Use of DHODH inhibitor compounds in cancer combination therapy

Abstract

Provided herein are methods of treating lymphoma with anti-cancer agents and therapies, wherein a first anti-cancer agent has the chemical formula (I): [Formula 1] TIFF2023540206000010.tif44162 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 disclosure of that priority application is incorporated herein by reference.

[0002] Lymphoma is a type of cancer that begins in the cells of the lymphatic system. Lymphomas are generally classified as either Hodgkin's lymphoma or non-Hodgkin's lymphoma. Hodgkin's lymphoma is characterized by the presence of specific white blood cells called Reed-Sternberg cells and is generally rarer. Non-Hodgkin's lymphoma is characterized by the absence of Reed-Sternberg cells and accounts for approximately 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's 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 course of DLBCL, approximately 50% to 70% of patients are cured with standard treatment with R-CHOP. Nevertheless, R-CHOP alone is insufficient in 30% to 50% of patients. Among patients who do not respond to R-CHOP therapy, 20% develop primary refractory disease (progression during or after treatment), and 30% relapse after achieving complete remission.

[0004] In view of the above, there remains an unmet need for new and more effective therapeutic approaches targeting lymphoma. Summary of the Invention

[0005] The dihydroorotate dehydrogenase inhibitor 1-methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid and pharmaceutically acceptable salts thereof, also referred to as "the compound of formula (I)" or "Compound 1," have been found to be particularly useful in the treatment of hematological malignancies and to provide therapeutic benefit when used in combination with CHOP-based therapies.

[0006] For example, complete tumor regression was observed in various mouse lymphoma models using a combination of Compound 1 and R-CHOP, while tumor growth continued in mice treated with CHOP or rituximab alone. See, e.g., Figures 1-3, which show complete regression in several mouse models of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma, Hodgkin lymphoma, and anaplastic lymphoma after treatment with Compound 1 and R-CHOP.

[0007] That is, in one aspect, the present disclosure provides a method for treating lymphoma in a subject, comprising administering to the subject an effective amount of an anti-cancer agent and an effective amount of an anti-cancer therapy, The anticancer agent has the following chemical structural formula (I): [ka] or a pharmaceutically acceptable salt thereof; and wherein the anticancer therapy (agent) 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 (agent) 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.

[0008] In another aspect, the present application provides the use of an anti-cancer agent in the manufacture of a therapeutic medicament for treating lymphoma, wherein the therapeutic agent is used in combination with an effective amount of an anti-cancer therapy (agent); The anticancer agent has the following chemical structure: [ka] or a pharmaceutically acceptable salt thereof; and wherein the anticancer therapy (agent) 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 (agent) 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.

[0009] In yet another aspect, the present application provides an anti-cancer agent for use in treating lymphoma in combination with an anti-cancer therapy (agent), wherein the anti-cancer agent has the following chemical structural formula (I): [ka] or a pharmaceutically acceptable salt thereof; and wherein the anticancer therapy (agent) 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 (agent) 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.

[0010] In a further aspect, the present application provides a pharmaceutical composition comprising an anti-cancer agent and an anti-cancer therapy (agent); wherein the pharmaceutical composition optionally and additionally comprises an excipient; wherein the anti-cancer agent has the following chemical structural formula (I): [ka] or a pharmaceutically acceptable salt thereof; and wherein the anticancer therapy (agent) 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 (agent) 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.

[0011] Other features and advantages will be apparent from the drawings and detailed description of several embodiments, and from the appended claims. [Brief explanation of the drawings]

[0012] [Figure 1]Compound 1 (100 mg / kg twice daily), rituximab (20 mg / kg twice weekly), CHOP (C - 30 mg / kg once daily intraperitoneally, D - 2.475 mg / kg once daily intravenously, V - 0.375 mg / kg once daily intravenously, P - 0.15 mg / kg once daily orally for 5 doses), and Compound 1 (100 mg / kg twice daily) with R-CHOP (R - 20 mg / kg twice weekly intraperitoneally, C - 30 mg / kg once daily intraperitoneally, D - 2.475 mg / kg once daily intravenously, V - 0.375 mg / kg once daily intravenously, P - Figure 1 shows the % change in tumor volume in a DLBCL mouse model treated with a combination of 100 mg / kg PO once daily (0.15 mg / kg x 5). [Figure 2] Compound 1 (100 mg / kg twice daily), rituximab (20 mg / kg twice weekly), CHOP (C - 30 mg / kg once daily intraperitoneally, D - 2.475 mg / kg once daily intravenously, V - 0.375 mg / kg once daily intravenously, P - 0.15 mg / kg once daily orally for 5 doses), and Compound 1 (100 mg / kg twice daily) with R-CHOP (R - 20 mg / kg twice weekly intraperitoneally, C - 30 mg / kg once daily intraperitoneally, D - 2.475 mg / kg once daily intravenously, V - 0.375 mg / kg once daily intravenously, P - Figure 1 shows the % change in tumor volume in an MCL mouse model treated with a combination of 100 mg / kg PO once daily (0.15 mg / kg x 5). [Figure 3]Compound 1 (100 mg / kg twice daily), rituximab (20 mg / kg twice weekly), CHOP (C - 30 mg / kg once daily intraperitoneally, D - 2.475 mg / kg once daily intravenously, V - 0.375 mg / kg once daily intravenously, P - 0.15 mg / kg once daily intravenously), and Compound 1 (100 mg / kg twice daily) with R-CHOP (R - 20 mg / kg twice weekly intraperitoneally, C - 30 mg / kg once daily intraperitoneally, D - 2.475 mg / kg once daily intravenously, V - 0.375 mg / kg once daily orally, P - Figure 1 shows the % change in tumor volume in mouse models of Burkitt's lymphoma, anaplastic lymphoma, and Hodgkin's lymphoma treated with a combination of 100 mg / kg PO once daily (0.15 mg / kg PO once daily x 5). DETAILED DESCRIPTION OF THE INVENTION

[0013] 1-Methyl-5-(2'-methyl-[1,1'-biphenyl]-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid, hereinafter also referred to as "the 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 WO2014 / 128669 and WO2019 / 164794, and U.S. Patent No. 9,630,932; the contents of which are incorporated herein by reference. [ka] The compounds of formula (I) have been developed for the treatment of conditions and disorders that may benefit from DHODH inhibition, including, but not limited to, solid cancers and hematological cancers.

[0014] In one aspect, the present application is directed to a method for treating lymphoma in a subject, comprising administering to the subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an effective amount of an anti-cancer therapy comprising cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof, vincristine or a pharmaceutically acceptable salt thereof, and prednisolone. In one embodiment, the anti-cancer 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 anti-cancer therapy (agent) is a combination of cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof (such as the hydrochloride salt), vincristine or a pharmaceutically acceptable salt thereof (such as the sulfate salt), and prednisolone. In another aspect, the anti-cancer therapy (agent) is a combination of rituximab, cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof (such as the hydrochloride salt), vincristine or a pharmaceutically acceptable salt thereof (such as the sulfate salt), and prednisolone.

[0015] In one aspect, the lymphoma treated by the methods of the present disclosure is Hodgkin's lymphoma.

[0016] In one aspect, the lymphoma treated by the method of the present disclosure 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 a B-cell lymphoma DLBCL. In some embodiments, the non-Hodgkin's lymphoma is a 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 embodiments, the 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 gamma-delta T-cell lymphoma.

[0017] In some embodiments, the lymphoma is selected from lymphocytic lymphoma carcinoma of the bladder, diffuse mixed cell lymphoma, primary effusion lymphoma, double-hit diffuse large B-cell lymphoma, and triple-hit diffuse large B-cell lymphoma. In some embodiments, the lymphoma is selected from angioimmunoblastic lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, blastic NK-cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, and Waldenstrom's macroglobulinemia.

[0018] In one embodiment, the treated subject belongs to a subpopulation of non-Hodgkin's lymphoma and Hodgkin's lymphoma patients whose non-Hodgkin's lymphoma or Hodgkin's lymphoma has progressed despite pre-treatment, and there is no other effective (curative or life-prolonging) standard therapy. In other words, the treated subject belongs to a subpopulation of resistant or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma. In one embodiment, the standard curative therapy is high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT). In one embodiment, 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 subpopulation of relapsed non-Hodgkin's lymphoma or Hodgkin's lymphoma (e.g., relapsed from HD-ASCT). In another embodiment, the subject is not suitable for HD-ASCT. In another embodiment, the subject has rejected HD-ASCT.

[0019] In one embodiment, the lymphoma treated by the methods of the present disclosure is a mature B-cell neoplasm, a mature T-cell neoplasm, or a mature NK-cell neoplasm, Hodgkin's lymphoma, or an immunodeficiency-associated lymphoproliferative dysplasia.

[0020] In one aspect, the cancer treated by the methods of the present disclosure is selected from chronic lymphocytic leukemia and small lymphocytic lymphoma.

[0021] The terms "subject" and "patient" herein may be used synonymously and may refer to a mammal in need of treatment. For example, pet animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0022] An "effective amount" of a compound of Formula (I) or a pharmaceutically acceptable salt thereof is an amount sufficient, when combined with an anti-cancer therapy (agent), such as CHOP or R-CHOP, to provide a 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 anti-cancer therapy (agent) is an amount sufficient, when combined with a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to provide a therapeutic benefit in the treatment of a condition (such as lymphoma) or to delay or minimize one or more symptoms associated with a condition (such as lymphoma). The terms "therapeutically effective amount" and "effective amount" are used synonymously. The term "effective amount" can include an amount that improves overall treatment, reduces or avoids symptoms, signs, or causes of lymphoma, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, an effective amount is an amount sufficient to exert a therapeutic effect in the treatment of lymphoma.

[0023] The exact amount of the compound of formula (I) (or a pharmaceutically acceptable salt thereof) or anti-cancer therapy (agent) administered to a subject depends on various factors, such as the administered drug, pharmaceutical formulation, route of administration, type of disease or disorder, and condition of the individual being treated, but such amount can be routinely determined by one of ordinary skill in the art. For example, determining the effective amount will also depend on the degree, severity, and type of cell proliferation. Those of ordinary skill in the art can determine the appropriate dose depending on these and other factors. Suitable doses are known for approved drugs and may be adjusted by those of ordinary skill in the art according to 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. If an amount is not explicitly stated, the effective amount should be estimated. Non-limiting examples of effective amounts of the compound of formula (I) or a pharmaceutically acceptable salt thereof are provided below.

[0024] An effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof generally ranges from 0.1 μg to 100 mg per kg of recipient (mammal) body weight per day, with a more typical range being 1 to 10 mg per kg of body weight per day. Thus, the actual daily amount for a 70 kg adult mammal (or adult) is usually 70 to 700 mg, which can be administered as an individual daily dose or, typically, as a series of divided daily sub-doses (e.g., 2, 3, 4, 5, or 6 doses) so that the total daily dose is the same. An effective dose of a compound of formula (I) or a pharmaceutically acceptable salt thereof for a subject can range from 10 μg to 500 mg. Effective amounts of the anticancer therapeutic agents CHOP and R-CHOP are known to those skilled in the art. Exemplary amounts are further described below.

[0025] The term "treat" means to slow, inhibit, attenuate, reduce, arrest, or stabilize the development or progression of lymphoma; to reduce the severity of lymphoma; or to ameliorate the symptoms associated with lymphoma. Treatment may also be continued after symptoms have resolved, for example, to reduce the likelihood of or delay recurrence.

[0026] Beneficial therapeutic effects in lymphoma can be assessed in a variety of ways. As described herein, administration of therapeutically effective amounts of a combination is advantageous over the individual component compounds. As used herein, an "advantageous combination" is a combination that provides at least one of the following improved properties when compared to the component compounds administered individually at therapeutically effective amounts: (i) more potent anticancer activity than the most active single agent; (ii) synergistic anticancer effect; or (iii) additive activity.

[0027] The term "relapsed" refers to the situation in which cancer cells return in a patient who had a remission of lymphoma after therapeutic treatment.

[0028] The term "refractory or resistant" refers to the situation where a patient has residual cancer cells in their body, even after intensive treatment.

[0029] "Dual-hit diffuse large B-cell lymphoma" herein refers to a form of lymphoma or diffuse large B-cell lymphoma in which the lymphoma cells are mutated in two oncogenes: c-MYC and BCL2 or BCL6. In one embodiment, the dual-hit diffuse large B-cell lymphoma is treated with the methods described herein and is characterized by genetic mutations in c-MYC and BCL2. In another embodiment, the dual-hit diffuse large B-cell lymphoma is treated with the methods described herein and is characterized by genetic mutations in c-MYC and BCL6.

[0030] "Triple-hit diffuse large B-cell lymphoma" herein refers to a form of lymphoma or diffuse large B-cell lymphoma in which the lymphoma cells are mutated in three oncogenes: c-MYC, BCL2, and BCL6. In one embodiment, triple-hit diffuse large B-cell lymphoma is treated by the methods herein.

[0031] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic acid salt or organic or inorganic base salt of a compound described herein. Representative pharmaceutically acceptable organic or inorganic base salts include, for example, alkali metal salts (e.g., sodium), alkaline earth salts (e.g., calcium), and ammonium salts (e.g., tris(hydroxymethyl)aminomethane, hydrabamine, and N-methylglucamine ammonium salts). Representative pharmaceutically acceptable organic or inorganic acid salts or organic or inorganic base salts include, for example, acetate, amsonate (4,4-diaminostilbene-2,2-disulfate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, and methyl sulfate. , mucate, napsylate, nitrate, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, embonate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable salt may have more than one charged atom in its structure. In this example, a pharmaceutically acceptable salt may have multiple counter ions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counter ions.

[0032] In one embodiment, the methods described herein include administering or co-administering the anti-cancer therapy CHOP or R-CHOP. As used herein, the term "co-administering" with respect to an anti-cancer therapy means administering the anti-cancer therapy with Compound 1 or a pharmaceutically acceptable salt thereof, either as part of a single dosage form (such as a composition comprising Compound 1 or a pharmaceutically acceptable salt thereof and the anti-cancer therapy) or as separate multiple dosage forms. Alternatively, the anti-cancer therapy may be administered before, consecutively 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 anti-cancer therapy are administered by conventional methods. The administration of a composition comprising both Compound 1 or a pharmaceutically acceptable salt thereof and an anti-cancer therapy to a subject does not exclude the separate administration of the same therapeutic agent, any other second therapeutic agent, or any agent described herein to the subject at different times during the course of treatment. As used herein, the term "co-administered" with respect to an additional cancer treatment means that the other cancer treatment may occur prior to, sequentially with, or following the administration of a compound described herein.

[0033] In one embodiment, the anti-cancer therapy (agent) is R-CHOP (i.e., a combination of rituximab, cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof (such as the hydrochloride salt), vincristine or a pharmaceutically acceptable salt thereof (such as the sulfate salt), and prednisolone).

[0034] Depending on the lymphoma being treated and the condition of the subject, the cyclophosphamide of the anticancer therapies described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. Cyclophosphamide, alone or with Compound 1 and / or one or more other active agents, may be formulated in suitable dosage units containing pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

[0035] In one embodiment, cyclophosphamide is administered, for example, intravenously (IV), subcutaneously (SC), or orally.

[0036] In certain embodiments, a treatment cycle comprises multiple doses of cyclophosphamide administered to a subject in need thereof over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days or more). In certain embodiments, a treatment cycle comprises multiple doses of cyclophosphamide administered to a subject in need thereof over multiple weeks (e.g., 1, 2, 3, 4, or more than 5 weeks). Suitable doses for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts. For example, in certain embodiments, the amount of cyclophosphamide administered by the method is, for example, about 100 mg / m 2 ~about 1500mg / m 2 , about 200mg / m 2 ~about 1500mg / m 2 , about 300mg / m 2 ~about 1500mg / m 2 , about 400mg / m 2 ~about 1500mg / m 2 , about 450mg / m 2 ~about 1500mg / m 2 , about 500mg / m 2 ~about 1500mg / m 2 , about 550mg / m 2 ~about 1500mg / m 2 , about 600mg / m 2 ~about 1500mg / m 2 , about 650mg / m 2 ~about 1500mg / m 2 , about 700mg / m 2 ~about 1500mg / m 2 , about 750mg / m 2 ~about 1500mg / m 2 , about 100mg / m 2 ~about 1250mg / m 2 , about 100mg / m 2~about 1150mg / m 2 , about 100mg / m 2 ~about 1000mg / m 2 , about 100mg / m 2 ~about 900mg / m 2 , about 100mg / m 2 ~about 850mg / m 2 , about 100mg / m 2 ~about 800mg / m 2 , about 100mg / m 2 ~about 750mg / m 2 , about 200mg / m 2 ~about 1400mg / m 2 , about 300mg / m 2 ~About 1300mg / m 2 , about 400mg / m 2 ~about 1200mg / m 2 , about 500mg / m 2 ~about 1100mg / m 2 , about 600mg / m 2 ~about 1000mg / m 2 , about 600mg / m 2 ~about 900mg / m 2 , about 600mg / m 2 ~about 800mg / m 2 , about 700mg / m 2 ~about 800mg / m 2 , or about 725 mg / m 2 ~about 775mg / m 2 In certain embodiments, the amount of cyclophosphamide administered by the method may range from about 500 mg / m 2 , about 550mg / m 2 , about 600mg / m 2 , about 650mg / m 2 , about 700mg / m 2 , about 750mg / m 2 , about 800mg / m 2 , or approximately 850 mg / m 2 In certain embodiments, the amount of cyclophosphamide administered by the method is about 750 mg / m 2 is.

[0037] In certain embodiments, the amount of cyclophosphamide is from about 1 mg / kg to about 100 mg / kg, from about 5 mg / kg to about 100 mg / kg, from about 10 mg / kg to about 100 mg / kg, from about 15 mg / kg to about 100 mg / kg, from about 20 mg / kg to about 100 mg / kg, from about 25 mg / kg to about 100 mg / kg, from about 30 mg / kg to about 100 mg / kg, from about 35 mg / kg to about 100 mg / kg, from about 1 mg / kg to about 90 mg / kg, from about 1 mg / kg to about 80 mg / kg, or from about 100 mg / kg to about 150 mg / kg. The cyclophosphamide dose is about 1 mg / 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 certain embodiments, the cyclophosphamide dose 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 certain embodiments, the cyclophosphamide dose is about 30 mg / kg. In certain embodiments, cyclophosphamide is administered QD at one or more of the doses recited herein. In certain embodiments, cyclophosphamide is administered QD at one or more of the doses recited herein on certain days of treatment (e.g., days 1 and 22).

[0038] Depending on the lymphoma being treated and the condition of the subject, the anticancer therapy (agent) doxorubicin (e.g., doxorubicin hydrochloride) described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. Doxorubicin or doxorubicin hydrochloride, alone or together with Compound 1 and / or one or more other active agents, may be formulated in suitable dosage units containing pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

[0039] In one embodiment, doxorubicin (eg, doxorubicin hydrochloride) is administered, for example, by the intravenous (IV) route.

[0040] In certain embodiments, a treatment cycle comprises multiple doses of doxorubicin (e.g., doxorubicin hydrochloride) administered to a subject in need thereof over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more days). In certain embodiments, a treatment cycle comprises multiple doses of doxorubicin (e.g., doxorubicin hydrochloride) administered to a subject in need thereof over multiple weeks (e.g., more than 1, 2, 3, 4, or 5 weeks). Suitable doses for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts. For example, in certain embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by the method is about 1 mg / m 2 ~about 200mg / m 2 , about 1mg / m 2 ~about 150mg / m 2 , about 1mg / m 2 ~about 100mg / m 2 , about 10mg / m 2 ~about 100mg / m 2 , about 15mg / m 2 ~about 100mg / m 2 , about 20mg / m 2 ~about 100mg / m 2 , about 25mg / m 2 ~about 100mg / m 2 , about 30mg / m 2 ~about 100mg / m 2 , about 35mg / m 2 ~about 100mg / m 2 , about 40mg / m 2 ~about 100mg / m 2 , about 45mg / m 2 ~about 100mg / m 2 , about 50mg / m 2 ~about 100mg / m 2 , about 1mg / m 2 ~about 95mg / m 2, about 1mg / m 2 ~about 90mg / m 2 , about 1mg / m 2 ~about 85mg / m 2 , about 1mg / m 2 ~about 80mg / m 2 , about 1mg / m 2 ~about 75mg / m 2 , about 1mg / m 2 ~about 70mg / m 2 , about 1mg / m 2 ~about 65mg / m 2 , about 1mg / m 2 ~about 60mg / m 2 , about 1mg / m 2 ~about 55mg / m 2 , or approximately 1 mg / m 2 ~about 50mg / m 2 In certain embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by the method is about 25 mg / m 2 , about 30mg / m 2 , about 35mg / m 2 , about 40mg / m 2 , about 45mg / m 2 , about 50mg / m 2 , about 55mg / m 2 , about 60mg / m 2 , or approximately 65 mg / m 2 In certain embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by the method is about 50 mg / m 2 is.

[0041] In certain embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by the 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. ... In certain embodiments, the amount of doxorubicin (e.g., doxorubicin hydrochloride) administered by the method is about 2.475 mg / kg. In certain embodiments, doxorubicin (e.g., doxorubicin hydrochloride) is administered at one or more of the doses recited herein, each day (QD). In certain embodiments, doxorubicin (e.g., doxorubicin hydrochloride) is administered QD on certain days of treatment (e.g., days 1 and 22) at one or more of the doses recited herein.

[0042] Depending on the lymphoma being treated and the condition of the subject, the vincristine (e.g., vincristine sulfate) of the anticancer therapies described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. Vincristine (e.g., vincristine sulfate), alone or together with Compound 1 and / or one or more other active agents, may be formulated in suitable dosage units containing pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

[0043] In one embodiment, vincristine (eg, vincristine sulfate) is administered, for example, by intravenous (IV), subcutaneous (SC) or oral routes.

[0044] In certain embodiments, a treatment cycle comprises multiple doses of vincristine (e.g., vincristine sulfate) administered to a subject in need thereof over multiple days (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more days). In certain embodiments, a treatment cycle comprises multiple doses of vincristine (e.g., vincristine sulfate) administered to a subject in need thereof over multiple weeks (e.g., more than 1, 2, 3, 4, or 5 weeks). Suitable doses for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts. For example, in certain embodiments, the amount of vincristine (e.g., vincristine sulfate) administered by the method is about 0.2 mg / m 2 ~10mg / m 2 , about 0.2mg / m 2 ~5mg / m 2 , about 0.4mg / m 2 ~5mg / m 2 , about 0.6mg / m 2 ~5mg / m 2 , about 0.8mg / m 2 ~5mg / m 2 , about 1mg / m 2 ~5mg / m 2 , about 1.2mg / m 2 ~5mg / m 2 , about 1.4mg / m 2 ~5mg / m 2 , about 0.2mg / m 2 ~3mg / m 2 , about 0.2mg / m 2 ~2.5mg / m 2 , about 0.2mg / m 2 ~2.2 mg / m 2 , about 0.2mg / m 2 ~2.0mg / m 2 , about 0.2mg / m 2 ~1.8mg / m 2 , about 1.6mg / m 2 ~1.4mg / m 2 , about 0.4mg / m 2 ~2.5mg / m 2, 0.6 mg / m 2 ~2.2 mg / m 2 , 0.8 mg / m 2 ~2.0mg / m 2 , 0.8 mg / m 2 ~2.0mg / m 2 , 1 mg / m 2 ~1.8mg / m 2 , or 1.2 mg / m 2 ~1.6 mg / m 2 In certain embodiments, the amount of vincristine (e.g., vincristine sulfate) administered by the method is about 1 mg / m 2 , 1.2 mg / m 2 , about 1.4mg / m 2 , 1.4 mg / m 2 , 1.6 mg / m 2 , 1.8 mg / m 2 , or 2 mg / m 2 In certain embodiments, the amount of vincristine (e.g., vincristine sulfate) administered by the method is about 1.4 mg / m 2 is.

[0045] In certain embodiments, the amount of vincristine (e.g., vincristine sulfate) administered by the method is from about 0.1 mg / kg to about 1 mg / kg, from about 0.2 mg / kg to about 1 mg / kg, from about 0.25 mg / kg to about 1 mg / kg, from about 0.275 mg / kg to about 1 mg / kg, from about 0.3 mg / kg to about 1 mg / kg, from about 0.325 mg / kg to about 1 mg / kg, from about 0.35 mg / kg to about 1 mg / kg, from about 0.375 mg / kg to about 1 mg / kg, from about 0.4 mg / kg to about 1 mg / kg, or from about 0.5 mg / kg to about 1 mg / kg. In certain embodiments, the amount of vincristine (e.g., vincristine sulfate) administered by the method is about 0.375 mg / kg.

[0046] Depending on the lymphoma being treated and the condition of the subject, the prednisone in the anticancer therapies described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. Prednisone, alone or with Compound 1 and / or one or more other active agents, may be formulated in suitable dosage units containing pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

[0047] In one embodiment, prednisone is administered, for example, by intravenous (IV), subcutaneous (SC) or oral routes.

[0048] In certain embodiments, a treatment cycle comprises multiple doses of prednisone administered to a subject in need thereof 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 certain embodiments, a treatment cycle comprises multiple doses of prednisone administered to a subject in need thereof over multiple weeks (e.g., more than 1, 2, 3, 4, or 5 weeks). Suitable doses for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts. For example, in certain embodiments, the amount of prednisone administered by the method is about 25 mg / m 2 ~about 200mg / m 2 , about 50mg / m 2 ~about 200mg / m 2 , about 75mg / m 2 ~about 200mg / m 2 , about 100mg / m 2 ~about 200mg / m 2 , about 25mg / m 2 ~about 175mg / m 2 , about 125mg / m 2 ~about 150mg / m 2 , about 25mg / m 2 ~about 125mg / m 2 , about 25mg / m 2 ~about 100mg / m 2 , about 50mg / m 2 ~about 175mg / m 2 , about 75mg / m 2 ~about 150mg / m 2 , or about 75 mg / m 2 ~about 125mg / m 2 is.

[0049] In certain embodiments, the amount of prednisone administered by the method is about 25 mg / m 2 , about 50mg / m 2 , about 75mg / m 2 , about 100mg / m 2 , about 125mg / m 2 , or about 150 mg / m 2In certain embodiments, the amount of prednisone is about 100 mg / m 2 is.

[0050] In certain embodiments, the amount of prednisone administered by the 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.

[0051] In certain embodiments, the amount of prednisone administered by the method is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg. In certain embodiments, the amount of prednisone is about 100 mg.

[0052] In certain embodiments, the amount of prednisone administered by the method is from about 0.05 mg / kg to about 0.3 mg / kg, from about 0.075 mg / kg to about 0.3 mg / kg, from about 0.1 mg / kg to about 0.3 mg / kg, from about 0.125 mg / kg to about 0.3 mg / kg, from about 0.15 mg / kg to about 0.3 mg / kg, from about 0.175 mg / kg to about 0.3 mg / kg, The dose ranges from 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 certain embodiments, the amount of prednisone administered by the method is about 0.15 mg / kg. In certain embodiments, prednisone is administered QD at one or more of the doses recited herein. In certain embodiments, prednisone is administered QD at one or more of the doses recited herein on certain days of treatment (e.g., days 1-5 and days 22-27).

[0053] Depending on the lymphoma being treated and the condition of the subject, the rituximab of the anticancer therapies described herein may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. Rituximab, alone or with Compound 1 and / or one or more other active agents, may be formulated in suitable dosage units containing pharmaceutically acceptable excipients, carriers, adjuvants, and vehicles appropriate for each route of administration.

[0054] In one embodiment, rituximab is administered, for example, by intravenous (IV), subcutaneous (SC) or oral routes.

[0055] In certain embodiments, a treatment cycle comprises multiple doses of rituximab administered to a subject in need thereof 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 certain embodiments, a treatment cycle comprises multiple doses of rituximab administered to a subject in need thereof over multiple weeks (e.g., 1, 2, 3, 4, or more than 5 weeks). Suitable doses for the methods provided herein include, for example, therapeutically effective amounts and prophylactically effective amounts. For example, in certain embodiments, the amount of rituximab is about 200 mg / m 2 ~about 500mg / m 2 , about 225mg / m 2 ~about 500mg / m 2 , about 250mg / m 2 ~about 500mg / m 2 , about 275mg / m 2 ~about 500mg / m 2 , about 300mg / m 2 ~about 500mg / m 2 , about 325mg / m 2 ~about 500mg / m 2 , about 350mg / m 2 ~about 500mg / m 2 , about 375mg / m 2~about 500mg / m 2 , about 200mg / m 2 ~about 475mg / m 2 , about 200mg / m 2 ~about 450mg / m 2 , about 200mg / m 2 ~about 425mg / m 2 , about 200mg / m 2 ~about 400mg / m 2 , about 200mg / m 2 ~about 375mg / m 2 , about 225mg / m 2 ~about 475mg / m 2 , about 250mg / m 2 ~about 450mg / m 2 , about 275mg / m 2 ~about 425mg / m 2 , about 300mg / m 2 ~about 400mg / m 2 , about 325mg / m 2 ~about 400mg / m 2 , or approximately 350 mg / m 2 ~about 400mg / m 2 In certain embodiments, the amount of rituximab is about 250 mg / m 2 , 275 mg / m 2 , 300 mg / m 2 , 325 mg / m 2 , 350 mg / m 2 , 375 mg / m 2 , 400 mg / m 2 , or 425 mg / m 2 In certain embodiments, the amount of rituximab is about 375 mg / m 2 is.

[0056] In certain embodiments, the amount of rituximab is from about 1 mg / kg to about 100 mg / kg, from about 5 mg / kg to about 100 mg / kg, from about 10 mg / kg to about 100 mg / kg, from about 15 mg / kg to about 100 mg / kg, from about 20 mg / kg to about 100 mg / kg, from about 25 mg / kg to about 100 mg / kg, from about 30 mg / kg to about 100 mg / kg, from about 1 mg / kg to about 90 mg / kg, from about 1 mg / kg to about 80 mg / kg, or from about 1 mg / kg to about 100 mg / kg. In certain embodiments, the amount of rituximab is about 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg. In certain embodiments, the amount of rituximab is about 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, or 30 mg / kg. In certain embodiments, the amount of rituximab is about 20 mg / kg.

[0057] In certain embodiments, rituximab is administered twice weekly (BIW) at one or more of the doses recited herein.

[0058] Depending on the lymphoma being treated and the condition of the subject, the second anti-cancer therapy may be administered at a dose of about 250 mg / m 2 ~about 450mg / m 2 of rituximab, approximately 650 mg / m 2 ~about 850mg / m 2 of cyclophosphamide, approximately 1 mg / m 2 ~about 100mg / m 2 of doxorubicin or doxorubicin hydrochloride, approximately 0.5 mg / m 2 ~about 3mg / m 2 of vincristine or vincristine sulfate, and about 10 mg to about 200 mg or about 10 mg / m 2 ~about 200mg / m 2For example, in some embodiments, the anti-cancer therapy of the present method comprises administering about 375 mg / m of prednisone. 2 of rituximab, approximately 750 mg / m 2 of cyclophosphamide, approximately 50 mg / m 2 of doxorubicin or doxorubicin hydrochloride, approximately 1.4 mg / m 2 of vincristine or vincristine sulfate, and 100 mg or 100 mg / m 2 In some embodiments, rituximab, cyclophosphamide, doxorubicin (e.g., doxorubicin hydrochloride), and vincristine (vincristine sulfate) are administered intravenously.

[0059] Depending on the lymphoma being treated and the subject's condition, the second anticancer therapy(ies) may include administration of about 10 mg / kg to about 30 mg / kg of rituximab, about 20 mg / kg to about 40 mg / kg of cyclophosphamide, about 2 mg / kg to about 3 mg / kg of doxorubicin or doxorubicin hydrochloride, about 0.3 mg / kg to about 0.4 mg / kg of vincristine or vincristine sulfate, and about 0.1 mg / kg to about 0.2 mg / kg of prednisone. For example, in some embodiments, the anticancer therapy(ies) of the present method includes administration of about 20 mg / kg of rituximab, about 30 mg / kg of cyclophosphamide, about 2.475 mg / kg of doxorubicin or doxorubicin hydrochloride, about 0.375 mg / kg of vincristine or vincristine sulfate, and 0.15 mg / kg of prednisone. In some embodiments, rituximab, cyclophosphamide, doxorubicin (eg, doxorubicin hydrochloride), and vincristine (vincristine sulfate) are administered intravenously.

[0060] In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof and the anti-cancer therapy (agent) can be administered simultaneously in the same or different formulations. In another embodiment, Compound 1 or a pharmaceutically acceptable salt thereof and the anti-cancer therapy (agent) can be administered sequentially, i.e., at different times.

[0061] 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).

[0062] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a solid-state or crystalline form of the compound of Formula (I), as described in PCT / US2019 / 067897 (WO2020 / 132471), filed December 20, 2019. The entire contents of PCT / US2019 / 067897 (WO2020 / 132471) are incorporated herein by reference. In one embodiment, the compound of Formula (I) is Form A, Form B, Form C, or Form D of the crystalline form of the compound of Formula (I). In one embodiment, the compound of Formula (I) is Form A, Form B, or Form C of the crystalline form of the tris salt of the compound of Formula (I). In one embodiment, the compound of Formula (I) or a tris salt thereof is amorphous.

[0063] In one embodiment, the dosing regimen for lymphoma treatment described in the paragraph above comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) once weekly for one or more 28-day or four-week cycles.

[0064] In one embodiment, the administration regimen for lymphoma treatment described in the paragraph above comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of a compound of formula (I) and a sodium salt of a compound of formula (I)) for a period of 2 to 5 days each week in one cycle of therapy, defined as 4 consecutive weeks of treatment.

[0065] In one embodiment, the dosing regimen for lymphoma treatment described in the paragraph above comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) for 2 to 5 consecutive days followed by 2 to 5 days of rest each week in one or more 28-day or 4-week cycles.

[0066] In one embodiment, the dosing regimen for lymphoma treatment described in the paragraph above comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) for two consecutive days followed by a five-day rest period each week in one or more 28-day or four-week cycles.

[0067] In one embodiment, the dosing regimen for lymphoma treatment described in the above paragraph comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) for three consecutive days followed by four days of rest each week in one or more 28-day or four-week cycles.

[0068] In one embodiment, the dosing regimen for lymphoma treatment described in the paragraph above comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) for four consecutive days followed by a three-day rest period each week in one or more 28-day or four-week cycles.

[0069] In one embodiment, the dosing regimen for lymphoma treatment described in the above paragraph comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) for five consecutive days followed by two days of rest each week in one or more 28-day or four-week cycles.

[0070] In one embodiment, the dosing regimen for lymphoma treatment described in the paragraph above comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) during a period of 2 to 5 consecutive days followed by a 2 to 5 day rest period each week in one or more 28-day or 4-week cycles, wherein the number of consecutive days of treatment 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.

[0071] In another embodiment, the dosing regimen for lymphoma treatment described in the paragraph above comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) during a period of 2 to 5 consecutive days each week, followed by a 2 to 5 day rest period, in one or more 28-day or 4-week cycles, wherein the number of consecutive days of treatment is reduced in at least one week of the 28-day or 4-week cycle in one or more of the 28-day or 4-week cycles.

[0072] In another embodiment, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) is administered to a subject for two consecutive days followed by a five-day rest period during the first week of a 28-day or four-week cycle, wherein the number of consecutive days of treatment is increased during at least one week of the 28-day or four-week cycle.

[0073] In another embodiment, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) is administered to a subject for two consecutive days followed by a five-day rest period during the first week of a 28-day or four-week cycle, wherein the number of consecutive days of treatment is reduced during at least one week of the 28-day or four-week cycle.

[0074] In another embodiment, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) is administered to a subject for three consecutive days followed by a four day rest period during the first week of a 28 day or four week cycle, wherein the number of consecutive days of treatment is increased in at least one week of the 28 day or four week cycle.

[0075] In another embodiment, an effective amount of a 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 a subject for three consecutive days followed by a four-day rest period during the first week of a 28-day or four-week cycle, wherein the number of consecutive days of treatment is reduced during at least one week of the 28-day or four-week cycle.

[0076] In another embodiment, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) is administered to a subject for four consecutive days followed by a three-day rest period during the first week of a 28-day or four-week cycle, wherein the number of consecutive days of treatment is increased in at least one week of the 28-day or four-week cycle.

[0077] In another embodiment, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) is administered to a subject for four consecutive days followed by a three-day rest period during the first week of a 28-day or four-week cycle, wherein the number of consecutive days of treatment is reduced during at least one week of the 28-day or four-week cycle.

[0078] In another embodiment, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (e.g., a Tris salt of a compound of Formula (I) and a sodium salt of a compound of Formula (I)) is administered to a subject for 5 consecutive days followed by a 2-day rest period during the first week of a 28-day or 4-week cycle, wherein the number of consecutive days of treatment is increased in at least one week of the 28-day or 4-week cycle.

[0079] In another embodiment, an effective amount of a 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 a subject for 5 consecutive days followed by 2 days of rest during the first week of a 28-day or 4-week cycle, wherein the number of consecutive days of treatment is reduced during at least one week of the 28-day or 4-week cycle.

[0080] In one embodiment, the dosing regimen for lymphoma therapy described in the paragraph above comprises orally 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)). In one embodiment, 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)) 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., the Tris salt of the compound of Formula (I) and the sodium salt of the compound of Formula (I)) is administered as an oral tablet.

[0081] In one embodiment, the dosage regimen for lymphoma therapy described in the paragraph above comprises administering an effective amount of a 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 daily (QD). In another embodiment, the dosage regimen for cancer therapy described in the paragraph above comprises administering an effective amount of a 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)) twice daily (BID).

[0082] composition In a further aspect, the present application is directed to a pharmaceutical composition comprising a drug and an anti-cancer therapeutic agent, the pharmaceutical composition optionally and additionally comprising an excipient, wherein the anti-cancer agent has the following chemical structural formula (I): [ka] or a pharmaceutically acceptable salt thereof; and the anti-cancer therapeutic agent 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 anti-cancer therapeutic agent further comprises rituximab. In one embodiment, the pharmaceutically acceptable salt of Compound 1 is tris(hydroxymethyl)aminomethane salt or sodium salt. In one embodiment, the pharmaceutically acceptable salt of doxorubicin is hydrochloride. In one embodiment, the pharmaceutically acceptable salt of vincristine is sulfate.

[0083] The anti-cancer agent and / or anti-cancer therapeutic agent may be formulated with a pharmaceutically acceptable carrier, adjuvant, or vehicle into a pharmaceutical composition prior to administration to a subject.

[0084] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a carrier, adjuvant, or vehicle that may be administered to a subject with a compound of Formula (I) or a pharmaceutically acceptable salt thereof and / or an anti-cancer therapeutic agent, which does not impair the pharmacological activity and is non-toxic when administered in a dosage sufficient to deliver a therapeutic amount of the compound. Those skilled in the art will understand how to prepare a formulation suitable for administration. The anti-cancer therapeutic agent may optionally be part of the same formulation as the formulation for the anti-cancer agent (i.e., the compound of Formula (I) or a pharmaceutically acceptable salt thereof) if it is administered simultaneously with a first anti-cancer agent, or may be administered separately.

[0085] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in pharmaceutical compositions include, but are not limited to: Ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween) or other similar multimeric delivery matrices, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphoric acid, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium monohydrogen phosphate, potassium dihydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, carboxymethylcellulose Sodium cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and wool fat. Cyclodextrins, such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins (including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizing derivatives), may also be advantageously used to enhance delivery of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and / or a second anticancer agent.

[0086] Pharmaceutical compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir, preferably by oral administration or injection. Pharmaceutical compositions may contain any conventional pharmaceutically acceptable non-toxic carrier, adjuvant, or vehicle. 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 "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0087] The pharmaceutical compositions may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, parenterally administrable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include mannitol, water, Ringer's solution, and physiological saline. Additionally, sterile, fixed oils are commonly used as solvents or suspending media. For this purpose, any bland fixed oil may be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated form. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethylcellulose or similar dispersing agent, which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as 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 utilized for formulation purposes.

[0088] Pharmaceutical compositions may be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and / or emulsions are orally administered, the active ingredient may be suspended or dissolved in an oily phase in combination with an emulsifier and / or suspending agent. If desired, certain sweeteners and / or flavorings and / or coloring agents may be added.

[0089] The pharmaceutical composition may also be administered in the form of a suppository for rectal administration. These compositions can be prepared by mixing the compound of formula (I) or a pharmaceutically acceptable salt thereof and / or a second anticancer agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the active ingredient. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0090] The amount of active ingredient that may be combined with one or more pharmaceutical excipients to produce a single dosage form will vary depending on the patient being treated and the particular method of administration. Typical preparations contain from about 5% to about 95% active compound (w / w). Alternatively, such preparations contain from about 20% to about 80% active compound. In certain embodiments, the pharmaceutical composition contains from 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 conformers, salt formers, water of hydration, solvent of solvates, etc.). In some embodiments, the pharmaceutical composition contains from about 90 mg to about 240 mg; from about 95 mg to about 240 mg; from about 100 mg to about 240 mg; from about 10 mg to about 500 mg; or from about 10 mg to 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 certain embodiments, the pharmaceutical composition is in the form of an orally administrable dosage form (e.g., 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 the Tris salt of the compound of Formula (I).

[0091] As used herein, the terms "about" and "approximately" when used in conjunction with a numerical value or numerical range means that the numerical value or numerical range allows for a degree of variation that would be reasonable to one of ordinary skill in the art.

[0092] The compound of formula (I) and its formulations can be prepared according to the methods described in WO2014 / 128669, WO2019 / 164794, WO2020 / 132471, and U.S. Pat. No. 9,630,932, the contents of which are incorporated herein by reference.

[0093] Example Growth inhibition test of compound 1 and R-CHOP in tumor-bearing mice 5x10 mice required for each model 6 ~2X10 7 Cells were implanted subcutaneously. Tumor volume was determined when the tumor was approximately 150 mm 3 Once tumor burden reached this level, mice were randomized and treated with:

[0094] [Table 1]

[0095] At the end of the study, tumor tissue and plasma were collected 1 hour after the final dose of Compound 1. Treatment was well tolerated. Figures 1-3 show the percent change in tumor volume for the treated mouse models. As shown in Figures 1-3, the various models responded significantly to treatment with Compound 1 and R-CHOP. The degree of response varied, ranging from complete tumor regression, as seen in the Farage (DLBCL) and JVM-2 (MCL) models (see Figures 1-2), to tumor growth arrest, as seen in the WSU DLBCL-2 (DLBCL) model (see Figure 1). Similar results were seen across multiple lymphoma subsets tested.

Claims

1. A pharmaceutical composition for treating lymphoma in a subject, comprising an anti-cancer agent and an anti-cancer therapy, wherein the anti-cancer agent has the following chemical structural formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof; and A pharmaceutical composition wherein the anti-cancer therapy (agent) comprises a combination of rituximab, cyclophosphamide, doxorubicin or a pharmaceutically acceptable salt thereof, vincristine or a pharmaceutically acceptable salt thereof, and prednisolone.

2. The pharmaceutical composition of claim 1, wherein the lymphoma is Hodgkin's lymphoma.

3. The pharmaceutical composition of claim 1, wherein the lymphoma is non-Hodgkin's lymphoma.

4. The pharmaceutical composition according to claim 1 or 3, wherein the lymphoma is a B-cell lymphoma.

5. 2. The pharmaceutical composition of claim 1, wherein the lymphoma is selected from follicular lymphoma, DLBCL, MCL, Burkitt's lymphoma, and lymphoplasmacytic lymphoma.

6. The pharmaceutical composition according to claim 1 or 3, wherein the lymphoma is a T-cell lymphoma.

7. The pharmaceutical composition of claim 1, wherein the lymphoma is cutaneous T-cell lymphoma.

8. 2. The pharmaceutical composition of claim 1, wherein the lymphoma is selected from mycosis fungoides, PTCL, AITL, ALCL, EATL, and hepatosplenic gamma / delta T-cell lymphoma.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the anti-cancer agent and anti-cancer therapy (agents) are administered simultaneously or sequentially in the same or different formulations.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the anti-cancer agent is a tris(hydroxymethyl)aminomethane salt of the compound of formula (I).

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the anti-cancer agent is the sodium salt of the compound of formula (I).

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the doxorubicin is doxorubicin hydrochloride and the vincristine is vincristine sulfate.

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