Pharmaceutical compositions containing protein kinase inhibitors and chemotherapeutic agents and uses thereof

Abstract

The present invention relates to the field of biotechnology, particularly to a pharmaceutical composition containing a protein kinase inhibitor and a chemotherapeutic agent and its use. In the treatment of platinum-refractory, drug-resistant, recurrent late-stage ovarian cancer, the present invention found that when etoposide and paclitaxel were administered in combination with chiauranib, the remission rates were 40% and 50%, respectively, while the remission rates for etoposide alone were approximately 27% and for paclitaxel alone were approximately 21%. This indicates that chiauranib in combination with etoposide or paclitaxel achieved an unexpected synergistic effect in the treatment of platinum-refractory, drug-resistant, recurrent late-stage ovarian cancer.

Description

[Technical Field]

[0001] The present invention relates to the field of biotechnology, and in particular to pharmaceutical compositions comprising a protein kinase inhibitor and a chemotherapeutic agent, and uses thereof. [Background technology]

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues on proteins. They are broadly divided into tyrosine and serine / threonine kinases and represent a large family of proteins that play important roles in regulating various cellular processes and maintaining cellular function. Protein kinases are enzymatic components of signal transduction pathways that catalyze the transfer of the terminal phosphate of ATP to the hydroxyl groups of tyrosine, serine, and / or threonine residues of proteins. Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been extensively studied and shown to play an important role in the development of many diseases, including cancer. A partial, non-exhaustive list of these kinases includes nonreceptor tyrosine kinases such as the Janus kinase family (Jak1, Jak2, Jak3, and Tyk2), receptor tyrosine kinases such as platelet-derived growth factor receptor kinase (PDGFR), and serine / threonine kinases such as b-RAF. Abnormal kinase activity is observed in many disease states, including benign and malignant proliferative disorders and diseases due to inappropriate activation of the immune and nervous systems.

[0003] Protein kinases are a large family of structurally related enzymes responsible for regulating various intracellular signal transduction processes (see, e.g., Hardie and Hanks, The Protein Kinase Facts Book, I and II, Academic Press, San Diego, Calif., 1995). Protein kinases are thought to have evolved from a common ancestral gene due to the conservation of their structure and catalytic function. Most kinases contain similar catalytic domains of 250–300 amino acids. Kinases are classified into families based on the receptors they phosphorylate (e.g., protein-tyrosine, protein-serine / threonine, lipid, etc.). Sequence motifs that generally correspond to each of these families have been identified (see, e.g., Hanks and Hunter, (1995), FASEB J. 9:576-596; Knighton et al., Science, (1991) 253:407-414; Hiles et al., Cell, (1992), 70:419-429; Kunz et al., Cell (1993), 73:585-596; Garcia-Bustos et al., EMBO J., (1994), 13:2352-2361).

[0004] Inappropriate kinase activity due to mutation, overexpression or improper regulation, dysregulation, or overproduction or underproduction of growth factors or cytokines can be involved in many diseases, including, but not limited to, cancer. Protein kinases have become an important class of enzymes as targets for therapeutic intervention. In particular, overactivation of the tyrosine kinase cKit has been associated with hematological malignancies and has been targeted for cancer therapy (Heinrich, Griffith, et al., Blood 2000, 96(3):925-32). Similarly, JAK3 signaling has been associated with leukemia and lymphoma and has been used as a potential therapeutic target (Heinrich, Griffith, et al., 2000). Protein kinases also play a central role in regulating the cell cycle. Defects in various components of signaling pathways have been shown to cause a variety of diseases, including various forms of cancer (Gaestel et al., Current Medicinal Chemistry, (2007) 14:2214-2234). In recent years, protein kinases involved in oncogenic signaling pathways have become important drug targets for the treatment of various diseases, including various types of cancer, and various protein kinase inhibitors are also used as antitumor drugs.

[0005] Chiauranib is a novel protein kinase inhibitor independently developed by Shenzhen Weixin Biotechnology Co., Ltd., with full intellectual property rights. Chiauranib is a small molecule antitumor targeted drug that targets multiple protein kinases. Its highly selective inhibitory activity against VEGFR / PDGFR / c-Kit, Aurora B, and CSF-1R targets allows it to exert a comprehensive antitumor effect through a three-way synergistic mechanism of action: antitumor angiogenesis, inhibition of tumor cell mitosis, and modulation of the tumor inflammatory microenvironment. Compared with conventional VEGFR-targeted inhibitors (such as sunitinib and sorafenib), this product has unique inhibitory activity against Aurora B, a key enzyme in mitosis, potentially reducing genomic instability in tumor tissues and inhibiting tumor cell metastasis. Chiauranib exerts its antitumor activity by inhibiting three complementary mechanisms of action: tumor angiogenesis, cell mitosis, and the tumor inflammatory microenvironment. At the same time, its high target selectivity reduces the risk of side effects due to off-target effects.

[0006] DNA topoisomerases are important intracellular ribozymes that primarily change the topological structure of DNA through catalytic activity. Eukaryotic topoisomerases are primarily divided into topoisomerase I (Topo I) and topoisomerase II (Topo II). The intermediate product formed during the catalytic process, which temporarily breaks the DNA double strand, is called Topo II. Topo II plays an important role in vital life processes such as cellular DNA replication, transcription, and mitosis.

[0007] DNA Topo II mediates the unwinding of DNA double strands (breakage and reunion) and normally forms a scissile complex with DNA. Topo II inhibitors are antitumor drugs that target Topo II. Their anticancer effects are not due to inhibition of the enzyme's activity, but rather to promoting the formation of the enzyme-DNA cleavage complex, shifting the equilibrium toward the enzyme-DNA cleavage complex, prolonging its half-life and stabilizing it. This disrupts the DNA Topo II-mediated DNA reunion reaction, leading to single- or double-strand breaks in DNA, affecting DNA replication, and exerting cell-killing effects. The formation and stable existence of the scissile complex promotes aberrant DNA recombination, thereby initiating the apoptotic program and causing cell death.

[0008] Given the knowledge of the important role of Topo II in cells, the study of such compounds has always been one of the hot spots in the development of antitumor drugs.Currently available topoisomerase II inhibitors include etoposide and teniposide.

[0009] Paclitaxel is the most effective natural anticancer drug discovered and is widely used clinically to treat breast cancer, ovarian cancer, and some head and neck and lung cancers. Paclitaxel is a diterpene alkaloid compound with anticancer activity. Its novel and complex chemical structure, broad and important biological activities, novel and unique mechanism of action, and scarce natural resources have made it highly sought after by botanists, chemists, pharmacologists, and molecular biologists. It has become a popular anticancer drug and a research focus worldwide in the latter half of the 20th century. Its derivatives, such as docetaxel and nab-paclitaxel, have similar effects to paclitaxel.

[0010] In China, ovarian cancer is the third most common female reproductive system tumor after cervical cancer and uterine corpus malignant tumors in terms of annual incidence, and is showing an increasing trend. It has the highest mortality rate among female reproductive malignant tumors, and is a malignant tumor that poses a serious threat to women's health. Ovarian malignant tumors include various pathological types, the most common of which is epithelial carcinoma, accounting for approximately 70% of ovarian malignant tumors, followed by malignant germ cell tumors and sex cord stromal tumors, accounting for approximately 20% and 5%, respectively.

[0011] Ovarian cancer treatment has always been the most difficult challenge facing gynecological oncology, and the ideal basis for treatment is cytoreductive surgery, while the main chemotherapy regimen for ovarian cancer is a platinum-based combination chemotherapy regimen. Even if terminally ill patients achieve complete remission with the above treatment, there is a 70% to 80% risk of recurrence.

[0012] Clinical treatment of platinum-refractory / platinum-resistant recurrent late-stage ovarian cancer is the most difficult. To treat platinum-refractory / platinum-resistant recurrent late-stage ovarian cancer, it is very important to provide new treatment concepts and explore regimens that can effectively treat platinum-refractory / platinum-resistant recurrent late-stage ovarian cancer. Summary of the Invention

[0013] In the present invention, it was discovered that a pharmaceutical composition comprising a protein kinase inhibitor and a chemotherapeutic agent has an unexpected therapeutic effect on cancer, particularly platinum-refractory or platinum-resistant recurrent terminal ovarian cancer.

[0014] In a first aspect, the present invention provides a pharmaceutical composition comprising a protein kinase inhibitor and a chemotherapeutic agent, wherein the protein kinase inhibitor includes a compound described in CN200910223861.5, the entire contents of which are incorporated herein by reference. The protein kinase inhibitor is preferably a compound having a structure represented by general formula (I): [ka] wherein Z is CH or N; R 1 , R 2 and R 3 are each hydrogen, halogen, a methyl group, a methoxy group, or a trifluoromethyl group, R 4 teeth, [ka] and X is a benzene ring or a pyridine ring; R 5 is one or more substituents selected from the group consisting of hydrogen, halogen, methyl, methoxy, or trifluoromethyl. The protein kinase inhibitors include the free form, salt forms, enantiomers or diastereomers of the compounds of formula (I).

[0015] In a preferred embodiment, the protein kinase inhibitor has the formula (II): [ka] It is a compound having the structure represented by the formula: Its chemical name is N-(2-aminophenyl)-6-(7-methoxyquinolin-4-oxy)-1-naphthalenecarboxamide, and its generic name is Chiauranib.

[0016] The chemotherapeutic agent includes a topoisomerase II inhibitor or paclitaxel or its derivative. The topoisomerase II inhibitor includes etoposide or teniposide. The paclitaxel or its derivative includes paclitaxel, docetaxel, and nab-paclitaxel.

[0017] The dosage of the protein kinase inhibitor is 1 to 100 mg, preferably 20 to 80 mg, and most preferably 50 mg. The dosage of the topoisomerase II inhibitor is 1 to 100 mg, preferably 20 to 80 mg, and most preferably 50 mg. The dosage of paclitaxel or a derivative thereof is 10 to 200 mg / m 2, preferably 50 to 100 mg / m 2 , most preferably 60 mg / m 2 is.

[0018] The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0019] In a second aspect, the present invention provides use of the pharmaceutical composition described above in the preparation of a medicament for preventing and / or treating cancer, wherein the cancer is ovarian cancer, including malignant epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

[0020] In a preferred embodiment, the cancer is platinum-refractory or platinum-resistant recurrent ovarian cancer. Platinum-refractory refers to tumor progression during treatment with a platinum-containing regimen. Platinum-resistant refers to tumor progression or recurrence within six months of completing treatment with a platinum-containing regimen.

[0021] In a preferred embodiment, the cancer is platinum-refractory / platinum-resistant recurrent late-stage ovarian cancer. The late stages include stage III and stage IV. Stage III: primary peritoneal cancer when the tumor affects one or both of the ovaries and fallopian tubes, or with cytologically or histologically confirmed extrapelvic peritoneal spread and / or metastasis to retroperitoneal lymph nodes; Stage IV: metastasis to distant sites outside the peritoneal cavity.

[0022] In a third aspect, the present invention provides a method for the treatment and / or prevention of cancer, comprising the step of administering a therapeutically effective amount of the pharmaceutical composition to a patient in need thereof, wherein the cancer is ovarian cancer, preferably platinum-refractory / platinum-resistant recurrent ovarian cancer, most preferably platinum-refractory / platinum-resistant recurrent late-stage ovarian cancer.

[0023] In a preferred embodiment, the dose of the protein kinase inhibitor is 1 to 100 mg, preferably 20 to 80 mg, and most preferably 50 mg. The protein kinase inhibitor is preferably in an oral dosage form, most preferably a capsule, and is preferably taken orally once daily, each morning on an empty stomach.

[0024] In a preferred embodiment, the dosage of the topoisomerase II inhibitor is 1 to 100 mg, preferably 20 to 80 mg, most preferably 50 mg. The topoisomerase II inhibitor is preferably in an oral dosage form, most preferably a capsule, and is preferably taken orally every morning on an empty stomach, for 21 consecutive days followed by 7 days off, with one treatment cycle every 28 days, for a maximum of six treatment cycles.

[0025] In a preferred embodiment, the dose of paclitaxel or a derivative thereof is 10 to 200 mg / m 2 , preferably 50 to 100 mg / m 2 , most preferably 60 mg / m 2 The paclitaxel or derivative thereof is preferably in a parenteral dosage form, more preferably in an intravenous dosage form, and is preferably administered once a week (d1, d8, d15), with one treatment cycle every three weeks, for a maximum of six treatment cycles.

[0026] In a preferred embodiment, the protein kinase inhibitor and the chemotherapeutic agent may be administered separately, simultaneously or sequentially.

[0027] In a preferred embodiment, the protein kinase inhibitor can continue to be administered for treatment after the combined treatment cycle of the protein kinase inhibitor and chemotherapeutic agent has been completed.

[0028] In a fourth aspect, the present invention provides a kit comprising an effective amount of the above-described pharmaceutical composition.

[0029] In a preferred embodiment, the protein kinase inhibitor and the topoisomerase II inhibitor or paclitaxel or its derivatives in the kit are each a unit dosage form having the same or different specifications. The protein kinase inhibitor is preferably an oral dosage form. The topoisomerase II inhibitor is preferably an oral dosage form. The paclitaxel or its derivatives is preferably an intravenous infusion dosage form.

[0030] In a preferred embodiment, the protein kinase inhibitor and the chemotherapeutic agent are provided in separate containers. The protein kinase inhibitor and the chemotherapeutic agent can be administered simultaneously, before or after each other, or sequentially.

[0031] In one preferred embodiment, the kit comprises, in the same package: a first container containing a protein kinase inhibitor; and a second container containing a chemotherapy agent.

[0032] Finally, the present invention further provides the use of a compound having a structure represented by Formula (II) in the preparation of a medicament for treating platinum-refractory / platinum-resistant recurrent late-stage ovarian cancer. [ka]

[0033] In this study, a "single-arm, multi-center, non-randomized, open-label clinical trial to investigate the efficacy and safety of chiauranib capsules in the treatment of recurrent / refractory late-stage ovarian cancer" confirmed that chiauranib alone showed preliminary efficacy in tumor remission in patients with late-stage ovarian cancer who had undergone multiple chemotherapy regimens and platinum-refractory / chemoresistant recurrence. A "stage II multi-center clinical trial of chiauranib in combination with chemotherapy in the treatment of platinum-refractory / platinum-resistant recurrent ovarian cancer" preliminarily suggested the treatment of platinum-refractory / chemoresistant recurrent late-stage ovarian cancer, and improved the objective response rate when etoposide and paclitaxel were administered in combination with chiauranib. While the response rate for etoposide alone was approximately 27%, and for paclitaxel alone approximately 21%, the objective response rates when these two chemotherapy drugs were combined with chiauranib reached 40% and 50%, respectively. This demonstrated that chiauranib in combination with etoposide or paclitaxel provided an unexpected synergistic effect in the treatment of platinum-refractory, drug-resistant, recurrent, late-stage ovarian cancer. Based on the clinical data of registered cases, chiauranib in combination with etoposide or paclitaxel demonstrated excellent therapeutic effects in the treatment of platinum-refractory, drug-resistant, recurrent, late-stage (stage III and stage IV) malignant epithelial ovarian cancer, especially in metastatic stage III and stage IV malignant epithelial ovarian cancer.

[0034] As used herein, the terms "containing," "including," or "comprising" mean the inclusion of the stated elements, integers, or steps, but not the exclusion of any other elements, integers, or steps. When the terms "containing," "comprising," or "comprising" are used herein, unless otherwise indicated, they also encompass situations consisting of the stated elements, integers, or steps.

[0035] The term "prophylaxis" includes inhibiting or delaying the occurrence or frequency of occurrence of a disease or condition or a symptom thereof, and generally refers to administration of a drug prior to the onset of the disease or condition, particularly prior to the onset of the disease or condition in an at-risk individual.

[0036] As used herein, the term "treatment" refers to the slowing, halting, or reversing the progression of cancer in a subject, as evidenced by the reduction or elimination of clinical or diagnostic symptoms of the disease. Treatment can include, for example, reducing the severity, number, or frequency of recurrence of symptoms, such as inhibiting tumor growth, halting tumor growth, or causing regression of an existing tumor.

[0037] The term "pharmaceutical composition" refers to an open-ended combination product or a defined combination product. The term "open-ended combination" means, for example, that the active ingredients, a protein kinase inhibitor and a chemotherapeutic drug, are administered to a patient as separate entities simultaneously, without specific time restrictions, or sequentially at the same or different time intervals. Such administration provides prophylactically or therapeutically effective levels of the two active agents in the patient. In some embodiments, the two molecules, the protein kinase inhibitor and the chemotherapeutic drug, used in the pharmaceutical composition are administered at levels that do not exceed those when used alone. The term "defined combination" means that the two active agents are administered to a patient simultaneously in the form of a single entity. The doses and / or time intervals of the two active agents are preferably selected so that the combined use of each component produces an effect in the treatment of a disease or condition that exceeds the effect achieved by either component alone. Each component may be in a separate formulation, which may be the same or different formulations.

[0038] As used herein, the term "therapeutically effective amount" when referring to a combination therapy refers to the combined doses that, when administered together, produce the desired biological or medical response (e.g., suppression or amelioration of one or more clinical or diagnostic symptoms of cancer, including relapsed / refractory ovarian cancer). For example, when referring to a combination therapy, the term "therapeutically effective amount" when used herein refers to amounts that, when administered together (sequentially or simultaneously) on the same or different days during a treatment cycle, produce a therapeutically effective and / or synergistic combined effect.

[0039] The term "administration" refers to the physical introduction of each active ingredient in the pharmaceutical combination of the present invention into an individual using any of a variety of methods and delivery systems known to those skilled in the art. Routes of administration for each active ingredient in the pharmaceutical combination of the present invention include oral, intravenous (e.g., infusion (also known as infusion) or injection), intramuscular, subcutaneous, intraperitoneal, spinal, topical, or other parenteral routes of administration. As used herein, the term "parenteral administration" refers to modes of administration other than gastrointestinal and topical administration, typically intravenous injection or infusion, and includes, but is not limited to, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection or infusion, and also includes in vivo electroporation. Correspondingly, each active ingredient in the pharmaceutical combination of the present invention can be formulated into capsules, tablets, injections (including infusions or injection solutions), syrups, sprays, lozenges, liposomes, suppositories, or the like.

[0040] The term "dose" refers to the amount of drug that elicits efficacy. Dose refers to the amount of drug in free form unless otherwise specified. When the drug is in the form of a pharmaceutically acceptable salt, the amount of drug is increased proportionately to the amount of drug in free form. For example, the dose may be listed on the product packaging or product information sheet.

[0041] The term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. DETAILED DESCRIPTION OF THE INVENTION

[0042] The present invention discloses a pharmaceutical composition containing a protein kinase inhibitor and a chemotherapeutic agent and its use, and those skilled in the art can make appropriate modifications and realize the present invention by referring to the contents of this specification. All similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The use according to the present invention has been described through preferred embodiments, but it is clear that those skilled in the art can realize and apply the technology of the present invention by making modifications or appropriate changes and combinations to the use described herein without departing from the content, spirit and scope of the present invention. [Example]

[0043] The present invention is further illustrated by the following non-limiting examples, which are not intended to limit the scope of the invention.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For purposes of the present invention, the following terms are defined:

[0045] The term "about," when used in conjunction with a numerical value, is meant to encompass numerical values ​​in a range having a lower limit of 5% less than the stated numerical value and an upper limit of 5% greater than the stated numerical value.

[0046] The term "adverse event" (AE) refers to any untoward medical occurrence in a patient or clinical trial subject receiving a drug, but which is not necessarily causally related to the treatment. It also includes the recurrence of other pre-existing diseases that occur during the course of a clinical investigation, regardless of whether the occurrence is related to the treatment. Invasive laboratory tests are not themselves considered adverse events, but the causes that lead to these tests should be considered adverse events. Example 1: A single-arm, multicenter, non-randomized, open-label clinical trial to investigate the efficacy and safety of chiauranib capsules in the treatment of recurrent / refractory ovarian cancer 1. Study Design

[0047] · Single-arm, multicenter, non-randomized, open-label, phase Ib study. Main registration criteria: Histologically diagnosed epithelial ovarian, fallopian tube, or primary peritoneal cancer; Patients must have received a platinum-containing chemotherapy regimen. Platinum-resistant patients must have experienced disease progression or recurrence after receiving two or more different chemotherapy regimens; Platinum-sensitive patients must have undergone two or more different chemotherapy regimens before experiencing disease progression or recurrence or refuse to receive further chemotherapy. Dosage: Chiauranib 50 mg was taken orally once daily on an empty stomach every morning, with treatment cycles every 28 days, with no treatment-free periods between cycles. Treatment continued until one of the following occurred (whichever occurred first): disease progression, intolerable toxic reactions, death, withdrawal of informed consent, or loss of follow-up. Efficacy measures: Evaluated by researchers and imaging experts according to RECIST 1.1 criteria. Primary endpoint: Objective response rate (ORR) Secondary: progression-free survival (PFS), time to progression (TTP), 16-week disease control rate (16W-DCR), disease control rate (DOR), overall survival (OS). 2. Subject population

[0048] This study enrolled 25 patients with recurrent or refractory ovarian cancer who had received ≥3 prior treatment regimens. Three patients (12.0%) were sensitive to their final platinum-containing chemotherapy, and 22 patients (88.0%) were refractory or tolerant to their final platinum-containing chemotherapy. As of the study data cutoff date (March 20, 2019), 16 patients (64.0%) had discontinued treatment due to disease progression, and 3 patients (12.0%) had discontinued treatment due to adverse events. Other causes of treatment discontinuation included subject voluntary withdrawal, study termination, and loss to follow-up.

[0049] The full analysis set (FAS) and safety data set (SS) were used for analysis, and each data set included 25 subjects. 3. Efficacy Results

[0050] The evaluation status of each efficacy endpoint is shown in Table 1. Among the 25 subjects, the best confirmed treatment responses were partial response (PR) in 1 patient (4.0%), stable disease (SD) in 14 patients (56.0%), progressive disease (PD) in 7 patients (28.0%), and not evaluable (NE) in 3 patients (12.0%). The ORR was 4.0%.

[0051] As of the data cutoff date (March 20, 2019), 12 patients had achieved PFS after a study event (disease progression or death), with a median PFS of 3.7 months (95% CI, 1.8-NE). The median TTP was 3.7 months (95% CI, 1.8-NE), the 16W-DCR was 32.0%, and the median DOR and OS were not estimable.

[0052] [Table 1] 4. Efficacy Conclusions

[0053] In patients with ovarian cancer who had undergone multiple chemotherapy regimens and had platinum-refractory or drug-resistant relapses, single-agent chiauranib demonstrated preliminary efficacy in tumor remission. 5. Safety Assessment

[0054] Safety endpoints included adverse events, vital signs, ECG, and abnormal laboratory results, and were assessed using CTCAE V4.03. All 25 patients with recurrent or refractory ovarian cancer enrolled in the study were entered into a safety data set (SS) and analyzed. The results are shown in Table 2.

[0055] [Table 2]

[0056] These data suggest that the toxic reaction profile of chiauranib monotherapy is similar to that reported for VEGFR-targeted drugs (e.g., sorafenib, sunitinib), can be tolerated by most subjects, and its safety is manageable. Example 2: A Phase II Multicenter Clinical Trial of Chiauranib in Combination with Chemotherapy in the Treatment of Platinum-Refractory / Platinum-Resistant Recurrent Late-Stage Ovarian Cancer 1. Study Design

[0057] · Multicenter, randomized, open-design, phase II study. Patients were stratified according to whether they had a treatment-free interval (TFI) of 3 months or more at screening, and were randomly assigned in a 1:1 ratio to receive either the chiauranib plus etoposide group (CE group) or the chiauranib plus paclitaxel group (CP group). The study was divided into two phases: a pilot study and a formal study. Before the formal study began, three subjects from each group were included in the pilot study to preliminarily evaluate the safety of the combination of chiauranib and chemotherapy and to analyze the potential impact of chemotherapy on the pharmacokinetics of chiauranib. After all pilot study subjects completed the first cycle of safety and pharmacokinetic evaluations, enrollment in the formal study began. Key inclusion criteria: histologically or cytologically diagnosed malignant epithelial ovarian, fallopian tube, or primary peritoneal cancer; platinum-refractory or platinum-resistant recurrent ovarian cancer; patients who had previously received at least one line of platinum-containing chemotherapy (at least four treatment cycles of platinum-containing therapy) and had not received more than one line of platinum-refractory or platinum-resistant therapy. Treatment: The study included two treatment phases: a combination chemotherapy phase and a chiaranib monotherapy maintenance phase. All subjects were treated until disease progression, intolerable toxicity, withdrawal of informed consent, or death (whichever occurred first). Combination chemotherapy phase: CE group: In the preliminary study, chiauranib capsules were administered orally at a dose of 25 mg once daily. After completing pharmacokinetic study sampling at designated time points throughout the regimen, investigators decided whether to increase the oral dose to 50 mg once daily based on comprehensive consideration of tolerability and preliminary efficacy observations. In the formal study, chiauranib capsules were administered orally at a dose of 50 mg once daily on an empty stomach, and etoposide soft capsules were administered orally at a dose of 50 mg every morning on an empty stomach. Patients were treated with 21 consecutive days of administration followed by 7 days off, with a treatment cycle of 28 days, for a maximum of six treatment cycles. CP group: The dosing regimen of chiauranib in the preliminary experiment and the formal trial phase was the same as that in the CE group, and paclitaxel infusion was administered at 60 mg / m 2 The drug was administered intravenously once a week (days 1, 8, and 15). Treatment cycles were every 3 weeks, with a maximum of six treatment cycles. - Single-agent maintenance phase: Both the CE and CP groups received single-agent chiauranib maintenance treatment. Efficacy endpoint: Efficacy was assessed using RECIST in Solid Tumors, version 1.1 (2009). Primary endpoint: progression-free survival (PFS) Secondary: Objective response rate (ORR), overall survival (OS), time to progression (TTP), disease control rate (DOR) 2. Subject population

[0058] As of December 26, 2019, a total of 21 patients (10 in the CE group and 11 in the CP group) had been enrolled. The treatment duration of enrolled patients ranged from 0 to 5 cycles. The following efficacy results were based on evaluable data before the cutoff date. 3. Efficacy Results

[0059] The evaluation status of each efficacy index is shown in Table 3. Of the 21 subjects, 11 had efficacy assessment records (5 in the CE group, 6 in the CP group). The best efficacy response was 2 patients (40.0%) in the CE group who achieved PR, 3 patients who achieved SD, and 3 patients (50.0%) in the CP group who achieved PR, 2 patients who achieved SD, and 1 patient who achieved PD.

[0060] [Table 3] 4.Efficacy Conclusions

[0061] Previous data showed that in the treatment of platinum-refractory / chemoresistant, recurrent, late-stage ovarian cancer, etoposide alone achieved a remission rate of approximately 27%, while paclitaxel alone achieved a remission rate of approximately 21%. These data suggest that when etoposide and paclitaxel were administered in combination with chiauranib, remission rates were 40% and 50%, respectively, demonstrating that chiauranib in combination with etoposide or paclitaxel achieved an unexpected synergistic effect in the treatment of platinum-refractory / chemoresistant, recurrent, late-stage ovarian cancer. Based on the clinical data of registered cases, chiauranib in combination with etoposide or paclitaxel demonstrated excellent therapeutic effects in the treatment of platinum-refractory / chemoresistant, recurrent, late-stage (stage III and stage IV) malignant epithelial ovarian cancer, especially in metastatic stage III and stage IV malignant epithelial ovarian cancer. 5. Safety Assessment

[0062] Safety endpoints included safety assessments by detecting or observing vital signs, adverse events, and laboratory test parameters. The severity of adverse events was judged according to the CTCAE V4.03 criteria.

[0063] As of December 26, 2019, a total of 21 patients (10 in the CE group and 11 in the CP group) had been enrolled. The treatment duration of enrolled patients ranged from 0 to 5 cycles. Safety results were based on data available for evaluation before the cutoff date. The results are shown in Table 4.

[0064] [Table 4]

[0065] These data show that the types of adverse events observed after etoposide and paclitaxel were administered in combination with chiauranib were similar to those reported for each chemotherapy drug alone and chiauranib alone, and no new safety signals were observed. Although the incidence of adverse events increased, most patients were able to tolerate them, and there were no treatment discontinuations due to adverse events, suggesting that safety was manageable.

[0066] The present invention has been described in detail above. While specific examples have been used in this specification to describe the principles and embodiments of the present invention, the description of the above examples is intended to help understand the best mode, the method and gist of the present invention, thereby enabling those skilled in the art to practice the present invention, including the manufacture and use of any device or system, and any combination thereof. It should be noted that those skilled in the art may make some improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications are also included within the scope of the claims of the present invention. The scope of patent protection for the present invention is limited by the claims, but also includes other embodiments that may occur to those skilled in the art. If these other embodiments have structural elements that are not different from the literal language of the claims, or if they contain equivalent structural elements that are not substantially different from the literal language of the claims, then these other embodiments should also be included within the scope of the claims.

Claims

1. A pharmaceutical composition for use in the prevention and / or treatment of platinum-refractory or platinum-resistant recurrent ovarian cancer, comprising: The composition comprises a chemotherapeutic agent and a compound having a structure represented by formula (II), in free form, in salt form, an enantiomer, or a diastereomer thereof: 【Chemistry 1】 The pharmaceutical composition, wherein the chemotherapeutic agent is etoposide or paclitaxel.

2. 2. The pharmaceutical composition according to claim 1, wherein the platinum-refractory or platinum-resistant recurrent ovarian cancer is platinum-refractory or platinum-resistant recurrent advanced ovarian cancer.

3. the compound of formula (II) is administered in an amount of 1 to 100 mg; the dose of etoposide is 1 to 100 mg; The dose of paclitaxel is 10 to 200 mg / m ２ The pharmaceutical composition according to claim 1 or 2,

4. A kit for use in the prevention and / or treatment of platinum-refractory or platinum-resistant recurrent ovarian cancer, comprising a pharmaceutical composition described in any one of claims 1 to 3.

5. A kit as described in claim 4, wherein the compound of formula (II), etoposide or paclitaxel are each unit dosage forms having the same or different specifications.

6. A kit as described in claim 5, wherein the compound of formula (II) is an oral formulation, etoposide is an oral formulation, and paclitaxel is an intravenous infusion formulation.

7. A kit according to claim 4 or 5, wherein the compound of formula (II), etoposide or paclitaxel are each provided in separate containers.

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