Anti-VEGF antibody in combination with PARP inhibitor for tumor treatment

Abstract

The present disclosure relates to anti-VEGF antibodies in combination with PARP inhibitors for the treatment of tumors. Specifically, the invention relates to application of a compound as shown in a formula 1 or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody in preparation of medicines for treating tumors. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to the field of biomedicine, and particularly to the use of PARP inhibitors and anti-VEGF antibodies for the preparation of drugs for treating tumors, as well as pharmaceutical compositions. Background Art

[0002] Poly(ADP-ribose) polymerase (PARP) is a class of multifunctional post-translational modification enzymes widely present in eukaryotic cells and plays an important role in maintaining gene stability, keeping telomere length, etc. There are currently 17 known members of the PARP superfamily, and only PARP1, PARP2, and PARP3 are involved in DNA repair. Among them, PARP1 accounts for 80-90% of the enzyme activity of the PARP family and is a key factor in DNA damage repair.

[0003] Recent studies have shown that the inhibition of PARP2 is closely related to hematological toxicity, and the synthetic lethal effect of BRCA mutations is mainly driven by PARP1. Therefore, it can be inferred that the development of highly selective PARP1 inhibitors will be beneficial to reducing hematological toxicity and improving the therapeutic index to meet higher clinical treatment needs. Summary of the Invention

[0004] The present disclosure provides the use of PARP inhibitors and anti-VEGF antibodies in the preparation of drugs for treating tumors.

[0005] In some embodiments, the PARP inhibitor is a PARP1 inhibitor.

[0006] In some embodiments, the PARP inhibitor is selected from the compounds shown in Formula 1 or pharmaceutically acceptable salts thereof

[0007]

[0008] In some embodiments, the pharmaceutically acceptable salts of the compounds shown in Formula 1 are selected from hydrochloride, sulfate, phosphate, mesylate, succinate, fumarate, maleate, p-toluenesulfonate, L-tartrate, D-malate, L-malate, and citrate. In some specific embodiments, the pharmaceutically acceptable salt of the compound shown in Formula 1 is succinate.

[0009] In some embodiments, the anti-VEGF antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2, and

[0010] HCDR3 as shown in SEQ ID NO: 1-3, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 4-6.

[0011] Among them, the CDR sequences described above are shown in the following table:

[0012] CDR sequences of anti-VEGF antibody

[0013] Antibody Sequence HCDR1 NYGMN (SEQ ID NO: 1) HCDR2 WINTYTGEPTYAADFKR (SEQ ID NO: 2) HCDR3 YPHYYGSSHWYFDV (SEQ ID NO: 3) LCDR1 SASQDISNYLN (SEQ ID NO: 4) LCDR2 FTSSLHS (SEQ ID NO: 5) LCDR3 QQYSTVPWT (SEQ ID NO: 6)

[0014] The above CDRs are defined according to the Kabat, IMGT, Chothia, AbM or Contact definition schemes. In some specific embodiments, the CDRs are defined according to the Kabat definition scheme.

[0015] In some embodiments, the anti-VEGF antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1-3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4-6.

[0016] In some embodiments, the use of the compound of formula 1 or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating tumors, wherein the VH of the anti-VEGF antibody comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1-3, and the VL of the anti-VEGF antibody or an antigen-binding fragment thereof comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4-6.

[0017] In some embodiments, the anti-VEGF antibody or an antigen-binding fragment thereof is a chimeric, humanized, fully human antibody or an antigen-binding fragment thereof.

[0018] In some embodiments, for the anti-VEGF antibody or an antigen-binding fragment thereof, the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO: 7, or an amino acid sequence having at least 80%, 90% sequence identity therewith; the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO: 8, or an amino acid sequence having at least 80%, 90% sequence identity therewith.

[0019] Heavy chain variable region:

[0020] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFTFSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSS

[0021] SEQ ID NO: 7;

[0022] Light chain variable region:

[0023] DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK

[0024] SEQ ID NO: 8;

[0025] In some embodiments, the heavy chain variable region of the anti-VEGF antibody comprises an amino acid sequence as shown in SEQ ID NO: 7 or having at least 80%, at least 90% identity thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 8 or having at least 80%, at least 90% identity thereto.

[0026] In some embodiments, the anti-VEGF antibody further comprises a heavy chain constant region and / or a light chain constant region. For example, the heavy chain constant region of the antibody constant region is selected from human IgG1, IgG2, IgG3, and IgG4 constant regions and variants thereof; the light chain constant region of the antibody constant region is selected from human antibody κ and λ chain constant regions and variants thereof.

[0027] In some embodiments, the anti-VEGF antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 9 or having at least 80%, at least 90% sequence identity thereto; and / or, the light chain comprising an amino acid sequence as shown in SEQ ID NO: 10 or having at least 80%, at least 90% identity thereto.

[0028] In some embodiments, the anti-VEGF antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 9 and a light chain having the amino acid sequence shown in SEQ ID NO: 10.

[0029] Heavy chain sequence of the anti-VEGF antibody:

[0030] EVQLVESGGGLVQPGGSLRLSCAASGYTFTNYGMNWVRQAPGKGLEWVGWINTYTGEPTYAADFKRRFT FSLDTSKSTAYLQMNSLRAEDTAVYYCAKYPHYYGSSHWYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0031] SEQ ID NO: 9;

[0032] Light chain sequence of anti-VEGF antibody:

[0033] DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKVLIYFTSSLHSGVPSRFSGSGSGT DFTLTISSLQPEDFATYYCQQYSTVPWTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0034] SEQ ID NO: 10;

[0035] Note: The underlined part is the variable region sequence of the heavy or light chain of the antibody, and the non-underlined part is the constant region sequence of the antibody.

[0036] In some embodiments, the use of the compound of formula 1 or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody in the preparation of a medicament for treating tumors, wherein the heavy chain of the anti-VEGF antibody comprises the amino acid sequence shown in SEQ ID NO: 9, and the light chain comprises the amino acid sequence shown in SEQ ID NO: 10.

[0037] In some embodiments, the tumor is selected from solid tumors.

[0038] In some embodiments, the tumor is selected from advanced solid tumors.

[0039] In some embodiments, the tumor is ovarian cancer. In some specific embodiments, the tumor is recurrent ovarian cancer.

[0040] In some embodiments, the ovarian cancer or recurrent ovarian cancer is platinum-resistant ovarian cancer or recurrent platinum-resistant ovarian cancer or platinum-sensitive ovarian cancer or recurrent platinum-sensitive ovarian cancer.

[0041] In some embodiments, the ovarian cancer or recurrent ovarian cancer is associated with a pathogenic variant in at least one homologous recombination-related gene.

[0042] In some embodiments, the ovarian cancer or recurrent ovarian cancer is selected from recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0043] In some embodiments, the ovarian cancer or recurrent ovarian cancer is selected from recurrent high-grade serous ovarian cancer, high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0044] The present disclosure also provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof in combination with an anti-VEGF antibody in the preparation of a medicament for treating a tumor.

[0045] The present disclosure also provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for treating a tumor, wherein the compound of formula 1 or a pharmaceutically acceptable salt thereof is used in combination with an anti-VEGF antibody.

[0046] The present disclosure also provides the use of an anti-VEGF antibody for treating a tumor, wherein the anti-VEGF antibody is used in combination with a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[0047] The present disclosure also provides an anti-VEGF antibody for treating a tumor, wherein the anti-VEGF antibody is used in combination with a compound of formula 1 or a pharmaceutically acceptable salt thereof.

[0048] The present disclosure also provides a compound of formula 1 or a pharmaceutically acceptable salt thereof for treating a tumor, wherein the compound of formula 1 or a pharmaceutically acceptable salt thereof is used in combination with an anti-VEGF antibody.

[0049] The present disclosure also provides a method for treating a tumor, comprising administering to a subject a therapeutically effective amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody.

[0050] Dosing regimen

[0051] In some embodiments, the administration dosage of the anti-VEGF antibody is from 1.0 mg / kg to 30 mg / kg, for example, from 2.0 mg / kg to 25 mg / kg, from 2.0 mg / kg to 20 mg / kg, from 2.0 mg / kg to 19 mg / kg, from 2.0 mg / kg to 18 mg / kg, from 2.0 mg / kg to 17 mg / kg, from 2.0 mg / kg to 16 mg / kg, from 2.0 mg / kg to 15 mg / kg, from 3.0 mg / kg to 25 mg / kg, from 3.0 mg / kg to 20 mg / kg, from 3.0 mg / kg to 19 mg / kg, from 3.0 mg / kg to 18 mg / kg, from 3.0 mg / kg to 17 mg / kg, from 3.0 mg / kg to 16 mg / kg, from 3.0 mg / kg to 15 mg / kg, from 4.0 mg / kg to 25 mg / kg, from 4.0 mg / kg to 20 mg / kg, from 4.0 mg / kg to 19 mg / kg, from 4.0 mg / kg to 18 mg / kg, from 4.0 mg / kg to 17 mg / kg, from 4.0 mg / kg to 16 mg / kg, from 4.0 mg / kg to 15 mg / kg, from 5.0 mg / kg to 25 mg / kg, from 5.0 mg / kg to 20 mg / kg, from 5.0 mg / kg to 19 mg / kg, from 5.0 mg / kg to 18 mg / kg, from 5.0 mg / kg to 17 mg / kg, from 5.0 mg / kg to 16 mg / kg, from 5.0 mg / kg to 15 mg / kg, from 6.0 mg / kg to 25 mg / kg, from 6.0 mg / kg to 20 mg / kg, from 6.0 mg / kg to 19 mg / kg, from 6.0 mg / kg to 18 mg / kg, from 6.0 mg / kg to 17 mg / kg, from 6.0 mg / kg to 16 mg / kg, from 6.0 mg / kg to 15 mg / kg, from 7.0 mg / kg to 20 mg / kg, from 7.0 mg / kg to 19 mg / kg, from 7.0 mg / kg to 18 mg / kg, from 7.0 mg / kg to 17 mg / kg, from 7.0 mg / kg to 16 mg / kg, from 7.0 mg / kg to 15 mg / kg, from 7.5 mg / kg to 20 mg / kg, from 7.5 mg / kg to 19 mg / kg, from 7.5 mg / kg to 18 mg / kg, from 7.5 mg / kg to 17 mg / kg, from 7.5 mg / kg to 16 mg / kg, from 7.5 mg / kg to 15 mg / kg; or any range between these point values.

[0052] In some embodiments, the dosage of the anti-VEGF antibody is selected from 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, 10.0 mg / kg, 10.5 mg / kg, 11.0 mg / kg, 11.5 mg / kg, 12.0 mg / kg, 12.5 mg / kg, 13.0 mg / kg, 13.5 mg / kg, 14.0 mg / kg, 14.5 mg / kg, 15.0 mg / kg, 15.5 mg / kg, 16.0 mg / kg, 16.5 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg, 21.0 mg / kg, 22.0 mg / kg, 23.0 mg / kg, 24.0 mg / kg, 25.0 mg / kg, 30.0 mg / kg.

[0053] In some embodiments, the administration frequency of the anti-VEGF antibody is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks.

[0054] In some embodiments, the administration frequency of the anti-VEGF antibody is once every three weeks.

[0055] In some embodiments, the administration route of the anti-VEGF antibody is oral administration, parenteral administration, or transdermal administration; the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the administration route of the anti-VEGF antibody is intravenous injection.

[0056] The present disclosure also provides a pharmaceutical composition comprising the aforementioned anti-VEGF antibody and further comprising one or more pharmaceutically acceptable excipients.

[0057] In some embodiments, the anti-VEGF antibody described in the present disclosure is selected from bevacizumab.

[0058] In some embodiments, the dosage of the compound represented by Formula 1 or its pharmaceutically acceptable salt is 10 - 300 mg. For example, the dosage of the PARP inhibitor is 10 - 250 mg, 10 - 200 mg, 10 - 150 mg, 10 - 100 mg.

[0059] In some embodiments, the dosage of the compound represented by Formula 1 or its pharmaceutically acceptable salt is selected from: 30 mg, 50 mg, 75 mg, 100 mg.

[0060] In some embodiments, the dosing frequency of the compound of Formula 1 or a pharmaceutically acceptable salt thereof is selected from once a day, twice a day, and three times a day.

[0061] In some embodiments, the dosing frequency of the compound of Formula 1 or a pharmaceutically acceptable salt thereof is selected from once a day.

[0062] The present disclosure also provides a pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as described above, further comprising one or more pharmaceutically acceptable excipients.

[0063] In some embodiments, for the uses or methods described above in the present disclosure, the aforementioned pharmaceutical composition can be administered.

[0064] The present disclosure co-administers the compound of Formula 1 or a pharmaceutically acceptable salt thereof with an anti-VEGF antibody, thereby enhancing the anti-tumor activity and improving the therapeutic effect of tumor diseases. Detailed Description of the Invention

[0065] Definition

[0066] To facilitate a better understanding of the present disclosure, certain technologies and sciences are specifically defined below. Unless otherwise clearly defined in the present disclosure, all other technologies and sciences used in the present disclosure have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure pertains.

[0067] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising", "having", "including", etc. should be understood to have an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of "including but not limited to".

[0068] The numerical values in the present disclosure are instrument measurement values or calculated values after instrument measurement, and there is a certain degree of error. Generally speaking, plus or minus 10% is within a reasonable error range. Of course, it is necessary to consider the context in which the numerical value is used. For example, for the content of total impurities, the error of this numerical value after measurement does not exceed plus or minus 10%, and can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, or plus or minus 1%, preferably plus or minus 5%.

[0069] The three-letter codes and single-letter codes of amino acids used in the present disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0070] "Antibody" is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (such as bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments, or antigen-binding portions), provided that they exhibit the desired antigen-binding activity. An antibody can refer to an immunoglobulin, which is a tetrameric chain structure composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The amino acid composition and arrangement order of the constant region of the immunoglobulin heavy chain are different, so its antigenicity is also different. Accordingly, immunoglobulins can be divided into five classes, or called isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, and their corresponding heavy chains are μ chain, δ chain, γ chain, α chain, and ε chain, respectively. The same class of Ig can be further divided into different subclasses according to the differences in the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. The light chain is divided into κ chain or λ chain according to the difference in the constant region. Each of the five classes of Ig can have κ chain or λ chain. The sequences of approximately 110 amino acids near the N-terminus of the antibody heavy chain and light chain vary greatly and are variable regions (V regions); the remaining amino acid sequences near the C-terminus are relatively stable and are constant regions (C regions). The variable region includes 3 hypervariable regions (CDRs) and 4 relatively conserved framework regions (FRs). The 3 hypervariable regions determine the specificity of the antibody and are also called complementarity-determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) is composed of 3 CDR regions and 4 FR regions, and the order arranged from the amino terminus to the carboxyl terminus is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

[0071] For the determination or definition of CDRs, the definitive delineation of CDRs and the identification of the residues that comprise the binding site of the antibody can be accomplished by resolving the structure of the antibody and / or resolving the structure of the antibody-ligand complex. This can be achieved by any of a variety of techniques known to those skilled in the art, such as X-ray crystallography. A variety of analytical methods can be used to identify CDRs, including but not limited to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, the contact definition, and the conformational definition.

[0072] The Kabat numbering system is the standard for numbering residues in antibodies and is commonly used to identify CDR regions (see, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28:214-8). The Chothia numbering system is similar to the Kabat numbering system, but the Chothia numbering system takes into account the positions of certain structural loop regions. (See, e.g., Chothia et al., 1986, J. Mol. Biol., 196:901-17; Chothia et al., 1989, Nature, 342:877-83). The AbM numbering system uses an integrated suite of computer programs produced by Oxford Molecular Group for modeling antibody structures (see, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; “AbM™, A Computer Program for Modeling Variable Regions of Antibodies,” Oxford, UK; Oxford Molecular, Ltd). The AbM numbering system uses a combination of knowledge databases and ab initio methods to model the tertiary structure of an antibody from the primary sequence (see those described in Samudrala et al., 1999, in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198, “Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach”). Contact definitions are based on the analysis of available complex crystal structures (see, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732-45). In conformational definitions, the positions of CDRs can be identified as residues that make an enthalpic contribution to antigen binding (see, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166). Additionally, other CDR boundary definitions may not strictly follow one of the above methods, but still overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened based on the prediction or experimental results that specific residues or groups of residues do not significantly affect antigen binding. As used in this disclosure, CDR can refer to CDRs defined by any method known in the art (including combinations of methods). The correspondence between the various numbering systems is well known to those skilled in the art, and exemplary, as shown in Table 1 below.

[0073] Table 1. Relationships between CDR numbering systems

[0074] CDR IMGT Kabat AbM Chothia Contact HCDR1 27-38 31-35 26-35 26-32 30-35 HCDR2 56-65 50-65 50-58 52-56 47-58 HCDR3 105-117 95-102 95-102 95-102 93-101 LCDR1 27-38 24-34 24-34 24-34 30-36 LCDR2 56-65 50-56 50-56 50-56 46-55 LCDR3 105-117 89-97 89-97 89-97 89-96

[0075] "Antigen-binding fragment" includes single-chain antibodies (i.e., heavy or light chains); Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab-dsFv, single-domain antibodies (such as VH or VL or VHH), scFv, bivalent or trivalent or tetravalent antibodies, Bis-scFv, diabody, tribody, tetrabody, and epitope-binding fragments of any of the above (see, e.g., Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews-Online 2(3), 209-217). Methods for generating and preparing these antibody fragments are well known in the art (see, e.g., Verma et al., 1998, Journal of Immunological Methods, 216, 165-181). The Fab-Fv form was first disclosed in WO2009 / 040562, and its disulfide bond-stabilized form Fab-dsFv was first disclosed in WO2010 / 035012. The antigen-binding fragments of the present disclosure also include Fab and Fab' fragments described in WO2005 / 003169, WO2005 / 003170, and WO2005 / 003171. Multivalent antibodies can be multispecific, such as bispecific or monospecific (see, e.g., WO92 / 22583 and WO05 / 113605).

[0076] The terms "homology", "identity", or "sequence identity" refer to sequence similarity between two polynucleotide sequences or between two polypeptides. When the positions in two compared sequences are occupied by the same nucleotide or amino acid monomer, for example, if each position of two DNA molecules is occupied by the same nucleotide, then the molecules are homologous at that position. The percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared × 100%. For example, when two sequences are optimally aligned, if 6 out of 10 positions in the two sequences match or are homologous, then the two sequences are 60% homologous. Generally, comparison is made when the maximum percentage of homology is obtained by aligning the two sequences.

[0077] "Effective amount" includes an amount sufficient to ameliorate or prevent the symptoms or condition of a medical disorder. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a subject can vary depending on factors such as the disorder to be treated, the overall health of the subject, the method of administration and dosage, and the severity of side effects. The effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects. The subjects of the present disclosure can be animal or human subjects.

[0078] The term "pharmaceutical composition" refers to a mixture containing one or more of the active ingredients described herein, or a physiologically / pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert a biological activity.

[0079] The term "pharmaceutically acceptable adjuvant" or "pharmaceutically acceptable excipient" includes any material that, when combined with an active ingredient, allows the ingredient to retain its biological activity and does not react with the immune system of the subject. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th Edition, A. Gennaro, Editor, Mack Publishing Co., Easton, PA, 1990; and R Remington, The Science and Practice of Pharmacy 20th Edition Mack Publishing, 2000).

[0080] "Cancer", "cancerous", "proliferative disorder", and "tumor" are not mutually exclusive when referred to in the present disclosure.

[0081] The terms "administering", "applying" and "treating", when applied to animals, humans, experimental subjects, cells, tissues, organs or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent or composition with the animal, human, subject, cell, tissue, organ or biological fluid, such as in therapeutic, pharmacokinetic, diagnostic, research and experimental methods. Treating a cell includes contacting the cell with a reagent, and contacting the reagent with a fluid that contacts the cell. "Administering", "applying" and "treating" also mean treating a cell in vitro and ex vivo by a reagent, diagnostic, binding composition or by another cell. When applied to humans, veterinary medicine or research subjects, it refers to therapeutic treatment, preventive or prophylactic measures, research and diagnostic applications.

[0082] The term "treatment" means administering a therapeutic agent to a subject, such as a subject who has, is suspected of having, or is predisposed to having one or more diabetes or hyperglycemia-related diseases or symptoms thereof, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Generally, a therapeutic agent is administered to a treated subject or population in an amount effective to relieve one or more symptoms of the disease, by preventing or delaying the onset of symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition or disorder to any clinically measurable extent. The amount of a therapeutic agent effective to relieve any particular disease symptom (also referred to as a "therapeutically effective amount") can vary depending on a variety of factors, such as the disease state, age and weight of the subject, and the ability of the drug to produce the desired effect in the subject. Whether the disease symptoms have been alleviated can be evaluated by any clinical test method commonly used by a doctor or other professional healthcare provider to evaluate the severity or progression of the symptom. Although an embodiment of the present disclosure (such as a treatment method or article) may be ineffective in alleviating the symptoms of a target disease in a particular subject, it should alleviate the symptoms of the target disease in a statistically significant number of subjects as determined by any statistical test method known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test and Wilcoxon test. The patient to be treated is a mammal, and preferably a human.

[0083] The term "prevention" refers to reducing the risk or incidence of one or more conditions, symptoms, complications or disorders, or eliminating or slowing the progression of one or more conditions, symptoms, complications or disorders.

[0084] The terms "subject" and "patient" mean a mammal, particularly a primate, and especially a human.

[0085] As used herein, "combination" refers to a method of administration in which at least one dose of a compound of formula 1 or a pharmaceutically acceptable salt thereof, and at least one dose of an anti-VEGF antibody are administered over a certain time period, and both of the administered drugs exhibit pharmacological effects. The time period may be within one dosing cycle, preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, or within 24 hours, more preferably within 12 hours. The compound of formula 1 or a pharmaceutically acceptable salt thereof and the anti-VEGF antibody may be administered simultaneously or sequentially. Such a time period includes treatments in which the compound of formula 1 or a pharmaceutically acceptable salt thereof and the anti-VEGF antibody are administered via the same or different routes of administration. The methods of administration of the combinations described herein are selected from simultaneous administration, co-administration of separately formulated agents, or sequential administration of separately formulated agents.

[0086] As used herein, "recurrent ovarian cancer" refers to ovarian cancer patients in whom the tumor is not controlled after cytoreductive surgery and postoperative chemotherapy, or the tumor recurs or metastasizes after a period of drug withdrawal. According to the sensitivity of the patient to platinum drugs and the time of recurrence, recurrent ovarian cancer is roughly divided into the following types: platinum-sensitive, platinum-resistant, and platinum-refractory ovarian cancer.

[0087] Overall survival (OS) refers to the period from the randomization period to death from any cause. For subjects who are still alive at the time of the last follow-up, their OS is censored at the time of the last follow-up. For subjects who are lost to follow-up, their OS is censored at the last confirmed survival time before the loss to follow-up. The censored OS is defined as the time from randomization to censoring.

[0088] Objective response rate (ORR) refers to the proportion of patients in whom the tumor shrinks by a certain amount and remains so for a certain period of time, and includes cases of CR and PR. The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) are used to evaluate objective tumor response. Subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to the RECIST 1.1 criteria.

[0089] Disease Control Rate (DCR) refers to the percentage of cases of confirmed complete response, partial response, and stable disease (≥8 weeks) among patients with evaluable efficacy.

[0090] Complete response (CR): All target lesions disappear, and the short diameter of all pathological lymph nodes (including target and non-target nodules) must be reduced to <10 mm.

[0091] Partial response (PR): The sum of the diameters of the target lesions is reduced by at least 30% compared to the baseline level.

[0092] Disease Progression (PD): Referenced by the minimum value of the sum of the diameters of all measured target lesions throughout the entire experimental study process, with a relative increase in the diameter sum of at least 20% (if the baseline measurement is the smallest, it is referenced by the baseline value); in addition, it must satisfy an absolute increase in the diameter sum of at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0093] Disease Stable (SD): The degree of reduction of the target lesions does not reach PR, and the degree of increase does not reach the PD level, being between the two. During the study, the minimum value of the sum of the diameters can be used as a reference.

[0094] Example

[0095] The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

[0096] Example 1. Treatment of cancer with the compound shown in Formula 1 in combination with an anti-VEGF antibody

[0097] 1. Test drugs

[0098] (1) The succinate salt of the compound shown in Formula 1, the preparation method can refer to WO2022247816A, and it is provided by Jiangsu Hengrui Medicine Co., Ltd. in this test.

[0099]

[0100] (2) Anti-VEGF antibody (bevacizumab). Its heavy chain sequence is SEQ ID NO: 9, and its light chain sequence is SEQ ID NO: 10.

[0101] 2. Enrolled subjects

[0102] (1) Voluntarily joined this study, signed the informed consent form, had good compliance, and could cooperate with follow-up.

[0103] (2) Aged 18 to 75 years (including the boundary values, calculated on the day of signing the informed consent).

[0104] (3) Cytologically or histologically diagnosed recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer

[0105] (4) For cohort 1 in the dose escalation, dose expansion phase, and efficacy expansion phase: Patients with platinum-resistant, recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who had previously received a platinum-containing regimen and had a non-PD response during the last platinum-based drug treatment period (from the start of treatment to within 1 month after the last dose), and had disease progression or recurrence within 6

[0106] months (183 calendar days) after the end of treatment, and had received ≤

[0107] 1 line of systemic treatment after platinum resistance;

[0108] Efficacy Expansion Phase Cohort 2: Patients with platinum-sensitive, recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have previously received ≥2 lines of platinum-containing regimens and have had disease progression or recurrence more than 6

[0109] months (183 calendar days) after the end of the last platinum-based drug treatment.

[0110] (5) At least one measurable lesion that meets the RECIST v1.1 criteria (the longest diameter of the measurable lesion by spiral CT scan ≥10 mm or the short axis of the enlarged lymph node ≥15 mm according to the requirements of RECIST v1.1); For lesions treated locally, if there is clear evidence of significant progression after treatment, they can be selected as target lesions.

[0111] (6) ECOG score: 0 - 1.

[0112] (7) Expected survival ≥12 weeks.

[0113] (8) The functions of important organs meet the following requirements:

[0114] Blood routine (no use of any blood components or cell growth factor correction therapy within 14 days before screening):

[0115] a) Absolute neutrophil count (ANC) ≥1.5×10 9 / L;

[0116] b) Platelets (PLT) ≥100×10 9 / L;

[0117] c) Hemoglobin (Hb) ≥90 g / L;

[0118] Blood biochemistry

[0119] a) Serum albumin (ALB) ≥30 g / L (no receipt of human albumin injection within 14 days before screening);

[0120] b) Total bilirubin ≤1.5×ULN;

[0121] c) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤3×ULN;

[0122] d) Alkaline phosphatase (ALP) ≤2.5×ULN, or ≤5×ULN if accompanied by bone metastasis or liver metastasis;

[0123] e) Serum creatinine (Cr) ≤1.5×ULN or creatinine clearance rate (Clcr) ≥50 mL / min (calculated according to the Cockcroft-Gault formula);

[0124] Urinalysis

[0125] a) Urine protein < 2+; if urine protein ≥ 2+, then the 24-hour urine protein quantification shows that the protein must be < 1 g; coagulation function

[0126] a) Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

[0127] b) International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN;

[0128] (9) For fertile subjects, highly effective contraceptive measures are required from the signing of the informed consent until 210 days after the last dose of the study drug; for fertile subjects, the serum HCG test must be negative within 7 days before the first dose, and they must be non-lactating.

[0129] 3. Exclusion criteria

[0130] (1) Subjects who have received chemotherapy, immune checkpoint inhibitors, major surgical operations, or anti-tumor vaccines within 4 weeks before the first dose; subjects who have received palliative radiotherapy within 2 weeks before the first dose; oral molecular targeted therapy (including other investigational targeted drugs for clinical trials) with a time interval from the first study drug administration < 5 drug half-lives; subjects who have received live vaccines within 4 weeks before the first dose or may receive live vaccines during the study period.

[0131] (2) According to the NCI-CTCAE v5.0 grading, the toxicity caused by previous anti-tumor treatment has not recovered to ≤ Grade 1 (except for reduced lymphocyte count, hair loss, fatigue, and the indicators mentioned in the inclusion criteria; according to the judgment of the investigator, after consultation with the sponsor, some tolerable chronic Grade 2 toxicities may be excluded).

[0132] (3) Subjects with a history of or concurrent other malignancies, excluding cured basal cell carcinoma of the skin, cervical carcinoma in situ, ductal carcinoma in situ of the breast (DCIS), papillary carcinoma of the thyroid, and other malignancies that have been fully treated and cured ≥ 3 years before the first dose and have evidence of no recurrence or metastasis.

[0133] (4) Subjects with carcinomatous meningitis or untreated central nervous system metastases; those who have received systemic and radical brain metastasis treatment (radiotherapy or surgery) and, if imaging shows stability has been maintained for at least 1 month, and

[0134] have stopped systemic hormonal therapy (dose > 10 mg / day of prednisone or other equivalent-effect hormones) for more than 2 weeks and have no clinical symptoms can be included.

[0135] (5) Imaging shows that the tumor invades large blood vessels or has an unclear boundary with blood vessels; or in cases where the investigator judges that the patient's tumor has a very high probability of invading important blood vessels during treatment, leading to fatal massive hemorrhage.

[0136] (6) Patients with cancerous ascites or pleural effusion with clinical symptoms who require puncture and drainage; or those who have received ascites or pleural effusion drainage within 14 days before the first dose of medication.

[0137]

[0138] (7) Severe bone damage caused by tumor bone metastasis, including severe bone pain that is not well controlled, pathological fractures and spinal cord compression in important parts that occurred within the last 6 months or are likely to occur in the near future.

[0139] (8) History or current presence of interstitial pneumonia / interstitial lung disease (except those with only imaging changes), pneumonia that requires systemic glucocorticoid treatment (such as radiation pneumonia, etc.); currently having active pneumonia or severe impairment of lung function confirmed by pulmonary function tests.

[0140] (9) Known allergy to bevacizumab or severe allergic reactions to other monoclonal antibodies.

[0141] (10) Patients with active pulmonary tuberculosis; those who have received adequate treatment and stopped anti-tuberculosis treatment for ≥3 months before the first dose of medication can be included in the study.

[0142] (11) Suffering from hypertension and unable to achieve good control with antihypertensive medications (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg); having a history of hypertensive crisis or hypertensive encephalopathy.

[0143] (12) Having cardiac clinical symptoms or diseases that are not well controlled, such as: (1) NYHA class 2 or higher heart failure or LVEF <50%; (2) Unstable angina; (3) Myocardial infarction occurred within 1 year before the first dose of medication; (4) Clinically significant supraventricular or ventricular arrhythmias that require treatment or intervention; (5) QTc >470 msec.

[0144] (13) Abnormal coagulation function, with a bleeding tendency or receiving thrombolytic or anticoagulant treatment. Small-dose low-molecular-weight heparin or oral aspirin for anticoagulation prophylaxis is allowed during the trial.

[0145] (14) NCI-CTCAE v5.0 grade ≥2 bleeding events occurred within 4 weeks before the first dose of medication, including but not limited to hemoptysis (single episode hemoptysis volume ≥2 mL), vaginal bleeding, gastrointestinal bleeding, etc.

[0146] (15) Arterial / venous thromboembolic events occurred within 6 months before the first dose of medication, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism, etc.; those with lower extremity muscular venous thrombosis who do not require anticoagulant treatment after evaluation, and those with mural thrombus caused by catheterization that has disappeared and does not require drug treatment can be considered for inclusion in the study

[0147] (16) Subjects who had a gastrointestinal perforation or fistula (except artificial fistula), urethral fistula, abdominal abscess, intestinal obstruction, or required parenteral nutrition within 3 months before the first dose.

[0148] (17) Subjects who were unable to swallow tablets normally or had abnormal gastrointestinal function, which was judged by the investigator to possibly affect drug absorption.

[0149] (18) Subjects who had a severe infection within 1 month before the first dose, including but not limited to infectious complications requiring hospitalization, bacteremia, severe pneumonia, etc.; subjects with any active infection requiring intravenous systemic treatment, or those with an unexplained fever > 38.5 °C during the screening period or before the first dose; subjects who had used antibiotics within 2 weeks before the first dose.

[0150] (19) Subjects with a positive history of human immunodeficiency virus (HIV) test; those with active hepatitis (for hepatitis B reference: HBsAg positive and HBV DNA test value ≥ 500 IU / mL (if the research center only has the copy / mL test unit, those with ≥ 2500 copy / mL cannot be included); for hepatitis C reference: HCV antibody positive and HCV virus titer test value exceeding the upper limit of the normal value).

[0151] (20) Subjects who received treatment with strong inhibitors of CYP3A4, CYP2D6, P-gp, or BCRP less than 5 drug half-lives or 14 days before the first dose; those who received treatment with strong inducers of the above enzymes less than 28 days before the first dose.

[0152] (21) Subjects who, in the judgment of the investigator, had other factors that might affect the research results or lead to the forced termination of this study midway, such as alcoholism, drug abuse, other serious diseases (such as severe diabetes, thyroid diseases, spinal cord compression, superior vena cava syndrome, mental diseases) requiring combined treatment, having severe abnormal laboratory tests, and having family or social factors that would affect the safety of the subjects.

[0153] 4. Administration Method

[0154] Bevacizumab is administered by intravenous infusion at a dose of 15 mg / kg once every three weeks (Q3W).

[0155] The compound shown in Formula 1 is taken orally once a day (QD), with a starting dose of 75 mg, and the tolerance is observed in combination with bevacizumab; after completing the tolerance observation at this dose level and confirming that it is tolerable, the tolerance of 100 mg in combination with bevacizumab will continue to be investigated.

[0156] 5. Result Evaluation

[0157] The efficacy indicators include: ORR, DCR, DoR, PFS, and OS evaluated by the researchers.

[0158] Safety evaluation: The safety of the study drug was evaluated through adverse event records (including serious adverse events), laboratory tests, vital signs and physical examinations, electrocardiograms, echocardiograms, etc.

[0159] Example 2. Treatment of ovarian cancer with the compound shown in Formula 1 in combination with an anti-VEGF antibody

[0160] 1. Test drugs

[0161] (1) The succinate salt of the compound shown in Formula 1, the preparation method can refer to WO2022247816A, and in this experiment, it was provided by Jiangsu Hengrui Medicine Co., Ltd.

[0162]

[0163] (2) Anti-VEGF antibody (bevacizumab). Its heavy chain sequence is SEQ ID NO: 9, and its light chain sequence is SEQ ID NO: 10.

[0164] 2. Enrolled subjects

[0165] (1) Voluntarily participated in this study, signed the informed consent form, had good compliance, and could cooperate with follow-up.

[0166] (2) Aged 18 - 75 years (including the boundary values, calculated on the day of signing the informed consent form).

[0167] (3) Recurrent high-grade serous ovarian cancer, high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer diagnosed by cytology or histology

[0168] (4) Safety lead-in phase: The patient had previously received a platinum-containing regimen, and the efficacy was non-PD during the last platinum-based drug treatment (within 1 month after the start of treatment to the last dose), and the disease progressed or recurred within 6 months (183 calendar days) after the end of treatment. The number of lines of systemic treatment after platinum resistance was ≤1 line; Dose expansion phase and efficacy expansion phase: (1) The patient had previously received ≥2 lines of platinum-containing regimens, and the disease progressed or recurred 6 - 12 months (184 - 365 calendar days) after the last platinum-containing treatment; (2) Had received at most 1 line of non-platinum-based systemic treatment; (3) Had clear imaging progression before enrollment.

[0169] (5) At least one measurable lesion that meets the RECIST v1.1 criteria (the long diameter of the measurable lesion on spiral CT scan ≥ 10 mm or the short diameter of enlarged lymph nodes ≥ 15 mm according to the requirements of RECIST v1.1); for lesions after local treatment, if there is clear evidence to confirm significant progression compared with after the end of treatment, they can be selected as target lesions.

[0170] (6) ECOG performance status: 0 - 1.

[0171] (7) The expected survival period ≥ 12 weeks.

[0172] (8) The functions of important organs meet the following requirements:

[0173] Blood routine (no use of any blood components or cell growth factor correction therapy within 14 days before screening):

[0174] a) Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L;

[0175] b) Platelets (PLT) ≥ 100 × 10 9 / L;

[0176] c) Hemoglobin (Hb) ≥ 100 g / L;

[0177] Blood biochemistry

[0178] a) Serum albumin (ALB) ≥ 30 g / L (no receipt of human albumin injection within 14 days before screening);

[0179] b) Total bilirubin ≤ 1.5 × ULN;

[0180] c) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 3 × ULN;

[0181] d) Alkaline phosphatase (ALP) ≤ 2.5 × ULN, ≤ 5 × ULN if accompanied by bone metastasis or liver metastasis;

[0182] e) Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance rate (Clcr) ≥ 50 mL / min (calculated according to the Cockcroft - Gault formula);

[0183] Urine routine

[0184] a) Urine protein < 2+; if urine protein ≥ 2+, then the 24 - hour urine protein quantification shows that the protein must < 1 g; Coagulation function

[0185] a) Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

[0186] b) International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN;

[0187] (9) For fertile subjects, highly effective contraceptive measures are required from the signing of the informed consent until 210 days after the last dose of the study drug; for fertile subjects, serum HCG test must be negative within 7 days before the first dose, and they must be non-lactating.

[0188] 3. Exclusion Criteria

[0189] (1) Subjects who have received chemotherapy, immune checkpoint inhibitors, major surgery, anti-tumor vaccines within 4 weeks before the first dose; subjects who have received palliative radiotherapy within 2 weeks before the first dose; oral molecular targeted therapy (including other investigational targeted drugs for clinical trials) with a time interval from the first study drug administration < 5 drug half-lives; subjects who have received live vaccines within 4 weeks before the first dose or may receive live vaccines during the study period.

[0190] (2) According to the NCI-CTCAE v5.0 grading, the toxicity caused by previous anti-tumor treatment has not recovered to ≤ Grade 1 (except for reduced lymphocyte count, hair loss, fatigue, and the indicators mentioned in the inclusion criteria; according to the judgment of the investigator and after consultation with the sponsor, some tolerable chronic Grade 2 toxicities may be excluded).

[0191] (3) Subjects with a history of or concurrent other malignancies, excluding cured basal cell carcinoma of the skin, cervical carcinoma in situ, ductal carcinoma in situ of the breast (DCIS), papillary carcinoma of the thyroid, and other malignancies that have been fully treated and cured ≥ 3 years before the first dose and there is evidence to confirm no recurrence or metastasis.

[0192] (4) Subjects with carcinomatous meningitis or untreated central nervous system metastasis; those who have received systemic and radical brain metastasis treatment (radiotherapy or surgery) and, if imaging shows stability has been maintained for at least 1 month, and systemic hormonal therapy (dose > 10 mg / day prednisone or other equivalent efficacy hormones) has been stopped for more than 2 weeks and there are no clinical symptoms can be included.

[0193] (5) Imaging shows that the tumor invades large blood vessels or the boundary with blood vessels is unclear; or in cases where the investigator judges that the patient's tumor is highly likely to invade important blood vessels during treatment, leading to fatal massive bleeding.

[0194] (6) Subjects with symptomatic carcinomatous ascites or pleural effusion who require puncture or drainage; or those who have received ascites or pleural effusion drainage within 14 days before the first dose.

[0195] (7) Severe bone damage caused by tumor bone metastasis, including poorly controlled severe bone pain, pathological fractures and spinal cord compression at important sites that occurred within the last 6 months or are likely to occur in the near future.

[0196] (8) History of or current interstitial pneumonia / interstitial lung disease (except for those with only imaging changes), pneumonia requiring systemic glucocorticoid treatment (such as radiation pneumonia, etc.); currently having active pneumonia or those with severely impaired lung function confirmed by pulmonary function tests.

[0197] (9) Known allergy to bevacizumab or those who have had a severe allergic reaction to other monoclonal antibodies.

[0198] (10) Those with active pulmonary tuberculosis; those who have been fully treated and have stopped antituberculosis treatment for ≥3 months before the first dose can be included in the study.

[0199] (11) Having hypertension and unable to achieve good control with antihypertensive drugs (systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥90 mmHg); having a history of hypertensive crisis or hypertensive encephalopathy.

[0200] (12) Having poorly controlled cardiac clinical symptoms or diseases, such as: (1) Heart failure of NYHA class 2 or above or LVEF <50%; (2) Unstable angina; (3) Myocardial infarction occurred within 1 year before the first dose; (4) Clinically significant supraventricular or ventricular arrhythmias requiring treatment or intervention; (5) QTc >470 msec.

[0201] (13) Abnormal coagulation function, with a bleeding tendency or being on thrombolytic or anticoagulant therapy. Small-dose low-molecular-weight heparin or oral aspirin for anticoagulation prophylaxis is allowed during the trial.

[0202] (14) Having had an NCI-CTCAE v5.0 grade ≥2 bleeding event within 4 weeks before the first dose, including but not limited to hemoptysis (single episode hemoptysis volume ≥2 mL), vaginal bleeding, gastrointestinal bleeding, etc.

[0203] (15) Having had an arterial / venous thromboembolic event within 6 months before the first dose, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism, etc.; those with lower limb muscular vein thrombosis who do not require anticoagulant treatment after evaluation and those with mural thrombus caused by catheterization that has disappeared and does not require drug treatment can be considered for inclusion in the study.

[0204] (16) Having had a gastrointestinal perforation or fistula (except artificial fistula), urethral fistula, abdominal abscess, intestinal obstruction, or those requiring parenteral nutrition within 3 months before the first dose.

[0205] (17) Unable to swallow tablets normally or having abnormal gastrointestinal function, which may affect drug absorption as judged by the investigator.

[0206] Subjects who had severe infections within 1 month before the first dose, including but not limited to infectious complications requiring hospitalization, bacteremia, severe pneumonia, etc.; subjects with any active infections requiring intravenous systemic treatment, or those with unexplained fever > 38.5°C during the screening period or before the first dose; those who had used antibiotics within 2 weeks before the first dose.

[0207] (19) Subjects with a known history of positive human immunodeficiency virus (HIV) test; those with known active hepatitis (for hepatitis B reference: HBsAg positive and HBV DNA test value ≥ 500 IU / mL (if the research center only has the copy / mL test unit, those with ≥ 2500 copy / mL cannot be included); for hepatitis C reference: HCV antibody positive and HCV virus titer test value exceeding the upper limit of the normal value).

[0208] (20) Those who received treatment with strong inhibitors of CYP3A4, CYP2D6, P-gp or BCRP within < 5 drug half-lives or 14 days before the first dose; those who received treatment with strong inducers of the above enzymes within < 28 days before the first dose.

[0209] (21) As judged by the investigator, those with other factors that may affect the study results or lead to the forced termination of this study midway, such as alcoholism, drug abuse, other serious diseases (such as severe diabetes, thyroid diseases, spinal cord compression, superior vena cava syndrome, mental diseases) requiring combined treatment, with serious abnormal laboratory tests, accompanied by family or social factors that will affect the safety of the subjects.

[0210] (22) Those who had received PARP inhibitor treatment in the past, including but not limited to olaparib, niraparib, fluzoparib, etc.

[0211] 4. Administration Method

[0212] Bevacizumab, administered by intravenous infusion, 15 mg / kg, once every three weeks (Q3W);

[0213] The compound shown in Formula 1, orally, once a day (QD), with 75 mg as the starting dose, combined with bevacizumab for tolerance observation; after completing the tolerance observation at this dose level and confirming it to be tolerable, the safety and efficacy of combining 30 mg or 50 mg or 75 mg with bevacizumab will continue to be investigated.

[0214] 5. Result Evaluation

[0215] The efficacy indicators include: ORR, DCR, DoR, PFS and OS evaluated by the investigator.

[0216] Safety evaluation: The safety of the drug in this study was evaluated through adverse event records (including serious adverse events), laboratory tests, vital signs and physical examinations, electrocardiograms, echocardiograms, etc.

[0217] A total of 14 subjects with recurrent and metastatic ovarian cancer were enrolled in the study. The best efficacy was as follows: 4 cases of PR, 7 cases of SD, 3 cases of PD, the ORR was 36%, and the DCR was 79%.

[0218]

[0219] Although the specific embodiments of the present disclosure have been described above, those skilled in the art should understand that these are only examples. Without departing from the principle and essence of the present disclosure, various changes or modifications can be made to these embodiments. Therefore, the protection scope of the present disclosure is defined by the appended claims.

Claims

1. Use of the compound shown in Formula 1 or a pharmaceutically acceptable salt thereof and an anti-VEGF antibody in the preparation of a medicament for treating tumors, 2. The use according to claim 1, wherein wherein the anti-VEGF antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprises HCDR1, HCDR2 and HCDR3 shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 respectively, and the VL comprises LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively.

3. The use according to claim 1, wherein, The anti-VEGF antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprises an amino acid sequence shown in SEQ ID NO:7 or having at least 90% identity therewith, and the VL comprises an amino acid sequence shown in SEQ ID NO:8 or having at least 90% identity therewith; Preferably, the anti-VEGF antibody comprises a heavy chain and a light chain, the heavy chain comprises an amino acid sequence shown in SEQ ID NO:9 or having at least 90% identity therewith, and the light chain comprises an amino acid sequence shown in SEQ ID NO:10 or having at least 90% identity therewith.

4. The use according to claim 1, wherein, The dosage of the anti-VEGF antibody is 1.0 mg / kg to 30 mg / kg, preferably 2.0 mg / kg to 25 mg / kg, 2.0 mg / kg to 20 mg / kg, 2.0 mg / kg to 19 mg / kg, 2.0 mg / kg to 18 mg / kg, 2.0 mg / kg to 17 mg / kg, 2.0 mg / kg to 16 mg / kg, more preferably 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, 5.0 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 10.0 mg / kg, 11.0 mg / kg, 12.0 mg / kg, 13.0 mg / kg, 14.0 mg / kg, 14.5 mg / kg, 15.0 mg / kg, 16.0 mg / kg, 16.5 mg / kg, 17.0 mg / kg, 18.0 mg / kg, 19.0 mg / kg, 20.0 mg / kg.

5. The use according to claim 1, wherein, The administration frequency of the anti-VEGF antibody is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks; preferably once every three weeks.

6. According to the use described in claim 1, wherein The dosage of the compound of Formula 1 or a pharmaceutically acceptable salt thereof is selected from 10 - 300 mg, preferably 10 - 250 mg, more preferably 10 - 150 mg, and most preferably 30 mg, 50 mg, 75 mg, 100 mg.

7. The use according to claim 1, wherein The administration frequency of the compound of Formula 1 or a pharmaceutically acceptable salt thereof is selected from once a day, twice a day, three times a day.

8. Use according to any one of the preceding claims, wherein, The tumor is selected from solid tumors, preferably ovarian cancer, more preferably recurrent ovarian cancer.

9. The use according to claim 8, wherein the ovarian cancer or recurrent ovarian cancer is selected from platinum-resistant ovarian cancer, recurrent platinum-resistant ovarian cancer, platinum-sensitive ovarian cancer, and recurrent platinum-sensitive ovarian cancer.

10. The use according to claim 8, wherein the ovarian cancer or recurrent ovarian cancer is selected from recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

11. The use according to claim 8, wherein the ovarian cancer or recurrent ovarian cancer is selected from recurrent high-grade serous ovarian cancer, high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

12. The use according to any one of the preceding claims, wherein, The anti-VEGF antibody is selected from bevacizumab.

13. A pharmaceutical composition comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as described in any one of claims 1-12 and an anti-VEGF antibody.

14. A pharmaceutical kit comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as described in any one of claims 1-12 and an anti-VEGF antibody, preferably the compound of formula 1 or a pharmaceutically acceptable salt thereof and the anti-VEGF antibody are independently packaged.

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