WO2020238932A1 - Use of parp inhibitor in combination with vegfr inhibitor for treating ovarian cancer or breast cancer - Google Patents

Abstract

Use of a pharmaceutical composition containing a PARP inhibitor in combination with a VEGFR inhibitor in preparation of drugs for treating ovarian cancer and breast cancer.

Description

Use of PARP inhibitor combined with VEGFR inhibitor for treating ovarian cancer or breast cancer Technical field

The invention belongs to the field of medicine, and relates to the use of a PARP inhibitor combined with a VEGFR inhibitor in preparing a medicine for treating ovarian cancer or breast cancer.

Background technique

Breast cancer is one of the most common malignant tumors in women. There are approximately 1.3 million new cases worldwide each year. In my country, the incidence of breast cancer accounts for 7%-10% of the incidence of various malignant tumors throughout the body, and about 18% of all female tumors. At present, the number of patients in China has exceeded 500,000, and its incidence is increasing rapidly in some large cities. It has been ranked first in the spectrum of female tumor incidence, and nearly 50% of patients have recurrence and metastasis after treatment. In recent years, with the deepening of tumor molecular biology research, molecular targeted therapy has become more and more widely used in the treatment of breast cancer and has achieved more significant curative effects. It has become the first after the three traditional modes of surgery, radiotherapy and chemotherapy. This new treatment model is also a hot spot in the field of breast cancer treatment.

Epithelial ovarian cancer (epithelial ovarian cancer, EOC) is the gynecological malignant tumor with the highest fatality rate. Nearly 75% of patients are in the advanced stage at the time of consultation, and require radical surgery and standard treatment with platinum-based chemotherapy. After standard treatment is completed Although the complete remission rate can reach 40% to 60%, more than 90% of patients will relapse in an average of 18 months, and then face the risk of death due to chemotherapy resistance and disease progression.

For recurrent ovarian cancer, if the platinum-containing chemotherapy regimen is sensitive to treatment (from the last chemotherapy to tumor recurrence/progression time ≥ 6 months), the follow-up treatment will continue to select platinum-containing regimens, if the platinum-containing chemotherapy regimens are resistant Drugs (from the last chemotherapy to tumor recurrence/progression time <6 months), then single-agent chemotherapy will be used in the follow-up. The chemotherapy regimens include docetaxel, paclitaxel weekly therapy, liposomal adriamycin, gemcitabine, etc., these treatments The effectiveness is limited. The tumor remission rate during treatment is generally 15-20%, and the disease-free survival period is about 3 to 4 months. For recurrent ovarian cancer, it is urgent to develop an efficient and low-toxic treatment plan.

Polyadenosine diphosphate ribose polymerase or poly ADP ribose polymerase (PARP) plays an important role in repairing DNA single-strand breaks (SSB) induced by different reasons. Since the PARP inhibitor Olaparib was marketed for the treatment of BRCA1/2 mutant ovarian cancer in 2014, the development of PARP inhibitors for anti-tumor therapy has been rapidly developed. Pre-clinical studies have confirmed that in addition to single-agent application, PARP inhibitors can also be used as radiotherapy and chemotherapy sensitizers in combination with radiotherapy and chemotherapy to enhance the anti-tumor efficacy and reduce radiotherapy and chemotherapy drugs or radiation doses, and reduce toxic side effects. The results of a recent phase II clinical trial showed that Olaparib showed an 88% response to advanced prostate cancer patients with DNA repair gene mutations, which can inhibit or even shrink tumor growth, and the overall survival period is longer than the expected survival of similar patients time. Therefore, the continuous expansion of the use of PARP inhibitors and the scope of indications has a good role in promoting the development and application of PARP inhibitors. According to literature reports, the remission rate of a single PARP inhibitor in BRCA1/2 unmutated platinum-sensitive recurrent ovarian cancer is 20-25% (Gelmon, Karen A., et al. The lancet oncology 12.9 (2011): 852 -861, and Swiss, Elizabeth M., et al. The lancet oncology 18.1(2017):75-87). WO2012019427A1 (published 2012-02-16) discloses a PARP inhibitor, which can inhibit the growth of a variety of tumors, and its structure is shown in formula I,

Vascular endothelial growth factor (VEGF) is the most important positive regulatory protein confirmed so far. VEGF binds to its receptor subtype VEGFR-2, induces VEGFR-2 phosphorylation, and then activates a series of cascade reactions, causing the proliferation of vascular endothelial cells and inducing angiogenesis. Studies have shown that VEGF and its receptors are highly expressed in gastric cancer tissues, and their expression is positively correlated with the prognosis of gastric cancer. Therefore, treatments that target VEGF or its receptors to destroy angiogenesis can undoubtedly provide new treatment directions and molecular targets for gastric cancer patients. 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 (published on 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 new blood vessels in tumors ultimately achieves the goal of treating tumors. The structure of Apatinib is shown in Formula II,

The combined use of more than one anti-tumor drugs with different and interrelated targets can give full play to the advantages of each component, which can not only improve the anti-tumor activity of a single drug but also reduce the toxicity of the drug. It is a generally accepted anti-tumor therapy. A phase II clinical trial that combines the PARP inhibitor Olaparib with Cediranib, an anti-angiogenesis drug that inhibits VEGFR activity, preliminarily confirms that the combined regimen is compared to the two drugs alone in the treatment of recurrent platinum compounds for sensitive ovarian cancer The curative effect is more significant in patients, indicating that the combination of the above two types of target drugs has good feasibility for tumor treatment.

Patent applications WO2010096627, WO2014004376, WO2016116602, WO2016179123 disclose the combined use of VEGFR and PARP inhibitors in the treatment of malignant tumors (such as breast cancer or ovarian cancer).

Summary of the invention

One aspect of the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with apatinib or a pharmaceutically acceptable salt thereof in preparation for treatment Use in drugs for ovarian cancer or breast cancer,

Another aspect of the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with apatinib or a pharmaceutically acceptable salt thereof in preparation Use in medicine for reducing the adverse reaction of apatinib or its pharmaceutically acceptable salt.

Another aspect of the present invention provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient for reducing the effect of apatinib or a pharmaceutically acceptable salt thereof Use of adverse reactions.

The breast cancer described in the present invention is preferably triple-negative breast cancer, more preferably recurrent and metastatic triple-negative breast cancer.

The ovarian cancer described in the present invention is preferably recurrent ovarian cancer.

In some embodiments, the ovarian cancer or breast cancer described in the present invention may be ovarian cancer or breast cancer that is sensitive to or resistant to chemotherapy drugs.

In some embodiments, the ovarian cancer or breast cancer is platinum compound-sensitive ovarian cancer or breast cancer.

Chemotherapy drugs for the treatment of ovarian cancer are selected from but not limited to gemcitabine, paclitaxel, bevacizumab, sorafenib, sunitinib, pazopanib, levatinib mesylate, carboplatin, docetaxel, Pemetrexed disodium, everolimus, erlotinib, lenatinib, gefitinib, Nintedanib, dasatinib, Trametinib, avelumab, ribociclib, Ipilimumab, Lobaplatin, Enzalutamide, Mifes Ketones, Olaparib, alkylating agents, camphorsulfonic acid, Clovis, imatinib, s-malate 184, azacitidine, cetuximab, Alza, anastrozole, exemestane, copanlisib hydrochloride , Irinotecan, lenalidomide, Pertuzumab, vemodedil, aflibercept, interleukin, topotecan, docetaxel, levonorgestrel, panitumumab, vinblastine Ning, filgrastim, letrozole, cabazitaxel, doxorubicin, hexamethylmelamine, viscosol, sirolimus, aminopterin, vandetanib, interferon α-2b follow-up biological , Pharmbiotek, recombinant human interferon alpha-2b, bendamustine, belinostat, immuncell LC, interferon gamma-1b, catumaxomab, glutoxim, Vorinostat, cetrorelix, ponatinib, treosulfan, etoposide, bexaro Tine, paclitaxel, lobaplatin, ixabepilone, docetaxel, mitoxantrone, mifepristone, paclitaxel, doxorubicin hydrochloride, belotecan, raltitrexed, paclitaxel, alitretinoin At least one of Doxorubicin Hydrochloride, Sartorumomab Penditide, Topotecan Hydrochloride, Nedaplatin, Docetaxel, Cisplatin, Oxaliplatin/Platinum Oxalate, etc., preferably platinum compounds , Such as carboplatin, cisplatin, oxaliplatin/oxaliplatin, epithioplatin, nedaplatin or lobaplatin. The chemotherapeutic drugs for the treatment of breast cancer are selected from but not limited to trastuzumab, atezolizumab, gemcitabine, paclitaxel, Pembrolizumab, ramucirumab, durvalumab, bevacizumab, oxaliplatin, capecitabine, Nivolumab, Russo Tinib, tamoxifen, levatinib mesylate, paclitaxel, everolimus, lenatinib, gefitinib, avelumab, ribociclib, Enzalutamide, pabociclib, alkylating agent, aza Cytidine, trastuzumab, abiraterone, doxorubicin, abemaciclib, anastrozole, zoledronic acid, Eribulin mesylate, Pertuzumab, docetaxel, epirubicin, La Patinib, letrozole, cabazitaxel, trastuzumab, vandetanib, axitinib, interferon gamma-1b, trastuzumab biosimilars, romidepsin, bica At least one of lutamide, docetaxel, uropolypeptide, amrubicin, ixabepilone, mifepristone, paclitaxel, toremifene, cisplatin, paclitaxel, etc., preferably selected from gemcitabine, Sitaxel, epirubicin, paclitaxel, lapatinib, or platinum compounds, such as carboplatin, cisplatin, oxaliplatin/oxaliplatin, cyclothioplatin, nedaplatin, or lobaplatin.

In some embodiments, the ovarian cancer or breast cancer is BRCA1/2 mutant ovarian cancer or breast cancer or BRCA1/2 non-mutant ovarian cancer or breast cancer.

In some embodiments, the ovarian cancer is BRCA1/2 non-mutated platinum compound-sensitive or chemotherapeutic drug-resistant ovarian cancer.

In some embodiments, the pharmaceutically acceptable salt of apatinib is selected from but not limited to hydrochloride, methanesulfonate, maleate, malate or besylate, etc., preferably from methanesulfonate. Sulfonate.

In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical composition comprising the compound represented by formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient The dosage is 0.1-1000mg, which can be 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; preferably from 40mg, 50mg, 60mg, 80mg, 100mg, 120mg, 160mg, 200mg or 300mg.

In some embodiments, the administration dose of apatinib or a pharmaceutically acceptable salt thereof is 100-500 mg, which can be 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350mg, 375mg, 400mg, 500mg, preferably 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 500mg. In some embodiments, the administration dose of apatinib or its pharmaceutically acceptable salt is at least 375 mg.

The administration route of the combination of the present invention is selected from oral administration, parenteral administration, and transdermal administration. The parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.

In some embodiments, the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. For example, it can be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays Agent.

In certain embodiments, the pharmaceutical composition includes a filler. The filler of the present invention includes, but is not limited to, one or more of microcrystalline cellulose, dibasic calcium phosphate, mannitol, pregelatinized starch, and lactose. The content of the filler is 1%-99% relative to the total weight of the composition, preferably 5%-95%.

In certain embodiments, the pharmaceutical composition includes a disintegrant, including but not limited to croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone One or more. Based on the total weight of the composition, the content of the disintegrant may be 0.01%-40%, preferably 1%-20%.

In some embodiments, the pharmaceutical composition includes a lubricant, including but not limited to magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, and micronized silica gel One or more of talcum powder and colloidal silica, preferably one or more of magnesium stearate and colloidal silica. Based on the total weight of the composition, the content of the lubricant may be 0.01%-25%, preferably 0.1%-10%.

Other suitable excipients include binders, suspending agents, sweeteners, flavoring agents, preservatives, buffering agents, wetting agents, effervescent agents and the like. These excipients are well known in the art.

The present invention further relates to a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with apatinib or a pharmaceutically acceptable salt thereof in preparation for the treatment of ovarian cancer or breast Use in cancer medicines, wherein the frequency of administration of apatinib or its pharmaceutically acceptable salt is once a day, once every two days, once every three days, the drug is stopped for five days for two days, and the drug is stopped for seven days for seven days. The frequency of administration of the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients can be once a day, twice a day, three times a day, and once every two days , Once every three days, once a week, once every two weeks, once every three weeks, once a month.

In some embodiments, the frequency of administration of the apatinib or its pharmaceutically acceptable salt is once a day, and the administration dose is 250 mg/time or 375 mg/time or 500 mg/time; including formula (I) The frequency of administration of the pharmaceutical composition of the compound or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients can be twice a day, and the dosage is 100 mg/time or 80 mg/time or 60 mg/time or 50 mg/time. Time or 40mg/time.

In the solution of the present invention, the combination optionally further includes other components, and the other components include but are not limited to other anti-tumor drugs.

The present invention also provides a method for treating tumor diseases, which comprises administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and apatinib or a pharmaceutically acceptable salt thereof to a patient to reduce adverse reactions. Preferably, the adverse reactions of apatinib or its pharmaceutically acceptable salt are reduced.

The present invention also provides a method for reducing the adverse reaction of apatinib or its pharmaceutically acceptable salt, which comprises administering to a patient a compound represented by formula (I) or its pharmaceutically acceptable salt and apatinib or its pharmaceutically acceptable salt Use salt.

The present invention also provides a method for treating tumor diseases, which comprises administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and apatinib or a pharmaceutically acceptable salt thereof to a patient to shorten apatinib or The elimination half-life of pharmaceutically acceptable salts.

The present invention also provides a method for shortening the elimination half-life of apatinib or a pharmaceutically acceptable salt thereof, which comprises administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and apatinib or a pharmaceutically acceptable salt thereof to a patient Use salt.

The present invention also provides a pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in combination with apatinib or a pharmaceutically acceptable salt thereof in preparation for treating tumors Wherein the compound represented by formula (I) or its pharmaceutically acceptable salt reduces the AUC of apatinib or its pharmaceutically acceptable salt in patients.

The present invention also provides a use of the compound represented by formula (I) or its pharmaceutically acceptable salt in the preparation of a medicine for reducing the AUC of apatinib or its pharmaceutically acceptable salt in a patient.

In an open, single-arm, multi-center phase II clinical trial of apatinib mesylate tablets in the treatment of advanced triple-negative breast cancer, the pharmacokinetics of apatinib mesylate in patients with triple-negative breast cancer was studied feature. After the patient took 500 mg of apatinib mesylate after a meal, the elimination half-life of the original drug and metabolites was longer. After 2 consecutive cycles of administration (28 days in a cycle), the plasma exposure (AUC _{0_24h} ) of the original drug and metabolites was 1.44 to 2.39 times that after a single administration.

By adopting the combined dosing regimen of the present invention, the AUC of apatinib is reduced to about 50% of a single drug, and the AUC is reduced to less than 30% or lower than that of a single drug for multiple administrations. This has resulted in a shortened effective/toxic exposure time of apatinib and reduced toxic and side effects; at the same time, it can also produce a synergistic therapeutic effect, which is unexpected.

On the other hand, the present invention provides a method for reducing the AUC of apatinib or its pharmaceutically acceptable salt in a patient by a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, comprising administering to the patient A therapeutically effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of apatinib or a pharmaceutically acceptable salt thereof.

In the present invention, "reducing the AUC of apatinib or its pharmaceutically acceptable salt in the patient" refers to the AUC produced in the patient's body by administering the same dose of apatinib or its pharmaceutically acceptable salt alone.

In some embodiments, by administering to the patient an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and an effective amount of apatinib or a pharmaceutically acceptable salt thereof, compared to administering the same dose of apatin alone The AUC produced by Nitraria or its pharmaceutically acceptable salt in the patient’s body is reduced to no more than 90%, optionally, the AUC is reduced to 10%-90%; optionally, the AUC is reduced to 10%-80%; optional, AUC is reduced to 15%-75%; specifically, the AUC of apatinib or its pharmaceutically acceptable salt is reduced to about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17% , 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34 %, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67% , 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84 %, 85%, 86%, 87%, 88%, 89%, 90%.

In some embodiments, by administering to the patient an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and an effective amount of apatinib or a pharmaceutically acceptable salt thereof, apatinib or a pharmaceutically acceptable salt thereof It can provide an AUC of 1200-6000 ng*h/mL in the patient's body; optionally, apatinib or its pharmaceutically acceptable salt can provide an AUC of 1200-5800 ng*h/mL in the patient's body; optionally, apatin Ninetil or its pharmaceutically acceptable salt provides an AUC of 1300-5800 ng*h/mL in the patient's body; optionally, apatinib or its pharmaceutically acceptable salt provides an AUC of 1300-5700 ng*h/mL in the patient's body; Optionally, apatinib or its pharmaceutically acceptable salt provides an AUC of 1300-5500 ng*h/mL in the patient's body; optionally, apatinib or its pharmaceutically acceptable salt provides 1500-5500 ng*h in the patient's body /mL AUC; optionally, apatinib or its pharmaceutically acceptable salt provides an AUC of 1500-5300 ng*h/mL in the patient's body; optionally, apatinib or its pharmaceutically acceptable salt in the patient's body Provide an AUC of 1700-5300 ng*h/mL; optionally, apatinib or its pharmaceutically acceptable salt can provide an AUC of 1700-5000 ng*h/mL in the patient's body; optionally, apatinib or its available The medicinal salt provides an AUC of 1900-5000ng*h/mL in the patient's body; optionally, apatinib or its pharmaceutically acceptable salt provides an AUC of 2000-5000ng*h/mL in the patient's body; optional, AUC Patinib or its pharmaceutically acceptable salt provides an AUC of 2000-4800 ng*h/mL in the patient's body; optionally, apatinib or its pharmaceutically acceptable salt provides an AUC of 2000-4500 ng*h/mL in the patient's body ; Preferably, apatinib or its pharmaceutically acceptable salt provides an AUC of 1700-5000 ng*h/mL in the patient’s body; preferably, apatinib or its pharmaceutically acceptable salt provides 2000-4500 ng*h in the patient’s body /mL of AUC.

In the present invention, a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and apatinib are more effective in treating tumors than the compound represented by formula (I) or a single drug of a pharmaceutically acceptable salt thereof Effectiveness, which can be expressed as a better objective response rate (ORR) or disease control rate (DCR) after medication, the ratio of complete remission (CR) and/or partial remission (PR) and/or stable disease (SD) higher. In addition, the combined administration can also reduce the incidence of adverse reactions caused by apatinib, which can also be used to prove the effect of the present invention.

Term Description

"Treatment" includes preventive and therapeutic treatments (including but not limited to alleviation, cure, symptom relief, symptom reduction) and delay of progression of tumor diseases or conditions.

The platinum compound-resistant type of the present invention refers to the recurrence within 6 months after the completion of the platinum-containing regimen chemotherapy; and the relapser 6 months after the end of the chemotherapy is the platinum compound sensitive type (or called the platinum treatment sensitive type).

"Pharmaceutical composition" refers to a mixture containing at least one therapeutic agent and at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient includes, but is not limited to, diluents, binders, disintegrants, and lubricants. The diluent includes but is not limited to mannitol, dextrose microcrystalline cellulose, pregelatinized starch, dibasic calcium phosphate, lactose, sorbitol; the binder can be selected from starch, carboxymethyl One or more of sodium cellulose, polyvinylpyrrolidone, pregelatinized starch, hypromellose and hydroxypropyl cellulose; the disintegrant can be selected from croscarmellose sodium, One or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and cross-linked povidone; the lubricant can be selected from talc, magnesium stearate, zinc stearate, and beech One or more of acid glycerides.

The pharmaceutical composition of the present invention containing the compound represented by formula (I) or its pharmaceutically acceptable salt and apatinib can also be administered parenterally, and the composition may contain pharmaceutically acceptable excipients The excipient is selected from one or more of preservatives, stabilizers, solubilizers, emulsifiers, osmotic pressure regulators, and buffers.

"Therapeutically effective" preferably refers to an amount of a therapeutic agent that is therapeutically effective or, more broadly, also prophylactically effective against tumor progression.

The "combination" in the present invention is a mode of administration, which means that at least one dose of a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and aparin are administered within a certain period of time. Tinib, two of these drugs show pharmacological effects. The said time period can be within one administration cycle, preferably within 24 hours. The pharmaceutical composition containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and apatinib can be administered simultaneously or sequentially. Such a period includes treatment in which a pharmaceutical composition containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and apatinib are administered through the same route of administration or different routes of administration.

The "C _max "in the present invention refers to the peak concentration of the pharmacokinetic drug in the blood. This parameter is an important index for evaluating the drug absorption rate and reflects the exposure characteristics of the drug in the body.

"AUC" refers to the area enclosed by the pharmacokinetic blood drug concentration curve against the time axis. This parameter is an important indicator for evaluating the degree of drug absorption and reflects the drug's exposure characteristics in the body. Since the blood drug concentration in pharmacokinetic studies can only be observed up to a certain time point t, there are two ways to express AUC: AUC ( _0-t ) and AUC ( _0-∞ ), the former is obtained by the trapezoidal area method, and the latter is calculated Formula: AUC( _0-∞ )=AUC( _0-t )+end point concentration/end elimination rate. The AUC in the present invention refers to the average AUC _0-24 of the patient after a single administration or multiple administrations reach the steady state, preferably the average AUC _0-24 of the patient after multiple administrations reach the steady state (ie AUC _ss ).

The criteria for judging the severity of adverse events in the present invention refer to the NCI-CTC AE 4.03 version of the grading standard for adverse drug events. If there are adverse events that are not listed in the NCI-CTC AE 4.03 version table, the following standards can be referred to:

Description of the drawings

Figure 1 shows the effect of combined administration of the compound represented by Chinese formula (I) on the C _max of apatinib;

Figure 2 _shows the effect of combined administration of the compound represented by Chinese formula (I) on the AUC _{0-24h of apatinib} ;

Figure 3 is a drug-time curve of apatinib under the action of the compound represented by formula (I);

Figure 4 shows the effect of apatinib on the C _max of the compound represented by formula (I) in combined administration;

Figure 5 shows the effect of apatinib on the AUC of the compound represented by formula (I) in combined administration;

Figure 6 shows the C _max value of the compound of formula (I) in a steady state after a single agent of the compound of formula (I) or in combination with different doses of apatinib;

Figure 7 shows the steady state AUC of the compound of formula (I) after a single agent of the compound of formula (I) or in combination with different doses of apatinib.

Detailed ways

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example 1: Capsules of the compound represented by formula (I) (compound I for short), the compound represented by formula (I) is mixed with a carrier material containing PVP K30 to prepare a solid dispersion, and then an appropriate amount of disintegrant and lubricant are added. Forms, mix evenly, fill the capsules to prepare capsules.

Example 2: The effectiveness of the compound represented by formula (I) alone in the treatment of recurrent chemotherapy-resistant ovarian cancer

In phase I clinical trials, compound I was administered at a dose level of 120 mg/d and above, and 23 patients with histological or cytologically confirmed recurrent ovarian cancer who failed standard treatment were enrolled. These patients had passed at least two lines in the recurrence and metastasis of ovarian cancer. Systemic chemotherapy, chemotherapy regimens with platinum-containing chemotherapy regimens, are resistant to platinum-containing therapy or intolerant of chemotherapy toxicity during treatment.

Dosing regimen:

Compound I: The starting dose is 10 mg, 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 150 mg, orally twice a day, or 120 mg, 160 mg, orally once a day.

in conclusion:

Judging from the evaluable clinical data of 22 of 23 cases, the objective disease response rate (ORR) of single use and daily dose of 120 mg compound I against recurrent platinum-resistant ovarian cancer was 18.2%, and the disease control rate (DCR) was 81.8%.

From the clinical data of 13 cases, the objective disease response rate (ORR) of the single-use, daily dose of 120 mg of compound I against platinum-resistant BRCA non-mutated ovarian cancer was 15.4%, and the disease control rate (DCR) was 84.6%.

Example 3. Phase I study of compound represented by formula (I) combined with apatinib in the treatment of recurrent ovarian cancer or triple negative breast cancer

1. Test drugs

1) Compound I, prepared according to the method disclosed in CN102686591A, capsules, specifications: 10mg/capsule, 40mg/capsule, 50mg/capsule;

2) Commercially available apatinib mesylate tablets.

2. Enrolled subjects

(1) Female, aged ≥18 years;

(2) Patients with recurrent ovarian cancer (including platinum-sensitive recurrent ovarian cancer and platinum-resistant recurrent ovarian cancer) or triple-negative breast cancer patients who have received at least 1 line of chemotherapy at the recurrence/metastasis stage.

3. Method of administration

Compound I: 100mg/time or 80mg/time or 60mg/time or 40mg/time, 2 times a day, continuous medication, every 4 weeks as a cycle.

Apatinib mesylate tablets: 250mg/time or 375mg/time or 500mg/time, once a day, continuous medication, every 4 weeks as a cycle.

Combination medication is a cycle every 4 weeks, and the medication is used until the disease progresses, intolerance, the subject voluntarily withdraws from the treatment or the investigator determines.

4. Data analysis

(1) The effect of compound I on the pharmacokinetics of apatinib

First give compound I single agent, and complete the single-drug PK blood collection of compound I; 72h after compound I single-drug administration, give a single dose of apatinib, and complete the single-agent PK blood collection of apatinib; 72 hours after a single administration, the combined administration of compound I and apatinib (continuous administration) was started, and a cycle was 28 days: on the first day of the combined administration, a single PK blood sample was collected for the combined administration; continuous administration After 28 days, multiple PK blood samples were collected for combined administration. The C _max and AUC of apatinib and the drug-time curve were determined, as shown in the following table and Figures 1-3. The dosage of apatinib is 250 mg qd.

Table 1 The effect of compound I on the pharmacokinetics of apatinib

It can be seen from the graph that as the dose of Compound I increases, the clearance rate (CL) of apatinib increases and the AUC decreases. Generally speaking, after multiple administrations, due to the accumulation effect of the drug, the AUC of the drug will be further increased compared to a single administration, and can be increased to twice or higher than the AUC of a single administration. From this experiment, it can be seen that after multiple administrations, the AUC of apatinib drops to about 50% of a single drug; compared to multiple administrations of a single drug, the AUC is reduced to less than 30% or Lower. After combined administration, the clearance of apatinib is accelerated, the elimination half-life is shortened, and the effective/toxic exposure time is shortened.

(2) Security

Statistics of adverse events (AE) during the combined administration period:

Table 2 Main AE (>20%))

AE name	N(%)
Major hematological toxicity	54 (56.8%)
Decreased white blood cell count	41 (43.2%)
Decreased neutrophil count	32 (33.7%)
anemia	24 (25.3%)
Decreased platelet count	22 (23.2%)
Major non-hematological toxicity	75 (78.9%)
nausea	36 (37.9%)
Fatigue	34 (35.8%)
hypertension	34 (35.8%)
Vomiting	26 (27.4%)
dizziness	23 (24.2%)
cough	19 (20%)
Upper respiratory tract infection	19 (20%)
headache	17 (17.9%)

Table 3 Mainly ≥3 grade AE (≥2 cases)

The main adverse reactions of apatinib alone are hand-foot syndrome, stomatitis/mucositis and urine protein (according to the drug instructions and clinical trial data of apatinib). From the statistics of adverse events during the co-administration period, it can be seen that the incidence and severity of proteinuria caused by apatinib decreased, and adverse reactions such as hand-foot syndrome and stomatitis/mucositis did not occur during the study period. After the combined administration, the clearance of apatinib is accelerated, the elimination half-life is shortened, and the effective/toxic exposure time is shortened, resulting in a decrease in the incidence and severity of apatinib-related toxicity. Compound I was less affected by apatinib. In other words, the combined administration reduces the toxicity of apatinib and improves the compliance of subjects during medication. The combined regimen can reduce the clinical toxicity of apatinib.

(3) Preliminary efficacy of the combined program

For the efficacy analysis of 35 platinum-sensitive patients with recurrent ovarian cancer, the dosage regimen was compound I 100 mg bid combined with apatinib 250 mg qd. The therapeutic effect of combined administration is as follows.

Table 4 The therapeutic effect of recurrent ovarian cancer

To	Number of cases	CR	PR	SD	PD	NE	ORR	DCR
gBRCA mutation	4	1	2	1	0	0	75%	100%
gBRCA wild	31	1	14	11	2	3	48.4%	83.9%

Note: "CR" complete remission, "PR" partial remission, "SD" disease stable, "PD" disease progression, "NE" not evaluated, "ORR" objective remission rate, "DCR" disease control rate.

For BRCA1/2 unmutated platinum-sensitive recurrent ovarian cancer, the remission rate of combined administration: ORR: 48.4% (15/31), which is significantly better than the objective remission of 20-25% of PARP inhibitors in the same population The combination of compound I and apatinib can increase the efficacy of compound I in recurrent ovarian cancer.

The curative effect analysis of 22 patients with triple-negative breast cancer who had failed at least 1 line of chemotherapy at the recurrence/metastasis stage, the therapeutic effect of combined administration is as follows.

Table 5 The therapeutic effect of triple negative breast cancer

When the dose of apatinib was 250 mg/d, the ORR of combined administration was 8.3% (1/12), and the therapeutic effect was poor. When the dose of apatinib was 375 mg/d, the remission rate of combined administration was significantly increased, ORR: 40% (4/10). The longest medication among patients reaches 16 cycles.

Claims (21)

1. A pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is combined with apatinib or a pharmaceutically acceptable salt thereof in the preparation of a compound for the treatment of ovarian cancer or breast cancer Use in medicine,

   
2. Use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in combination with apatinib or a pharmaceutically acceptable salt thereof in preparing a medicine for reducing the adverse reactions of apatinib or a pharmaceutically acceptable salt thereof.
3. A use of the compound represented by formula (I) or its pharmaceutically acceptable salt for reducing the adverse reactions of apatinib or its pharmaceutically acceptable salt.
4. The use according to any one of claims 1 to 3, wherein the ovarian cancer or breast cancer is ovarian cancer or breast cancer sensitive to or resistant to chemotherapy drugs.
5. The use according to claim 4, wherein the ovarian cancer or breast cancer is platinum compound sensitive ovarian cancer or breast cancer.
6. The use according to any one of claims 1-5, wherein the breast cancer is triple negative breast cancer, preferably recurrent and metastatic triple negative breast cancer.
7. The use according to any one of claims 1-5, wherein the ovarian cancer is recurrent ovarian cancer.
8. The use according to any one of claims 1-7, wherein the ovarian cancer or breast cancer is BRCA1/2 mutant ovarian cancer or breast cancer or BRCA1/2 non-mutant ovarian cancer or breast cancer.
9. The use according to any one of claims 1-8, wherein the pharmaceutically acceptable salt of apatinib is selected from hydrochloride, methanesulfonate, maleate, malate or besylate Etc., preferably methanesulfonate.
10. The use according to any one of claims 1-8, wherein the pharmaceutical composition comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is represented by formula (I) The dosage of the compound or its pharmaceutically acceptable salt is 0.1-1000 mg.
11. The use according to any one of claims 1-10, wherein the administration dose of apatinib or a pharmaceutically acceptable salt thereof is 100-500 mg, preferably at least 375 mg.
12. The use according to any one of claims 1-11, wherein the frequency of administration of apatinib or its pharmaceutically acceptable salt is once a day, once every two days, and once every three days.
13. The use according to any one of claims 1-12, wherein the frequency of administration of the pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is one day Once, twice a day, three times a day, once every two days, and once every three days.
14. The use according to any one of claims 1-13, wherein the frequency of administration of apatinib or its pharmaceutically acceptable salt is once a day, and the dosage is 250 mg/time or 375 mg/time or 500 mg/time. The frequency of administration of the pharmaceutical composition containing the compound represented by formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients is twice a day, and the dosage is 100 mg/time or 80 mg/time Or 60mg/time or 50mg/time or 40mg/time.
15. The use according to any one of claims 1-14, wherein the pharmaceutical composition comprising the compound represented by formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients and apatinib are both oral Administration.
16. The use according to any one of claims 1-15, wherein the excipient is selected from fillers, binders, disintegrants, lubricants.
17. The use according to claims 1-16, wherein the pharmaceutically acceptable excipient comprises a lubricant, and the content of the lubricant is 0.01%-25% relative to the total weight of the composition, preferably 0.1%- 10%.
18. The use according to claims 1-17, wherein the pharmaceutically acceptable excipient comprises a disintegrant, and the content of the disintegrant is 0.01%-40% relative to the total weight of the composition, preferably 1 %-20%.
19. Use of the compound represented by formula (I) or its pharmaceutically acceptable salt in the preparation of a medicament for reducing the AUC of apatinib or its pharmaceutically acceptable salt in patients.
20. According to the use according to claim 19, the AUC of apatinib or its pharmaceutically acceptable salt produced by the same dose of apatinib or its pharmaceutically acceptable salt in the patient's body is reduced to no more than 90%, Preferably, AUC is reduced to 10%-90%, more preferably AUC is reduced to 10%-80%.
21. The use according to claim 19, by administering to the patient an effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and an effective amount of apatinib or a pharmaceutically acceptable salt thereof, apatinib or a pharmaceutically acceptable salt thereof The medicinal salt provides an AUC of 1200-6000 ng*h/mL in the patient's body, preferably, apatinib or its pharmaceutically acceptable salt provides an AUC of 1700-5000 ng*h/mL in the patient's body, preferably, apatin Nitraria or its pharmaceutically acceptable salts provide AUC of 2000-4500 ng*h/mL in patients.

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