Cancer treatment with a combination of anti-CD20 antibody and acylfluben

Abstract

A method of treating cancer involves administering a combination of activators comprising a therapeutically effective dose of acylfluben or a pharmaceutically acceptable salt thereof and a therapeutically effective dose of an anti-CD20 antibody. The anti-CD20 antibody can be selected from rituximab, obinutuzumab, ofatumumab, and tocitumomab. The cancer may be a B-cell carcinoma.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims the interests of U.S. Provisional Patent Application No. 63 / 504,946, filed on 30 May 2023, which is incorporated herein by reference in its entirety.

[0002] (Field of invention) This application relates to cancer treatment, and more specifically, to cancer treatment (e.g., lymphoma) using combination therapy comprising rituximab and acilfluben. [Background technology]

[0003] Non-Hodgkin lymphoma (NHL) is a group of cancers that originate in the lymphatic system, which is part of the body's immune system. Unlike Hodgkin lymphoma, which is characterized by the presence of Reed-Sternberg cells, NHL encompasses a diverse set of lymphoid malignancies with different subtypes and characteristics.

[0004] NHL is classified into various subtypes based on the specific type of lymphocytes involved (B cells, T cells, or natural killer cells), the stage of cell maturation, and other factors such as gene mutations and growth patterns. Common subtypes include diffuse large B-cell lymphoma (DLBCL), the most common and aggressive form; follicular lymphoma (FL), which typically grows more slowly; mantle cell lymphoma (MCL), known for its poor prognosis and invasive nature; and Burkitt lymphoma, a highly invasive cancer associated with the Epstein-Barr virus. Each subtype has different clinical manifestations, prognoses, and treatment approaches.

[0005] Anti-CD20 antibodies have revolutionized the treatment of various diseases by specifically targeting B cells and modulating the immune response. These monoclonal antibodies, such as rituximab, act by binding to the CD20 protein on the surface of B cells, leading to their destruction through mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cell-mediated cytotoxicity (CDC), and direct apoptosis. This targeted approach has significantly improved outcomes in patients with B-cell malignancies, including many subtypes of NHL. However, anti-CD20 monoclonal antibodies alone typically cannot cure B-cell malignancies, particularly the more invasive forms.

[0006] Therefore, improved treatments for NHL and other hematological cancers are always needed. This application relates, in particular, to this need. [Overview of the project]

[0007] One embodiment includes a method for treating cancer, comprising administering to a subject requiring treatment a combination of an activator, specifically, a therapeutically effective amount of acylflubene or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an anti-CD20 antibody. The acylflubene may be hydroxyureamethylacylflubene. Acylflubene has the following structure:

[0008] [ka] Or it has the following structure.

[0009] [ka]

[0010] Another embodiment includes a method of selecting the anti-CD20 antibody from the group consisting of rituximab, obinutuzumab, ofatumumab, and tositumomab. The anti-CD20 antibody may be rituximab or an antigen-binding fragment of the antibody.

[0011] Another embodiment includes a method in which the hematological cancer to be treated is a B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or Burkitt lymphoma.

[0012] Another embodiment includes a method in which acylfluben and anti-CD20 antibody are administered sequentially or simultaneously.

[0013] Another embodiment includes a method for formulating acylfluben and an anti-CD20 antibody for intravenous administration.

[0014] Another embodiment includes a method in which the combination therapy results in enhanced apoptosis of cancerous B cells compared to the administration of either an illidine analog or an anti-CD20 antibody alone.

[0015] Another embodiment includes a method in which the presence of one or more cancer cells lacking HR-dependent DNA damage repair indicates that a subject responds to treatment.

[0016] Another embodiment includes a method of administering an illidine analog and an anti-CD20 antibody together with a pharmaceutically acceptable carrier or excipient.

[0017] Another embodiment includes a method in which the combination therapy reduces the proliferation of cancerous B cells and inhibits tumor growth.

[0018] Another embodiment includes a method for treating recurrent or refractory B-cell carcinoma. [Brief explanation of the drawing]

[0019] [Figure 1] This study demonstrates the synergistic effect of LP-284 or (+)-hydroxyureamethylacylfluben combined with an anti-CD20 monoclonal antibody (rituximab) on tumor growth in xenograft models. [Figure 2] This figure shows tumor growth curves obtained with treatment using LP-284 or (+)-hydroxyureamethylacylfluben in combination with rituximab, a standard lymphoma treatment drug. [Figure 3] Treatment with LP-284 significantly reduced B cells (CD19+ or CD20+) by approximately 30% in mice with sufficient immunity after 3 doses. **DETAILED DESCRIPTION OF THE INVENTION**

[0020] The present application provides a combination therapy for treating blood cancer. In an embodiment, the therapy comprises administering a combination of agents including acylfulvene or iludin and an anti-CD20 antibody. In other embodiments, the therapy comprises administering combinations of various therapies. In other embodiments, the therapy comprises a combination therapy that can be used to treat the biochemical development and recurrence of blood cancer, wherein acylfulvene (e.g., hydroxyurea methyl acylfulvene) or a salt thereof and an anti-CD20 antibody are administered to a patient in a therapeutically effective amount. In certain embodiments, the combination can provide treatment for lymphomas such as mantle cell lymphoma (MCL) and double hit lymphoma (DHL). In certain embodiments, the combination is used to treat non-Hodgkin lymphoma that is homologous recombination deficiency positive (HRD+). <​​​​​​​​​​​​​

[0024] In another example, acylflubene is (+)-hydroxyureamethylacylflubene( This is called LP-284 by Lantern Pharma Inc., and it negatively shifts light, as shown below.

[0025] [ka]

[0026] (+)hydroxyureamethylacylflubene and (-)hydroxyureamethylacylflubene are enantiomers and are now publicly known.

[0027] In another example, acylfulben is ilolfulben.

[0028] Anti-CD20 antibody Anti-CD20 antibodies are a type of monoclonal antibody that specifically targets the CD20 protein found on the surface of certain immune cells called B cells. These antibodies are designed to selectively bind to CD20 and produce various therapeutic effects. The term "anti-CD20 antibody" refers to an antibody that specifically binds to the CD20 antigen. There are two main types of anti-CD20 antibodies, depending on their binding properties and biological activity against the CD20 antigen.

[0029] One specific and well-known anti-CD20 antibody is rituximab, which was the first approved monoclonal antibody targeting CD20. Rituximab is used to treat several conditions, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), and certain autoimmune disorders. Rituximab works by targeting the CD20 protein found on the surface of B cells. By binding to CD20, rituximab helps selectively destroy B cells that may be overactive or cancerous in certain conditions. In the case of non-Hodgkin lymphoma (NHL), rituximab is often used in combination with chemotherapy. In the case of chronic lymphocytic leukemia (CLL), rituximab may be used in combination with other drugs to treat this type of cancer that affects white blood cells.

[0030] Rituximab is a genetically engineered chimeric mouse / human monoclonal antibody against the CD20 antigen, as described in U.S. Patent No. 5,736,137 (Anderson et al.), issued on April 7, 1998.

[0031] In certain embodiments, the anti-CD20 antibody may include, or be derived from, a rituximab biosimilar such as Britzima, Ritembia, or Taxela. Rituximab and its biosimilars belong to a class of drugs known as monoclonal antibodies and are primarily used to treat certain types of cancer and autoimmune diseases.

[0032] In one embodiment, rituximab can be administered intravenously, and the treatment protocol may vary depending on the condition being treated.

[0033] Homologous recombination deficiency (HRD) positive Homologous recombination deficiency (HRD) positivity refers to the presence of genetic or genomic alterations in tumors that indicate defects or impairments in the homologous recombination DNA repair pathway. HRD positivity is often evaluated in cancer contexts, particularly in relation to predicting responses to specific treatments.

[0034] If tumors have HRD, they are likely to have difficulty repairing DNA damage such as double-strand breaks. This may make them more susceptible to certain therapies that exploit these repair deficiencies.

[0035] HRD positivity can be determined by a variety of methods, including genetic testing, genomic profiling, or specific biomarker assays. These tests aim to identify HRD-related genetic or genomic changes, such as mutations or loss of function in genes involved in homologous recombination pathways.

[0036] Evaluating HRD positivity can influence treatment decisions. For example, in ovarian cancer, HRD positivity is used as a predictive biomarker for drug response. Drugs that block alternative DNA repair pathways on which HRD-positive cancer cells depend lead to their selective targeting and cell death.

[0037] In one embodiment, acylflubene or hydroxyureamethylacylflubene or a salt thereof may be administered before, concurrently with, or after the administration of an anti-CD20 antibody (e.g., rituximab).

[0038] One aspect of this application includes a method for treating cancer in a subject requiring such treatment. The method includes administering an effective dose of an anti-CD20 antibody (e.g., rituximab) and an effective dose of acylfluben to the subject. The anti-CD20 antibody (e.g., rituximab) may be administered before or simultaneously with acylfluben for optimal synergistic effect.

[0039] Another embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of illidine or an illidine analog, derivative thereof, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an anti-CD20 antibody (e.g., rituximab) or an analog, derivative thereof, or a pharmaceutically acceptable salt thereof. The illidine analog may be hydroxyureamethylacylflubene.

[0040] In another embodiment, a kit for treating cancer in a subject comprises a therapeutically effective amount of illidine or its illidine analog, derivative, or pharmaceutically acceptable salt thereof, and a therapeutically effective amount of an anti-CD20 antibody (e.g., rituximab).

[0041] In another embodiment, the second therapeutic agent comprises one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epotilon B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and Raf kinase inhibitors.

[0042] In another embodiment, the second therapeutic agent is one or more chemotherapeutic agents selected from paclitaxel or cisplatin.

[0043] In one embodiment, acylflubene or hydroxyureamethylacylflubene or a salt thereof may be administered before, simultaneously with, or after the administration of an anti-CD20 antibody.

[0044] One aspect of this application includes a method for treating cancer in subjects requiring such treatment. The method includes administering an effective dose of anti-CD20 antibody and an effective dose of acylfluben to the subject. The anti-CD20 antibody may be administered before or concurrently with acylfluben for optimal synergistic effect. The anti-CD20 antibody degrades the important nucleotide excision repair (NER) protein XPB / ERCC3 (see: https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC7277409 / ), resulting in NER deficiency. Subjects with NER deficiency are more sensitive to illidine-based anticancer agents.

[0045] Another embodiment includes a pharmaceutical composition comprising a therapeutically effective amount of illidine or an illidine analog, derivative thereof, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of anti-CD20 antibody or an analog, derivative thereof, or a pharmaceutically acceptable salt thereof. The illidine analog may be hydroxyureamethylacylflubene.

[0046] In another embodiment, a kit for treating cancer in a subject comprises a therapeutically effective amount of illidine or its illidine analog, derivative, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of anti-CD20 antibody or its analog, derivative, or a pharmaceutically acceptable salt thereof.

[0047] In another embodiment, the second therapeutic agent is one or more chemotherapeutic agents selected from camptothecin derivatives, paclitaxel, docetaxel, epotilon B, 5-FU, gemcitabine, oxaliplatin, cisplatin, carboplatin, melphalan, dacarbazine, temozolomide, doxorubicin, imatinib, erlotinib, bevacizumab, cetuximab, and Raf kinase inhibitors.

[0048] In another embodiment, the second therapeutic agent is one or more chemotherapeutic agents selected from paclitaxel or cisplatin.

[0049] The term “combination therapy” may or may include the administration of the aforementioned therapeutic agent in further combination with other biologically active components and non-pharmacological therapies (e.g., surgery or radiotherapy). Where combination therapy further includes non-pharmacological treatment, the non-pharmacological treatment may be performed at any appropriate time, insofar as beneficial effects from the synergistic effects of the combination of the therapeutic agent and the non-pharmacological treatment are achieved. For example, where appropriate, beneficial effects may still be achieved if the non-pharmacological treatment is temporarily removed from the administration of the therapeutic agent, perhaps for several days or even weeks.

[0050] In another embodiment, the compositions or combination therapies of this specification, or pharmaceutically acceptable salts or solvates thereof, may be administered in combination with radiotherapy. Radiotherapy may also be administered as part of a multi-drug therapy in combination with the compositions of the present invention and other chemotherapeutic agents described herein.

[0051] Combination therapy can be achieved by administering two or more drugs, each formulated and administered separately, such as acylfluben, an anti-CD20 antibody, and one or more other therapeutic agents, or by administering two or more drugs in a single formulation. Other combinations are also included in combination therapy. For example, two drugs can be formulated together and administered in combination with a separate formulation containing a third drug. Two or more drugs in combination therapy can be administered simultaneously, but are not required. For example, the administration of the first drug (or combination of drugs) may precede the administration of the second drug (or combination of drugs) by several minutes, hours, days, or weeks. Thus, two or more drugs can be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases, longer intervals are possible. In many cases, it is desirable, but not necessary, for two or more drugs used in combination therapy to be present in the patient's body at the same time.

[0052] Combination therapy methods may or should produce synergistic effects, where the effect of a combination of compounds or other therapeutic agents is greater than the combined effect of administering either the compound or the other therapeutic agent as a single agent. Synergistic effects may also be effects that cannot be achieved by administering either the compound or the other therapeutic agent as a single agent. Synergistic effects may include, but are not limited to, effects that treat cancer by reducing tumor size, inhibiting tumor growth, or increasing the survival of the subject. Synergistic effects may also include reducing the survival rate of cancer cells, inducing cancer cell death, and inhibiting or delaying cancer cell growth.

[0053] The therapeutically effective dose can vary, as will be recognized by those skilled in the art, depending on the disease being treated, the severity of the disease, the route of administration, the patient's age and overall health, the use of excipients, the possibility of concomitant use with other therapeutic measures such as other drugs, and the judgment of the treating physician. For example, guidelines for selecting the effective dose can be determined by referring to the prescribing information for hydroxyureamethylacylfluben or the articles in its journal.

[0054] As used herein, the term “effective dose” refers to the amount of drug necessary to alleviate at least one symptom of a disease or disorder, and relates to a sufficient amount of a pharmaceutical composition to provide the desired effect. Thus, the term “therapeutic effective dose” refers to the amount of drug sufficient to provide a specific effect when administered to a typical subject. As used herein, effective doses also include, in various contexts, an amount sufficient to delay the onset of symptoms of a disease, alter the course of symptoms of a disease (e.g., slow the progression of symptoms of a disease), or reverse symptoms of a disease. Therefore, determining the exact “effective dose” is generally impractical. However, for any given case, a suitable “effective dose” can be determined by those skilled in the art using only routine experiments.

[0055] The dosage range for administering drugs according to the methods described herein depends, for example, on the form of the drug, its potency, and the desired degree of reduction in the symptoms, markers, or indicators of the condition described herein, for example, the desired rate of reduction in tumor growth. The dosage should not be so high as to cause adverse side effects. In general, the dosage will vary depending on the patient's age, condition, and sex and can be determined by those skilled in the art. The dosage may also be adjusted by the individual physician in the case of any complications.

[0056] As used herein, the term “therapeutic effective dose” refers to a sufficient amount of medicinal agent to treat, improve, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective dose for a subject depends on the subject’s weight, size, and health status; the nature and severity of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. A therapeutic effective dose for a given situation can be determined by routine experimentation, which is within the scope of the clinician’s skill and judgment. In a preferred embodiment, the disease or condition being treated is cancer. In another embodiment, the disease or condition being treated is a cytoproliferative disorder.

[0057] For example, the effectiveness of the agents described herein in treating the conditions described herein or in inducing the responses described herein (e.g., solid tumors or hematological malignancies) can be determined by a skilled clinician. However, if one or more signs or symptoms of the conditions described herein are beneficially altered, other clinically acceptable symptoms are improved or further improved, or the desired response is induced in at least 10% of cases after treatment by the method described herein, then the treatment is considered "effective treatment" as used herein. Effectiveness can be assessed, for example, by measuring markers, indicators, symptoms, and / or incidence of the condition treated according to the method described herein, or any other suitable measurable parameters, such as tumor size and / or growth rate. Effectiveness can also be measured by whether the individual being evaluated by hospitalization does not worsen or whether there is a need for medical intervention (i.e., cessation of disease progression). Methods for measuring these indicators are known to those skilled in the art and / or are described herein. Treatment includes any treatment of a disease in an individual or animal (some non-limiting examples include humans or animals), and includes (1) inhibiting the disease, e.g., preventing the worsening of symptoms (e.g., pain or inflammation), or (2) reducing the severity of the disease, e.g., causing regression of symptoms. An effective dose for treatment of a disease means an amount sufficient to produce an effective treatment for the disease, as defined herein, when administered to a subject in need of it. The effectiveness of a drug can be determined by evaluating physical indicators of the condition or desired response. Monitoring the effectiveness of administration and / or treatment by measuring any one of such parameters or any combination of parameters is well within the capabilities of those skilled in the art. Effectiveness can be evaluated in animal models of the conditions described herein, e.g., in the treatment of hematological malignancies in mouse models. When using experimental animal models, the effectiveness of a treatment is demonstrated when a statistically significant change in markers, e.g., tumor size and / or growth rate, is observed.In some embodiments, a therapeutically effective dose of hydroxyureamethyl-acylfluben, acylfluben, or ilofluben, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of 0.5 mg / day, 1 mg / day, 2.5 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 30 mg / day, 60 mg / day, 90 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day.

[0058] The dosage of anti-CD20 antibodies such as rituximab should be adjusted to suit the individual needs of each patient. For cancer treatment, rituximab is typically administered as an intravenous infusion at a dose of 375 mg / m². 2 It is administered in the following doses. Following the initial dose, 375 mg / m² is given once a week for a total of 4 to 8 weeks, depending on the specific treatment protocol and the patient's response. 2 Additional doses are often given. In maintenance therapy, rituximab is administered at 375 mg / m² every 2-3 months for up to 2 years. 2 It can be administered in the following doses. The infusion rate should be started at 50 mg / hour and can be increased by 50 mg / hour every 30 minutes up to a maximum of 400 mg / hour, provided there is no severe infusion reaction. Premedication with antihistamines such as acetaminophen and diphenhydramine is recommended to minimize the risk of infusion-related reactions.

[0059] The dosage of rituximab should be adjusted to suit the individual needs of each patient. For cancer treatment, rituximab is typically administered as an intravenous infusion at a dose of 375 mg / m². 2 It is administered in the following doses. Following the initial dose, 375 mg / m² is given once a week for a total of 4 to 8 weeks, depending on the specific treatment protocol and the patient's response. 2 Additional doses are often given. In maintenance therapy, rituximab is administered at 375 mg / m² every 2-3 months for up to 2 years.2 It can be administered at a dosage of. The infusion rate should start at 50 mg / h and can be increased by 50 mg / h every 30 minutes up to a maximum of 400 mg / h, provided there is no severe infusion reaction. Premedication with antihistamines such as acetaminophen and diphenhydramine is recommended to minimize the risk of infusion-related reactions.

[0060] In one example, the dosage of rituximab for treating cancer, specifically B-cell non-Hodgkin lymphoma, can include the following: (1) (initial dose) 375 mg / m 2 administered as an intravenous (IV) infusion of rituximab, (2) (subsequent doses) after this initial dose, depending on the specific treatment protocol and the response of the subject, additional doses of 375 mg / m 2 are often continued once a week over a total of 4 - 8 weeks, and / or (3) (maintenance therapy) in some cases, rituximab can be administered as maintenance therapy. For example, in follicular lymphoma, rituximab can be given at a dosage of 375 mg / m[[ID=IO]] 2 every 2 - 3 months for up to 2 years after the initial treatment regimen. When used in combination with other chemotherapeutic agents, the dosing schedule of rituximab can be adjusted based on the specific chemotherapy regimen. For example, in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, rituximab is typically administered on the first day of each chemotherapy cycle.

[0061] The term "treating" is used and includes both therapeutic treatment and prophylactic treatment (reducing the likelihood of onset). Both terms mean reducing, suppressing, attenuating, shrinking, stopping, or stabilizing the onset or progression of a disease (e.g., a disease or disorder described herein), reducing the severity of the disease, or improving the symptoms associated with the disease.

[0062] The pharmaceutical composition can be included in a container, pack, or dispenser, together with instructions for administration.

[0063] The compositions of the present invention can further form salts. Each molecule of the compositions can form two or more salts, such as mono-, di-, and tri-. All of these forms are also considered to be within the scope of the claimed invention.

[0064] As used herein, "pharmaceutically acceptable salt" refers to a derivative of the compound of the present invention in which the parent compound is modified by forming an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. Examples of pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolyarsanilic acid, hexylresorcinic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, and hydroxy Examples include, but are not limited to, salts derived from inorganic and organic acids selected from commonly existing amine acids, such as naphthoic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, peracetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly existing amine acids, such as glycine, alanine, phenylalanine, and arginine.

[0065] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvate, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-octa-2-ene-l-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, and muconic acid. The present invention also includes salts formed when the acidic proton in the parent compound is substituted with a metal ion, such as an alkali metal ion, an alkaline earth ion, or an aluminum ion, or when it coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, or N-methylglucamine.

[0066] Please understand that all references to pharmaceutically acceptable salts include the solvated form (solvate) of the same salt.

[0067] As used herein, the term “selectively” means that an event tends to occur more frequently in one population than in another. The population being compared may be a population of cells. Preferably, the compounds of the present invention, or their pharmaceutically acceptable salts or solvates, act selectively on cancer or precancerous cells but not on normal cells. Preferably, the compounds of the present invention, or their pharmaceutically acceptable salts or solvates, act selectively to modulate one molecular target (e.g., nucleotide excision repair (NER) player ERCC3). The present invention also provides a method for selectively inhibiting the activity of an enzyme, such as a NER protein. Preferably, an event occurs selectively in population A compared to population B if it occurs more than twice as frequently in population A compared to population B. An event occurs selectively if it occurs more than five times as frequently in population A. An event occurs selectively in population A compared to population B if it occurs more than ten times as frequently in population A, more preferably more than fifty times as frequently, even more preferably more than 1000 times as frequently, and most preferably more than 100 times as frequently. For example, if cell death occurs more than twice as frequently in cancer cells compared to normal cells, then cell death will likely occur selectively in cancer cells.

[0068] The composition, or a pharmaceutically acceptable salt or solvate thereof, may be administered orally, nasally, dermatologically, pulmonaryly, by inhalation, orally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of specific routes of administration.

[0069] A drug regimen utilizing a compound is selected according to various factors, including the patient's type, breed, age, weight, sex, and medical condition; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the specific compound or salt thereof to be used. A physician or veterinarian skilled in the art can easily determine and prescribe the effective dose of the drug necessary to prevent, counteract, or halt the progression of the condition.

[0070] Techniques for formulation and administration of the compounds disclosed in this invention can be found in Remington: The Science and Practice of Pharmacy, 19th sup.th edition, Mack Publishing Co., Easton, Pa. (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in combination with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds are present in such pharmaceutical compositions in an amount sufficient to provide a desired dose within the range described herein.

[0071] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present invention are evident from different examples. The provided examples illustrate different components and methodologies useful for carrying out the present invention. The examples do not limit the claimed invention. Based on this disclosure, those skilled in the art can identify and use other components and methodologies useful for carrying out the present invention.

[0072] As used herein, “subjects requiring it” are subjects having a precancerous condition. Preferably, subjects requiring it have cancer. “Subjects” include mammals. Mammals may be, for example, any mammal, e.g., humans, primates, birds, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. Preferably, the mammal is human. The subjects of the present invention include any human subject that has been diagnosed with cancer or a precancerous condition, has symptoms of cancer or a precancerous condition, or is at risk of developing cancer or a precancerous condition.

[0073] Subjects requiring this treatment may have refractory or resistant cancer. “Refractory or resistant cancer” means cancer that does not respond to treatment. The cancer may be resistant at the start of treatment, or may become resistant during treatment. In some embodiments, subjects requiring this treatment have experienced cancer recurrence after remission with the most recent therapy. In some embodiments, subjects requiring this treatment have received and failed all known effective therapies for cancer treatment. In some embodiments, subjects requiring this treatment have received at least one prior therapy. In certain embodiments, the prior therapy is monotherapy. In certain embodiments, the prior therapy is combination therapy.

[0074] In some embodiments, the subject requiring it may have a secondary cancer as a result of prior therapy. "Secondary cancer" means a cancer that arises as a result of or caused by prior oncogenic therapy, such as chemotherapy.

[0075] Cancer is a group of diseases that can cause almost any sign or symptom. The signs and symptoms depend on where the cancer is located, its size, and the extent to which it affects nearby organs or structures. If the cancer spreads (metastasizes), symptoms may appear in different parts of the body.

[0076] Treating cancer can result in a reduction in tumor size. This reduction in tumor size may also be referred to as "tumor regression." Preferably, after treatment, the tumor size is reduced by 5% or more compared to its size before treatment; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by 75% or more. Tumor size can be measured by any reproducible measuring means. Tumor size can be measured as the diameter of the tumor.

[0077] Treating cancer results in a reduction in the number and size of tumors. Preferably, after treatment, the number or size of tumors is reduced by 5% or more compared to the number before treatment; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of tumors can be measured by any reproducible measuring means. The number of tumors can be measured visually or by counting tumors visible at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0078] Treating cancer can result in a reduction in the number of metastatic lesions in other tissues or organs distant from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is reduced by 5% or more compared to the number before treatment; more preferably, by 10% or more; more preferably, by 20% or more; more preferably, by 30% or more; more preferably, by 40% or more; even more preferably, by 50% or more; and most preferably, by more than 75%. The number of metastatic lesions can be measured by any reproducible measuring means. The number of metastatic lesions can be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. Preferably, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

[0079] Treating cancer can result in an increase in the mean survival time of the treated population compared to the population receiving only the carrier. Preferably, the mean survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the mean survival time of the population can be measured by any reproducible means.

[0080] The increase in the mean survival time of a population can be measured, for example, by calculating the mean survival length for the population after the start of treatment with the active compound. The increase in the mean survival time of a population can also be measured, for example, by calculating the mean survival length for the population after the completion of the first round of treatment with the active compound.

[0081] Treating cancer can result in an increase in the mean survival time of the treated population compared to the untreated population. Preferably, the mean survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the mean survival time of the population can be measured by any reproducible means. The increase in the mean survival time of the population can be measured, for example, by calculating the mean survival length for the population after the start of treatment with the active compound. The increase in the mean survival time of the population can also be measured, for example, by calculating the mean survival length for the population after the completion of the first round of treatment with the active compound.

[0082] Treating cancer can result in an increase in the mean survival time of the treated population compared to a population receiving monotherapy with a drug other than the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof. Preferably, the mean survival time increases by more than 30 days, more preferably more than 60 days, more preferably more than 90 days, and most preferably more than 120 days. The increase in the mean survival time of the population can be measured by any reproducible means. The increase in the mean survival time of the population can be measured, for example, by calculating the mean survival length for the population after the start of treatment with the active compound. The increase in the mean survival time of the population can also be measured, for example, by calculating the mean survival length for the population after the completion of the first round of treatment with the active compound.

[0083] Treating cancer can result in a reduction in mortality in the treated population compared to a population administered only the carrier. Treating cancer can result in a reduction in mortality in the treated population compared to an untreated population. Treating cancer can result in a reduction in mortality in the treated population compared to a population receiving monotherapy with a drug other than the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof. Preferably, the mortality is reduced by more than 2%, more preferably more than 5%, more preferably more than 10%, and most preferably more than 25%. The reduction in mortality in the treated population can be measured by any reproducible means. The reduction in population mortality can be measured, for example, by calculating the average number of disease-related deaths per unit time after the start of treatment with the active compound for the population. The reduction in population mortality can also be measured, for example, by calculating the average number of disease-related deaths per unit time after the completion of the first round of treatment with the active compound for the population.

[0084] Treating cancer can result in a reduction in tumor growth rate. Preferably, after treatment, the tumor growth rate is reduced by at least 5% compared to the pre-treatment rate; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%. Tumor growth rate can be measured by any reproducible measuring means. Tumor growth rate can be measured according to the change in tumor diameter per unit time.

[0085] Treating cancer can result in a reduction in tumor regrowth. After treatment, tumor regrowth may be less than 5%, more preferably less than 10%, more preferably less than 20%, more preferably less than 30%, more preferably less than 40%, more preferably less than 50%, even more preferably less than 50%, and most preferably less than 75%. Tumor regrowth can be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring the increase in tumor diameter after the reduction of the previous tumor after treatment. A reduction in tumor regrowth is indicated by the absence of tumor recurrence after treatment is discontinued.

[0086] Treating or preventing cell proliferation disorders can lead to a decrease in the rate of cell proliferation. Preferably, after treatment, the rate of cell proliferation is reduced by at least 5%. [1] Those skilled in the art can refer to general reference texts for a detailed description of the known or equivalent technologies discussed herein. These texts can, of course, also be referred to when creating or using embodiments of the present invention. [Examples]

[0087] Examples are provided below to allow for a more efficient understanding of the disclosures disclosed herein. These examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way.

[0088] Example 1 Figure 1 shows the combined effect of LP-284 and the anti-CD20 monoclonal antibody (rituximab) on tumor growth in a xenograft model. HRD genomic scarring was examined from 107 B-NHL patients in a whole-genome pan-oncology analysis (PCAWG) study. At least 10% of B-NHL patients were likely HRD+, and approximately 90% of these cases were diffuse large B-cell lymphoma (DLBCL). LP-284 demonstrated antitumor activity in a preclinical model, inducing DNA DSB and cell apoptosis. In xenograft mice with OCI-LY1 (TP53 mutation; DLBCL / HGBL-MYC / BCL2 double translocation), treatment with 4 mg / kg of LP-284 resulted in 99% tumor growth inhibition (TGI) by day 24. Treatment with LP-284 at 2 mg / kg alone resulted in a 57% TGI, while combination with rituximab resulted in a 93% TGI at day 24. The calculated Bliss synergy score between LP-284 and rituximab at day 24 was 10, indicating a synergistic effect.

[0089] The efficacy of LP-284 in a DLBCL / HGBL-MYC / BCL2 xenograft model was evaluated. LP-284, a vehicle (saline), and rituximab were intravenously administered to mouse OCI-LY 1-derived tumor xenografts. All vehicle-treated mice were sacrificed by day 24 due to excessive tumor size. LP-284, either as a monotherapy or in combination with rituximab, significantly reduced tumor volume by day 24, as indicated by tumor growth inhibition and final tumor volume measurement.

[0090] Example 2 Figure 2 shows the tumor growth curves throughout the entire study process from the same study shown in Figure 1. The antitumor efficacy of LP-284 was tested as monotherapy and in combination with rituximab in tumor xenografts derived from the OCI-LY 1 DLBCL / HGBL-MYC / BCL2 cell line in mice. Methods: OCI-LY1 cells were subcutaneously transplanted into NOD.SCID mice. When the tumor volume reached over 100 mm3, the following treatments were initiated: vehicle (saline, intravenously administered on days 1, 8, and 15 of a 28-day cycle), 2 mg / kg or 4 mg / kg of LP-284 (intravenously administered on days 1, 8, and 15 of a 28-day cycle), 10 mg / kg of rituximab (intravenously administered on days 1 and 15 of a 28-day cycle), and combinations of 2 mg / kg of LP-284 and 10 mg / kg of rituximab. Four mice were used in each treatment group. Tumor growth inhibition (TGI) is calculated as %TGI=(1-((Tt / T0) / (Ct / C0))) / (l-(C0 / Ct)) * The calculation is performed with a value of 100, where Tt = mean tumor volume of treatment at time t, TO = mean tumor volume of treatment at time 0, Ct = mean tumor volume of control at time t, and CO = mean tumor volume of control at time 0. The SBliss synergy score was calculated as follows: SBliss = EA,B,...,N - 100(1 - (1 - EA100)(l - EB100)...(l - EN100)), where (1 - EA,B,...,N100) represents the probability that drugs A,B,...,N do not inhibit the target.

[0091] Example 3 Figure 3 shows that LP-284 treatment significantly reduced B cells (CD19+ or CD20+) by approximately 30% after 24 days in immunocompromised mice, comparable to the reduction achieved by cyclophosphamide. In this study, the vehicle, LP-284 (4 mg / kg), and cyclophosphamide (25 mg / kg, a clinically relevant dose) were administered intravenously to three mice per treatment group on days 1, 8, and 15. Blood samples were collected on day 16 and analyzed by flow cytometry to quantify the B cell population. The results showed that LP-284 was effective in reducing B cells, similar to cyclophosphamide. Furthermore, all mice maintained normal body weight, and no abnormal findings were observed during macroscopic necropsy, indicating that LP-284 was well tolerated.

Claims

1. A method of treating cancer, for a person who needs treatment, a. A therapeutically effective dose of acylfluben or a pharmaceutically acceptable salt thereof, b. A method comprising administering a combination of an activator containing a therapeutically effective amount of anti-CD20 antibody or an antigen-binding fragment of the antibody.

2. The method according to claim 1, wherein the anti-CD20 antibody is selected from the group consisting of rituximab, obinutuzumab, ofatumumab, and tositumomab.

3. The method according to claim 1, wherein the anti-CD20 antibody is rituximab or an antigen-binding fragment of the antibody.

4. The method according to claim 1, wherein the acylflubene is hydroxyureamethylacylflubene.

5. The aforementioned acylflubene has the following structure 【Chemistry 1】 The method according to claim 1, comprising:

6. The aforementioned acylflubene has the following structure 【Chemistry 2】 The method according to claim 1, comprising:

7. The method according to claim 1, wherein the B-cell carcinoma is a recurrent or refractory B-cell carcinoma.

8. The method according to claim 1, wherein the B-cell carcinoma is a B-cell non-Hodgkin lymphoma, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or Burkitt lymphoma.

9. The method according to claim 5, wherein the B-cell carcinoma is follicular lymphoma (FL).

10. The method according to claim 1, wherein the administration of the acylfluben and the anti-CD20 antibody is continuous or simultaneous.

11. The method according to claim 1, wherein the acylfluben and the anti-CD20 antibody are formulated for intravenous administration.

12. The method according to claim 1, wherein the combination therapy results in enhanced apoptosis of cancerous B cells compared to the administration of either acylfluben or the anti-CD20 antibody alone.

13. The method according to claim 9, wherein the B-cell carcinoma is follicular lymphoma (FL).

14. The method according to claim 1, wherein the combination therapy reduces the proliferation of cancerous B cells and inhibits tumor growth.

15. The method according to claim 1, wherein the presence of one or more cancer cells lacking HR-dependent DNA repair indicates that the subject responds to the treatment.

16. The method according to claim 1, further comprising administering a pharmaceutically acceptable carrier or excipient together with the acylfluben and the anti-CD20 antibody.

17. The method according to claim 1, wherein the subject has previously received standard chemotherapy, and the combination therapy using acylfluben and the anti-CD20 antibody is used as a second-line or salvage treatment.

18. A method for treating B-cell carcinoma, wherein the subject requiring treatment is a. A therapeutically effective amount of hydroxyureamethylacylfluben or a pharmaceutically acceptable salt thereof, b. A method comprising administering a combination of an activator comprising an anti-CD20 antibody in a therapeutically effective amount, selected from the group consisting of rituximab, obinutuzumab, ofatumumab, and tositumomab.

19. The method according to claim 18, wherein the anti-CD20 antibody is rituximab or an antigen-binding fragment of the antibody.

20. The method according to claim 18, wherein the B-cell carcinoma is follicular lymphoma (FL).

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