Use of dhodh inhibitor compounds in combination cancer therapy

Abstract

This article provides a method for treating lymphoma using anticancer agents and anticancer therapies, wherein the first anticancer agent is represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

Background Technology

[0001] This application claims priority to U.S. Provisional Application No. 63 / 070,984, filed August 27, 2020, the entire contents of which are incorporated herein by reference.

[0002] Lymphoma is a cancer that originates in the cells of the lymphatic system. Lymphomas are generally classified as Hodgkin lymphoma or non-Hodgkin lymphoma. Hodgkin lymphoma is characterized by the presence of specific white blood cells called Reed-Sternberg cells and is generally more rare. Non-Hodgkin lymphoma is characterized by the absence of Reed-Sternberg cells and accounts for nearly 90% of all lymphomas. It includes subtypes such as Burkitt's lymphoma, chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), cutaneous B-cell lymphoma (CBCL), cutaneous T-cell lymphoma (CTCL), and follicular lymphoma. According to the American Cancer Society, non-Hodgkin lymphoma is one of the most common cancers in the United States, affecting approximately 1 in 42 men and 1 in 52 women.

[0003] R-CHOP is the name of a combination of cancer drugs used as first-line treatment for non-Hodgkin's lymphoma, particularly DLBCL, which accounts for approximately 25% of all lymphomas. R-CHOP consists of the drugs rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone. Despite the aggressive nature of DLBCL, approximately 50% to 70% of patients can be cured with standard R-CHOP therapy. However, R-CHOP alone is insufficient to treat 30% to 50% of patients. Among patients who fail R-CHOP therapy, 20% develop primary refractory disease (progression during or immediately after treatment), and 30% relapse after achieving complete remission.

[0004] Given the above, the need for new, more effective treatments targeting lymphoma remains unmet. Summary of the Invention

[0005] The dihydroorotate dehydrogenase inhibitor 1-methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazol-7-carboxylic acid and its pharmaceutically acceptable salts, also known as "Compound of Formula (I)" or "Compound 1", is used in particular for the treatment of hematologic malignancies and has now been found to offer therapeutic advantages when used in combination with CHOP-based therapies.

[0006] For example, complete tumor regression was observed in various mouse lymphoma models treated with the combination of compound 1 and R-CHOP, while tumors continued to grow in mice treated with CHOP or rituximab alone. See, for example. Figure 1-3 It showed that certain mouse models of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, Hodgkin's lymphoma, and undifferentiated lymphoma completely regressed after treatment with compound 1 and R-CHOP.

[0007] Therefore, in one aspect, this article provides a method for treating lymphoma in a subject, the method comprising administering to the subject an effective amount of an anticancer agent and an effective amount of anticancer therapy, wherein the anticancer agent is of formula (I):

[0008]

[0009] The anticancer therapy comprises, in one embodiment, cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof; and wherein the anticancer therapy comprises a combination of cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof, vincristine, or a pharmaceutically acceptable salt thereof, and prednisolone. In one embodiment, the anticancer therapy further comprises rituximab. In one embodiment, a pharmaceutically acceptable salt of compound 1 is a tris(hydroxymethyl)aminomethane salt or a sodium salt. In one embodiment, a pharmaceutically acceptable salt of doxorubicin is a hydrochloride salt. In one embodiment, a pharmaceutically acceptable salt of vincristine is a sulfate salt.

[0010] On the other hand, this application provides the use of an anticancer agent in the manufacture of a pharmaceutical agent for treating lymphoma, wherein the pharmaceutical agent is used in combination with an effective amount of an anticancer therapy, wherein the anticancer agent has the following structural formula:

[0011]

[0012] The anticancer therapy comprises, in one embodiment, cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof; wherein the anticancer therapy includes a combination of cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof, vincristine, or a pharmaceutically acceptable salt thereof, and prednisolone. In one embodiment, the anticancer therapy further comprises rituximab. In one embodiment, the pharmaceutically acceptable salt of compound 1 is a tris(hydroxymethyl)aminomethane salt or a sodium salt. In one embodiment, the pharmaceutically acceptable salt of doxorubicin is a hydrochloride salt. In one embodiment, the pharmaceutically acceptable salt of vincristine is a sulfate salt.

[0013] On the other hand, this application provides an anticancer agent for use in combination with anticancer therapies to treat lymphoma, wherein the anticancer agent is of formula (I):

[0014]

[0015] The anticancer therapy comprises, in one embodiment, cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof; wherein the anticancer therapy includes a combination of cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof, vincristine, or a pharmaceutically acceptable salt thereof, and prednisolone. In one embodiment, the anticancer therapy further comprises rituximab. In one embodiment, the pharmaceutically acceptable salt of compound 1 is a tris(hydroxymethyl)aminomethane salt or a sodium salt. In one embodiment, the pharmaceutically acceptable salt of doxorubicin is a hydrochloride salt. In one embodiment, the pharmaceutically acceptable salt of vincristine is a sulfate salt.

[0016] On the other hand, this application provides a pharmaceutical composition comprising an anticancer agent and an anticancer therapy, wherein the pharmaceutical composition optionally and additionally comprises an excipient, wherein the anticancer agent is of formula (I):

[0017]

[0018] The anticancer therapy comprises, in one embodiment, cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof; wherein the anticancer therapy includes a combination of cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof, vincristine, or a pharmaceutically acceptable salt thereof, and prednisolone. In one embodiment, the anticancer therapy further comprises rituximab. In one embodiment, the pharmaceutically acceptable salt of compound 1 is a tris(hydroxymethyl)aminomethane salt or a sodium salt. In one embodiment, the pharmaceutically acceptable salt of doxorubicin is a hydrochloride salt. In one embodiment, the pharmaceutically acceptable salt of vincristine is a sulfate salt.

[0019] Other features or advantages will become apparent from the following drawings and detailed descriptions of several embodiments, as well as from the appended claims. Brief description of the attached diagram

[0021] Figure 1 The percentage changes in tumor volume in a mouse model of DLBCL treated with combination therapy of compound 1 (100 mg / kg BID), rituximab (20 mg / kg BIW), CHOP (C–30 mg / kg QD x1 IP, D–2.475 mg / kg QD x1 IV, V–0.375 mg / kg QD x1 IV, P–0.15 mg / kg QD x5 PO) and compound 1 (100 mg / kg BID) in combination with R-CHOP (R–20 mg / kg BIW IP, C–30 mg / kg QD x1 IP, D–2.475 mg / kg QD x1 IV, V–0.375 mg / kg QD x1 IV, P–0.15 mg / kg QD x5 PO) are shown.

[0022] Figure 2The percentage changes in tumor volume in MCL mouse models treated with combination of compound 1 (100 mg / kg BID), rituximab (20 mg / kg BIW), CHOP (C–30 mg / kg QD x1 IP, D–2.475 mg / kg QD x1 IV, V–0.375 mg / kg QD x1 IV, P–0.15 mg / kg QD x5 PO) and compound 1 (100 mg / kg BID) with R-CHOP (R–20 mg / kg BIW IP, C–30 mg / kg QD x1 IP, D–2.475 mg / kg QD x1 IV, V–0.375 mg / kg QD x1 IV, P–0.15 mg / kg QD x5 PO) are shown.

[0023] Figure 3 The percentage changes in tumor volume in mouse models of Burkitt's, undifferentiated, and Hodgkin's lymphoma treated with combination therapy of compound 1 (100 mg / kg BID), rituximab (20 mg / kg BIW), CHOP (C–30 mg / kg QD x1 IP, D–2.475 mg / kg QD x1 IV, V–0.375 mg / kg QD x1 IV, P–0.15 mg / kg QD x1 IV) and compound 1 (100 mg / kg BID) in combination with R-CHOP (R-20 mg / kg BIW IP, C–30 mg / kg QD x1 IP, D–2.475 mg / kg QD x1 IV, V–0.375 mg / kg QD x5 PO, P–0.15 mg / kg QD x5 PO). Detailed Implementation

[0024] 1-Methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazol-7-carboxylic acid, hereinafter also referred to as "Compound of Formula (I)" or "Compound 1", has the chemical structure shown below and is characterized as an inhibitor of DHODH. See, for example, International Patent Application Publications Nos. WO 2014 / 128669 and WO 2019 / 164794 and U.S. Patent No. 9,630,932, the contents of which are incorporated herein by reference.

[0025]

[0026] Compounds of formula (I) have been developed for the treatment of conditions and symptoms that would benefit from DHODH inhibition, such as, but not limited to, solid tumors and blood cancers.

[0027] In one aspect, this application relates to a method of treating a subject with lymphoma, the method comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and an effective amount of an anticancer therapy comprising cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof, vincristine or a pharmaceutically acceptable salt thereof, and prednisolone. In one embodiment, the anticancer therapy further comprises rituximab. In one embodiment, the pharmaceutically acceptable salt of compound 1 is a tris(hydroxymethyl)aminomethane salt or a sodium salt. In one embodiment, the pharmaceutically acceptable salt of doxorubicin is a hydrochloride salt. In one embodiment, the pharmaceutically acceptable salt of vincristine is a sulfate salt. In one aspect, the anticancer therapy is a combination of cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof such as hydrochloride, vincristine or a pharmaceutically acceptable salt thereof such as sulfate, and prednisolone. In another aspect, the anticancer therapy is a combination of rituximab, cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof such as hydrochloride, vincristine or a pharmaceutically acceptable salt thereof such as sulfate, and prednisolone.

[0028] In one respect, the lymphoma treated by the disclosed method is Hodgkin's lymphoma.

[0029] In one aspect, the lymphoma treated by the disclosed method is non-Hodgkin's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is selected from B-cell lymphoma and T-cell lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma selected from follicular lymphoma, DLBCL, MCL, Burkitt's lymphoma, and lymphoplasmacytic lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma selected from DLBCL, MCL, and Burkitt's lymphoma. In some embodiments, the non-Hodgkin's lymphoma is a B-cell lymphoma selected from DLBCL and MCL. In some embodiments, the non-Hodgkin's lymphoma is B-cell lymphoma DLBCL. In some embodiments, the non-Hodgkin's lymphoma is B-cell lymphoma MCL. In some embodiments, the non-Hodgkin's lymphoma is a T-cell lymphoma selected from cutaneous T-cell lymphoma. In some implementations, non-Hodgkin's lymphoma is a cutaneous T-cell lymphoma selected from mycosis fungoides, peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma (ALCL), enteropathy T-cell lymphoma (EATL), and hepatosplenic γ / δ T-cell lymphoma.

[0030] In some implementations, the lymphoma is selected from bladder lymphocytic lymphoma, diffuse mixed cell lymphoma, primary exudative lymphoma, double-hit diffuse large B-cell lymphoma, and triple-hit diffuse large B-cell lymphoma. In some implementations, the lymphoma is selected from angioimmunoblastic lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, blastic NK cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal large B-cell lymphoma, marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, and Waldenström macroglobulinemia.

[0031] In one implementation, the treated subject belongs to a subgroup of patients with non-Hodgkin's lymphoma or Hodgkin's lymphoma who have progressed despite prior treatment and for whom no additional effective (curative or life-prolonging) standard therapy is available. In other words, the treated subject belongs to a subgroup of drug-resistant or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma. In one implementation, the standard curative therapy is high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). In one implementation, the subject's non-Hodgkin's lymphoma or Hodgkin's lymphoma has relapsed after HD-ASCT. In other words, the treated subject belongs to a subgroup of relapsed non-Hodgkin's lymphoma or Hodgkin's lymphoma (e.g., HD-ASCT relapse). In another implementation, the subject is ineligible for HD-ASCT. In yet another implementation, the subject refuses HD-ASCT.

[0032] In one implementation, the lymphoma treated by the disclosed method is a mature B-cell tumor, a mature T-cell and NK-cell tumor, Hodgkin's lymphoma, or an immunodeficiency-associated lymphoid tissue proliferative disorder.

[0033] In one respect, the cancers treated by the disclosed methods are selected from chronic lymphocytic leukemia and small lymphocytic lymphoma.

[0034] As used herein, the terms “subject” and “patient” are used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, a subject is a person in need of treatment.

[0035] An "effective amount" of a compound of formula (I) or a pharmaceutically acceptable salt thereof is an amount sufficient, when combined with an anticancer therapy, such as CHOP or R-CHOP, to provide therapeutic benefit in the treatment of lymphoma or to delay or minimize one or more symptoms associated with lymphoma. As described herein, an "effective amount" of an anticancer therapy is an amount sufficient, when combined with a compound of formula (I) or a pharmaceutically acceptable salt thereof, to provide therapeutic benefit in the treatment of a condition (e.g., lymphoma) or to delay or minimize one or more symptoms associated with a condition (e.g., lymphoma). The terms "therapeutic effective amount" and "effective amount" are used interchangeably. The term "effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of lymphoma, and / or enhances the efficacy of another therapeutic agent. In some embodiments, an effective amount is an amount sufficient to elicit a therapeutic effect in the treatment of lymphoma.

[0036] The precise amount of a compound of formula (I) (or a pharmaceutically acceptable salt thereof) or anticancer therapy administered to a subject will depend on various factors, such as the given drug, pharmaceutical formulation, route of administration, type of disease or condition, and the identity of the subject receiving treatment, but can still be routinely determined by those skilled in the art. For example, the determination of an effective amount will also depend on the extent, severity, and type of cell proliferation. A skilled artisan will be able to determine the appropriate dose based on these and other factors. Appropriate doses are known for approved therapeutic agents and can be adjusted by a skilled artisan based on the subject's condition, the type of condition being treated, and the amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Where no amount is explicitly stated, an effective amount should be assumed. Non-limiting examples of effective amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof are provided below.

[0037] The effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is generally in the range of 0.1 μg to 100 mg / kg body weight of the recipient (mammal) per day, and particularly typically in the range of 1 to 10 mg / kg body weight per day. Therefore, the practical daily dose for an adult mammal weighing 70 kg is generally between 70 and 700 mg, which may be administered as a single daily dose or typically as a series of partial daily doses (e.g., two, three, four, five, or six) to ensure that the total daily dose is the same. The effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject may be 10 μg to 500 mg. The effective amounts of the anticancer therapies CHOP and R-CHOP are known to those skilled in the art. Exemplary amounts are further discussed below.

[0038] The term "treatment" refers to reducing, inhibiting, weakening, decreasing, stopping, or stabilizing the development or progression of lymphoma, alleviating the severity of lymphoma, or improving lymphoma-related symptoms. Treatment can also continue after symptoms subside, for example, to reduce the likelihood of relapse or delay relapse.

[0039] The efficacy of aggressive treatment for lymphoma can be measured in several ways. Administration of therapeutically effective amounts of the combinations described herein is superior to individual component compounds. As used herein, a “favorable combination” is one that provides at least one of the following improved properties compared to administration of a therapeutically effective amount of a component compound alone: ​​i) a stronger anticancer effect than the most active single agent alone; ii) synergistic anticancer effect; or iii) additional activity.

[0040] The term "relapse" refers to the return of cancer cells in patients who have been in remission from lymphoma after treatment.

[0041] The term "refractory or drug-resistant" refers to a situation where cancer cells remain in the patient's body even after intensive treatment.

[0042] As used herein, "double-hit diffuse large B-cell lymphoma" refers to a form of lymphoma or diffuse large B-cell lymphoma in which lymphoma cells have alterations at two oncogenes (c-MYC and BCL2 or BCL6). In one embodiment, double-hit diffuse large B-cell lymphoma is treated in the method, characterized by gene alterations at c-MYC and BCL2. In another embodiment, double-hit diffuse large B-cell lymphoma is treated in the method, characterized by gene alterations at c-MYC and BCL6.

[0043] As used herein, “triple-hit diffuse large B-cell lymphoma” refers to a form of lymphoma or diffuse large B-cell lymphoma in which lymphoma cells are altered at three oncogenes (c-MYC, BCL2, and BCL6). In one embodiment, triple-hit diffuse large B-cell lymphoma is treated in the method described herein.

[0044] In this specification, "pharmaceutically acceptable salt" means a pharmaceutically acceptable organic or inorganic acid or base salt of the compound described herein. Representative pharmaceutically acceptable organic or inorganic base salts include, for example, alkali metal salts (e.g., sodium), alkaline earth metal salts (e.g., calcium), and ammonium salts (e.g., tris(hydroxymethyl)aminomethane, hydrabamine, and N-methylglucosamine ammonium salt). Representative pharmaceutically acceptable organic or inorganic acid or base salts include, for example, acetates, 4,4-diaminostilbene-2,2-disulfonate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, calcium edetate, dextrorotatory camphor sulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, estolate, ethanesulfonate, fiunarate, glucohepanoate, glucuronate, glutamate, glycolamide benzoarsylate, hexafluorophosphate, hexylresorcinol, hydrobromide, hydrochloride, hydroxynaphthylcarbamate, iodide, isothiosulfonate, lactate. Lacturonates, laurates, malates, maleates, mandelates, methanesulfonates, methyl bromide, methyl nitrates, methyl sulfates, mucilages, naphthalenesulfonates, nitrates, 3-hydroxy-2-naphthoate, oleates, oxalates, palmitates, bis(hydroxynaphthoate) (1,1-methylene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenates, phosphates / bisphosphonates, picrates, polygalacturonates, propionates, p-toluenesulfonates, salicylates, stearates, hypoacetates, succinates, sulfates, sulfosalicylates, suramates, tannates, tartrates, teoclates, toluenesulfonates, triethyliodide, and valerates. Pharmaceutically acceptable salts may have more than one charged atom in their structure. In this case, pharmaceutically acceptable salts may have multiple counterions. Therefore, pharmaceutically acceptable salts may have one or more charged atoms and / or one or more counterions.

[0045] In one embodiment, the methods provided herein include administering or co-administering the anticancer therapy CHOP or R-CHOP. As used herein, the term "co-administered" with respect to the anticancer therapy means that the anticancer therapy may be administered as part of a single dosage form (e.g., a composition comprising compound 1 or a pharmaceutically acceptable salt thereof and the anticancer therapy) or as multiple separate dosage forms together with compound 1 or a pharmaceutically acceptable salt thereof. Alternatively, the anticancer therapy may be administered before, concurrently with, or after the administration of compound 1 or a pharmaceutically acceptable salt thereof. In such combination therapy treatments, both compound 1 or a pharmaceutically acceptable salt thereof and the anticancer therapy are administered by conventional methods. Administering a composition comprising compound 1 or a pharmaceutically acceptable salt thereof and the anticancer therapy to a subject does not preclude the separate administration of the same therapeutic agent, any other second therapeutic agent, or any compound provided herein to the subject at another time during treatment. As used herein, the term "co-administered" with respect to additional cancer treatment means that the additional cancer treatment may occur before, consecutively with, concurrently with, or after the administration of the compounds provided herein.

[0046] In one implementation, the anticancer therapy is R-CHOP (i.e., a combination of rituximab, cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof such as hydrochloride, vincristine or a pharmaceutically acceptable salt thereof such as sulfate, and prednisolone).

[0047] Depending on the lymphoma to be treated and the condition of the subject, the cyclophosphamide of the anticancer therapy described herein can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhaled, nasally, vaginally, rectally, sublingually, or topically (e.g., transdermal or local). Cyclophosphamide can be formulated alone or in combination with Compound 1 and / or one or more active agents in suitable dosage units with pharmaceutically acceptable excipients, carriers, adjuvants, and mediators for each route of administration.

[0048] In one implementation, cyclophosphamide is administered, for example, via intravenous (IV) or oral routes.

[0049] In some embodiments, the treatment cycle includes administering multiple doses of cyclophosphamide to the subject in need over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more than 14 days). In some embodiments, the treatment cycle includes administering multiple doses of cyclophosphamide to the subject in need over multiple weeks (e.g., 1, 2, 3, 4 weeks, or more than 5 weeks). Suitable dosages for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts. For example, in some embodiments, the amount of cyclophosphamide administered by this method may be in the range of, for example, about 100 mg / m². 2 Approximately 1500 mg / m2 Approximately 200 mg / m 2 Approximately 1500 mg / m 2 Approximately 300 mg / m 2 Approximately 1500 mg / m 2 Approximately 400 mg / m 2 Approximately 1500 mg / m 2 Approximately 450 mg / m 2 Approximately 1500 mg / m 2 Approximately 500 mg / m 2 Approximately 1500 mg / m 2 Approximately 550 mg / m 2 Approximately 1500 mg / m 2 Approximately 600 mg / m 2 Approximately 1500 mg / m 2 Approximately 650 mg / m 2 Approximately 1500 mg / m 2 Approximately 700 mg / m 2 Approximately 1500 mg / m 2 Approximately 750 mg / m 2 Approximately 1500 mg / m 2 Approximately 100 mg / m 2 Approximately 1250 mg / m 2 Approximately 100 mg / m 2 Approximately 1150 mg / m 2 Approximately 100 mg / m 2 Approximately 1000 mg / m 2 Approximately 100 mg / m 2 Approximately 900 mg / m 2 Approximately 100 mg / m 2 Approximately 850 mg / m 2 Approximately 100 mg / m 2 Approximately 800 mg / m 2 Approximately 100 mg / m 2 Approximately 750 mg / m 2 Approximately 200 mg / m 2 Approximately 1400 mg / m 2 Approximately 300 mg / m 2 Approximately 1300 mg / m 2 Approximately 400 mg / m 2 Approximately 1200 mg / m 2 Approximately 500 mg / m 2 Approximately 1100 mg / m 2 Approximately 600 mg / m 2 Approximately 1000 mg / m 2Approximately 600 mg / m 2 Approximately 900 mg / m 2 Approximately 600 mg / m 2 Approximately 800 mg / m 2 Approximately 700 mg / m 2 Approximately 800 mg / m 2 or approximately 725 mg / m 2 Approximately 775 mg / m 2 In some embodiments, the amount of cyclophosphamide applied by this method is approximately 500 mg / m³. 2 Approximately 550 mg / m 2 Approximately 600 mg / m 2 Approximately 650 mg / m 2 Approximately 700 mg / m 2 Approximately 750 mg / m 2 Approximately 800 mg / m 2 or approximately 850 mg / m 2 In some embodiments, the amount of cyclophosphamide applied by this method is approximately 750 mg / m³. 2 .

[0050] In some embodiments, the amount of cyclophosphamide is about 1 mg / kg to about 100 mg / kg, about 5 mg / kg to about 100 mg / kg, about 10 mg / kg to about 100 mg / kg, about 15 mg / kg to about 100 mg / kg, about 20 mg / kg to about 100 mg / kg, about 25 mg / kg to about 100 mg / kg, about 30 mg / kg to about 100 mg / kg, about 35 mg / kg to about 100 mg / kg, about 1 mg / kg to about 90 mg / kg, or about 1 mg / kg to about 80 mg / kg. / kg, about 1 mg / kg to about 70 mg / kg, about 1 mg / kg to about 60 mg / kg, about 1 mg / kg to about 50 mg / kg, about 1 mg / kg to about 40 mg / kg, about 1 mg / kg to about 35 mg / kg, about 1 mg / kg to about 30 mg / kg, about 1 mg / kg to about 100 mg / kg, about 10 mg / kg to about 40 mg / kg, about 15 mg / kg to about 40 mg / kg, about 20 mg / kg to about 40 mg / kg, or about 25 mg / kg to about 35 mg / kg. In some embodiments, the amount of cyclophosphamide is about 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, or 40 mg / kg. In some embodiments, the amount of cyclophosphamide is about 30 mg / kg. In some embodiments, cyclophosphamide is administered daily (QD) at one or more of the doses described herein. In some implementations, cyclophosphamide is administered daily (QD) at one or more doses described herein on certain days of treatment (e.g., day 1 and day 22).

[0051] Depending on the lymphoma to be treated and the condition of the subject, the anticancer therapy described herein, doxorubicin (e.g., doxorubicin hydrochloride), may be administered via oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes. Doxorubicin or doxorubicin hydrochloride may be formulated alone or with Compound 1 and / or one or more active agents in suitable dosage units having pharmaceutically acceptable excipients, carriers, adjuvants, and mediators for each route of administration.

[0052] In one implementation, doxorubicin (e.g., doxorubicin hydrochloride) is administered via, for example, intravenous (IV) route.

[0053] In some embodiments, the treatment cycle includes administering multiple doses of doxorubicin (e.g., doxorubicin hydrochloride) to the subject in need over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more than 14 days). In some embodiments, the treatment cycle includes administering multiple doses of doxorubicin (e.g., doxorubicin hydrochloride) to the subject in need over multiple weeks (e.g., 1, 2, 3, 4 weeks, or more than 5 weeks). Suitable dosages for the methods provided herein include, for example, therapeutically effective doses and prophylactically effective doses. For example, in some embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by this method is about 1 mg / m². 2 Approximately 200 mg / m 2 Approximately 1 mg / m 2 Approximately 150 mg / m 2 Approximately 1 mg / m 2 Approximately 100 mg / m 2 Approximately 10 mg / m 2 Approximately 100 mg / m 2 Approximately 15 mg / m 2 Approximately 100 mg / m 2 Approximately 20 mg / m 2 Approximately 100 mg / m 2 Approximately 25 mg / m 2 Approximately 100 mg / m 2 Approximately 30 mg / m 2 Approximately 100 mg / m 2 Approximately 35 mg / m 2 Approximately 100 mg / m 2 Approximately 40 mg / m 2 Approximately 100 mg / m 2 Approximately 45 mg / m 2 Approximately 100 mg / m 2 Approximately 50 mg / m 2 Approximately 100 mg / m 2 Approximately 1 mg / m 2 Approximately 95 mg / m 2 Approximately 1 mg / m 2 Approximately 90 mg / m 2 Approximately 1 mg / m 2 Approximately 85 mg / m 2 Approximately 1 mg / m 2 Approximately 80 mg / m 2 Approximately 1 mg / m 2 Approximately 75 mg / m 2 Approximately 1 mg / m 2 Approximately 70 mg / m 2 Approximately 1 mg / m2 Approximately 65 mg / m 2 Approximately 1 mg / m 2 Approximately 60 mg / m 2 Approximately 1 mg / m 2 Approximately 55 mg / m 2 or about 1 mg / m 2 Approximately 50 mg / m 2 In some embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by this method is approximately 25 mg / m². 2 Approximately 30 mg / m 2 Approximately 35 mg / m 2 Approximately 40 mg / m 2 Approximately 45 mg / m 2 Approximately 50 mg / m 2 Approximately 55mg / m 2 Approximately 60 mg / m 2 or approximately 65 mg / m 2 In some embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by this method is approximately 50 mg / m². 2 .

[0054] In some embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by this method is about 0.5 mg / kg to about 5 mg / kg, about 1 mg / kg to about 5 mg / kg, about 1.25 mg / kg to about 5 mg / kg, about 1.5 mg / kg to about 5 mg / kg, about 1.75 mg / kg to about 5 mg / kg, about 2 mg / kg to about 5 mg / kg, about 2.25 mg / kg to about 5 mg / kg, about 2.5 mg / kg to about 5 mg / kg, about 0.5 mg / kg to about 4 mg / kg, about 0.5 mg / kg to about 3.5 mg / kg, about 0.5 mg / kg to about 3.25 mg / kg, about 0.5 mg / kg to about 3.0 mg / kg, about 0.5 mg / kg to about 2.75 mg / kg, about 0.5 mg / kg to about 2.5 mg / kg, about 2 mg / kg to about 3 mg / kg, or 2.25 mg / kg to about 2.5 mg / kg. In some embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by this method is about 2.475 mg / kg. In some embodiments, doxorubicin (e.g., doxorubicin hydrochloride) is administered daily (QD) at one or more of the doses described herein. In some embodiments, doxorubicin (e.g., doxorubicin hydrochloride) is administered daily (QD) at one or more of the doses described herein on certain days of treatment (e.g., day 1 and day 22).

[0055] Depending on the lymphoma to be treated and the condition of the subject, the vincristine (e.g., vincristine sulfate) of the anticancer therapy described herein may be administered via oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. Vincristine (e.g., vincristine sulfate) may be formulated alone or in combination with Compound 1 and / or one or more active agents in suitable dosage units having pharmaceutically acceptable excipients, carriers, adjuvants, and mediators for each route of administration.

[0056] In one implementation, vincristine (e.g., vincristine sulfate) is administered via, for example, intravenous (IV) route.

[0057] In some embodiments, the treatment cycle includes administering multiple doses of vincristine (e.g., vincristine sulfate) to the subject in need over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more than 14 days). In some embodiments, the treatment cycle includes administering multiple doses of vincristine (e.g., vincristine sulfate) to the subject in need over multiple weeks (e.g., 1, 2, 3, 4 weeks, or more than 5 weeks). Suitable dosages for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts. For example, in some embodiments, the amount of vincristine (e.g., vincristine sulfate) administered by this method is about 0.2 mg / m². 2 Approximately 10 mg / m 2 Approximately 0.2 mg / m 2 Approximately 5 mg / m 2 Approximately 0.4 mg / m 2 Approximately 5 mg / m 2 Approximately 0.6 mg / m 2 Approximately 5 mg / m 2 Approximately 0.8 mg / m 2 Approximately 5 mg / m 2 Approximately 1 mg / m 2 Approximately 5 mg / m 2 Approximately 1.2 mg / m 2 Approximately 5 mg / m 2 Approximately 1.4 mg / m 2 Approximately 5 mg / m 2 Approximately 0.2 mg / m 2 Approximately 3 mg / m 2 Approximately 0.2 mg / m 2 Approximately 2.5 mg / m² 2 Approximately 0.2 mg / m 2 Approximately 2.2 mg / m³ 2 Approximately 0.2 mg / m2 Approximately 2.0 mg / m³ 2 Approximately 0.2 mg / m 2 Approximately 1.8 mg / m² 2 Approximately 1.6 mg / m³ 2 Approximately 1.4 mg / m² 2 Approximately 0.4 mg / m 2 Approximately 2.5 mg / m² 2 0.6 mg / m 2 Approximately 2.2 mg / m³ 2 0.8 mg / m 2 Approximately 2.0 mg / m³ 2 0.8 mg / m 2 Approximately 2.0 mg / m³ 2 1mg / m 2 Approximately 1.8 mg / m² 2 or 1.2 mg / m 2 Approximately 1.6 mg / m² 2 In some embodiments, the amount of vincristine (e.g., vincristine sulfate) applied by this method is approximately 1 mg / m³. 2 1.2 mg / m 2 Approximately 1.4 mg / m 2 1.4 mg / m 2 1.6 mg / m 2 1.8 mg / m 2 or 2mg / m 2 In some embodiments, the amount of vincristine (e.g., vincristine sulfate) applied by this method is approximately 1.4 mg / m³. 2 .

[0058] In some embodiments, the amount of vincristine (e.g., vincristine sulfate) applied by this method is about 0.1 mg / kg to about 1 mg / kg, about 0.2 mg / kg to about 1 mg / kg, about 0.25 mg / kg to about 1 mg / kg, about 0.275 mg / kg to about 1 mg / kg, about 0.3 mg / kg to about 1 mg / kg, about 0.325 mg / kg to about 1 mg / kg, about 0.35 mg / kg to about 1 mg / kg, about 0.375 mg / kg to about 1 mg / kg, about 0.4 mg / kg to about 1 mg / kg, about 0 The amounts are approximately 0.1 mg / kg to about 0.5 mg / kg, about 0.1 mg / kg to about 0.475 mg / kg, about 0.1 mg / kg to about 0.45 mg / kg, about 0.1 mg / kg to about 0.425 mg / kg, about 0.1 mg / kg to about 4 mg / kg, about 0.1 mg / kg to about 0.375 mg / kg, about 0.1 mg / kg to about 0.35 mg / kg, about 0.3 mg / kg to about 0.4 mg / kg, about 0.325 mg / kg to about 0.4 mg / kg, or about 0.35 mg / kg to about 0.4 mg / kg. In some embodiments, the amount of vincristine (e.g., vincristine sulfate) applied by this method is about 0.375 mg / kg.

[0059] Depending on the lymphoma to be treated and the condition of the subject, the prednisone of the anticancer therapy described herein can be administered via oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. Prednisone can be formulated alone or with Compound 1 and / or one or more active agents in appropriate dosage units having pharmaceutically acceptable excipients, carriers, adjuvants, and mediators suitable for each route of administration.

[0060] In one implementation, prednisone is administered, for example, via intravenous (IV) or oral routes.

[0061] In some embodiments, the treatment cycle includes administering multiple doses of prednisone to the subject in need over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more than 14 days). In some embodiments, the treatment cycle includes administering multiple doses of prednisone to the subject in need over multiple weeks (e.g., 1, 2, 3, 4 weeks, or more than 5 weeks). Suitable dosages for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts. For example, in some embodiments, the amount of prednisone administered by this method is about 25 mg / m². 2 Approximately 200 mg / m 2 Approximately 50 mg / m2 Approximately 200 mg / m 2 Approximately 75 mg / m 2 Approximately 200 mg / m 2 Approximately 100 mg / m 2 Approximately 200 mg / m 2 Approximately 25 mg / m 2 Approximately 175 mg / m 2 Approximately 125 mg / m 2 Approximately 150 mg / m 2 Approximately 25 mg / m 2 Approximately 125 mg / m 2 Approximately 25 mg / m 2 Approximately 100 mg / m 2 Approximately 50 mg / m 2 Approximately 175 mg / m 2 Approximately 75 mg / m 2 Approximately 150 mg / m 2 or approximately 75 mg / m 2 Approximately 125 mg / m 2 .

[0062] In some implementations, the amount of prednisone administered by this method is approximately 25 mg / m². 2 Approximately 50 mg / m 2 Approximately 75 mg / m 2 Approximately 100 mg / m 2 Approximately 125 mg / m 2 or approximately 150 mg / m 2 In some implementations, the amount of prednisone is approximately 100 mg / m². 2 .

[0063] In some embodiments, the amount of prednisone administered by this method is about 25 mg to about 200 mg, about 50 mg to about 200 mg, about 75 mg to about 200 mg, about 100 mg to about 200 mg, about 25 mg to about 175 mg, about 125 mg to about 150 mg, about 25 mg to about 125 mg, about 25 mg to about 100 mg, about 50 mg to about 175 mg, about 75 mg to about 150 mg, or about 75 mg to about 125 mg.

[0064] In some embodiments, the amount of prednisone administered by this method is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg. In some embodiments, the amount of prednisone is about 100 mg.

[0065] In some embodiments, the amount of prednisone applied by this method is about 0.05 mg / kg to about 0.3 mg / kg, about 0.075 mg / kg to about 0.3 mg / kg, about 0.1 mg / kg to about 0.3 mg / kg, about 0.125 mg / kg to about 0.3 mg / kg, about 0.15 mg / kg to about 0.3 mg / kg, about 0.175 mg / kg to about 0.3 mg / kg, about 0.05 mg / kg to about 0.275 mg / kg, about 0.05 mg / kg to about 0.25 mg / kg, about 0.05 mg / kg to about 0.2 mg / kg, about 0.05 mg / kg to about 0.175 mg / kg, about 0.05 mg / kg to about 0.15 mg / kg, about 0.01 mg / kg to about 0.2 mg / kg, or about 0.125 mg / kg to about 0.175 mg / kg. In some embodiments, the amount of prednisone administered by this method is about 0.15 mg / kg. In some embodiments, prednisone is administered daily (QD) at one or more of the doses described herein. In some embodiments, prednisone is administered daily (QD) at one or more of the doses described herein on certain days of treatment (e.g., days 1-5 and days 22-27).

[0066] Depending on the lymphoma to be treated and the condition of the subject, rituximab, the anticancer therapy described herein, can be administered via oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes. Rituximab can be formulated alone or in combination with Compound 1 and / or one or more active agents in appropriate dosage units with pharmaceutically acceptable excipients, carriers, adjuvants, and mediators suitable for each route of administration.

[0067] In one implementation, rituximab is administered via, for example, intravenous (IV) route.

[0068] In some embodiments, the treatment cycle includes administering multiple doses of rituximab to the subject in need over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or more than 14 days). In some embodiments, the treatment cycle includes administering multiple doses of rituximab to the subject in need over multiple weeks (e.g., 1, 2, 3, 4 weeks, or more than 5 weeks). Suitable dosages for the methods provided herein include, for example, therapeutically effective doses and prophylactically effective doses. For example, in some embodiments, the amount of rituximab is about 200 mg / m². 2 Approximately 500 mg / m 2 Approximately 225 mg / m 2 Approximately 500 mg / m 2Approximately 250 mg / m 2 Approximately 500 mg / m 2 Approximately 275 mg / m 2 Approximately 500 mg / m 2 Approximately 300 mg / m 2 Approximately 500 mg / m 2 Approximately 325 mg / m 2 Approximately 500 mg / m 2 Approximately 350 mg / m 2 Approximately 500 mg / m 2 Approximately 375 mg / m 2 Approximately 500 mg / m 2 Approximately 200 mg / m 2 Approximately 475 mg / m 2 Approximately 200 mg / m 2 Approximately 450 mg / m 2 Approximately 200 mg / m 2 Approximately 425 mg / m 2 Approximately 200 mg / m 2 Approximately 400 mg / m 2 Approximately 200 mg / m 2 Approximately 375 mg / m 2 Approximately 225 mg / m 2 Approximately 475 mg / m 2 Approximately 250 mg / m 2 Approximately 450 mg / m 2 Approximately 275 mg / m 2 Approximately 425 mg / m 2 Approximately 300 mg / m 2 Approximately 400 mg / m 2 Approximately 325 mg / m 2 Approximately 400 mg / m 2 or approximately 350 mg / m 2 Approximately 400 mg / m 2 In some implementations, the amount of rituximab is approximately 250 mg / m². 2 275mg / m 2 300mg / m 2 325mg / m 2 350mg / m 2 375mg / m 2 400mg / m 2 or 425mg / m 2 In some implementations, the amount of rituximab is approximately 375 mg / m². 2 .

[0069] In some embodiments, the amount of rituximab is about 1 mg / kg to about 100 mg / kg, about 5 mg / kg to about 100 mg / kg, about 10 mg / kg to about 100 mg / kg, about 15 mg / kg to about 100 mg / kg, about 20 mg / kg to about 100 mg / kg, about 25 mg / kg to about 100 mg / kg, about 30 mg / kg to about 100 mg / kg, about 1 mg / kg to about 90 mg / kg, about 1 mg / kg to about 80 mg / kg, about 1 mg / kg, etc. The amounts are approximately 70 mg / kg, 1 mg / kg, 60 mg / kg, 5 mg / kg, 30 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg. In some embodiments, the amount of rituximab is approximately 20 mg / kg.

[0070] In some implementations, rituximab is administered twice weekly (BIW) at one or more doses as described herein.

[0071] Depending on the type of lymphoma to be treated and the patient's condition, the second anticancer therapy includes administration of approximately 250 mg / m². 2 Approximately 450 mg / m 2 Rituximab, approximately 650 mg / m² 2 Approximately 850 mg / m 2 Cyclophosphamide, approximately 1 mg / m³ 2 Approximately 100 mg / m 2 Doxorubicin or doxorubicin hydrochloride, approximately 0.5 mg / m² 2 Approximately 3 mg / m 2 Vincristine or vincristine sulfate, and approximately 10 mg to approximately 200 mg or approximately 10 mg / m². 2 Approximately 200 mg / m 2 Prednisone. For example, in some implementations, the anticancer therapy of this method includes administration of approximately 375 mg / m². 2 Rituximab, approximately 750 mg / m² 2 Cyclophosphamide, approximately 50 mg / m³ 2 Doxorubicin or doxorubicin hydrochloride, approximately 1.4 mg / m² 2Vincristine or vincristine sulfate, and approximately 100 mg or 100 mg / m 2 Prednisone. In some implementations, rituximab, cyclophosphamide, doxorubicin (e.g., doxorubicin hydrochloride), and vincristine (vincristine sulfate) are administered intravenously.

[0072] Depending on the type of lymphoma to be treated and the patient's condition, the second anticancer therapy may include administration of rituximab at approximately 10 mg / kg to approximately 30 mg / kg, cyclophosphamide at approximately 20 mg / kg to approximately 40 mg / kg, doxorubicin or doxorubicin hydrochloride at approximately 2 mg / kg to approximately 3 mg / kg, vincristine or vincristine sulfate at approximately 0.3 mg / kg to approximately 0.4 mg / kg, and prednisone at approximately 0.1 mg / kg to approximately 0.2 mg / kg. For example, in some embodiments, the anticancer therapy of this method may include administration of rituximab at approximately 20 mg / kg, cyclophosphamide at approximately 30 mg / kg, doxorubicin or doxorubicin hydrochloride at approximately 2.475 mg / kg, vincristine or vincristine sulfate at approximately 0.375 mg / kg, and prednisone at approximately 0.15 mg / kg. In some implementations, rituximab, cyclophosphamide, doxorubicin (e.g., doxorubicin hydrochloride), and vincristine (vincristine sulfate) are administered intravenously.

[0073] In one embodiment, compound 1 or a pharmaceutically acceptable salt thereof and the anticancer therapy may be administered simultaneously in the same or different formulations. In an alternative embodiment, compound 1 or a pharmaceutically acceptable salt thereof and the anticancer therapy may be administered sequentially, i.e., at different time points.

[0074] In some embodiments, the anticancer agent is a pharmaceutically acceptable salt of a compound of formula (I). In one embodiment, the anticancer agent is a tris(hydroxymethyl)aminomethane (“Tris”) salt of a compound of formula (I). In another embodiment, the anticancer agent is a sodium salt of a compound of formula (I).

[0075] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is in a solid or crystalline form of the compound of formula (I), as described in PCT / US2019 / 067897 (WO 2020 / 132471), filed December 20, 2019. The entire teachings of PCT / US2019 / 067897 (WO 2020 / 132471) are incorporated herein by reference. In one embodiment, the compound of formula (I) is in crystalline form A, B, C, or D. In one embodiment, the compound of formula (I) is in crystalline form A, B, or C of a Tris salt of the compound of formula (I). In one embodiment, the compound of formula (I) or a Tris salt thereof is in an amorphous form.

[0076] In one embodiment, the administration regimen for the lymphoma treatment described in the preceding paragraph comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of the compound of formula (I) and the sodium salt of the compound of formula (I)) once a week in one or more 28-day or 4-week cycles.

[0077] In one embodiment, the administration regimen for the lymphoma treatment method described in the preceding paragraph includes administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of the compound of formula (I) and the sodium salt of the compound of formula (I)) for a period of 2 to 5 days per week, wherein one treatment cycle is defined as a treatment lasting 4 consecutive weeks.

[0078] In one embodiment, the dosing regimen for the lymphoma treatment described in the preceding paragraph comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) for a continuous period of 2 to 5 days per week in one or more 28-day or 4-week cycles, followed by a rest period of 2 to 5 days.

[0079] In one embodiment, the dosing regimen for the lymphoma treatment described in the preceding paragraph comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of the compound of formula (I) and the sodium salt of the compound of formula (I)) for two consecutive days each week in one or more 28-day or 4-week cycles, followed by a 5-day rest period.

[0080] In one embodiment, the dosing regimen for the lymphoma treatment described in the preceding paragraph comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of the compound of formula (I) and the sodium salt of the compound of formula (I)) for three consecutive days each week in one or more 28-day or 4-week cycles, followed by a 4-day rest period.

[0081] In one embodiment, the dosing regimen for the lymphoma treatment described in the preceding paragraph comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of the compound of formula (I) and the sodium salt of the compound of formula (I)) for four consecutive days each week in one or more 28-day or 4-week cycles, followed by a 3-day rest period.

[0082] In one embodiment, the dosing regimen for the lymphoma treatment described in the preceding paragraph comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., the Tris salt of the compound of formula (I) and the sodium salt of the compound of formula (I)) for five consecutive days each week in one or more 28-day or 4-week cycles, followed by a 2-day rest period.

[0083] In one embodiment, the dosing regimen for the lymphoma treatment described in the preceding paragraph comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) for a continuous period of 2 to 5 days per week in one or more 28-day or 4-week cycles, followed by a rest period of 2 to 5 days, wherein the number of consecutive treatment days is increased in at least one week of the 28-day or 4-week cycle in one or more 28-day or 4-week cycles.

[0084] In another embodiment, the dosing regimen for the lymphoma treatment described in the preceding paragraph comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) for a continuous period of 2 to 5 days per week in one or more 28-day or 4-week cycles, followed by a rest period of 2 to 5 days, wherein the number of consecutive treatment days is reduced in at least one week of the 28-day or 4-week cycle in one or more 28-day or 4-week cycles.

[0085] In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) is administered to the subject for two consecutive days during the first week of a 28-day or 4-week cycle, followed by a 5-day rest period, wherein the number of consecutive treatment days is increased in at least one week of a 28-day or 4-week cycle.

[0086] In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) is administered to the subject for two consecutive days during the first week of a 28-day or 4-week cycle, followed by a 5-day rest period, wherein the number of consecutive treatment days is reduced in at least one week of a 28-day or 4-week cycle.

[0087] In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt (e.g., the Tris salt of the compound of formula (I) and the sodium salt of the compound of formula (I)) is administered to the subject for three consecutive days during the first week of a 28-day or 4-week cycle, followed by a four-day rest period, wherein the number of consecutive treatment days is increased in at least one week of a 28-day or 4-week cycle.

[0088] In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) is administered to the subject for three consecutive days during the first week of a 28-day or 4-week cycle, followed by a four-day rest period, wherein the number of consecutive treatment days is reduced in at least one week of the 28-day or 4-week cycle.

[0089] In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) is administered to the subject for four consecutive days during the first week of a 28-day or 4-week cycle, followed by a three-day rest period, wherein the number of consecutive treatment days is increased in at least one week of a 28-day or 4-week cycle.

[0090] In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) is administered to the subject for four consecutive days during the first week of a 28-day or 4-week cycle, followed by a three-day rest period, wherein the number of consecutive treatment days is reduced in at least one week of a 28-day or 4-week cycle.

[0091] In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) is administered to the subject for five consecutive days during the first week of a 28-day or 4-week cycle, followed by a two-day rest period, wherein the number of consecutive treatment days is increased in at least one week of a 28-day or 4-week cycle.

[0092] In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of the compound of formula (I) and a sodium salt of the compound of formula (I)) is administered to the subject for five consecutive days during the first week of a 28-day or 4-week cycle, followed by a two-day rest period, wherein the number of consecutive treatment days is reduced in at least one week of a 28-day or 4-week cycle.

[0093] In one embodiment, the administration regimen of the lymphoma treatment method described in the preceding paragraph comprises oral administration of an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Tris salt of compound (I) and sodium salt of compound (I)). In one embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Tris salt of compound (I) and sodium salt of compound (I)) is administered as an oral capsule. In another embodiment, an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., Tris salt of compound (I) and sodium salt of compound (I)) is administered as an oral tablet.

[0094] In one embodiment, the administration regimen for the lymphoma treatment method described in the preceding paragraph comprises administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of compound (I) and a sodium salt of compound (I)) once daily (QD). In another embodiment, the administration regimen for the cancer treatment method described in the preceding paragraph comprises administering an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of compound (I) and a sodium salt of compound (I)) twice daily (BID).

[0095] Composition

[0096] On the other hand, this application relates to pharmaceutical compositions comprising an agent and an anticancer therapy, wherein the pharmaceutical composition optionally and additionally comprises an excipient, wherein the anticancer agent is of formula (I):

[0097]

[0098] The anticancer therapy comprises, in one embodiment, cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof; wherein the anticancer therapy includes a combination of cyclophosphamide, doxorubicin, or a pharmaceutically acceptable salt thereof, vincristine, or a pharmaceutically acceptable salt thereof, and prednisolone. In one embodiment, the anticancer therapy further comprises rituximab. In one embodiment, the pharmaceutically acceptable salt of compound 1 is a tris(hydroxymethyl)aminomethane salt or a sodium salt. In one embodiment, the pharmaceutically acceptable salt of doxorubicin is a hydrochloride salt. In one embodiment, the pharmaceutically acceptable salt of vincristine is a sulfate salt.

[0099] Anticancer agents and / or anticancer therapies may be formulated into pharmaceutical compositions with pharmaceutically acceptable carriers, adjuvants, or mediators before being administered to subjects.

[0100] The term "pharmaceutically acceptable carrier, adjuvant, or mediator" means a carrier, adjuvant, or mediator that can be administered to a subject in conjunction with a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or an anticancer therapy without destroying its pharmacological activity, and is non-toxic when administered at a dose sufficient to deliver a therapeutic amount of the compound. Those skilled in the art will know how to prepare formulations suitable for administration. If the anticancer therapy is administered concurrently with a first anticancer agent, the anticancer therapy may optionally be part of the same formulation as the anticancer agent (i.e., the compound of formula (I) or a pharmaceutically acceptable salt thereof), or it may be administered alone.

[0101] Pharmaceutically acceptable carriers, adjuvants, and mediators that can be used in pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tween or other similar polymer delivery matrices, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin. Cyclodextrins such as α-, β- and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkyl cyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other dissolved derivatives may also be advantageously used for the delivery of enhanced (I) compounds or their pharmaceutically acceptable salts, and / or secondary anticancer agents.

[0102] The pharmaceutical composition may be administered orally, parenterally, by nebulization, topically, rectally, nasally, buccally, vaginally, or through an implanted reservoir, preferably orally or by injection. The pharmaceutical composition may contain any conventional, non-toxic, pharmaceutically acceptable carrier, adjuvant, or mediator. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. As used herein, the term parenterally includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0103] Pharmaceutical compositions may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. Such suspensions may be formulated using suitable dispersants or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents, such as solutions in 1,3-butanediol. Mannitol, water, Ringer's solution, and isotonic sodium chloride solutions may be used among acceptable mediators and solvents. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glycerol derivatives are suitable for the preparation of injections, as are natural, pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylene form. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, or carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms (e.g., emulsions and / or suspensions). Other commonly used surfactants, such as Tween or Span, and / or other similar emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0104] Pharmaceutical compositions can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, emulsions, aqueous suspensions, dispersions, and solutions. For tablets used orally, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When administered orally in aqueous suspensions and / or emulsions, the active ingredient may be suspended or dissolved in the oil phase and combined with emulsifiers and / or suspending agents. If desired, certain sweeteners and / or flavoring agents and / or coloring agents may be added.

[0105] Pharmaceutical compositions can be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and / or an anticancer therapy with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and thus melts in the rectum to release the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

[0106] The amount of active ingredient that can be combined with one or more pharmaceutical excipients to produce a single dosage form will vary depending on the patient being treated and the specific administration method. Typical formulations will contain about 5% to about 95% of the active compound (w / w). Alternatively, such formulations contain about 20% to about 80% of the active compound. In some embodiments, the pharmaceutical composition comprises about 10 mg to about 1500 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof (based on the weight of the free form of the compound of formula (I), excluding the weight of any conformational isomers, salt-forming agents, hydrated water, solvating solvents, etc.). In some embodiments, the pharmaceutical composition comprises between about 90 mg and about 240 mg; between about 95 mg and about 240 mg; between about 100 mg and about 240 mg; between about 10 mg and about 500 mg; or between about 10 mg and about 1000 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, or about 300 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, or about 1450 mg, or about 1500 mg.In some embodiments, the pharmaceutical composition is in an orally acceptable dosage form, such as a capsule, and comprises about 50 mg, about 75 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 175 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 225 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, or about 300 mg of a Tris salt of a compound of formula (I).

[0107] As used herein, when used in conjunction with numerical values ​​or ranges of values, the terms “about” and “approximately” mean that the value or range of values ​​may deviate from what is considered reasonable by a person skilled in the art.

[0108] The compounds of formula (I) and their formulations may be prepared according to the methods described in WO 2014 / 128669, WO 2019 / 164794, WO 2020 / 132471 and U.S. Patent No. 9,630,932, the contents of which are incorporated herein by reference.

[0109] Example

[0110] Study on growth inhibition of compound 1 and R-CHOP in tumor-bearing mice.

[0111] Depending on the needs of each model, 5 × 10⁵ cells were implanted subcutaneously into the mice. 6 Up to 2×10 7 1 cell. Monitor tumor volume twice weekly until the tumor reaches approximately 150 mm. 3 Once the tumor burden reaches this level, the mice are randomly assigned to different groups and receive the following treatments.

[0112]

[0113] At the end of the study, tumor tissue and plasma were collected one hour after the final dose of compound 1. The treatment was well tolerated. Figure 1-3 The percentage change in tumor volume in the treated mouse model is shown. Figures 1-3 As shown, various models showed significant responses to treatment with compound 1 and R-CHOP. The magnitude of the response ranged from complete tumor regression seen in models such as Farage (DLBCL) and JVM-2 (MCL) (see...). Figure 1-2 Tumor arrest as seen in the WSUDLCL-2 (DLBCL) model (see...) Figure 1 The results varied. Similar results were observed in multiple lymphoma subsets tested.

Claims

1. Use in the manufacture of a medicament for treating lymphoma in a subject, in combination with an anticancer agent of formula (I) or a pharmaceutically acceptable salt thereof, for the purpose of using an anticancer therapy: (I)， The anticancer therapy described herein includes rituximab, cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof, vincristine or a pharmaceutically acceptable salt thereof, and a combination of prednisolone, wherein the lymphoma is diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), or Burkitt's lymphoma.

2. The use according to claim 1, wherein the lymphoma is diffuse large B-cell lymphoma (DLBCL).

3. The use according to claim 1, wherein the lymphoma is mantle cell lymphoma (MCL).

4. The use according to claim 1, wherein the lymphoma is Burkitt lymphoma.

5. The use according to any one of claims 1 to 4, wherein the anticancer agent and the anticancer therapy are administered simultaneously in the same or different formulations.

6. The use according to any one of claims 1 to 5, wherein the anticancer agent and the anticancer therapy are administered sequentially.

7. The use according to any one of claims 1 to 6, wherein the anticancer agent is a tris(hydroxymethyl)aminomethane salt of the compound of formula (I).

8. The use according to any one of claims 1 to 7, wherein the anticancer agent is a sodium salt of the compound of formula (I).

9. The use according to any one of claims 1 to 8, wherein the doxorubicin is doxorubicin hydrochloride.

10. The use according to any one of claims 1 to 9, wherein the vincristine is vincristine sulfate.

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