Drugs used in the treatment of locally advanced, unresectable or metastatic colorectal cancer and their use

Abstract

This invention relates to the pharmaceutical field, and more specifically to a drug used for the treatment of locally advanced, unresectable or metastatic colorectal cancer, and its use. Compared to a two-drug regimen of cintirimab + tucidinostat, the tripartite regimen of cintirimab + tucidinostat + IBI305 provided by this invention can significantly extend progression-free survival in patients with MSS / MSI-L locally advanced, unresectable or metastatic colorectal cancer. Furthermore, in terms of indicators such as ORR, PR, PD, NE, and DCR, patients with MSS / MSI-L locally advanced, unresectable or metastatic colorectal cancer can obtain significant benefits from the tripartite regimen of cintirimab + tucidinostat + IBI305.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and specifically relates to a drug used for the treatment of locally advanced unresectable or metastatic colorectal cancer and its use.

Background Art

[0002] Colorectal cancer refers to the malignant transformation of the mucosal epithelial cells of the large intestine, and includes abnormal differentiation, abnormal proliferation, abnormal cell metabolism and secretion, etc. Clinically, most (more than 95%) of colorectal cancers are adenocarcinomas, and 1% are squamous cell carcinomas. Colorectal cancer cells can metastasize to other sites such as the liver, lungs, and brain through the bloodstream, and may metastasize to nearby lymph nodes or lymph glands through the lymphatic system.

[0003] In recent years, with the improvement of people's living standards and the change in diet to high-protein, high-fat, and low-fiber diets, the incidence rate of colorectal cancer has been increasing year by year. In China, between 1972 and 1989, the incidence rate of colorectal cancer increased by 79% in both men and women. Since the 1970s, it has been increasing at a rate of 4.2% per year. In China, colorectal cancer ranks fifth among cancers, following gastric cancer, liver cancer, lung cancer, and esophageal cancer. According to statistics, the incidence rate of colorectal cancer in China was less than 10 per 100,000 population in the 1970s, but increased to 23.4 per 100,000 population in the early 1990s.

[0004] Early-stage colorectal cancer is mainly treated by surgical radical resection, and the 5-year survival rate is over 90%. However, about 25% of colorectal cancer patients have already metastasized at the time of the first diagnosis. In addition, as high as 50% of newly diagnosed patients will ultimately progress to metastatic colorectal cancer, and less than 5% of the patients with metastases survive for more than 5 years. The most common metastatic sites are the liver or the lymph nodes in its vicinity. The medical needs for metastatic colorectal cancer are very large.

[0005] Currently, advanced colorectal cancer is primarily treated with drug therapy. This includes, but is not limited to, standard first-line treatment with FOLFOX / FOLFIRI in combination with molecular targeted therapy. Standard second-line treatment after disease progression includes, but is not limited to, standard second-line treatment with FOLFIRI plus bevacizumab. However, the overall efficacy of second-line treatments is low, and progression-free survival and overall survival are relatively short. Therefore, there is a need to develop further new treatments.

[0006] Tucidinostat (or chidamide) is a novel Class 1.1 drug developed by Shenzhen Microbiotechnology Co., Ltd. It is a selective inhibitor of benzamide-type histone deacetylase (HDAC) subtypes, primarily subtypes 1, 2, and 3 of Class I HDACs and subtype 10 of Class IIb, and works to control abnormal epigenetic function in tumors. Currently, the approved indications for tucidinostat are 1) peripheral T-cell lymphoma and 2) postmenopausal patients with hormone receptor-positive, human epidermal growth factor receptor-2-negative locally advanced or metastatic breast cancer that has relapsed or progressed after endocrine therapy.

[0007] CN03139760.3 discloses tusidinostat compounds, specifically benzamide-type histone deacetylase inhibitors with differentiation and proliferation inhibitory activity, methods for preparing and using their pharmaceutical formulations, general structural formulas, and definitions of substituents. These compounds can be used as histone deacetylase inhibitors to treat diseases related to differentiation and proliferation, such as cancer and psoriasis.

[0008] CN201210489178.8 describes two crystalline forms of tusidinostat, tusidinostat crystalline form A and tusidinostat crystalline form B, and methods for preparing these new crystalline forms of tusidinostat. The aforementioned tusidinostat crystalline forms A and B exhibit excellent oral absorption, inhibition of cell differentiation and proliferation, low toxicity, good storage stability, and handling stability, and can be used in the preparation of therapeutic drugs for diseases related to cell differentiation and proliferation.

[0009] CN201410136761.X discloses an E-conformation benzamide compound, its pharmaceutical formulation, and its use. The E-conformation benzamide compound is tucidinostat, whose chemical name is N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridyl)acryloyl]aminomethyl]benzamide, in which the 3-pyridylacryloyl group has the E conformation in its structural formula. The E-conformation tucidinostat exhibits subtype-selective histone deacetylase inhibitory activity, primarily inhibiting HDAC1, HDAC2, HDAC3 in class I HDACs and HDAC10 in class IIb HDACs. The E-conformation tucidinostat can be used to treat diseases associated with abnormal histone deacetylase activity, such as cancers including lymphoma, solid tumors, and hematopoietic malignancies.

[0010] Sintilimab is a PD-1 inhibitor jointly developed in China by Cinda Biopharmaceuticals and Eli Lilly. As a human immunoglobulin G4 (IgG4) monoclonal antibody, it specifically binds to PD-1 molecules on the surface of T cells, thereby inhibiting the PD-1 / Programmed Death-Ligand 1 (PD-L1) pathway, which contributes to tumor immune tolerance, and reactivating the antitumor activity of lymphocytes, thus achieving the goal of tumor treatment. Currently, sintilimab is approved as a treatment for classical Hodgeggold lymphoma, non-squamous non-small cell lung cancer (NSCL), squamous cell lung cancer, and hepatocellular carcinoma.

[0011] Bevacizumab is a humanized monoclonal antibody IgG1 developed by Roche using recombinant DNA technology. It plays a crucial role in tumor growth by inhibiting vascular endothelial growth factor (VEGF). The VEGF family includes several related factors such as VEGF-A, VEGF-B, VEGF-C, and VEGF-D, but VEGF-A is the most important factor in tumor angiogenesis. VEGF-A promotes the growth and proliferation of vascular endothelial cells, binds to growth factor receptors produced by vascular endothelial cells, activates downstream signaling pathways, and ultimately promotes angiogenesis. Bevacizumab was first approved in the United States in 2004 for the treatment of advanced colorectal cancer and became the first anti-angiogenic therapy widely used in the treatment of patients with advanced cancer. Its trade name is Avastin, and it first entered the Chinese market in 2010. Avastin is approved in China for the following six indications: 1) in combination with chemotherapy for metastatic colorectal cancer; 2) as first-line treatment for unresectable advanced, metastatic, or recurrent non-squamous non-small cell lung cancer; 3) for the treatment of recurrent glioblastoma; 4) in combination with atezolizumab for the treatment of unresectable hepatocellular carcinoma that has not received prior systemic treatment; 5) in combination with carboplatin and paclitaxel for first-line treatment in patients with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; and 6) in combination with paclitaxel and cisplatin or paclitaxel and topotecan for the treatment of patients with persistent, recurrent, or metastatic cervical cancer. As of June 2022, nine types of bevacizumab are available in China: Avastin (Roche), Ankeda (Qilu), IBI305 / Dayoutong (Xinda), Beianting (Beida), Airuto (Hengrui), Hanbeitai, Pu Xinting, Pubexi, and Boyounuo.

[0012] MMR genes are DNA mismatch repair genes. Immunohistochemical testing measures the expression of four MMR proteins: MLH1, PMS2, MSH2, and MSH6. Positive expression is localized to the cell nucleus. Deletion of MMR expression leads to the accumulation of mismatches during DNA replication, causing microsatellite instability (MSI), which accounts for approximately 15% of colorectal cancers. dMMR is defined as deletion of MMR expression, while pMMR is defined as normal MMR expression without deletion. dMMR exhibits high-frequency microsatellite instability (MSI-H), while pMMR exhibits low-frequency microsatellite instability (MSI-L) or microsatellite stability (MSS). [Overview of the project] [Problems that the invention aims to solve]

[0013] The object of the present invention is to provide a drug used for the treatment of locally advanced, unresectable or metastatic colorectal cancer, and the use thereof. [Means for solving the problem]

[0014] In a first embodiment of the present invention, a tripartite application of components (1), (2), and (3) is provided for the primary, secondary, tertiary, and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein components (1), (2), and (3) are defined as described herein.

[0015] In a second aspect of the present invention, a tripartite application of components (1), (2), and (3) is provided in the preparation of agents for the primary, secondary, tertiary, and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein components (1), (2), and (3) are defined as described herein.

[0016] In a third aspect of the present invention, a pharmaceutical composition comprising component (1), component (2), and component (3) is provided for the primary, secondary, tertiary, and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein component (1), component (2), and component (3) are defined as described herein, respectively.

[0017] A fourth aspect of the present invention provides the use of the pharmaceutical composition in the primary, secondary, tertiary, and higher prevention and / or treatment and / or improvement of locally advanced, unresectable or metastatic colorectal cancer or disease progression.

[0018] A fifth embodiment of the present invention provides a kit containing the pharmaceutical composition.

[0019] In certain specific embodiments, the kit, component (1), component (2), and component (3) are unit formulations of the same or different specifications, and component (1), component (2), and component (3) are contained in the same container or in different containers.

[0020] In certain specific embodiments, the kit and component (1) are in a gastrointestinal dosage form, preferably an oral dosage form, and components (2) and (3) are in a non-gastrointestinal dosage form, preferably an injectable formulation.

[0021] In a particular embodiment, the kit further includes a label containing information that component (1) is taken twice a week starting from day 1 of the first cycle, with an interval of at least 3 days between doses; component (2) is administered on day 1 of each treatment cycle, with 3 weeks comprising one treatment cycle; and component (3) is administered on day 1 of each treatment cycle, with 3 weeks comprising one treatment cycle.

[0022] In a particular embodiment, the label of the kit further includes information that component (1) is 30 mg, administered orally 30 minutes after a meal, taken twice a week starting from day 1 of the first cycle, with an interval of at least 3 days between doses.

[0023] In certain specific embodiments, the label of the kit further includes the information that component (2) is administered by intravenous drip at 200 mg, with a 3-week treatment cycle, and administered on the first day of each cycle.

[0024] In certain specific embodiments, the label of the kit further includes the information that component (3) is administered by intravenous drip at 7.5 mg / kg, with a 3-week treatment cycle, and administered on the first day of each cycle.

[0025] In certain specific embodiments, the label of the kit further includes the information that component (3) is administered at least 5 minutes after the administration of component (2).

[0026] In a sixth aspect of the present invention, there is provided a method for the primary, secondary, tertiary and further prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, which includes administering to a patient who needs an effective amount of the pharmaceutical composition. <000009​​​​​​​​​​​​​​​​​​In certain specific embodiments, component (2) of the present invention is selected from cintilimab or its antigen-binding fragment or variant or biosimilar thereof.

[0032] In certain specific embodiments, component (2) of the present invention is selected from cintilimab or its antigen-binding fragment or a biosimilar thereof.

[0033] In certain specific embodiments, component (2) in the present invention is selected from syntilimab or its biosimilar.

[0034] In certain specific embodiments, component (2) of the present invention is selected from cintilimab.

[0035] In certain specific embodiments, component (3) of the present invention is selected from bevacizumab or its antigen-binding fragment or variant or biosimilar thereof.

[0036] In certain specific embodiments, component (3) of the present invention is selected from bevacizumab or its antigen-binding fragment or a biosimilar thereof.

[0037] In certain specific embodiments, component (3) of the present invention is selected from bevacizumab or its biosimilar.

[0038] In certain specific embodiments, component (3) of the present invention is selected from bevacizumab or IBI305.

[0039] In certain specific embodiments, component (3) of the present invention is selected from bevacizumab.

[0040] In certain specific embodiments, component (3) in the present invention is selected from IBI305.

[0041] In a particular embodiment, component (1) of the kit is tucidinostat, and its strength is 5 mg / tablet.

[0042] In a particular embodiment, component (2) of the kit is cintilimab, and its specification is 100 mg / 10 ml.

[0043] In a particular embodiment, component (3) of the kit is bevacizumab, and its specification is 100 mg / 4 ml or 400 mg / 16 ml.

[0044] In a particular embodiment, component (3) of the kit is IBI305, with a specification of 100 mg / 4 ml or 400 mg / 16 ml.

[0045] In certain specific embodiments, in the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, components (1), (2), and (3) are administered simultaneously, separately, or sequentially.

[0046] In a particular embodiment, the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein component (1) is administered once to four times per week, preferably twice per week; component (2) is administered once every two to five weeks, preferably once every three weeks; and component (3) is administered once every two to five weeks, preferably once every three weeks.

[0047] In a particular embodiment, in the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, component (1) is administered in doses of 10 to 60 mg, preferably 20 to 40 mg, more preferably 30 mg.

[0048] In a particular embodiment, in the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, component (2) is administered at a dose of 100 to 300 mg, preferably 200 mg.

[0049] In a particular embodiment, in the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, component (3) is administered at a dose of 5 to 10 mg / kg / dose, preferably 6 to 8 mg / kg / dose, and more preferably 7.5 mg / kg / dose.

[0050] In a particular embodiment, the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein component (2) is cintilimab or a biosimilar thereof, preferably cintilimab, and is administered on day 1 of each treatment cycle, with each cycle consisting of 2 to 4 weeks, preferably 3 weeks.

[0051] In a particular embodiment, the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein component (3) is bevacizumab or a biosimilar thereof, preferably bevacizumab or IBI305, and is administered on day 1 of each treatment cycle, with each cycle consisting of 2 to 4 weeks, preferably 3 weeks.

[0052] In a particular embodiment, the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein component (1) is tucidinostat, which is administered orally 30 minutes after a meal, twice a week starting from day 1 of the first cycle, with an interval of at least 3 days between doses.

[0053] In a particular embodiment, in the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, component (3) is administered at least 5 minutes after the administration of component (2), wherein component (2) is preferably cintilimab, and component (3) is preferably bevacizumab or IBI305.

[0054] In a particular embodiment, the method for the primary, secondary, tertiary and higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein component (2) and component (3) are both injectable preparations administered by intravenous infusion, and component (1) is an orally administered tablet.

[0055] In certain specific embodiments, the locally advanced, unresectable or metastatic colorectal cancer described in the present invention is a locally advanced, unresectable or metastatic colorectal cancer of the microsatellite-stable (MSS) type or low-frequency microsatellite-instability (MSI-L) type.

[0056] In certain specific embodiments, the locally advanced, unresectable or metastatic colorectal cancer described in the present invention is a microsatellite-stable (MSS) type locally advanced, unresectable or metastatic colorectal cancer.

[0057] In certain specific embodiments, the locally advanced, unresectable or metastatic colorectal cancer described in the present invention is locally advanced, unresectable or metastatic colorectal cancer of the low-frequency microsatellite instability (MSI-L) type.

[0058] In certain specific embodiments, the locally advanced unresectable or metastatic colorectal cancer described in the present invention is locally advanced unresectable or metastatic colorectal adenocarcinoma.

[0059] In certain specific embodiments, the colorectal adenocarcinoma described in the present invention is a mixed-type non-adenosquamous carcinoma.

[0060] In certain specific embodiments, the colorectal cancer described in the present invention is one in which at least two or more standard treatments have been ineffective in the past, or in which the patient cannot tolerate the toxicity of two or more standard treatments.

[0061] In certain specific embodiments, the colorectal cancer described in the present invention is microsatellite-stable (MSS) type or low-frequency microsatellite-instability-L type colorectal cancer that has previously been unresponsive to at least two-stage standard treatment or is unable to tolerate the toxicity of two-stage or higher standard treatment.

[0062] In certain specific embodiments, the standard treatment comprises a fluorouracil derivative, oxaliplatin, and irinotecan, wherein the fluorouracil derivative comprises 5-fluorouracil, capecitabine, tegafur, and the like.

[0063] Another aspect of the present invention relates to the use of tucidinostat in combination with a PD-1 monoclonal antibody and a VEGF monoclonal antibody in the preparation of therapeutic agents for locally advanced, unresectable, or metastatic colorectal cancer, wherein The aforementioned colorectal cancers are microsatellite-stable (MSS) type or low-frequency microsatellite-instability-L type colorectal cancers that have previously been unresponsive to at least two-stage standard treatment or are unable to tolerate the toxicity of two-stage or higher standard treatment.

[0064] In certain specific embodiments, the standard treatment comprises a fluorouracil derivative, oxaliplatin, and irinotecan, wherein the fluorouracil derivative comprises 5-fluorouracil, capecitabine, tegafur, and the like.

[0065] In a particular embodiment, the colorectal cancer is a colorectal adenocarcinoma.

[0066] In certain specific embodiments, the PD-1 monoclonal antibody includes nivolumab, pembrolizumab, cintilimab, tripalimab, camrelizumab, tislerizumab, penprimab, zimberelimab, celpurimab, pcotenlimab, and their biosimilars, and the VEGF monoclonal antibody includes bevacizumab and its biosimilars.

[0067] Another aspect of the present invention relates to a pharmaceutical composition for treating locally advanced, unresectable, or metastatic colorectal cancer, characterized by comprising tusidinostat, a PD-1 monoclonal antibody, and a VEGF monoclonal antibody, wherein The aforementioned colorectal cancers are microsatellite-stable (MSS) type or low-frequency microsatellite-instability-L type colorectal cancers that have previously been unresponsive to at least two-stage standard treatment or are unable to tolerate the toxicity of two-stage or higher standard treatment.

[0068] In certain specific embodiments, the standard treatment comprises a fluorouracil derivative, oxaliplatin, and irinotecan, wherein the fluorouracil derivative comprises 5-fluorouracil, capecitabine, tegafur, and the like.

[0069] In a particular embodiment, the colorectal cancer is a colorectal adenocarcinoma. In certain specific embodiments, the colorectal adenocarcinoma described in the present invention is a mixed-type non-adenosquamous carcinoma.

[0070] In certain specific embodiments, the PD-1 monoclonal antibody includes nivolumab, pembrolizumab, cintilimab, tripalimab, camrelizumab, tislerizumab, penprimab, zimberelimab, celpurimab, pcotenlimab, and their biosimilars, and the VEGF monoclonal antibody includes bevacizumab and its biosimilars.

[0071] Another aspect of the present invention relates to a kit comprising the above-mentioned pharmaceutical composition.

[0072] Another aspect of the present invention relates to a method for treating locally advanced, unresectable, or metastatic colorectal cancer, characterized by administering the pharmaceutical composition or kit to a patient requiring an effective amount of the said pharmaceutical composition or kit.

[0073] In certain specific embodiments, the standard treatment comprises a fluorouracil derivative, oxaliplatin, and irinotecan, wherein the fluorouracil derivative comprises 5-fluorouracil, capecitabine, tegafur, and the like.

[0074] In a particular embodiment, the colorectal cancer is a colorectal adenocarcinoma.

[0075] In certain specific embodiments, tucidinostat is administered at a dose of 10-60 mg / dose, preferably 10-40 mg / dose, more preferably 30 mg / dose; PD-1 monoclonal antibody is administered at a dose of 100-300 mg / dose, preferably 200 mg / dose; and VEGFD monoclonal antibody is administered at a dose of 5-10 mg / kg / dose, preferably 6-8 mg / kg / dose, more preferably 7.5 mg / kg / dose.

[0076] In certain specific embodiments, the colorectal cancer described in the present invention has not previously been treated with low-molecular-weight antivascular drugs.

[0077] In this invention, the term “treatment” means administering a drug or other adjunctive therapy to a subject in order to obtain a desired pharmacological and / or physiological effect. This effect is prophylactic if it completely or partially prevents the disease or its symptoms, and / or therapeutic if it partially or completely stabilizes or cures the disease and / or side effects caused by the disease. As used herein, “treatment” covers any treatment for a patient’s disease, and specifically includes (a) preventing the onset of a disease or symptoms in a patient who is susceptible to an infectious disease or symptoms but has not yet been diagnosed with the disease, (b) suppressing the symptoms of a disease and halting its progression, or (c) alleviating the symptoms of a disease and causing regression of the disease or symptoms.

[0078] In this invention, the term "effective dose" refers to the amount that effectively achieves the expected therapeutic or preventive effect in the required dose and time. The "therapeutic effective dose" of the pharmaceutical composition of this invention varies depending on factors such as the individual disease state, age, sex, weight, and the ability of the substance / molecule to elicit the expected response in the subject. The therapeutic effective dose also includes the amount in which the therapeutically beneficial effect of the substance / molecule outweighs any toxic or adverse consequences. The term "preventive effective dose" refers to the amount that effectively achieves the expected preventive effect in the required dose and time. Since preventive doses are administered to subjects before the onset of disease or in the early stages of disease, the preventive effective dose is usually lower than the therapeutic effective dose, but this is not always the case. In the case of cancer, the therapeutic effective dose of a drug may reduce the number of cancer cells, shrink the tumor size, inhibit (to some extent delay, preferably halt) the invasion of cancer cells into surrounding organs, inhibit (to some extent delay, preferably halt) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. [Brief explanation of the drawing]

[0079] [Figure 1] Figure 1 shows a comparison of progression-free survival (PFS) between a triple-agent CAP regimen and a dual-agent CP regimen in the treatment of patients with locally advanced, unresectable, or metastatic colorectal cancer (MSS / MSI-L). [Modes for carrying out the invention]

[0080] Beneficial effects of the present invention: Compared to the dual regimen of cintirimab + tucidinostat, the tripartite regimen of cintirimab + tucidinostat + IBI305 provided by the present invention can significantly extend progression-free survival in patients with locally advanced unresectable or metastatic colorectal cancer (MSS / MSI-L). Furthermore, in terms of indicators such as ORR, PR, PD, NE, and DCR, patients with MSS / MSI-L locally advanced unresectable or metastatic colorectal cancer receive a significant benefit from the tripartite regimen of cintirimab + tucidinostat + IBI305. Moreover, compared to similar commercially available drugs, patients who received the CAP tripartite regimen of the present invention achieved unexpected and promising therapeutic effects in terms of median progression-free survival (PFS), ORR, and other indicators.

[0081] This invention discloses agents and their uses for the treatment of locally advanced, unresectable or metastatic colorectal cancer (MSS / MSI-L). Those skilled in the art can refer to this specification and make appropriate substitutions or modifications. In particular, such similar substitutions and modifications are obvious to those skilled in the art and are all considered to be included in the invention. In this invention, agents and their uses for the treatment of locally advanced, unresectable or metastatic colorectal adenocarcinoma (MSS / MSI-L) are described through preferred embodiments. It will be apparent to those skilled in the art that the techniques of this invention can be realized and applied by making modifications and appropriate changes and combinations to the applications and pharmaceutical compositions described herein without departing from the content, spirit, and scope of the invention. [Examples]

[0082] Example 1: Phase II clinical trial on the treatment of locally advanced, unresectable or metastatic colorectal adenocarcinoma of type MSS / MSI-L with a CAP tridrug regimen and a CP dudrug regimen.

[0083] CAP triple regimen: Syntilimab + Tusidinostat + IBI305 triple combination regimen.

[0084] CP two-drug regimen: Syntilimab + Tusidinostat two-drug combination regimen.

[0085] 1. Study Objectives and Methods: This study is a Phase II clinical trial with the PFS rate at 18 weeks post-treatment (18wPFS) as the primary endpoint, and ORR, PFS, OS, DCR, DOR, and safety as secondary endpoints. The study aims to explore the efficacy and safety of a two-agent CP regimen and a three-agent CAP regimen in patients with advanced microsatellite-stable colorectal cancer who have failed standard treatment.

[0086] 2. Subjects of the examination:

[0087] Registration criteria:

[0088] 1. Locally advanced, unresectable, or metastatic adenocarcinoma of the colorectal colon (excluding mixed adenocarcinoma / squamous cell carcinoma and other pathological types) confirmed by histopathological or cytological examination.

[0089] 2. Individuals who have been definitively diagnosed with pMMR by PCR testing for microsatellite stability (MSS) or low-frequency microsatellite instability (MSI-L), or by immunohistochemical staining of DNA mismatch repair (MMR) proteins, including the expression status of MLH1, MSH2, MSH6, and PMS2 proteins, but who do not exhibit protein deletions.

[0090] 3. Patients who have previously received no or no second-line standard treatment, or who cannot tolerate the toxicity of second-line or no standard treatment. The standard treatment includes fluorouracil (including 5-fluorouracil, capecitabine, tegafur, etc.), oxaliplatin, and irinotecan.

[0091] 4. Individuals with at least one measurable lesion based on RECIST v1.1.

[0092] 5. Those with an ECOG PS score of 0-1.

[0093] 6. Persons aged 18 to 75 years.

[0094] 7. Individuals with sufficient organ and bone marrow function, who meet the following clinical laboratory values ​​within 7 days prior to registration, and who have no contraindications to chemotherapy, immunotherapy, or other treatments.

[0095] 1) General blood test: Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻¹⁰ 9 / L; Platelet count (PLT)≧100×10 9 / L; Hemoglobin (HGB) ≥ 9.0 g / dL

[0096] 2) Liver function: Serum total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN); in subjects without liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN; in subjects with liver metastases, ALT and AST ≤ 5.0 × ULN; serum albumin ≥ 25 g / L

[0097] 3) Renal function: Serum creatinine (Cr) ≤ 1.5 × ULN

[0098] 4) General urinalysis: Urine protein < 2+; Patients with urine protein ≥ 2+ relative to baseline should undergo a 24-hour urine collection and ensure that 24-hour urine protein < 1g.

[0099] 5) Coagulation function: International normalized ratio (INR) ≤ 1.5 × ULN, and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN

[0100] Exclusion criteria:

[0101] 1. Individuals who have previously been exposed to drugs such as anti-PD-1 antibodies, anti-PD-L1 antibodies, or HDAC inhibitors, or who have previously undergone small molecule anti-angiogenic therapy.

[0102] 2. Anyone who has received any investigational drug within four weeks prior to the first dose of the investigational drug.

[0103] 3. Individuals who have received their last dose of antitumor therapy (chemotherapy, molecular targeted therapy, tumor immunotherapy, tumor embolization, etc.) within three weeks prior to the first dose of the study drug.

[0104] 4. Individuals who have received radiation therapy within four weeks prior to the first dose of the investigational drug.

[0105] 5. Patients who have received immunosuppressants other than systemic glucocorticoids, administered topically or in physiological doses via nasal spray, inhalant, or other route within four weeks prior to the first dose of the study drug.

[0106] 6. Patients who, prior to the first dose of the study drug, have toxicity caused by previous antitumor therapy that has not recovered to NCI CTCAE version 5.0 grade 1 or lower.

[0107] 7. Individuals with symptomatic central nervous system metastases and / or carcinomatous meningitis.

[0108] 8. Acute or chronic active hepatitis B (HBsAg positive and HBV DNA ≥ 2000 IU / mL or ≥ 10 4 Individuals with a copy count of HCV (copy number / mL) or acute or chronic active hepatitis C (HCV antibody positive and HCV RNA positive).

[0109] 9. Individuals suffering from poorly controlled arterial hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg) despite standard treatment.

[0110] 10. Individuals who, at baseline, experienced loose stools more than three times a day and were suggested to be susceptible to colon or small intestinal disease with poorly controlled symptoms.

[0111] 11. Patients with a history of gastrointestinal perforation and / or fistula within the past six months, a history of peptic ulcer, a history of intestinal obstruction (including incomplete intestinal obstruction requiring enteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection with chronic diarrhea), Crohn's disease, ulcerative colitis, intra-abdominal abscess, or a history of long-term chronic diarrhea. Post-intestinal stent placement.

[0112] III. Test materials:

[0113] Syntilimab: Xinda Biopharmaceutical (Suzhou) Co., Ltd. (Trade name: Da Bo Shu (registered trademark))

[0114] Tusijinostat: Shenzhen Weixin Biotechnology Co., Ltd. (Trade name: Aipusha (registered trademark));

[0115] IBI305 (bevacizumab biosimilar): Xinda Biopharmaceutical (Suzhou) Co., Ltd.

[0116] 3. Clinical Trial Protocol:

[0117] Forty-eight patients were enrolled competitively and randomly divided into two groups: a CP two-agent group and a CAP three-agent group. Of these, 25 patients in the CAP three-agent group received a scintirimab + tucidinostat + IBI305 triple combination regimen, while 23 patients in the CP two-agent group received a scintirimab + tucidinostat dual combination regimen.

[0118] CAP triple regimen:

[0119] Scintilimab, 200 mg, is administered by intravenous infusion once every three weeks, on the first day of each cycle.

[0120] Tusidinostat, 30 mg, is administered orally, 30 minutes after a meal, twice a week starting from day 1 of the first cycle, with an interval of at least 3 days between doses (for example, Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.). If tusidinostat administration is interrupted, it should be resumed twice a week from the time of resumption.

[0121] IBI305 is administered by intravenous infusion at a dose of 7.5 mg / kg, with each treatment cycle lasting 3 weeks, administered on the first day of each cycle.

[0122] First, administer cintirimab by intravenous infusion over 60 (±15) minutes, and then administer IBI305 at a dose of 7.5 mg / kg by intravenous infusion at least 5 minutes later. If either drug is temporarily or permanently discontinued, the other drug can be continued.

[0123] CP two-drug regimen:

[0124] Scintilimab, 200 mg, is administered by intravenous infusion once every three weeks, on the first day of each cycle.

[0125] Tusidinostat, 30 mg, is administered orally, 30 minutes after a meal, twice a week starting from day 1 of the first cycle, with an interval of at least 3 days between doses (for example, Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.). If tusidinostat administration is interrupted, it should be resumed twice a week from the time of resumption.

[0126] Treatment efficacy evaluation: Based on RECIST v1.1, 18-week progression-free survival (PFS), ORR, PR, SD, PD, NE, and median DCR were evaluated for patients in both groups.

[0127] Safety assessment: 3 days before each cycle.

[0128] IV. Test Results

[0129] 1. Treatment efficacy indicators such as 18-week progression-free survival (18wPFS), objective response rate (ORR), partial response rate (PR), stable disease (SD), progression (PD), neutrophil count (NE), and disease control rate (DCR).

[0130] As shown in Table 1, the median 18-wPFS in patients in the CAP tri-agent group reached 66.7%, compared to only 21.7% in patients in the CP du-agent group, showing a statistically significant difference between the two groups (p=0.0006). The CAP tri-agent regimen demonstrated significantly superior therapeutic efficacy compared to the CP du-agent regimen. Furthermore, compared to the CP du-agent group, patients in the CAP tri-agent group showed significantly better ORR, PR, PD, NE, and DCR (shown in Table 1). The results suggest that the CAP tri-agent group demonstrated unexpected therapeutic efficacy in the treatment of advanced microsatellite-stable colorectal cancer compared to the CP du-agent group.

[0131] [Table 1]

[0132] 2. Median PFS

[0133] As shown in Figure 1, the median progression-free survival (PFS) for the CP duo group was approximately 1.6 months, while the median PFS for the CAP trio group was approximately 7.35 months, showing a statistically significant difference between the two groups (p=0.009). This suggests that the CAP trio unexpectedly extended PFS in patients with locally advanced, unresectable or metastatic colorectal adenocarcinoma of type MSS / MSI-L compared to the CP duo group. In conclusion, the tucidinostat + cintirimab + IBI305 triple combination therapy significantly extended progression-free survival in patients compared to the tucidinostat + cintirimab duo group, and patients in the triple combination therapy also showed significant benefits in indicators such as ORR, PR, PD, NE, and DCR.

[0134] Furthermore, compared to similar commercially available drugs, patients who received the CAP triplicate regimen of the present invention achieved unexpected and promising therapeutic effects in terms of median progression-free survival (PFS), ORR, and other parameters (Table 2).

[0135] [Table 2]

[0136] A detailed description of the present invention has been provided above. This specification illustrates the principles and embodiments of the present invention using specific examples. The above description of embodiments is provided as a reference for understanding the principles and core ideas of the present invention, including the best way to carry it out, and is intended to enable those skilled in the art to carry out the present invention. Those skilled in the art should understand that several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications are also included in the scope of the claims of the present invention. The scope of patent protection of the present invention is limited by the claims and may include other embodiments that those skilled in the art may conceive. If these other embodiments do not have structural elements different from the wording of the claims, or contain equivalent structural elements that do not substantially differ from the wording of the claims, these other embodiments are also included in the scope of the claims.

Claims

1. The use of component (2) and tucidinostat or its derivatives in combination with component (3) in the prevention and / or treatment and / or improvement of locally advanced, unresectable or metastatic colorectal cancer or disease progression at a third or higher level, The derivatives of tucidinostat are pharmaceutically acceptable salts, crystals, isomers, prodrugs, or metabolites of tucidinostat. The aforementioned component (2) is cintilimab or its antigen-binding fragment or variant or biosimilar thereof, The aforementioned component (3) is bevacizumab or its antigen-binding fragment or variant or biosimilar thereof.

2. The use of tucidinostat or its derivatives in the manufacture of combination drugs for the third or higher prevention and / or treatment and / or improvement of locally advanced, unresectable or metastatic colorectal cancer or disease progression, The aforementioned combination drug comprises tucidinostat or a derivative thereof, and further comprises component (2) and component (3), where, The derivatives of tucidinostat are pharmaceutically acceptable salts, crystals, isomers, prodrugs, or metabolites of tucidinostat. The aforementioned component (2) is cintilimab or its antigen-binding fragment or variant or biosimilar thereof, The aforementioned component (3) is bevacizumab or its antigen-binding fragment or variant or biosimilar thereof.

3. The aforementioned colorectal cancer is a colorectal adenocarcinoma. Preferably, the colorectal adenocarcinoma is a mixed-type non-adenosquamous carcinoma. Preferably, the colorectal cancer has previously been ineffective against at least two-stage standard treatment, or the patient could not tolerate the toxicity of two-stage or higher standard treatment. Preferably, the standard treatment includes a fluorouracil derivative, oxaliplatin, or irinotecan, and the fluorouracil derivative includes 5-fluorouracil, capecitabine, tegafur, etc. Preferably, the colorectal cancer is of the microsatellite-stable (MSS) type or the low-frequency microsatellite-instability (MSI-L) type. Preferably, the colorectal cancer is of the microsatellite-stable (MSS) type. Preferably, the colorectal cancer is of the low-frequency microsatellite instability (MSI-L) type. Preferably, the tusidinostat or its derivative is a tusidinostat or a pharmaceutically acceptable salt or crystal thereof. Preferably, the tusidinostat or its derivative is a crystal having tusidinostat or its crystal form A or crystal having crystal form B. More preferably, the tusidinostat or its derivative is tusidinostat, Preferably, component (2) is cintilimab or its antigen-binding fragment or a biosimilar thereof. More preferably, component (2) is cintilimab, The aforementioned component (3) is bevacizumab or its antigen-binding fragment or a biosimilar thereof. Preferably, the component (3) is bevacizumab or a biosimilar thereof. The use according to claim 1 or 2, more preferably characterized in that the component (3) is bevacizumab or IBI305.

4. A pharmaceutical composition comprising component (1), component (2), and component (3), The aforementioned component (1) is tusidinostat or a pharmaceutically acceptable salt, crystal, isomer, prodrug or metabolite thereof. The aforementioned component (2) is cintilimab or its antigen-binding fragment or variant or biosimilar thereof, The aforementioned component (3) is bevacizumab or its antigen-binding fragment or variant or biosimilar thereof. Preferably, the colorectal cancer is of the microsatellite-stable (MSS) type or the low-frequency microsatellite-instability (MSI-L) type. Preferably, the colorectal cancer is of the microsatellite-stable (MSS) type. Preferably, the colorectal cancer is of the low-frequency microsatellite instability (MSI-L) type. Preferably, the colorectal cancer is a colorectal adenocarcinoma. Preferably, the colorectal adenocarcinoma is a mixed-type non-adenosquamous carcinoma. Preferably, the colorectal cancer has previously been ineffective against at least two-stage standard treatment, or the patient could not tolerate the toxicity of two-stage or higher standard treatment. Preferably, the standard treatment includes a fluorouracil derivative, oxaliplatin, or irinotecan, and the fluorouracil derivative includes 5-fluorouracil, capecitabine, tegafur, etc. Preferably, the colorectal cancer has not previously been treated with a low-molecular-weight antivascular drug. Preferably, component (1) is tusidinostat, or a pharmaceutically acceptable salt or crystal thereof. More preferably, component (1) is tusidinostat, or a crystal having crystal form A or crystal having crystal form B thereof. More preferably, component (1) is tusidinostat, Preferably, component (2) is cintilimab or its antigen-binding fragment or a biosimilar thereof. More preferably, component (2) is cintilimab, The aforementioned component (3) is bevacizumab or its antigen-binding fragment or a biosimilar thereof. More preferably, component (3) is bevacizumab or a biosimilar thereof. A pharmaceutical composition for use in the third or later prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression, wherein the component (3) is bevacizumab or IBI305.

5. Preferably, the colorectal cancer is of the microsatellite-stable (MSS) type or the low-frequency microsatellite-instability (MSI-L) type. Preferably, the colorectal cancer is of the microsatellite-stable (MSS) type. Preferably, the colorectal cancer is of the low-frequency microsatellite instability (MSI-L) type. Preferably, the colorectal cancer is a colorectal adenocarcinoma. Preferably, the colorectal adenocarcinoma is a mixed-type non-adenosquamous carcinoma. Preferably, the colorectal cancer has previously been ineffective against at least two-stage standard treatment, or the patient could not tolerate the toxicity of two-stage or higher standard treatment. Preferably, the standard treatment comprises a fluorouracil derivative, oxaliplatin, or irinotecan, and the fluorouracil derivative comprises 5-fluorouracil, capecitabine, tegafur, etc., the pharmaceutical composition according to claim 4, used for the third or higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression.

6. A kit characterized by comprising the pharmaceutical composition described in claim 4.

7. The kit according to claim 6, characterized in that component (1), component (2), and component (3) are unit formulations having the same or different specifications, and component (1), component (2), and component (3) are contained in the same container or in different containers.

8. The kit according to claim 6 or 7, characterized in that component (1) is in a gastrointestinal dosage form, preferably an oral dosage form, and components (2) and (3) are in a non-gastrointestinal dosage form, preferably an injectable preparation.

9. The kit according to claim 6 or 7, characterized in that component (1) is tucidinostat, with a specification of 5 mg / tablet, component (2) is cintilimab, with a specification of 100 mg / 10 ml, and component (3) is IBI305 or bevacizumab, all with specifications of 100 mg / 4 ml or 400 mg / 16 ml.

10. The process involves administering the pharmaceutical composition according to claim 4 to a patient in need in an amount effective for prevention and / or treatment and / or improvement. Preferably, the colorectal cancer is of the microsatellite-stable (MSS) type or the low-frequency microsatellite-instability (MSI-L) type. Preferably, the colorectal cancer is of the microsatellite-stable (MSS) type. Preferably, the colorectal cancer is of the low-frequency microsatellite instability (MSI-L) type. Preferably, the colorectal cancer is a colorectal adenocarcinoma. Preferably, the colorectal adenocarcinoma is a mixed-type non-adenosquamous carcinoma. Preferably, the colorectal cancer has previously been ineffective against at least two-stage standard treatment, or the patient could not tolerate the toxicity of two-stage or higher standard treatment. Preferably, the standard treatment comprises a fluorouracil derivative, oxaliplatin, or irinotecan, wherein the fluorouracil derivative comprises 5-fluorouracil, capecitabine, tegafur, etc., a method for the tertiary or higher prevention and / or treatment and / or improvement of locally advanced unresectable or metastatic colorectal cancer or disease progression.

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