因导致死亡的日期。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。
生活质量评分QoL参考EORTC QLQ-C30(版本3，中文版)。评价方法：观察治疗前后肿瘤患者相关临床症状及客观检查结果的变化进行计分，按生活质量量表的要求将量表各领域的打分结果记录在eCRF表中。
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。
发明的有益效果
与现有技术相比，本发明的技术方案具有以下优点：
(1)本发明VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂联合用药可有效解决耐药性问题、提高药物的疗效。
(2)经研究表明，本发明VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶抑制剂联合用药可对一线化疗失败后的继续治疗；化学稳定性高，能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工业化生产。
具体实施方式
以下提供本发明的组合物在治疗胃癌的药物中的用途的示例性试验方案，以显示本发明组合物的有利活性或有益技术效果。但是应当理解，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、本发明组合物对人胃癌PDX模型STO#069荷瘤裸小鼠皮下移植瘤的疗效
供试品：化合物A(甲磺酸阿帕替尼，可按照专利申请WO2010031266A1中的方法制备)、化合物B(可按照专利申请WO2012019427A1中的方法制备)、顺铂(购自Sigma公司)、紫杉醇(购自台州市科瑞生物技术有限公司)。
实验动物：BALB/c裸小鼠，6-7周龄，雌性，购自北京维通利华实验动物技术有限公司，实验动物使用许可证号：SCXK(沪)2015-0022；动物合格证号：11400700166108，饲养环境：SPF级。
对照组：溶剂组。
供试品溶液配制：
化合物A：称取化合物A(100mg)，加入0.5％羧甲基纤维素溶液(10mL)，涡旋或超声至溶液溶清，4℃保存，给药体积为5mL/kg；
化合物B：称取化合物B(540mg)溶于纯水(31mL)中，然后加入0.2％吐温80(0.18mL)和10％PEG 400(9.0mL)，涡旋至溶清，再加入纯水至溶液体积为90mL，4℃保存，给药体积为5mL/kg；
顺铂：称取顺铂(3mg)溶于生理盐水(6.0mL)中，溶液浓度为0.5mg/mL，配制该溶液总计6.0mL，4℃保存，每次使用前用0.22μm Millipore
Figure PCTCN2017113899-appb-000005
膜过滤；
紫杉醇：取6mg/mL的紫杉醇(1.5mL)用生理盐水(6.0mL)配制1.5mg/mL的溶液，4℃保存，每次使用前新鲜配制。
肿瘤模型：
将病人胃癌STO#069肿瘤组织(病理诊断为胃低分化腺癌)剪成小块(～30mm3)，植入至裸鼠的右侧皮下，待肿瘤长至600-700mm3后在裸鼠身上进行传代，将其定义为0代(P0)，植入0代(P0)肿瘤后定义为1代(P1)，在裸小鼠中持续植入以此顺序定义，从FP5产生的下一代定义为FP6，以此类推，FP6肿瘤组织用于此研究。
实验方法：
(1)肿瘤植入：将STO#069FP6肿瘤组织(病理诊断为胃低分化腺癌)剪成小块(～30mm3)，植入至裸鼠的右侧皮下，待肿瘤大小平均接近150-250mm3后开始分组，治疗，共7组、每组6只荷瘤小鼠，对小鼠的实验方法按照表1实验设计中的预定方案进行：
表1、实验方案
Figure PCTCN2017113899-appb-000006
Figure PCTCN2017113899-appb-000007
备注：p.o.为口服，i.p.为腹腔注射，BID为每日两次，QD为每日一次，QW为每周一次。
(2)观察与记录：每周测2-3次瘤体积，称鼠重，记录数据。
(3)肿瘤测量与终点
肿瘤体积用卡尺每周测量两次、测量两个维度，单位为mm3；
肿瘤体积(V)计算公式为：
V＝1/2×a×b2，其中a、b分别表示长、宽。
T/C(％)＝(T-T0)/(C-C0)×100％，其中T、C分别为实验结束时给药组和溶剂组的肿瘤体积；T0、C0分别为为实验开始时给药组和溶剂组的肿瘤体积。
实验的终点：功效研究的终点设为21天，如果肿瘤体积＞2000mm3或如果裸鼠体重减少超过20％或者病得很严重，并且不能获得足够的食物或水，将该裸鼠移出实验组并安乐死。
数据分析：
汇总统计，包括平均值和平均值的标准误差(SEM)，组间肿瘤体积的差异统计分析和在最后一次给药(分组后的第21天)后在最佳治疗时间点进行的药物相互作用所获得的数据分析。通过单因素方差分析(One Way ANOVA)分析肿瘤体积数据，然后使用Dunnett(α＝0.05)进行个体比较，P＜0.05被认为是统计学上有意义。
实验结果：
Figure PCTCN2017113899-appb-000008
实验结论：
由实验结果可知化合物A单用(50mg/kg)能够抑制人胃癌STO#069裸小鼠皮下移植瘤的生长，在给药第21天时，肿瘤抑制率为55.32％，化合物B(30mg/kg，BID×21)分别与顺铂(5mg/kg，QW×3)、紫杉醇(15mg/kg，QW×3)、化合物A(50mg/kg，QD×21)联用的肿瘤抑制率分别为61.40％、55.34％、72.79％，说明化合物A与化合物B联用对胃癌细胞的肿瘤体积的抑制作用优于化合物A单一组分、化合物B与顺铂的联用、化合物B与紫杉醇的联用；化合物A(50mg/kg)、化合物B(30mg/kg)与顺铂(5mg/kg)或紫杉醇(15mg/kg)三药联用显示非常明显的抗肿瘤效果，肿瘤抑制率分别为84.86％、75.34％，说明三组分联用效果(化合物A/化合物B与顺铂的联用、化合物A/化合物B与顺紫杉醇的联用)优于单一组分或两组分联用；
综上所述，本发明的VEGFR抑制剂化合物A，PARP抑制剂化合物B联用具有显著的协同作用，对胃癌细胞增殖的抑制作用显著优于单一组分的VEGFR抑制剂化合物A。因此，本发明VEGFR抑制剂与PARP抑制剂联合应用对胃癌细胞的抑制效果显著。而进一步与顺铂或紫杉醇三药联用则更优于单药或两组分联用。
实施例2：本发明组合物治疗胃癌的有效和安全性
I期临床(NCT03026881)入组10位经一线化疗治疗失败或不耐受的受试者，一线化疗方案需包含以铂类和/或氟尿嘧啶类药物为基础的方案，且受试者的组织学或细胞学确诊为复发或转移性胃腺癌(包括胃食管结合部腺癌)。
注：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≥1个周期。
给药方案：
化合物A：初始剂量250mg，口服，每天一次；
化合物B：起始剂量20mg，30mg，40mg，每天两次；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。
紫杉醇：静脉注射
数据采集：
疗效数据采集见表3
表3
Figure PCTCN2017113899-appb-000009
Figure PCTCN2017113899-appb-000010
注：C2D1第2周期第1天
从10例临床病例数据来看，受试者的疾病部分缓解率(PR)为50％，2周期，受试者疾病稳定率(SD)为37.5％，疾病控制率(DCR)高达87.5％。
不良事件多发生在血液学毒性，包括白细胞减少，中性粒细胞减少和血红蛋白降低等，低磷血症不良事件仅在30mg剂量组中出现1例3级。

Claims (16)

  1. 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胃癌的药物中的用途。
  2. 如权利要求1所述的用途，其特征在于，所述VEGFR抑制剂选自VEGFR-2抑制剂。
  3. 如权利要求2所述的用途，其特征在于，所述VEGFR-2抑制剂结构如通式(I)所示或其可药用的盐，
    Figure PCTCN2017113899-appb-100001
  4. 如权利要求3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。
  5. 如权利要求1-4中任一项所述的用途，其特征在于，所述多聚二磷酸腺苷核糖聚合酶抑制剂选自奥拉帕尼、Niraparib、Talazoparib、Veliparib、Rucaparib、CEP-8983或BGB-290。
  6. 如权利要求1-4中任一项所述的用途，其特征在于，所述多聚二磷酸腺苷核糖聚合酶抑制剂结构如通式(B)所示或其可药用的盐，
    Figure PCTCN2017113899-appb-100002
  7. 如权利要求1所述的用途，其特征在于，所述胃癌选自腺癌、腺鳞癌或鳞状细胞癌。
  8. 如权利要求1所述的用途，其特征在于，所述胃癌选自晚期胃癌。
  9. 如权利要求1-8中任一项所述的用途，其特征在于，所述联合任选包含第三组分，所述第三组分选自铂类抗癌药或紫杉醇类抗癌药。
  10. 如权利要求9所述的用途，其特征在于，所述铂类抗癌药选自顺铂、卡铂、奥沙利铂、奈达铂或乐铂。
  11. 如权利要求9所述的用途，其特征在于，所述紫杉醇类抗癌药选自紫杉醇或多西他赛。
  12. 根据权利要求1-11中任一项所述的用途，其特征在于，所述联合具有协同药效作用。
  13. 根据权利要求1-12中任一项所述的用途，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比例为0.001～1000，优选1:1、5:3或2:1。
  14. 根据权利要求1-12中任一项所述的用途，其特征在于，所述VEGFR抑制剂的给药剂量为1-500mg，优选50mg、100mg、150mg、200mg、250mg、350mg、400mg或450mg。
  15. 根据权利要求1-12中任一项所述的用途，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10mg、15mg、20mg、25mg、30mg、40mg、60mg、100mg、250mg或300mg。
  16. 含有权利要求1-15中任一项所述的VEGFR抑制剂与多聚二磷酸腺苷核糖聚合酶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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