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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
  • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
• • A—HUMAN NECESSITIES
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  • 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
• • A—HUMAN NECESSITIES
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  • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
• • 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
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
  • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• • 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
  • A61K31/66—Phosphorus compounds
  • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• • 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
• • 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
• • 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
  • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
  • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
  • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
  • C07K16/2887—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
• • 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
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

• the present invention relates to the technical field of medicine, and specifically relates to the application of cidabenamine combined with R-CHOP and combined medicine.
• B-cell lymphoma mainly includes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone B-cell lymphoma (MZL), mantle cell lymphoma (MCL), etc.
• the object of the present invention is to provide the use of cidabenamide combined with R-CHOP in the preparation of a medicament for the treatment of B-cell lymphoma and / or the treatment of B-cell lymphoma.
• DICE refers to the R-CHOP combination drug regimen in the art, namely rituximab (R) combined with cyclophosphamide (CTX), doxorubicin or epirubicin (ADR / EPI), vincristine (VCR ), Prednisone (Pred) combined drug regimen; in a specific embodiment of the present invention, a clinical trial is conducted with diffuse large B-cell lymphoma as a specific treatment disease.
• Chidamide (Chidamide) is a subtype selective histone deacetylase (HDAC) inhibitor independently researched and developed in China, which is a new class 1.1 drug.
• HDAC histone deacetylase
• Cidabenamide mainly targets subtypes 1, 2, and 3 of type I HDAC and subtype 10 of type IIb, and has a regulatory effect on abnormal epigenetic function of tumors.
• chromatin remodeling by inhibiting related HDAC subtypes to increase the acetylation level of chromatin histones, and thus produces changes in gene expression (ie epigenetic changes) against multiple signaling pathways, thereby inhibiting tumor cells Cycle, induce tumor cell apoptosis, and have overall regulatory activity on the body's cellular immunity, and induce and enhance natural killer cells (NK) and antigen-specific cytotoxic T cells (CTL) mediated tumor killing.
• NK natural killer cells
• CTL antigen-specific cytotoxic T cells
• Cidabenamide also has the functions of inducing the differentiation of tumor stem cells and reversing the epithelial mesenchymal phenotype transformation (EMT) of tumor cells through epigenetic regulation mechanism, thereby restoring the sensitivity of drug-resistant tumor cells to drugs and inhibiting tumors Play a potential role in metastasis and relapse.
• EMT epithelial mesenchymal phenotype transformation
• the present invention unexpectedly finds that cidabenamide combined with R-CHOP has a synergistic effect in the treatment of diffuse large B-cell lymphoma, especially with a better effect on newly-treated, high-risk, elderly DLBCL patients; adopting the present invention
• a total of 31 evaluable patients had a CR rate of 90.3% and a PR rate of 6.5%.
• a total of 23 evaluable patients had a CR rate of 87% and an ORR of 100%.
• the results of this clinical trial showed that R-CHOP combined with cidabenamide in the treatment of primary, elderly, and high-risk diffuse large B-cell lymphoma has a significant improvement in efficacy compared to R-CHOP regimen.
• the present invention specifically provides a combination medicine comprising an effective dose of cidabenamide, rituximab, cyclophosphine for simultaneous, separate or sequential administration Amide, doxorubicin or epirubicin, vincristine and prednisone.
• the present invention also provides a preparation for preparing B-cell lymphoma, which uses the above-mentioned combined drug as the main active drug, and adds other active ingredients and / or pharmaceutical excipients that do not affect each other.
• the other active ingredients that do not affect each other may be active ingredients for treating B-cell lymphoma, active ingredients for treating other diseases, or a combination of both.
• the present invention also provides a method for treating B-cell lymphoma, simultaneous, separate or sequential administration of effective doses of cidabenamide, rituximab, cyclophosphamide, doxorubicin or epirubicin, Vincristine and prednisone.
• the present invention proposes the application of cidabenamide combined with R-CHOP for synergistic treatment of B-cell lymphoma, and has verified the diffuse treatment of cidabenamine combined with R-CHOP through clinical trials Large B-cell lymphoma is more effective than the R-CHOP regimen, and the application can more effectively treat patients with B-cell lymphoma.
• the invention discloses the application of cidabenamine combined with R-CHOP and the combined drugs.
• Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve.
• all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.
• the application of the present invention has been described through preferred embodiments, and it is obvious that relevant persons can modify or appropriately modify and combine the applications described herein without departing from the content, spirit, and scope of the present invention to implement and apply the technology of the present invention. .
• Example 1 Prospective, single-arm, open phase II study of cidabenamide combined with R-CHOP regimen in the treatment of primary, elderly, high-risk diffuse large B-cell lymphoma
• Test drug Cidabenamide tablets: off-white tablets, 5mg / tablet. Produced by Shenzhen Weixin Biotechnology Co., Ltd.
• R-CHOP combined chemotherapy drugs rituximab (R) combined with cyclophosphamide (CTX), doxorubicin or epirubicin (ADR / EPI), vincristine (VCR), prednisone (Pred) .
• CTX cyclophosphamide
• ADR / EPI doxorubicin or epirubicin
• VCR vincristine
• Pred prednisone
• Number of cases A total of 49 patients are planned to be included in this clinical trial.
• Inclusion criteria Patients must meet all of the following criteria before being enrolled.
• Histopathology confirmed the diagnosis of diffuse large B-cell lymphoma with positive CD20;
• ECOG physical status score is 0, 1 or 2 points
• the investigator judges patients with a life expectancy of at least 6 months;
• next course of treatment should be delayed by 3-4 days, while repeating the blood cell test. If the above target is not reached, the treatment will be delayed for another 3-4 days until the above chemotherapeutic standard is reached. If the treatment is delayed for more than 14 days and the standard is not met, the patient will withdraw from the treatment and be recorded as an adverse event. The patient will continue to be followed up as required by the protocol.
• VCR is reduced to 1 mg
• Cidabenamide If the disease has not progressed or there are no intolerable adverse reactions, it is recommended to continue taking the drug. Throughout the course of treatment, occurs when the bone marrow suppression 3-4, medication suspended until absolute neutrophil count returns to ⁇ 1.5 ⁇ 10 9 / L, platelet recovery to ⁇ 75.0 ⁇ 10 9 / L to continue treatment of this product.
• Patients with a large tumor load (large mass or lactate dehydrogenase greater than or equal to 500u / L) or PS equal to 2 or gastrointestinal NHL (prevention of gastrointestinal perforation) for first-pass chemotherapy should be given allopurinol and baking soda first Prednisone, if necessary, chemotherapy is performed in 2 days to prevent tumor lysis syndrome.
• G-CSF Granulocyte knockdown stimulating factor
• the concomitant treatment given due to adverse events also needs to be reported if they meet the reporting standards. This content should be filled in the adverse events page of the CRF form. If necessary, patients can be given enough supportive treatment, including whole blood and blood products transfusion, antibiotic treatment, antiemetic treatment and other treatment reasons, dose and treatment date should also be recorded in the CRF table.
• Clinical trial results mid-term evaluation, a total of 31 evaluable patients, CR rate 90.3%, PR rate 6.5%. In the final evaluation, a total of 23 evaluable patients had a CR rate of 87% and an ORR of 100%.

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