CN113874018A - Use of PARP inhibitors in combination with VEGFR inhibitors for the treatment of ovarian or breast cancer - Google Patents

Abstract

Use of a pharmaceutical composition comprising a PARP inhibitor in combination with a VEGFR inhibitor for the manufacture of a medicament for the treatment of ovarian cancer, breast cancer.

Description

Use of PARP inhibitors in combination with VEGFR inhibitors for the treatment of ovarian or breast cancer Technical Field

The invention belongs to the field of medicines, and relates to application of a PARP inhibitor and a VEGFR inhibitor in preparation of a medicine for treating ovarian cancer or breast cancer.

Background

Breast cancer is one of the most common malignancies in women, with about 130 million cases worldwide each year. In China, the incidence rate of breast cancer accounts for 7% -10% of the incidence rate of various malignant tumors of the whole body, approximately accounts for 18% of all female tumors, the number of patients in China currently exceeds 50 ten thousand, the incidence rate is rapidly increased, the first female tumor incidence spectrum is listed in some big cities, and nearly 50% of patients relapse and transfer after treatment. In recent years, with the deepening of the research of tumor molecular biology, molecular targeted therapy is more and more widely applied to breast cancer treatment and obtains more remarkable curative effect, becomes a brand new treatment mode following three traditional modes of operation, radiotherapy and chemotherapy, and is also a hotspot of the research in the field of breast cancer treatment at present.

Ovarian epithelial cancer (EOC) is the highest-mortality gynecological malignancy, nearly 75% of patients have been diagnosed at the middle and late stages, and require standard treatment modalities of radical surgery and platinum-based regimen chemotherapy, and after completion of standard treatment, the complete remission rate can reach 40% -60%, but over 90% of patients will relapse in 18 months on average, and then face the risk of death due to chemotherapy rejection and disease progression.

Aiming at recurrent ovarian cancer, if a patient is sensitive to treatment by a platinum-containing chemotherapy scheme (the time from last chemotherapy to tumor recurrence/progression is more than or equal to 6 months), the subsequent treatment continues to adopt a platinum-containing scheme for treatment, if the patient is resistant to the platinum-containing chemotherapy scheme (the time from last chemotherapy to tumor recurrence/progression is less than 6 months), the subsequent treatment adopts single-drug chemotherapy, the chemotherapy schemes comprise docetaxel, paclitaxel peritherapy, liposomal doxorubicin, gemcitabine and the like, the effectiveness of the treatments is limited, the tumor remission rate is generally 15-20% during the treatment period, the disease-progression-free survival period is about 3-4 months, and an efficient and low-toxicity treatment scheme is to be developed aiming at recurrent ovarian cancer.

Polyadenylated ribose polymerase (ADP) or poly (ADP-ribose) polymerase (PARP) plays an important role in the repair of DNA Single Strand Breaks (SSB) induced by different causes. The development of anti-tumor therapeutic PARP inhibitors has progressed rapidly since 2014 when the PARP inhibitor Olaparib was marketed for the treatment of BRCA1/2 mutant ovarian cancer. Preclinical studies have shown that, in addition to single-drug applications, PARP inhibitors can also be used as chemosensitizers and chemotherapeutics in combination with chemotherapeutics and radiotherapy to enhance the anti-tumor efficacy, thereby reducing the doses of chemotherapeutics or radiation and reducing the toxic and side effects. The results of a recent phase II clinical trial indicate that Olaparib showed 88% response in patients with advanced prostate cancer with mutations in the DNA repair gene, and could suppress or even reduce tumor growth, with overall survival longer than expected in similar patients. Therefore, the continuous expansion of the application mode and the indication range of the PARP inhibitor has good promotion effect on the research, development and application of the PARP inhibitor. According to literature reports, the remission rate of single PARP inhibitor in BRCA1/2 unmutated platinum-sensitive recurrent ovarian cancer is 20-25% (Gelmon, Karen A., et al, the local oncology 12.9(2011):852-861, and Swisher, Elizabeth M., et al, the local oncology 18.1(2017): 75-87). WO2012019427a1 (publication 2012-02-16) discloses PARP inhibitors capable of inhibiting the growth of a variety of tumors, having the structure shown in formula I,

vascular Endothelial Growth Factor (VEGF) is the most important positive regulatory protein that has been demonstrated to date. VEGF, by binding with its receptor subtype VEGFR-2, induces VEGFR-2 phosphorylation and, in turn, activates a series of cascade reactions, causing vascular endothelial cell proliferation and inducing angiogenesis. Research shows that VEGF and its receptor are expressed in stomach cancer tissue and their expression level is positively correlated with stomach cancer prognosis. Therefore, a therapy targeting VEGF or its receptor and thereby disrupting angiogenesis could undoubtedly provide a completely new therapeutic direction and molecular target for gastric cancer patients. Bevacizumab (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 (Apatinib) disclosed in WO2005000232a2 (publication 2005-01-06) has the advantages of high selectivity competition for the ATP binding site of VEGFR-2 in cells, blocking down-stream signal transduction, inhibiting the generation of tumor neovascularization, and finally achieving the purpose of treating tumors. The structure of Apatinib (Apatinib) is shown in formula II,

more than one anti-tumor drugs with different target points and mutual correlation are used in combination, the advantages of each component are fully exerted, the anti-tumor activity of a single drug can be improved, the drug toxicity can be reduced, and the anti-tumor drug is a generally accepted anti-tumor therapy. Phase II clinical trials of the combination of the PARP inhibitor Olaparib and the drug Cediranib which inhibits the activity of VEGFR and resists angiogenesis preliminarily confirm that the combination scheme has more remarkable curative effect compared with the combination scheme which is singly used for treating sensitive ovarian cancer patients by recurrent platinum compounds, and the combination scheme of the two types of targets has good feasibility for tumor treatment.

The patent applications WO2010096627, WO2014004376, WO2016116602, WO2016179123 disclose the use of VEGFR in combination with PARP inhibitors in the treatment of malignancies (e.g. breast or ovarian cancer, etc.).

Disclosure of Invention

The invention provides an application of a pharmaceutical composition containing a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and apatinib or a pharmaceutically acceptable salt thereof in preparing a medicament for treating ovarian cancer or breast cancer,

the invention also provides application of a pharmaceutical composition containing the compound shown in the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in preparation of a medicine for reducing adverse reactions of apatinib or the pharmaceutically acceptable salt thereof in combination with the apatinib or the pharmaceutically acceptable salt thereof.

In another aspect, the invention provides an application of a pharmaceutical composition containing a compound shown in formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in reducing adverse reactions of apatinib or a pharmaceutically acceptable salt thereof.

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

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

In certain embodiments, the ovarian or breast cancer described in the present invention can be a chemotherapeutic drug-sensitive or chemotherapeutic drug-resistant ovarian or breast cancer.

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

The chemotherapeutic agent for treating ovarian cancer is selected from, but not limited to, gemcitabine, paclitaxel, bevacizumab, sorafenib, sunitinib, pazopanib, lenvatinib mesylate, carboplatin, docetaxel, pemetrexed disodium, everolimus, erlotinib, lenatinib, gefitinib, Nintedanib, dasatinib, Trametinib, avelumab, ribociclib, Ipilimumab, lobaplatin, enzamide, mifepristone, Olaparib, alkylating agent, camphorsulfonic acid, Clovis, imatinib, s-malalate 184, azacitidine, cetuximab, Alza, anastrozole, exemestane, copulisib hydrochloride, irinotecan, lenalidomide, patulin, aprepirubicin, Abutide, Abutisin, interleukin, topotecan, docetaxel, levonorgestrel, vinorelbine, vinflufenadine, melflufenacetrin, mellitinid, docetaxel, trexorubicin, gefitinib, and so, Aminopterin, vandetanib, interferon alpha-2 b successor, pharmbiotek, recombinant human interferon alpha-2 b, bendamustine, belinostat, immucll LC, interferon gamma-1 b, catamaxomab, glutoxim, Vorinostat, cetrorelix, ponatinib, treosulfan, etoposide, bexarotene, paclitaxel, lobaplatin, ixabepilone, docetaxel, mitoxantrone, mifepristone, paclitaxel, doxorubicin hydrochloride, belotecan, raltitrexed, paclitaxel, alitretinol, doxorubicin hydrochloride, sartomodulab pentostatin, topotecan hydrochloride, nedaplatin, docetaxel, cisplatin, oxaliplatin/platinum oxalate and the like, preferably at least one platinum compound such as carboplatin, cisplatin, oxaliplatin, satraplatin/platinum oxalate, satraplatin, or carboplatin. The chemotherapeutic agent for treating breast cancer is selected from, but not limited to, trastuzumab, atezolizumab, gemcitabine, paclitaxel, Pembrolizumab, ramucirumab, durvalumab, bevacizumab, oxaliplatin, capecitabine, Nivolumab, ruxolitinib, tamoxifen, lervatinib mesylate, paclitaxel, everolimus, neratinib, gefitinib, avelumab, ribociclib, enzamide, palbociclib, alkylating agent, azacitidine, trastuzumab, abiraterone, adriamycin, emaciclib, anastrozole, zoledronic acid, erbulin mesylate, patulin, docetaxel, epirubicin, lapatinib, letrozole, kabat, trastuzumab, axizumab, acyclovir, interferon gamma-1 b, trastuzumab, idarubicin, paclitaxel, amitriptoresinone, paclitaxel, amitriptoresinolide, paclitaxel, and paclitaxel, or a, At least one of cisplatin, paclitaxel, etc., preferably selected from gemcitabine, docetaxel, epirubicin, paclitaxel, lapatinib or platinum-based compounds, such as carboplatin, cisplatin, oxaliplatin/oxaliplatin, sulfoplatin, nedaplatin or lobaplatin.

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

In certain embodiments, the ovarian cancer is BRCA1/2 unmutated platinum-based compound-sensitive or chemotherapeutic drug-resistant ovarian cancer.

In certain embodiments, the pharmaceutically acceptable salt of apatinib is selected from, but not limited to, the hydrochloride, mesylate, maleate, malate, or besylate salt, and the like, preferably from the mesylate salt.

In certain embodiments, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof administered in an amount of 0.1 to 1000mg, and may 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, 255mg, 245mg, 250mg, 270mg, 265mg, 180mg, 265mg, 60mg, 65mg, 70mg, 75mg, 100mg, and the like, 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, 1000 mg; preferably 40mg, 50mg, 60mg, 80mg, 100mg, 120mg, 160mg, 200mg or 300 mg.

In certain embodiments, the apatinib, or a pharmaceutically acceptable salt thereof, is administered in an amount of 100-500mg, and may be 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 500mg, preferably 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 500 mg. In certain embodiments, the apatinib, or pharmaceutically acceptable salt thereof, is administered at a dose of at least 375 mg.

The administration route of the combination of the present invention is selected from oral administration, parenteral administration, transdermal administration, and 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 into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.

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

In certain embodiments, the pharmaceutical composition comprises a disintegrant including, but not limited to, one or more of croscarmellose sodium, starch, sodium carboxymethyl starch, and crospovidone. The disintegrant may be present in an amount of 0.01% to 40%, preferably 1% to 20%, based on the total weight of the composition.

In certain embodiments, the pharmaceutical composition comprises a lubricant including, but not limited to, one or more of magnesium stearate, zinc stearate, glyceryl behenate, sodium lauryl sulfate, hydrogenated vegetable oil, aerosil, talc, colloidal silicon dioxide, preferably one or more of magnesium stearate and colloidal silicon dioxide. The lubricant may be present in an amount of 0.01% to 25%, preferably 0.1% to 10%, based on the total weight of the composition.

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

The invention further relates to application of a pharmaceutical composition containing the compound shown in the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and apatinib or a pharmaceutically acceptable salt thereof in preparation of a medicament for treating ovarian cancer or breast cancer, wherein the apatinib or the pharmaceutically acceptable salt thereof is administered once a day, once every two days, once every three days, five days for two days, and seven days for seven days; the frequency of administration of the pharmaceutical composition comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient may be once a day, twice a day, three times a day, once two days, once three days, once a week, once three weeks, once a month.

In certain embodiments, the apatinib, or a pharmaceutically acceptable salt thereof, is administered once a day at a dose of 250 mg/time or 375 mg/time or 500 mg/time; the administration frequency of the pharmaceutical composition comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient may be twice a day at an administration dose of 100 mg/time, or 80 mg/time, or 60 mg/time, or 50 mg/time, or 40 mg/time.

In the embodiment of the present invention, the combination optionally further comprises other components, including but not limited to other antitumor agents, etc.

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

The invention also provides a method for reducing adverse reactions of apatinib or a pharmaceutically acceptable salt thereof, which comprises administering the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof and apatinib or the pharmaceutically acceptable salt thereof to a patient.

The invention also provides a method for treating tumor diseases, which comprises the step of administering the compound shown as the formula (I) or the pharmaceutically acceptable salt thereof and the apatinib or the pharmaceutically acceptable salt thereof to a patient so as to shorten the clearing half-life of the apatinib or the pharmaceutically acceptable salt thereof.

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

The invention also provides an application of a pharmaceutical composition containing the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and apatinib or the pharmaceutically acceptable salt thereof in preparing a medicament for treating tumors, wherein the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof reduces the AUC of the apatinib or the pharmaceutically acceptable salt thereof in a patient.

The invention also provides application of the compound shown in the formula (I) or a pharmaceutically acceptable salt thereof in preparing a medicament for reducing AUC (AUC) of apatinib or the pharmaceutically acceptable salt thereof in a patient.

In an open, single-arm and multicenter phase II clinical test of the apatinib mesylate tablet for treating advanced triple negative breast cancer, the pharmacokinetic characteristics of the apatinib mesylate in a triple negative breast cancer patient are researched. After a patient takes 500mg apatinib mesylate orally after meal to stabilize, the elimination half-life of both the prototype drug and the metabolite is longer. Plasma exposure (AUC) of prototype drug and metabolite after 2 consecutive cycles (28 days in one cycle)_{0_24h}) Is 1.44-2.39 times of the single administration.

By adopting the combined administration scheme, the AUC of the apatinib is reduced to about 50% of that of a single drug; AUC decreased to below 30% or less compared to multiple dosing with a single drug. This results in a reduction in the effective/toxic exposure time of apatinib, with reduced toxic side effects; it is surprising that synergistic therapeutic effects can also be produced.

In another aspect, the present invention provides a method for reducing AUC for apatinib, or a pharmaceutically acceptable salt thereof, in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of apatinib, or a pharmaceutically acceptable salt thereof.

The term "reducing the AUC of apatinib, or a pharmaceutically acceptable salt thereof, in a patient" as used herein refers to the AUC that occurs in the patient relative to an equivalent dose of apatinib, or a pharmaceutically acceptable salt thereof, administered alone.

In some embodiments, by administering to a patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an effective amount of apatinib or a pharmaceutically acceptable salt thereof, the AUC that is produced in the patient is reduced to no greater than 90%, optionally to 10% -90%, compared to an equivalent dose of apatinib or a pharmaceutically acceptable salt thereof administered alone; alternatively, AUC decreased to 10% -80%; alternatively, AUC decreased to 15% -75%; in particular, the AUC of apatinib, or a pharmaceutically acceptable salt thereof, 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% and 90%.

In some embodiments, by administering to a patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and an effective amount of apatinib or a pharmaceutically acceptable salt thereof, the apatinib or pharmaceutically acceptable salt thereof is capable of providing an AUC of 1200-6000ng x h/mL in the patient; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1200 and 5800ng x h/mL in the patient; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1300-; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1300-; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1300-; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1500-; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1500-; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1700-5300ng x h/mL in the patient; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1700 + 5000ng x h/mL in the patient; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1900-; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 2000-; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 2000-; optionally, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 2000 and 4500ng h/mL in the patient; preferably, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 1700-5000ng x h/mL in a patient; preferably, apatinib, or a pharmaceutically acceptable salt thereof, provides an AUC of 2000 and 4500ng x h/mL in a patient.

The effect of the pharmaceutical composition containing the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof and the apatinib in combination therapy on tumors is better than the effect of the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof in single drug therapy, and specifically can show that the pharmaceutical composition has better effect on Objective Remission Rate (ORR) or Disease Control Rate (DCR) and higher proportion of Complete Remission (CR) and/or Partial Remission (PR) and/or stable lesion (SD). In addition, the combined administration can also reduce the incidence of adverse reactions brought by apatinib, and the same can be used for proving the effect of the invention.

Description of the terms

"treatment" includes both prophylactic and therapeutic treatment (including but not limited to alleviation, cure, alleviation of symptoms, diminishment of symptoms) and delay of progression of a neoplastic disease or disorder.

The platinum compound drug-resistant type is recurrent within 6 months after the platinum-containing regimen chemotherapy is finished; while those who relapse after 6 months after the end of chemotherapy are platinum-compound-sensitive (otherwise known as platinum-treatment-sensitive).

"pharmaceutical composition" refers to a mixture comprising at least one therapeutic agent and at least one pharmaceutically acceptable excipient including, but not limited to, diluents, binders, disintegrants, lubricants, including, but not limited to, mannitol, microcrystalline cellulose dextrose, pregelatinized starch, dibasic calcium phosphate, lactose, sorbitol; the adhesive can be selected from one or more of starch, sodium carboxymethylcellulose, polyvinylpyrrolidone, pregelatinized starch, hypromellose and hydroxypropyl cellulose; the disintegrant can be one or more selected from croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone; the lubricant can be one or more selected from pulvis Talci, magnesium stearate, zinc stearate, and glyceryl behenate.

The pharmaceutical composition containing the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof and the apatinib can also be administered in a parenteral form, and the composition can contain pharmaceutically acceptable excipients which are selected from one or more of preservatives, stabilizing agents, solubilizing agents, emulsifying agents, osmotic pressure regulating agents and buffering agents.

"therapeutically effective" preferably relates to an amount of a therapeutic agent which is therapeutically or more broadly also prophylactically effective against tumor progression.

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

"C" in the invention_max"refers to the peak concentration of a pharmacokinetic drug in blood, and this parameter is an important index for evaluating the absorption rate of a drug and reflects the exposure characteristics of the drug in vivo.

"AUC" refers to the area enclosed by the pharmacokinetic plasma concentration curve along the time axis, and this parameter is an important index for evaluating the degree of drug absorption, and reflects the exposure characteristics of the drug in vivo. Because the blood concentration can only be observed to a certain time point t in the pharmacokinetic researchTherefore, AUC has two expression modes of AUC: (AUC:)_0-t) And AUC: (_0-∞) The former is obtained by trapezoidal area method, and the latter is calculated by AUC: (_0-∞)＝AUC( _0-t) + end point concentration/end elimination rate. AUC in the present invention means the mean AUC of patients after a single administration or multiple administrations reach the steady state_0-24Preferably, the mean AUC of the patient after multiple administrations have reached steady state_0-24(i.e., AUC)_ss)。

The criteria for determining the severity of adverse events in the present invention are referred to the criteria for grading adverse drug events, NCI-CTC AE version 4.03. If adverse events not listed in the NCI-CTC AE version 4.03 table occur, reference may be made to the following criteria:

Drawings

FIG. 1 shows C for apatinib in combination with the compound of formula (I)_maxThe influence of (a);

FIG. 2 is AUC of apatinib in combination with a compound of formula (I)_0-24hThe influence of (a);

FIG. 3 is a time course of apatinib under the action of the compound of formula (I);

FIG. 4 shows C of apatinib on Compound of formula (I) in combination_maxThe influence of (a);

FIG. 5 is a graph of the effect of apatinib on AUC for a compound of formula (I) when administered in combination;

FIG. 6 shows the steady state C of the compound of formula (I) after single administration or combination of different doses of apatinib_maxA value;

FIG. 7 is the steady state AUC of the compound of formula (I) after single or combined administration of varying doses of apatinib.

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Example 1: a compound (compound I) capsule shown in formula (I) is prepared by mixing the compound shown in formula (I) with a carrier material containing PVP K30 to prepare a solid dispersion, adding appropriate amount of excipient such as disintegrant and lubricant, mixing uniformly, and filling into capsules to prepare capsules.

Example 2: effectiveness of the Compound of formula (I) alone in treating recurrent chemotherapy-resistant ovarian cancer

In phase I clinic, compound I at a dose level of 120mg/d and above was administered to 23 histologically or cytologically confirmed patients with recurrent ovarian cancer who failed standard therapy and who underwent at least 2-line systemic chemotherapy during the recurrent metastatic stages of ovarian cancer, with the chemotherapy regimen being a platinum-containing chemotherapy regimen that was resistant to platinum-containing therapies or intolerant to chemotherapy toxicity during the course of treatment.

The administration scheme is as follows:

a compound I: the initial dose is 10mg, 20mg, 40mg, 60mg, 80mg, 100mg, 150mg, taken orally twice daily, or 120mg, 160mg, taken orally once daily.

And (4) conclusion:

from 22 of 23 evaluable clinical data, the objective disease remission rate (ORR) and Disease Control Rate (DCR) for recurrent platinum-resistant ovarian cancer was 18.2% for compound I administered alone at a daily dose of 120 mg.

From 13 clinical data, the objective disease remission rate (ORR) and Disease Control Rate (DCR) for platinum-resistant BRCA non-mutated ovarian cancer was 15.4% and 84.6% for a single daily dose of 120mg compound I.

EXAMPLE 3 phase I Studies of treatment of recurrent ovarian cancer or triple negative breast cancer with Compounds of formula (I) in combination with Apatinib

1. Test drugs

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

2) commercially available apatinib mesylate tablets.

2. Subjects in group

(1) Female, age ≥ 18 years;

(2) recurrent ovarian cancer (including platinum-sensitive recurrent ovarian and platinum-resistant recurrent ovarian cancer) or triple-negative breast cancer patients who have failed at least 1-line chemotherapy in the recurrent/metastatic stage.

3. Method of administration

A compound I: the preparation is administered 2 times daily at a dose of 100 mg/time, 80 mg/time, 60 mg/time, or 40 mg/time, and is administered for 1 cycle every 4 weeks.

Apatinib mesylate tablets: 250 mg/time or 375 mg/time or 500 mg/time, once daily, and continuously taking the medicine, wherein 1 cycle is performed every 4 weeks.

The combination is administered for 1 cycle every 4 weeks until disease progression, intolerance, voluntary withdrawal of the subject from treatment or judgment by the investigator.

4. Data analysis

(1) Effect of Compound I on Apatinib pharmacokinetics

Compound I single drug was given first and a single drug PK bleed of compound I was completed; after 72 hours of single drug administration of the compound I, single drug administration of apatinib is carried out, and blood sampling of the PK of the apatinib single drug is completed; compound I and apatinib were started in combination (continuous) 72h after a single administration of apatinib, with a cycle of 28 days: on day 1 of the combined dose, a single PK blood sample collection was performed for the combined dose; after 28 consecutive days, PK blood samples were collected by co-administration. Determination of C of Apatinib_maxAnd AUC and time of drug curves, as shown in the table below, and figures 1-3. Apatinib was administered at a dose of 250mg qd.

TABLE 1 Effect of Compound I on Apatinib pharmacokinetics

As can be seen from the graph, the Clearance (CL) of apatinib increases and AUC decreases with increasing dose of compound I administered. Generally, after multiple administrations, the AUC of the drug is further increased compared to a single administration due to the cumulative effect of the drug, which may be 2-fold or higher than the AUC of a single administration. From the experiment, the AUC of the apatinib is reduced to about 50% of that of a single drug after combined administration for multiple times; AUC decreased to below 30% or less compared to multiple dosing with a single drug. Following co-administration, apatinib clearance is accelerated, clearance half-life is shortened, and effective/toxic exposure time is shortened.

(2) Safety feature

Adverse Event (AE) statistics during combination dosing:

table 2 main AEs (> 20%)

AE name	N(％)
Major hematological toxicity	54(56.8％)
Reduction of white blood cell count	41(43.2％)
Decreased neutrophil count	32(33.7％)
Anemia (anemia)	24(25.3％)
Decrease in platelet count	22(23.2％)
Major non-hematologic toxicity	75(78.9％)
Nausea	36(37.9％)
Debilitation	34(35.8％)
Hypertension (hypertension)	34(35.8％)
Vomiting	26(27.4％)
Dizziness (lightheadedness)	23(24.2％)
Cough with asthma	19(20％)
Upper respiratory tract infection	19(20％)
Headache (headache)	17(17.9％)

TABLE 3 Main grade 3 AE ≥ 2 cases)

Adverse reactions of apatinib single administration mainly include hand-foot syndrome, stomatitis/mucositis, urine protein and the like (according to the specifications of apatinib marketed drugs and clinical test data). According to the statistics of adverse events during the combined administration, the incidence rate and the severity of proteinuria caused by apatinib are reduced, and adverse reactions such as hand-foot syndrome, stomatitis/mucositis and the like do not occur during the research period. Following co-administration, apatinib clearance is accelerated, clearance half-life is shortened, and effective/toxic exposure time is shortened, resulting in decreased apatinib-related toxicity incidence and severity. While compound I was less affected by apatinib. That is, the co-administration reduces the toxicity of apatinib, increasing compliance of the subject during dosing. The combination regimen can reduce the clinical toxicity of apatinib.

(3) Preliminary therapeutic effects of the combination regimen

Analysis of efficacy in 35 patients with platinum-sensitive recurrent ovarian cancer, compound I100 mg bid in combination with apatinib 250mg qd. The therapeutic effect of the combination is given in the table below.

TABLE 4 therapeutic Effect of recurrent ovarian cancer

	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 stabilization, "PD" disease progression, "NE" not assessed, "ORR" objective remission rate, "DCR" disease control rate.

For recurrent ovarian cancer that is not platinum-sensitive with BRCA1/2 mutations, the remission rate was given in combination: 48.4% (15/31) of ORR, which is significantly superior to the 20-25% objective remission rate of a single PARP inhibitor in the same population, and the combination of the compound I and apatinib can increase the curative effect of the compound I in recurrent ovarian cancer.

Efficacy of 22 patients with triple negative breast cancer who had received at least 1 line of chemotherapy failure in the relapsed/metastatic stage was analyzed and the efficacy of the combination was as follows.

TABLE 5 therapeutic Effect of triple negative Breast cancer

The remission rate ORR of the combined administration is 250mg/d for apatinib: 8.3 percent (1/12), the treatment effect is poor. When the apatinib dose is 375mg/d, the remission rate of combined administration is obviously improved, and ORR: 40% (4/10). The longest of the patients was dosed for 16 cycles.

Claims (21)

1. The application of the combination of a pharmaceutical composition containing a compound shown as a formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and apatinib or a pharmaceutically acceptable salt thereof in preparing a medicament for treating ovarian cancer or breast cancer,

   
2. an application of a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof and apatinib or a pharmaceutically acceptable salt thereof in preparing a medicament for reducing adverse reactions of the apatinib or the pharmaceutically acceptable salt thereof.
3. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for reducing adverse effects of apatinib or a pharmaceutically acceptable salt thereof.
4. The use according to any one of claims 1 to 3, wherein the ovarian or breast cancer is chemotherapeutic drug-sensitive or chemotherapeutic drug-resistant ovarian or breast cancer.
5. The use according to claim 4, wherein the ovarian or breast cancer is a platinum-based compound-sensitive ovarian or breast cancer.
6. Use according to any one of claims 1 to 5, wherein the breast cancer is triple negative breast cancer, preferably recurrent metastatic triple negative breast cancer.
7. The use according to any one of claims 1 to 5, wherein the ovarian cancer is recurrent ovarian cancer.
8. The use according to any one of claims 1 to 7, wherein the ovarian or breast cancer is BRCA1/2 mutant ovarian or breast cancer or BRCA1/2 non-mutant ovarian or breast cancer.
9. Use according to any one of claims 1 to 8, wherein the pharmaceutically acceptable salt of apatinib is selected from the group consisting of hydrochloride, mesylate, maleate, malate or besylate salts and the like, preferably from the mesylate salt.
10. The use according to any one of claims 1 to 8, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in an amount of 0.1 to 1000 mg.
11. The use according to any one of claims 1 to 10, wherein the apatinib or the pharmaceutically acceptable salt thereof is administered in a dose of 100-500mg, preferably at least 375 mg.
12. The use according to any one of claims 1 to 11, wherein apatinib, or a pharmaceutically acceptable salt thereof, is administered once daily, once every two days, once every three days.
13. The use according to any one of claims 1 to 12, wherein the pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is administered once a day, twice a day, three times a day, once every two days, once every three days.
14. The use according to any one of claims 1 to 13, wherein the apatinib, or a pharmaceutically acceptable salt thereof, is administered once daily at a dose of 250 mg/time or 375 mg/time or 500 mg/time; the administration frequency of the pharmaceutical composition containing the compound shown in the formula (I) or the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable excipient is twice a day, and the administration dose is 100 mg/time, or 80 mg/time, or 60 mg/time, or 50 mg/time, or 40 mg/time.
15. The use according to any one of claims 1 to 14, wherein the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient and apatinib are both administered orally.
16. Use according to any one of claims 1-15, wherein the excipient is selected from the group consisting of fillers, binders, disintegrants, lubricants.
17. Use according to claims 1-16, wherein the pharmaceutically acceptable excipient comprises a lubricant in an amount of 0.01% to 25%, preferably 0.1% to 10%, relative to the total weight of the composition.
18. Use according to claims 1-17, wherein the pharmaceutically acceptable excipient comprises a disintegrant in an amount of 0.01% to 40%, preferably 1% to 20%, relative to the total weight of the composition.
19. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for reducing the AUC of apatinib or a pharmaceutically acceptable salt thereof in a patient.
20. The use according to claim 19, wherein the AUC of apatinib, or a pharmaceutically acceptable salt thereof, produced in the patient is reduced to no more than 90%, preferably reduced to 10% -90%, more preferably reduced to 10% -80%, compared to the AUC of apatinib, or a pharmaceutically acceptable salt thereof, administered alone at an equivalent dose.
21. The use according to claim 19, by administering to the patient an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which provides an AUC of 1200 + 6000ng h/mL in the patient, preferably wherein apatinib or a pharmaceutically acceptable salt thereof provides an AUC of 1700 + 5000ng h/mL in the patient, and an effective amount of apatinib or a pharmaceutically acceptable salt thereof, which provides an AUC of 2000 + 4500ng h/mL in the patient.

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