CN116459336A - Medicament for treating locally advanced unresectable or metastatic colorectal cancer and application thereof - Google Patents
Medicament for treating locally advanced unresectable or metastatic colorectal cancer and application thereof Download PDFInfo
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- CN116459336A CN116459336A CN202310481472.2A CN202310481472A CN116459336A CN 116459336 A CN116459336 A CN 116459336A CN 202310481472 A CN202310481472 A CN 202310481472A CN 116459336 A CN116459336 A CN 116459336A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the field of medicines, in particular to a medicine for treating locally advanced unresectable or metastatic colorectal cancer and application thereof. Compared with the combination scheme of the Xindi Li Shan anti-Sidamide and the IBI305, the combination scheme of the Xindi Li Shan anti-Sidamide and the Sidamide can obviously prolong the progression-free survival time of patients with MSS/MSI-L locally advanced unresectable or metastatic colorectal cancer. In addition, in ORR, PR, PD, NE, DCR and other aspects, the patients with local advanced unresectable or metastatic colorectal cancer can also benefit remarkably by combining the three medicines of the Li Shan antibody, the sitagliptin and the IBI305.
Description
Technical Field
The invention relates to the field of medicines, in particular to a medicine for treating locally advanced unresectable or metastatic colorectal cancer and application thereof.
Background
Colorectal cancer refers to malignant changes in large intestinal intimal epithelial cells, including abnormal differentiation, abnormal proliferation, abnormal cell metabolism and secretion, and the like. The vast majority (> 95%) of colorectal cancers clinically are adenocarcinoma, 1% squamous cell carcinoma. Intestinal cancer cells can be transferred to other parts of the body, such as liver, lung, brain, etc., by blood circulation, and also can be transferred to adjacent lymph nodes or glands by lymphatic circulation.
With the continuous improvement of the living standard of people in recent years, the incidence of colorectal cancer is increased year by year due to the change of the dietary structure and the dietary structure of high protein, high fat and low cellulose.
Early colorectal cancer mainly eradicates by surgery, and the survival rate of early colorectal cancer after surgery for 5 years can reach more than 90 percent. However, about 25% of patients with colorectal cancer have metastasized at the time of their initial visit. In addition, up to 50% of newly diagnosed patients will eventually progress to metastatic colorectal cancer, with metastatic patients surviving for more than 5 years less than 5%, with the most common metastatic sites being the liver or lymph nodes in the vicinity. The medical need for metastatic colorectal cancer is very large.
Advanced colorectal cancer is mainly treated by medicines at present. Including but not limited to standard first line therapies with FOLFOX/FOLFIRI combination targeted therapies. And standard two-line treatment regimens following disease progression including, but not limited to, combination with folfiri+bevacizumab. However, the overall second-line treatment has low effective rate, and has a short progression-free survival time and overall survival time. Thus, new therapeutic regimens remain to be developed.
The novel class 1.1 drug is developed by Shenzhen micro-core biotechnology Co., ltd, and mainly aims at the class 1, 2, 3 subtype and class IIb 10 subtype of the class I HDAC (HDAC) selectively inhibitors of the class 10 subtype of the class I benzamide histone deacetylase (Histone Deacetylase, HDAC) and has the regulation and control effect on the tumor abnormal epigenetic function. The indications currently approved for ciladalim include: 1) Peripheral T cell lymphoma; 2) For patients with locally advanced or metastatic breast cancer who are hormone receptor positive, human epidermal growth factor receptor-2 negative, postmenopausal, recurrent or progressive via endocrine treatment.
CN03139760.3 discloses a cidamine compound, in particular a benzamide histone deacetylase inhibitor with differentiation and antiproliferative activity, and a preparation method and application of a pharmaceutical preparation thereof, which discloses a structural general formula and defines substituents. The compounds are useful as inhibitors of histone deacetylase and in the treatment of diseases associated with differentiation and proliferation such as cancer and psoriasis.
CN201210489178.8 discloses two crystalline forms of cetosteanamine, namely cetosteanamine form a and cetosteanamine form B, and a process for preparing new crystalline forms of cetosteanamine. The crystalline form A and the crystalline form B of the Sidamide have excellent performance in oral absorbability and inhibition of cell differentiation and proliferation, have weak toxicity, have good storage and treatment stability, and can be used for preparing medicaments for treating diseases related to cell differentiation and proliferation.
CN201410136761.X discloses an E-configuration benzamide compound, a medicinal preparation and application thereof, wherein the E-configuration benzamide compound is sitagliptin, the chemical name of the E-configuration benzamide compound is N- (2-amino-4-fluorophenyl) -4- [ N- [ (E) -3- (3-pyridine) acryloyl ] aminomethyl ] benzamide, and in the structural formula, the configuration of the 3-pyridine acryloyl is E-type. The E-configuration cidamine has subtype selective histone deacetylase inhibiting activity and mainly inhibits HDAC1, HDAC2, HDAC3 in class I HDAC and HDAC10 in class IIb HDAC. The E-configuration ciladalimine can be used for treating diseases related to abnormal histone deacetylase activity, such as cancers, including lymphomas, solid tumors, blood system tumors and the like.
The Xindi Li Shan anti (sintillimab) is a PD-1 inhibitor drug which is developed by the co-operation of Xindabiological pharmacy and Gift pharmacy in China, is a human immunoglobulin G4 (IgG 4) monoclonal antibody, can specifically bind to PD-1 molecules on the surface of T cells, thus blocking a PD-1/Programmed Death receptor Ligand 1 (PD-L1) path which leads to tumor immune tolerance, and reactivating the anti-tumor activity of lymphocytes, thereby achieving the purpose of treating tumors. Currently, the indications for which the Xindi Li Shan anti-cancer has been batched include classical hodgkin's lymphoma, first-line non-squamous non-small cell lung cancer, first-line squamous lung cancer and first-line hepatocellular carcinoma.
Bevacizumab (bevacizumab) is a humanized monoclonal antibody IgG1 prepared by Luo Shiyuan and by recombinant DNA technology and plays an important role in the growth and proliferation process of tumors by inhibiting Vascular Endothelial Growth Factor (VEGF). The VEGF family comprises Sub>A plurality of related factors such as VEGF-A, VEGF-B, VEGF-C, VEGF-D, and the most important factor in tumor neovascularization is VEGF-A factor, which can promote the growth and proliferation of vascular endothelial cells, and can be combined with growth factor receptors generated by the vascular endothelial cells to activate downstream signal transduction pathways, and finally promote the generation of new blood vessels. Bevacizumab was first approved in the united states for advanced colorectal cancer in 2004, the first of which was widely used in anti-angiogenic therapy for treating patients with advanced cancer. The product name is Avastin (Avastin), which enters china for the first time in 2010. Avastin has been approved in china for 6 indications, respectively: 1) Combination chemotherapy for metastatic colorectal cancer; 2) First line treatment for unresectable advanced, metastatic, or recurrent non-squamous cell non-small cell lung cancer; 3) For recurrent glioblastoma; 4) Combination of atili beads for the treatment of unresectable hepatocellular carcinoma that has not previously received systemic treatment; 5) Combination carboplatin and paclitaxel for first line treatment of patients with advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer; 6) Combination of paclitaxel and cisplatin or paclitaxel and topotecan is used in the treatment of patients with persistent, recurrent or metastatic cervical cancer. By 2022, 6 months, there were 9 domestic accessible bevacizumabs, including: avastin (roche), ambula (zilu), IBI 305/das (belief), bei Anting (beda), ai Ruituo (henry), han Bei Tai, pamphlet, pu Bei Xi, bosunon.
MMR gene is DNA mismatch repair gene, and the immunohistochemical method detects the expression of 4 common MMR proteins, namely MLH1, PMS2, MSH2 and MSH6, and positive expression is positioned in cell nucleus. Its lack of expression can cause the accumulation of mismatches during DNA replication, leading to the occurrence of microsatellite instability (MSI), about 15% of colorectal cancers being initiated via the MSI pathway. dMMR is MMR expression deletion, and pMMR is MMR expression normal without deletion. dMMR exhibits high frequency microsatellite instability (MSI-H), pMMR exhibits low frequency microsatellite instability (MSI-L) or microsatellite stability (MSS).
Disclosure of Invention
The invention aims to provide a medicament for treating locally advanced unresectable or metastatic colorectal cancer and application thereof.
The present invention provides in a first aspect the use of a combination of three components (1), component (2) and component (3) in the prevention and/or treatment and/or amelioration of a locally advanced unresectable or metastatic colorectal cancer disease or disease progression, wherein component (1), component (2) and component (3) are each as defined herein.
In a second aspect the present invention provides the use of a combination of three components (1), component (2) and component (3) for the manufacture of a medicament for the prevention and/or treatment and/or amelioration of a locally advanced unresectable or metastatic colorectal cancer disease or disease progression, wherein component (1), component (2) and component (3) are each as defined herein.
In a third aspect the present invention provides a pharmaceutical composition for the prevention and/or treatment and/or amelioration of a locally advanced unresectable or metastatic colorectal cancer disease or disease progression by first, second or third wire comprising component (1), component (2) and component (3), wherein component (1), component (2) and component (3) are defined as described herein, respectively.
In a fourth aspect the present invention provides a pharmaceutical composition as described above for use in the prevention and/or treatment and/or amelioration of a locally advanced unresectable or metastatic colorectal cancer disease or disease progression, in a first, second or third line.
In a fifth aspect the invention provides a kit comprising a pharmaceutical composition as described above.
In some embodiments, the kit as described above, the component (1), component (2) and component (3) are unit formulations having the same or different specifications, and the component (1), component (2) and component (3) are placed in the same container or in different containers, respectively.
In some embodiments, the kit as described above, the component (1) is in a gastrointestinal administration dosage form, preferably an oral formulation; component (2) and component (3) are in the form of parenteral administration, preferably injection.
In some embodiments, the kit as described above further contains a label comprising information: component (1), starting from 1 st day of 1 st cycle, is taken twice a week, at an interval of not less than 3 days; component (2), administered on day 1 of each cycle, every 3 weeks for a treatment cycle; component (3) was administered every 3 weeks for a treatment period, day 1 of each period.
In some embodiments, the kit as described above, the label further comprises information: component (1), 30mg, 30 minutes PO after meal, was taken twice weekly from day 1 of cycle 1, at an interval of not less than 3 days.
In some embodiments, the kit as described above, the label further comprises information: component (2), 200mg, iv clip, was administered every 3 weeks for a treatment period, day 1 of each period.
In some embodiments, the kit as described above, the label further comprises information: component (3), 7.5mg/kg, IV clip, was administered every 3 weeks for a treatment period, day 1 of each period.
In some embodiments, the kit as described above, the label further comprises information: component (3) is administered at least 5 minutes after the administration of component (2).
In a sixth aspect the present invention provides a method for the prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer by first, second or third line comprising administering to a patient in need thereof a prophylactically and/or therapeutically and/or ameliorating effective amount of a pharmaceutical composition as described above.
In some embodiments, component (1) of the present invention is selected from the group consisting of cetosteanamine or a pharmaceutically acceptable salt, crystal form, isomer, prodrug or metabolite thereof.
In some embodiments, component (1) of the present invention is selected from the group consisting of cetadamine, or a pharmaceutically acceptable salt, crystalline form thereof.
In some embodiments, component (1) of the present invention is selected from the group consisting of cetadalimamine, or forms a and B thereof.
In some embodiments, component (1) of the present invention is cidamine.
In some embodiments, component (2) of the present invention is selected from the group consisting of a syndesmosis Li Shan antibody or antigen-binding fragment or variant thereof, or a biological analog thereof.
In some embodiments, component (2) of the present invention is selected from the group consisting of a syndesmosidic Li Shan antibody or antigen-binding fragment thereof, or a biological analog thereof.
In some embodiments, component (2) of the present invention is selected from the group consisting of a syndesmoside Li Shan antibody or a biosimilar thereof.
In some embodiments, component (2) of the present invention is selected from the group consisting of the anti-bezoar agents Li Shan.
In some embodiments, component (3) of the present invention is selected from bevacizumab or an antigen binding fragment or variant thereof or a biological analogue thereof.
In some embodiments, component (3) of the present invention is selected from bevacizumab or an antigen binding fragment thereof or a biological analogue thereof.
In some embodiments, component (3) of the present invention is selected from bevacizumab or a biological analog thereof.
In some embodiments, component (3) of the present invention is selected from bevacizumab or IBI305.
In some embodiments, component (3) of the present invention is selected from bevacizumab.
In some embodiments, component (3) of the present invention is selected from IBI305.
In some embodiments, the kit as described above, component (1) is cidamine, having a gauge of 5 mg/tablet.
In some embodiments, the kit as described above, component (2) is a bedi Li Shan antibody, which is 100mg/10ml in size;
in some embodiments, a kit as described above, component (3) is bevacizumab; the specification is 100mg/4ml or 400mg/16ml.
In some embodiments, a kit as described above, component (3) IBI305; the specification is 100mg/4ml or 400mg/16ml.
In some embodiments, the component (1), component (2) and component (3) are administered simultaneously, separately or sequentially as described above for use in a method of first-line, second-line or third-line prophylaxis and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer.
In some embodiments, the component (1) is administered 1-4 times per week, preferably 2 times per week, as described above for a method for the first, second or third line prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer; the component (2) is administered 1 time every 2-5 weeks, preferably 1 time every 3 weeks; the component (3) is administered 1 time every 2 to 5 weeks, preferably 1 time every 3 weeks.
In some embodiments, the component (1) is administered at a dose of 10-60mg per dose, preferably 20-40mg per dose, more preferably 30mg per dose, as described above for use in a method for the first, second or third line prophylaxis and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer.
In some embodiments, the component (2) is administered 100-300mg per administration, preferably 200mg per administration, as described above for a method for the first, second or third line prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer.
In some embodiments, the component (3) is administered 5-10mg/Kg per administration, preferably 6-8mg/Kg per administration, more preferably 7.5mg/Kg per administration, as described above for a method for the first, second or third line prophylaxis and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer.
In some embodiments, the component (2) is a bedi Li Shan antibody or a biological analogue thereof, preferably a bedi Li Shan antibody, as described above for use in a method of first, second or third line prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer; a treatment cycle every 2-4 weeks, preferably every 3 weeks; day 1 of each cycle.
In some embodiments, the component (3) is bevacizumab or a biological analogue thereof, preferably bevacizumab or IBI305, as described above for use in a method of first, second or third line prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer; a treatment cycle every 2-4 weeks, preferably every 3 weeks; day 1 of each cycle.
In some embodiments, the component (1) is cibutamine as described above for use in a method of first, second or third line prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer; orally taking 30 minutes after meal; the medicine is taken twice weekly from 1 st day of 1 st period, and the interval between the two medicines should not be less than 3 days.
In some embodiments, component (2) is preferably a bevacizumab or IBI305, and component (3) is preferably a bevacizumab or IBI Li Shan antibody, administered at least 5 minutes after an interval following the administration of component (2) as described above for a method of first, second or third line prophylaxis and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer.
In some embodiments, the component (2) and the component (3) are both injections, intravenous drip, as described above for use in a method of first-line, second-line or third-line prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer; component (1) is a tablet for oral administration.
In some embodiments, the locally advanced unresectable or metastatic colorectal cancer described herein is a microsatellite stabilized (MSS) type or a low microsatellite unstable (MSI-L) type locally advanced unresectable or metastatic colorectal cancer.
In some embodiments, the locally advanced unresectable or metastatic colorectal cancer described herein is a microsatellite stabilized (MSS) locally advanced unresectable or metastatic colorectal cancer.
In some embodiments, the locally advanced unresectable or metastatic colorectal cancer described herein is low microsatellite instability (MSI-L) locally advanced unresectable or metastatic colorectal cancer.
In some embodiments, the locally advanced unresectable or metastatic colorectal cancer of the present invention is locally advanced unresectable or metastatic colorectal adenocarcinoma.
In the present invention, "treatment" refers to administration of a drug or other adjuvant therapy to a subject in order to obtain a desired pharmacological and/or physiological effect. The effect may be prophylactic according to the prevention of the disease or symptoms thereof, in whole or in part; and/or may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) Preventing diseases or symptoms which occur in patients who are susceptible to the diseases or symptoms but are not yet diagnosed with the disease; (b) inhibiting the symptoms of the disease, i.e., arresting its development; or (c) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.
In the present invention, an "effective amount" refers to an amount effective to achieve the desired therapeutic or prophylactic effect at the necessary dosages and times. The "therapeutic/effective amount" of the pharmaceutical composition of the present invention may vary depending on factors such as the disease state, age, sex and weight of the individual, the ability of the substance/molecule to elicit a desired response in the individual, and the like. A therapeutically effective amount also encompasses an amount of the substance/molecule that has a therapeutic benefit over any toxic or detrimental effect. "prophylactically effective amount" refers to an amount effective to achieve the desired prophylactic effect at the dosages and for the time necessary. Generally, but not necessarily, since the prophylactic dose is for the subject prior to the onset of the disease or early in the disease, the prophylactically effective amount will be less than the therapeutically effective amount. In the case of cancer, a therapeutically effective amount of the drug may reduce the number of cancer cells; reducing the tumor volume; inhibit (i.e., slow, preferably stop to some extent) infiltration of cancer cells into surrounding organs; inhibit (i.e., slow, preferably stop to some extent) tumor metastasis; inhibit tumor growth to a certain extent; and/or to some extent, alleviate one or more symptoms associated with cancer.
Description of the drawings:
FIG. 1 is a PFS comparison of a CAP three drug combination regimen with a CP two drug combination regimen for treating MSS/MSI-L locally advanced unresectable or metastatic colorectal cancer patients.
The invention has the beneficial effects that:
compared with the combination scheme of the Xindi Li Shan anti-Sidamide and the IBI305, the combination scheme of the Xindi Li Shan anti-Sidamide and the Sidamide can obviously prolong the progression-free survival time of patients with MSS/MSI-L locally advanced unresectable or metastatic colorectal cancer. In addition, in ORR, PR, PD, NE, DCR and other aspects, the patients with local advanced unresectable or metastatic colorectal cancer can also benefit remarkably by combining the three medicines of the Li Shan antibody, the sitagliptin and the IBI305.
Detailed Description
The invention discloses a medicament for treating MSS/MSI-L locally advanced unresectable or metastatic colorectal cancer and application thereof. Those skilled in the art can make appropriate substitutions and modifications based on the description herein. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. The medicament for treating locally advanced unresectable or metastatic colorectal adenocarcinoma of MSS/MSI-L and the use thereof according to the present invention have been described in the preferred embodiments, and it will be apparent to those skilled in the relevant art that modifications and combinations of the uses and pharmaceutical compositions described herein can be made to practice and use the techniques of the present invention without departing from the spirit and scope of the invention.
EXAMPLE 1 phase II clinical study of CAP triple regimen and CP double regimen treatment of MSS/MSI-L locally advanced unresectable or metastatic colorectal adenocarcinoma
Three drug regimens of CAP: combination of Xindi Li Shan anti-ciladamine and IBI305.
CP double drug regimen: a dual drug combination regimen of meldi Li Shan anti + ciladalim.
1. Purpose of test and test method: the study was a phase II clinical study with PFS rate at week 18 after treatment (18 wPFS) as the primary endpoint, ORR, PFS, OS, DCR, DOR, safety as the secondary endpoint. The effectiveness and the safety of the CP double-drug regimen and the CAP triple-drug regimen on advanced microsatellite stabilized colorectal cancer patients with standard treatment failure are explored.
2. Test object:
group entry criteria:
1. locally advanced unresectable or metastatic colorectal adenocarcinoma (excluding adenosquamous carcinoma mixed type and other pathological types) confirmed by histopathological or cytological examination.
2. Microsatellite stabilization (MSS) or low microsatellite instability (MSI-L) was confirmed by PCR detection, or DNA mismatch repair (MMR) proteins including MLH1, MSH2, MSH6 and PMS2 proteins were detected by immunohistochemistry, and as a result, no protein loss was detected, and pMMR was confirmed.
3. Receiving failure of the first-line oxaliplatin-containing standard therapy, during or after the treatment, there is imaging evidence (e.g., CT scan) or clinical evidence (e.g., cytological reporting of new ascites or pleural effusion) that the disease is progressing or that the first-line oxaliplatin-containing standard therapy is stopped due to intolerance of toxicity; or receiving oxaliplatin-containing adjuvant chemotherapy, and recurrence within 180 days after last administration.
4. There is at least one measurable lesion according to RECIST v 1.1.
Ecog PS score 0-1 points.
6. The age is more than or equal to 18 years old and less than or equal to 75 years old.
7. Has sufficient organ and bone marrow functions, and laboratory examination values within 7 days before the administration meet the following requirements, and no treatment contraindications such as chemotherapy, immunotherapy and the like exist:
1) Blood convention: absolute Neutrophil Count (ANC) 1.5X109/L; platelet count (PLT) is not less than 100X 109/L; the hemoglobin content (HGB) is more than or equal to 9.0g/dL
2) Liver function: serum Total Bilirubin (TBIL) is less than or equal to 1.5 times the Upper Limit of Normal (ULN); alanine Aminotransferase (ALT) and aspartic acid Aminotransferase (AST) are not present in liver-metastatic subjects not more than 3.0 XULN, and ALT and AST are not more than 5.0 XULN in liver-metastatic subjects; serum albumin not less than 25g/L
3) Renal function: serum creatinine (Cr) is less than or equal to 1.5 XULN
4) Urine convention: the results showed that urine protein < 2+; for patients with urine at baseline, routine detection shows that urine protein is more than or equal to 2+, 24-hour urine collection should be carried out and 24-hour urine protein ration is less than 1g
5) Coagulation function: international Normalized Ratio (INR) is less than or equal to 1.5 XULN, and Activated Partial Thromboplastin Time (APTT) is less than or equal to 1.5 XULN
Exclusion criteria:
1. the traditional exposure to any anti-PD-1 antibody, anti-PD-L1 antibody, HDAC inhibitor, irinotecan and other drugs.
2. Any study drug was received within 4 weeks prior to the first dose of study treatment.
3. The last dose of anti-tumor treatment (chemotherapy, targeted therapy, tumor immunotherapy, tumor embolism, etc.) was received within 3 weeks before the first dose was administered.
4. Radiation was received within 4 weeks prior to the first dose.
5. Immunosuppressant drugs are used within 4 weeks prior to the first administration, excluding topical or physiological doses of systemic glucocorticoids that are nasal spray, inhaled or otherwise.
6. Before the first administration, toxicity which is not recovered to NCI CTCAE 5.0 grade or less than grade 1 caused by the prior anti-tumor treatment exists.
7. Symptomatic central nervous system metastasis and/or cancerous meningitis are known to exist.
8. Is known to suffer from acute or chronic active hepatitis B (HBsAg positive and HBV DNA not less than 2000IU/mL or not less than 10) 4 Copy number/mL) or acute or chronic active hepatitis c (HCV antibody positive and HCV RNA positive).
9. Arterial hypertension (systolic or diastolic pressure. Gtoreq.150 mmHg. Gtoreq.100 mmHg) which remains uncontrolled even with normative therapy
10. The baseline is a few times daily, which indicates colon or small intestine diseases with symptoms that are not easy to control.
11. There was a history of gastrointestinal perforation and/or fistula in the past 6 months, a history of peptic ulcer, a history of ileus (including incomplete ileus requiring parenteral nutrition), extensive intestinal resection (partial colectomy or extensive small intestinal resection with chronic diarrhea), crohn's disease, ulcerative colitis, celiac abscess, or chronic diarrhea in the long term. After the intestinal stent implantation operation.
3. Test materials:
signal di Li Shan antibody: the company of Xinda biopharmaceutical (su state) limited (trade name:)
sidamine: shenzhen micro-core biotechnology Co., ltd (trade name:)；
IBI305 (bevacizumab antibiotic analogue): xinda biopharmaceutical (su state) limited.
3. Test protocol:
the total 48 patients compete into groups, and are randomly divided into a CP double-drug group and a CAP three-drug group, and the total two groups are divided into two groups; wherein, the CAP three-drug group is used for 25 people, and the combination treatment scheme of the Sidamide, the IBI and the Sidamide is given to the Xindi Li Shan; CP two-drug group 23, given a treatment regimen of the combination of the singeing Li Shan anti + cidamine two-drug.
Three dosing regimens for CAP:
the Xindi Li Shan antibody, 200mg, IV clip, was administered once every 3 weeks, on day 1 of each cycle.
The administration of the Sidamine, 30mg, PO, and 30 minutes after meal is carried out, and the administration is carried out twice a week from 1 st day of 1 st period, wherein the interval between the two administrations is not less than 3 days (such as Monday and Tuesday, tuesday and Friday, tuesday and Saturday, etc.). If the administration of the ciladalam is stopped, the administration is resumed, and the administration is calculated twice per week from the time of the resumption of the administration.
IBI305,7.5mg/kg, IV clip, one treatment cycle every 3 weeks, with 1 st day of each cycle.
First, the Xindi Li Shan antibody, IV clip 60 (+ -15) minutes; IBI305,7.5mg/kg IV clip was administered after at least 5 minutes of interval. When any drug is stopped temporarily or permanently, other drugs can be used continuously.
Dosing regimen of CP dual drug group:
the Xindi Li Shan antibody, 200mg, IV clip, was administered once every 3 weeks, on day 1 of each cycle.
The administration of the Sidamine, 30mg, PO, and 30 minutes after meal is carried out, and the administration is carried out twice a week from 1 st day of 1 st period, wherein the interval between the two administrations is not less than 3 days (such as Monday and Tuesday, tuesday and Friday, tuesday and Saturday, etc.). If the administration of the ciladalam is stopped, the administration is resumed, and the administration is calculated twice per week from the time of the resumption of the administration.
Efficacy evaluation: two groups of patients were evaluated for 18 week progression free survival PFS, median PFS, ORR, PR, SD, PD, NE, DCR according to RECIST v 1.1.
Security assessment: 3 days before each cycle.
4. Test results
1. Efficacy indexes such as progression-free survival (18 wPFS), objective Remission Rate (ORR), partial remission rate (PR), lesion Stabilization (SD), lesion Progression (PD), neutrophil (NE), disease Control Rate (DCR) and the like in 18 weeks.
As shown in table 1, median PFS in CAP three-drug group patients 18w reached 66.7%, median PFS in CP two-drug group patients 18w was only 21.7%, and both had significant statistical differences (p=0.0006), and CAP three-drug regimen efficacy was significantly better than CP two-drug regimen. In addition, compared with the CP double-drug group, the patients in the CAP three-drug group are also significantly superior to the CP double-drug group in ORR, PR, PD, NE, DCR and other aspects. Test results show that the CAP three-drug group exhibits unexpected therapeutic effects in treating advanced microsatellite stabilized colorectal cancer disease compared to the CP two-drug group.
TABLE 1
2. Median PFS
As shown in fig. 1, the median progression-free survival (PFS) of the CP two-drug group was about 1.6 months, the median PFS of the CAP three-drug group was about 7.35 months, and there was a significant statistical difference between the two (p=0.009). The CAP three-drug group unexpectedly prolonged PFS in MSS/MSI-L locally advanced unresectable or metastatic colorectal adenocarcinoma patients compared to the CP two-drug group. In conclusion, the combination of the three medicines of the Sidamine, the Xindi Li Shan and the IBI305 can obviously prolong the progression-free survival time of the disease of the patients, and in the aspects of ORR, PR, PD, NE, DCR and the like, the patients in the three medicines can also obviously benefit.
The foregoing has outlined rather broadly the more detailed description of the invention in order that the detailed description of the invention herein may be better understood, and in order that the present invention may be better understood. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the invention can be made without departing from the principles of the invention and these modifications and adaptations are intended to be within the scope of the invention as defined in the following claims. The scope of the patent protection is defined by the claims and may include other embodiments that occur to those skilled in the art. Such other embodiments are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal language of the claims.
Claims (11)
1. Use of a combination of three components (1), component (2) and component (3) in the prevention and/or treatment and/or amelioration of a locally advanced unresectable or metastatic colorectal cancer disease or disease progression by one, two or three-wire administration and/or in the manufacture of a medicament for the prevention and/or treatment and/or amelioration of a locally advanced unresectable or metastatic colorectal cancer disease or disease progression by one, two or three-wire administration, wherein:
component (1) is selected from the group consisting of cetosteanamine or a pharmaceutically acceptable salt, crystal form, isomer, prodrug or metabolite thereof;
component (2) is selected from the group consisting of a syndesmosis Li Shan antibody or antigen-binding fragment or variant thereof or a biological analogue thereof;
component (3) is selected from bevacizumab or an antigen binding fragment or variant thereof or a biological analogue thereof;
preferably, the locally advanced unresectable or metastatic colorectal cancer is microsatellite stabilized (MSS) or low microsatellite unstable (MSI-L) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is a microsatellite stabilized (MSS) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is low microsatellite instability (MSI-L) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is locally advanced unresectable or metastatic colorectal adenocarcinoma;
preferably, component (1) is selected from the group consisting of cetrimide, or a pharmaceutically acceptable salt, crystalline form thereof;
further preferred, component (1) is selected from the group consisting of cetadalimamine, or forms a and B thereof;
further preferably, component (1) is selected from the group consisting of cetadamine;
preferably, component (2) is selected from the group consisting of a syndesmosidic Li Shan antibody or antigen-binding fragment thereof or a biological analogue thereof;
further preferably, component (2) is selected from the group consisting of the bezoar Li Shan antibody;
preferably, component (3) is selected from bevacizumab or an antigen binding fragment thereof or a biological analogue thereof;
further preferred, component (3) is selected from bevacizumab or a biological analogue thereof;
further preferred, component (3) is selected from bevacizumab or IBI305.
2. A pharmaceutical composition for the prevention and/or treatment and/or amelioration of a locally advanced unresectable or metastatic colorectal cancer disease or disease progression, in one, two or three wire, characterized by comprising: component (1), component (2) and component (3), wherein,
component (1) is selected from the group consisting of cetosteanamine or a pharmaceutically acceptable salt, crystal form, isomer, prodrug or metabolite thereof;
component (2) is selected from the group consisting of a syndesmosis Li Shan antibody or antigen-binding fragment or variant thereof or a biological analogue thereof;
component (3) is selected from bevacizumab or an antigen binding fragment or variant thereof or a biological analogue thereof;
preferably, the locally advanced unresectable or metastatic colorectal cancer is microsatellite stabilized (MSS) or low microsatellite unstable (MSI-L) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is a microsatellite stabilized (MSS) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is low microsatellite instability (MSI-L) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is locally advanced unresectable or metastatic colorectal adenocarcinoma;
preferably, component (1) is selected from the group consisting of cetrimide, or a pharmaceutically acceptable salt, crystalline form thereof;
further preferred, component (1) is selected from the group consisting of cetadalimamine, or forms a and B thereof;
further preferably, component (1) is selected from the group consisting of cetadamine;
preferably, component (2) is selected from the group consisting of a syndesmosidic Li Shan antibody or antigen-binding fragment thereof or a biological analogue thereof;
further preferably, component (2) is selected from the group consisting of the bezoar Li Shan antibody;
preferably, component (3) is selected from bevacizumab or an antigen binding fragment thereof or a biological analogue thereof;
further preferred, component (3) is selected from bevacizumab or a biological analogue thereof;
further preferred, component (3) is selected from bevacizumab or IBI305.
3. The pharmaceutical composition according to claim 2 for use in the prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer disease or disease progression by first, second or third line;
preferably, the locally advanced unresectable or metastatic colorectal cancer is microsatellite stabilized (MSS) or low microsatellite unstable (MSI-L) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is a microsatellite stabilized (MSS) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is low microsatellite instability (MSI-L) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is locally advanced unresectable or metastatic colorectal adenocarcinoma.
4. A kit comprising the pharmaceutical composition of claim 2.
5. The kit according to claim 4, wherein the component (1), the component (2) and the component (3) are unit preparations having the same or different specifications, and the component (1), the component (2) and the component (3) are placed in the same container or in different containers, respectively.
6. The kit according to claim 4 or 5, wherein component (1) is in a gastrointestinal administration form, preferably an oral formulation; component (2) and component (3) are in the form of parenteral administration, preferably injection.
7. The kit of claim 4 or 5, wherein: the component (1) is the cetrimide, and the specification of the cetrimide is 5 mg/tablet; component (2) is Xindi Li Shan antibody, and the specification is 100mg/10ml; the component (3) is IBI305 or bevacizumab, and the specification of the component is 100mg/4ml or 400mg/16ml.
8. The kit of any one of claims 4-7, wherein: the kit further contains a label comprising information: component (1), starting from 1 st day of 1 st cycle, is taken twice a week, at an interval of not less than 3 days; component (2), administered on day 1 of each cycle, every 3 weeks for a treatment cycle; component (3), administered on day 1 of each cycle, every 3 weeks for a treatment cycle;
preferably, the tag further comprises information: component (1), 30mg, 30 minutes PO after meal, taken twice a week from 1 st period 1 st day, at a time interval of not less than 3 days;
preferably, the tag further comprises information: component (2), 200mg, iv clip, administered on day 1 of each cycle, every 3 weeks for a treatment cycle;
preferably, the tag further comprises information: component (3), 7.5mg/kg, IV clip, administered on day 1 of each cycle, one treatment cycle every 3 weeks;
preferably, the tag further comprises information: component (3) is administered at least 5 minutes after the administration of component (2).
9. A method for the first, second or third line prevention and/or treatment and/or amelioration of locally advanced unresectable or metastatic colorectal cancer, comprising administering to a patient in need thereof a prophylactically and/or therapeutically and/or ameliorating effective amount of a pharmaceutical composition according to claim 2;
preferably, the locally advanced unresectable or metastatic colorectal cancer is microsatellite stabilized (MSS) or low microsatellite unstable (MSI-L) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is a microsatellite stabilized (MSS) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is low microsatellite instability (MSI-L) locally advanced unresectable or metastatic colorectal cancer;
preferably, the locally advanced unresectable or metastatic colorectal cancer is locally advanced unresectable or metastatic colorectal adenocarcinoma.
10. The method of claim 9, wherein component (1), component (2) and component (3) are administered simultaneously, separately or sequentially.
11. The method according to claim 10, wherein component (1) is administered 1-4 times per week, preferably 2 times per week; the component (2) is administered 1 time every 2-5 weeks, preferably 1 time every 3 weeks; the component (3) is administered 1 time every 2-5 weeks, preferably 1 time every 3 weeks;
preferably, said component (1) is administered at a dose of 10-60mg each time, preferably 20-40mg each time, more preferably 30mg each time;
preferably, said component (2) is administered 100-300mg each time, preferably 200mg each time;
preferably, said component (3) is administered 5-10mg/Kg per administration, preferably 6-8mg/Kg per administration, more preferably 7.5mg/Kg per administration;
further preferred, said component (2) is a bedi Li Shan antibody or a biological analogue thereof, preferably a bedi Li Shan antibody; a treatment cycle every 2-4 weeks, preferably every 3 weeks; day 1 of each cycle;
further preferred, the component (3) is bevacizumab or a biological analogue thereof, preferably bevacizumab or IBI305; a treatment cycle every 2-4 weeks, preferably every 3 weeks; day 1 of each cycle;
further preferred, the component (1) is cetadamine; orally taking 30 minutes after meal; taking medicine twice every week from 1 st day of 1 st period, wherein the interval between taking medicine twice is not less than 3 days;
preferably, component (2) is administered at least 5 minutes after administration, said component (2) is preferably a bevacizumab or IBI305 and said component (3) is preferably a bevacizumab;
further preferably, both the component (2) and the component (3) are injections and intravenous drip; component (1) is a tablet for oral administration.
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| CN202310481472.2A CN116459336A (en) | 2023-04-27 | 2023-04-27 | Medicament for treating locally advanced unresectable or metastatic colorectal cancer and application thereof |
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