Combination therapy of pralatrexate and COP for the treatment of patients with peripheral T-cell lymphoma.

Abstract

This disclosure provides compositions and methods for the treatment of peripheral T-cell lymphoma (PTCL) using combination therapy with pralatrexate and COP.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and benefit to U.S. Application No. 63 / 525,585, filed on 7 July 2023, which is incorporated herein by reference in whole. [Background technology]

[0002] Background of the present invention Lymphoma is a group of hematological and lymphoid tumors that originate from lymphocytes (a type of white blood cell). The term "lymphoma" encompasses a variety of conditions, including non-Hodgkin lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin's disease, Burkitt lymphoma, cutaneous T-cell lymphoma, primary central nervous system lymphoma, and metastatic lymphoma. In most cases, lymphoma is characterized by the presence of cancerous B cells. However, in peripheral T-cell lymphoma (PTCL), the condition is characterized by the presence of cancerous T lymphocytes.

[0003] While the treatment approach for PTCL mimics that of diffuse large B-cell lymphoma, the majority of PTCL cases have a poorer prognosis compared to their B-cell counterparts. Combination chemotherapy with CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], and prednisone) is the most commonly used first-line treatment and is considered the "standard treatment" despite its limited effectiveness. Given this limited effectiveness, improved treatments for PTCL are urgently needed.

[0004] Andrei R. Shustov et al. (Blood (2016) 128 (22): 5355) (which is incorporated herein by reference in its entirety) disclose that pralatrexate was the first drug approved in the United States for the treatment of patients with relapsed or refractory PTCL (R / R PTCL). Pralatrexate is administered at a dose of 30 mg / m² weekly for 6 weeks of a 7-week treatment cycle. 2 It is administered intravenously (IV) at the specified dose. Because the components of pralatrexate and the CHOP regimen target different aspects of tumor cell growth and proliferation, there is a possibility of synergistic antitumor effects and limited additional toxicity.

[0005] Andrei R. Shustov et al. (Blood (2017) 130 (Supplement 1): 818) (which is incorporated herein by reference in whole) disclose a Phase I dose-escalation study of pralatrexate in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Part one of this 3+3 dose-escalation study involved a standard 21-day CHOP regimen (cyclophosphamide 750 mg / m² on day 1). 2 , Doxorubicin 50 mg / m² 2 Vincristine 1.4 mg / m² 2 [Maximum 2 mg] and oral prednisone 100 mg on days 1-5, and 10, 15, 20, 25, or 30 mg / m² as an intravenous injection on days 1 and 8. 2 Pralatrexate was administered in the first part of the study. In the second part of the study, patients were treated with the MTD of pralatrexate established in the first part using standard CHOP. In both parts of the study, patients were treated for up to 6 cycles, or until toxicity or disease progression. [Overview of the project] [Problems that the invention aims to solve]

[0006] The present disclosure provides a composition and method for treating peripheral T-cell lymphoma, characterized by the combined use of pralatrexate, cyclophosphamide, vincristine, and prednisone.

Means for Solving the Problems

[0007] According to the present disclosure, T-cell non-Hodgkin lymphoma is treated by using a combination therapy of pralatrexate and COP (cyclophosphamide, vincristine, and prednisone). Thus, according to one aspect of the present disclosure, a method is provided for the treatment of T-cell non-Hodgkin lymphoma, which includes administering to a patient suffering from lymphoma a combination therapy of a therapeutically effective amount of pralatrexate and COP (cyclophosphamide, vincristine, and prednisone).

[0008] A method for treating peripheral T-cell lymphoma (PTCL) that may include administering to a subject in need thereof a combination therapy comprising cyclophosphamide, vincristine, prednisone, and pralatrexate, wherein the combination therapy does not include doxorubicin, is provided. In some embodiments, the combination therapy consists of cyclophosphamide, vincristine, prednisone, and pralatrexate. In various practical embodiments, administration occurs in 3-week cycles, optionally including a drug-free day (e.g., a period during a cycle in which no drug or a different drug is administered). In various practical embodiments, cyclophosphamide, vincristine, prednisone, and pralatrexate are administered independently daily, weekly, or every two weeks for up to two weeks of a 3-week cycle such that the 3-week cycle includes a one-week drug-free day. In some embodiments, the 3-week cycle is repeated at least 1 to 10 times. For example, the 3-week cycle is repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times. In some embodiments, pralatrexate is administered on days 1 and 8 of the treatment cycle. In certain aspects, cyclophosphamide and / or vincristine, and / or prednisone are administered daily over a period during the treatment cycle. In some embodiments, cyclophosphamide and / or vincristine, and / or prednisone are administered daily from day 1 to day 15, day 1 to day 10, day 1 to day 8, day 1 to day 6, day 1 to day 5, day 1 to day 4, or day 1 to day 3 of the treatment cycle.

[0009] The method may include a 21-day treatment cycle, the treatment cycle comprising: a) Intravenous administration of pralatrexate at a dose of at least about 10 mg / m 2 on days 1 and 8; b) Intravenous administration of cyclophosphamide at a dose of at least about 700 mg / m 2 on day 1, and at least about 1 mg / m 2administering vincristine intravenously at a dosage of wherein the cyclophosphamide and / or vincristine is optionally administered, independently, following or simultaneously with the administration of pralatrexate on day 1; and c) orally administering prednisone at a dosage of at least about 50 mg each day from day 1 to day 5, wherein the prednisone is optionally administered on day 1 following the administration of pralatrexate, comprising.

[0010] In certain embodiments, the 21-day cycle is repeated 1 to 6 times. In certain aspects, the treatment cycle is as follows: a) administering pralatrexate intravenously at a dosage of about 20 to about 30 mg / m 2 on days 1 and 8; b1) administering cyclophosphamide at a dosage of about 700 mg / m 2 to about 800 mg / m 2 on day 1; b2) administering cyclophosphamide intravenously at a dosage of about 750 mg / m 2 on day 1; b3) administering vincristine intravenously at a dosage of about 1 mg / m 2 to about 2 mg / m 2 on day 1; b4) administering vincristine intravenously at a dosage of about 1.2 mg / m 2 to about 1.6 mg / m 2 on day 1; b5) administering vincristine intravenously at a dosage of about 1.4 mg / m 2 on day 1; c1) administering prednisone at a dosage of about 50 mg to 150 mg on day 1 following the administration of pralatrexate; c2) administering prednisone at a dosage of about 80 mg to about 120 mg on day 1 following the administration of pralatrexate; and c3) Administer prednisone orally at a dose of approximately 100 mg on day 1 following the administration of pralatrexate. It includes at least one of the following.

[0011] Kits containing pralatrexate, cyclophosphamide, vincristine, and prednisone are also provided, but these kits do not contain doxorubicin. In some embodiments, pralatrexate is formulated separately from cyclophosphamide, vincristine, and prednisone. In certain practical forms, the kit contains approximately 20-30 mg / m² 2 A first pharmaceutical composition comprising pralatrexate and a first pharmaceutically acceptable excipient, and / or about 500-1000 mg / m² 2 A second pharmaceutical composition comprising cyclophosphamide and a second pharmaceutically acceptable excipient, and / or about 1-3 mg / m² 2 A third pharmaceutical composition may include vinicristine and a third pharmaceutically acceptable excipient, and / or a fourth pharmaceutical composition may include about 50-150 mg of prednisone and a fourth pharmaceutically acceptable excipient. In certain embodiments, at least two of the first, second, third, and fourth pharmaceutical compositions are the same pharmaceutical composition. In some embodiments, the first pharmaceutical composition is for intravenous injection. In some embodiments, the second pharmaceutical composition is for intravenous injection. In various practical forms, the third pharmaceutical composition is for intravenous injection. In some embodiments, the fourth pharmaceutical composition is for oral use. In various practical forms, the second composition is about 700-800 mg / m² 2 It contains cyclophosphamide. In a particular embodiment, the second composition is approximately 750 mg / m² 2 It contains cyclophosphamide. In some embodiments, the third composition is about 1-2 mg / m² 2 It contains vincristine. In a specific practical form, the third composition is approximately 1.2 to 1.6 mg / m². 2It contains vincristine. In some embodiments, the third composition is about 1.4 mg / m² 2 It contains vincristine. In some embodiments, the fourth composition contains about 75 to 125 mg of prednisone. In various embodiments, the fourth composition contains about 100 mg of prednisone.

[0012] definition Unless otherwise defined, the academic and scientific terms used herein have the meanings generally understood by those skilled in the art in the field to which the present invention pertains. The following references provide general definitions of many of the terms used herein, and are incorporated herein by reference by those skilled in the art. As used herein, the following terms have the meanings attributed below unless otherwise indicated.

[0013] "To improve" means to reduce, suppress, weaken, reduce, prevent, or stabilize the onset or progression of a disease.

[0014] "Combination therapy" means, and is not limited to, the administration of two or more therapeutic agents in a coordinated manner, including, but not limited to, simultaneous administration. Specifically, combination therapy includes both simultaneous administration (e.g., administration of a co-formulation or simultaneous administration of separate therapeutic compositions) and sequential or consecutive administration, provided that the administration of one therapeutic agent is somehow coordinated with the administration of another therapeutic agent. For example, one therapeutic agent may only be administered after a different therapeutic agent has been administered and may act over a specified period of time.

[0015] In this disclosure, “includes,” “contains,” “contains,” and “possesses,” etc., may have the meanings given to them under U.S. patent law, and may mean “includes,” “contains,” etc.; “essentially from” or “essentially from,” etc., may have the meanings given to them under U.S. patent law, and this term is open, allowing for entities other than those described, provided that such entities do not alter the fundamental or novel features of those described, but excluding prior art embodiments.

[0016] "Decrease" means a reduction of at least approximately 5% from the baseline level. The decrease may be 5%, 10%, 15%, 20%, 25%, or 50%, and even up to 75%, 85%, 95%, or any percentage in between. The word "decrease" is not found in the text.

[0017] "Disease" means any condition or disorder that impairs or interferes with the normal function of a cell, tissue, or organ. In some embodiments, a disease is a T-cell malignant lymphoma (e.g., lymphoblastic lymphoma, pre-T-cell lymphocytic leukemia, T-cell granular lymphocytic leukemia, rapidly progressive NK-cell leukemia, cutaneous T-cell lymphoma (mycosis fungoides / Sézary syndrome), anaplastic large cell lymphoma, T-cell type, enteric disease type T-cell lymphoma, adult T-cell leukemia / lymphoma including those associated with HTLV-1, and angioimmunoblastic T-cell lymphoma, as well as subcutaneous panniculitis-like T-cell lymphoma, peripheral T-cell lymphoma).

[0018] "Effective dose" refers to the amount of therapeutic agent necessary to improve the symptoms of a disease in an untreated patient. Examples of therapeutic agents described herein include cyclophosphamide, vincristine, prednisone, and pralatrexate. The effective dose of one or more active compounds used in carrying out the present invention for the treatment of a disease will vary depending on the method of administration, the patient's age, weight, and health condition. Ultimately, the attending physician or veterinarian will determine the appropriate amount and dosage. Such a amount is referred to as the "effective dose."

[0019] "Reference" means a standard or control condition. In some embodiments, the effects of combination therapies for diseases such as PTCL described herein are compared to the effects of conventional therapies (e.g., CHOP) or to the effects of diseases for which there is no treatment.

[0020] "Subject" refers to humans or non-human mammals, such as cattle, horses, dogs, sheep, or cats.

[0021] The ranges provided herein will be understood as abbreviations for all values ​​within a range. For example, the range 1 to 50 will be understood to include any number, combination of numbers, or subrange from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0022] As used herein, terms such as "treat" and "cure" refer to reducing or improving a disorder and / or its associated symptoms. It should be understood that treatment of a disorder or condition does not require (but does not exclude) the complete elimination of the disorder, condition, or its associated symptoms.

[0023] Unless otherwise specified or evident from the context, the term "or" as used herein should be understood to be inclusive. Unless otherwise specified or evident from the context, "one," "a," and "it" should be understood to be singular or plural.

[0024] "T-cell lymphoma" refers to a neoplasm characterized by the presence of cancerous T cells in the subject. While T-cell lymphoma is not limited to this, the following are examples: (a) Lymphoblastic lymphoma, in which malignant tumors arise in primitive lymphoid progenitor cells from the thymus; (b) Pre-T-cell lymphocytic leukemia, T-cell granular lymphocytic leukemia, rapidly progressive NK-cell leukemia, cutaneous T-cell lymphoma (mycosis fungoides / Sézary syndrome), anaplastic large cell lymphoma, T-cell type, enteric disease type T-cell lymphoma, adult T-cell leukemia / lymphoma including those associated with HTLV-1, and angioimmunoblastic T-cell lymphoma, as well as mature or peripheral T-cell neoplasms including subcutaneous panniculitis-like T-cell lymphoma; and (c) Peripheral T-cell lymphoma (PTCL) that initially involves the paracortical lymph node and does not develop into a typical follicular pattern. It encompasses a variety of states, including those mentioned above.

[0025] Unless otherwise stated or evident from the context, the term “about” as used herein shall be understood to mean within the normal range of acceptance in the art, for example, within two standard deviations of the mean. “About” can be understood to mean within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise evident from the context, all numerical values ​​provided herein shall be modified by the term “about.”

[0026] Pharmaceutical carriers, excipients, and diluents useful for preparing the compositions herein may be solids, liquids, or gases. These include any and all solvents, dispersions, coatings, antibacterial and antifungal agents, isotonic agents, and absorption retarders. Pharmaceutically acceptable carriers or excipients do not destroy the pharmacological activity of the disclosed compounds and are nontoxic when administered in doses sufficient to deliver therapeutic amounts of the compounds. Accordingly, compositions may take the form of tablets, pills, capsules, suppositories, powders, enteric-coated formulations, or other protective formulations (e.g., binding on ion-exchange resins or packaging in lipid-protein vesicles), sustained-release formulations, solutions, suspensions, elixirs, and aerosols. Carriers may be selected from a variety of oils, including crude oil, animal, plant, or synthetic oils, such as peanut oil, soybean oil, mineral oil, and sesame oil. Water, saline, dextrose aqueous solutions, and glycols are examples of liquid carriers for injectable solutions, particularly (when isotonic with blood). For example, formulations for intravenous administration include a sterile aqueous solution of the active ingredient, prepared by dissolving the solid active ingredient in water to produce an aqueous solution and then sterilizing the solution. Suitable pharmaceutically acceptable excipients include starch, cellulose, chitosan, talc, glucose, lactose, gelatin, malt, rice, wheat flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, and ethanol. The composition may be modified with conventional pharmaceutically acceptable additives such as preservatives, stabilizers, wetting agents, or emulsifiers, salts for adjusting osmotic pressure, and buffers. Suitable pharmaceutically acceptable carriers and formulations thereof are described in Remington's Pharmaceutical Sciences by E.W. Martin (which is incorporated herein by reference in whole). Such compositions will, in any case, contain an effective amount of the active compound together with a suitable carrier to prepare a dosage form suitable for administration to the recipient.

[0027] Non-limiting examples of pharmaceutically acceptable carriers and excipients include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; celluloses and their derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth, malt, gelatin, talc, cocoa butter, and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as polyethylene glycol and propylene glycol; esters such as ethyl oleate and ethyl laurate; buffers such as agar, magnesium hydroxide, and aluminum hydroxide; non-toxic, suitable lubricants such as alginic acid, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, sodium lauryl sulfate, and magnesium stearate; colorants. Examples include release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives, antioxidants, ion exchange agents, self-emulsifying drug delivery systems (SEDDS) such as alumina, aluminum stearate, lecithin, d-atocopherol 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, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyacrylates, waxes, and polyethylene-polyoxypropylene block polymers. Cyclodextrins such as α-, β-, and γ-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins containing 2- and 3-hydroxypropyl-cyclodextrins, or other solubilizing derivatives may also be used to improve the delivery of the compounds described herein.

[0028] Any description of a variable in this specification that includes a list of chemical groups in any definition of a variable includes the definition of the variable as any one group or a combination of the listed groups. Any description of an aspect of a variable in this specification includes the aspect as any one aspect or as a combination of any other aspect or part thereof. Any composition or method provided herein may be combined with any one or more of the other compositions and methods provided herein. [Modes for carrying out the invention]

[0029] Detailed description of the present invention This disclosure provides a composition and method for treating peripheral T-cell lymphoma, characterized by a combination of pralatrexate, cyclophosphamide, vincristine, and prednisone.

[0030] Current treatments for PTCL are inadequate. Aggressive combination chemotherapy regimens such as hyper-CVAD (divided cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) and VIP-ABVD (pepsid, ifosfamide, platinum-based chemotherapy [cisplatin], doxorubicin, bleomycin, vinblastine, and dacarbazine) have shown toxicity and have not been shown to be superior to CHOP, and yet they remain the conventional treatment for PTCL.

[0031] Pralatrexate Pralatrexate was the first drug approved for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma, or PTCL—a rapidly progressing hematological cancer of a biologically diverse group. Pralatrexate is currently marketed under the brand name FOLOTYN®.

[0032] Pralatrexate is also chemically known as "(2S)-24[4-[(1RS)-1-[(2,4-diaminopteridine-6-yl)methyl]buta-3-inyl]benzoyl]-amino]pentanedioic acid," and it is also known as "10-propargyl-10-deazaminopterin" or "PDX." It has been tested and found to be useful in cancer treatment. Its racemic mixture, (2S)-24[4-[(1RS)-1-[(2,4-diaminopteridine-6-yl)methyl]buta-3-inyl]benzoyl (Thenzoyl)]amino]pentanedioic acid, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed and refractory peripheral T-cell lymphoma.

[0033] Pralatrexate is described by DeGraw et al. in the Journal of Medicinal Chemistry. 36: 2228-2231 (1993), followed by US 5374726, US 5354741, and US 6028071, each of which is incorporated herein by reference. It has the following structure: [ka] It is represented by [this].

[0034] CHOP treatment Cyclophosphamide, also known as cytophosphan, is a drug therapy used as chemotherapy to suppress the immune system. As chemotherapy, it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma. It is administered orally or by intravenous injection.

[0035] Vincristine, also known as leulocristine and marketed under the brand name Oncovin, is a chemotherapy drug used to treat many types of cancer. These include, among others, acute lymphoblastic leukemia, acute myeloid leukemia, Hodgkin's disease, neuroblastoma, and small cell lung cancer. It is administered intravenously.

[0036] Prednisone is a glucocorticoid drug therapy primarily used to suppress the immune system and reduce inflammation in conditions such as asthma, COPD, and rheumatic diseases. It is also used in conjunction with other steroids to treat elevated blood calcium levels in cancer and adrenal insufficiency. It is taken orally.

[0037] CHOP / CHOP-like therapy is currently the recommended first-line treatment for PTCL, but most patients experience relapse within five years, and the prognosis remains poor. Therefore, improved treatment strategies are needed for patients with PTCL.

[0038] CHOP is generally considered the preferred regimen among the most advanced treatments for non-Hodgkin lymphoma. Rituximab, an immunotherapy drug for the treatment of B-cell NHL, is combined with chemotherapy, and this combo is called R-CHOP. Furthermore, A+CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone) is used to treat CD30-positive peripheral T-cell lymphoma (PTCL). Due to the lack of better alternatives, CHOP remains the standard of care for PTCL.

[0039] CHOP / CHOP-like therapy is currently the recommended first-line treatment for PTCL, but most patients experience relapse within five years, and the prognosis remains poor. Therefore, improved treatment strategies are needed for patients with PTCL.

[0040] Doxorubicin is often considered a key component of CHOP regimens, but these studies were conducted in the 1960s when PTCL was not identified as a distinct disease, so it has not been clearly evaluated in monotherapy studies for PTCL. However, a recent meta-analysis of the effects of anthracycline-based regimens in PTCL concluded that the inclusion of doxorubicin in multi-agent chemotherapy regimens was not associated with improved survival (AbouYabis A et al. ISRN Hematology Volume 2011, Article ID 623924, p. 14).

[0041] To optimize the development of new, cutting-edge strategies, various approaches were explored. These included moving away from standard anthracycline-based regimens associated with multidrug resistance (MDR), such as CHOP, and incorporating novel agents (such as pralatrexate) into modern regimens.

[0042] The short-term toxicities of doxorubicin and pralatrexate overlap. Mucositis and hematological toxicity are major safety issues to manage clinically. In some embodiments, to maintain the CHOP dose as a key element, the treatment regimen reduces the pralatrexate dose, even if toxicity is associated with the CHOP drug, particularly doxorubicin. Therefore, pralatrexate will likely be systematically dose-reduced first.

[0043] Initial clinical and asymptomatic cardiotoxicity was more frequent in patients receiving the CHOP regimen. The threshold for doxorubicin accumulation appeared low: dose >200 mg / m². 2 In this study, 27% of patients experienced cardiac events. Elderly patients appeared to be at higher risk for such toxicity. There is an urgent need for the development of cardioprotective strategies or alternative therapies for patients with rapidly progressive non-Hodgkin lymphoma (S. Limat et. al. Annals of Oncology 14: 277-281, 2003).

[0044] The inventors found that removing doxorubicin from the CHOP treatment regimen resulted in a better safety and efficacy profile. This disclosure provides a method for treating peripheral T-cell lymphoma using combination therapy with pralatrexate and COP. The term COP refers to a triple therapy involving cyclophosphamide, vincristine, and prednisone.

[0045] Treatment regimen This disclosure further relates to a method for treating peripheral T-cell lymphoma (PTCL) using combination therapy with pralatrexate and COP for a 21-day treatment cycle, in which pralatrexate is administered intravenously on days 1 and 8; cyclophosphamide on day 1; vincristine IV on day 1; and 100 mg of prednisone orally from day 1 (after completion of pralatrexate administration) to day 5. The 21-day treatment cycle includes at least 7 days of drug-free periods and can be repeated up to a maximum of 10 cycles.

[0046] This disclosure describes a cycle repeated every 21 days for up to 10 cycles, with doses of 10-30 mg / m² on days 1 and 8. 2 Administer pralatrexate (for example, intravenously); followed by 750 mg / m² on day 1. 2 Administer cyclophosphamide (for example, intravenously); on day 1, 1.4 mg / m³ 2 This describes a treatment method for peripheral T-cell lymphoma (PTCL) using combination therapy with pralatrexate and COP, in which vincristi is administered (e.g., intravenously); and 100 mg of prednisone is administered (e.g., orally) from day 1 (after completion of pralatrexate administration) to day 5.

[0047] In some embodiments, pralatrexate is administered intravenously as an IV injection over 3-5 minutes on days 1 and 8, followed by administration of cyclophosphamide and vincristine on day 1, and 100 mg of prednisone over 5 days.

[0048] In some embodiments, pralatrexate is administered intravenously as an IV injection over 3-5 minutes on days 1 and 8. In some embodiments, the amount of pralatrexate is 10, 20, or 30 mg / m². 2 That is the case.

[0049] In some embodiments, 50-100 mg of prednisone is administered daily (e.g., orally) for 5 days starting from day 1 (after completion of pralatrexate administration). In another embodiment, 500-1000 mg / m² in IV 2 Administer cyclophosphamide after the completion of pralatrexate administration on day 1.

[0050] In another embodiment, 1.2-1.6 mg / m² 2 Vincristine (up to 2 mg) is administered intravenously after the completion of pralatrexate administration on day 1. In another embodiment, the disclosure relates to the sequential administration of pralatrexate plus COP combination therapy to a patient for the treatment of peripheral T-cell lymphoma (PTCL).

[0051] The cycle is repeated every 21 days for up to 10 cycles, with a dose of 20-30 mg / m² on days 1 and 8. 2 Pralatrexate was administered intravenously as an IV injection, and COP was administered intravenously at a dose of 750 mg / m² on day 1. 2 Cyclophosphamide; 1.4 mg / m² IV on day 1. 2 Vincristine (maximum 2 mg); Prednisone 100 mg orally daily from day 1 (after completion of pralatrexate administration) to day 5, starting after completion of pralatrexate administration on day 1.

[0052] In another embodiment, cyclophosphamide and / or vincristine and / or prednisone are administered daily for the duration of the treatment cycle.

[0053] In another embodiment, cyclophosphamide and / or vinicristine and / or prednisone are administered daily over days 1–15, 1–10, 1–8, 1–6, 1–5, 1–4, or 1–3 of the treatment cycle.

[0054] In another embodiment, the 21-day treatment cycle is as follows: a) at least approximately 10 mg / m² on days 1 and 8. 2 Administer pralatrexate intravenously at the following dose; b) at least approximately 700 mg / m² on day 1. 2 Administer cyclophosphamide intravenously at a dose of at least approximately 1 mg / m². 2 a) administering vincristine intravenously in a dose of cyclophosphamide and / or vincristine, optionally administered independently, following or concurrently with the administration of pralatrexate on day 1; and a) administering prednisone orally in a dose of at least about 50 mg on each of days 1 through 5, optionally administered on day 1 following the administration of pralatrexate.

[0055] A further aspect of the present invention relates to a kit comprising pralatrexate, cyclophosphamide, vincristine, and prednisone, wherein the kit does not contain doxorubicin. The pralatrexate in the kit is formulated separately from cyclophosphamide, vincristine, and prednisone.

[0056] In another aspect, the kit contains approximately 10-30 mg / m². 2 A first pharmaceutical composition comprising pralatrexate and a first pharmaceutically acceptable excipient, and / or about 500-1000 mg / m² 2 A second pharmaceutical composition comprising cyclophosphamide and a second pharmaceutically acceptable excipient, and / or about 1-3 mg / m² 2A third pharmaceutical composition comprising vinicristine and a third pharmaceutically acceptable excipient, and / or a fourth pharmaceutical composition comprising about 50-150 mg of prednisone and a fourth pharmaceutically acceptable excipient.

[0057] In another embodiment of the kit, the first pharmaceutical composition is a composition for intravenous injection, the second pharmaceutical composition is a composition for intravenous injection, the third pharmaceutical composition is a composition for intravenous injection, and the fourth pharmaceutical composition is an oral composition.

[0058] In another embodiment of the present invention, the kit contains approximately 700-800 mg / m² 2 Cyclophosphamide, preferably about 750 mg / m² 2 Cyclophosphamide, approximately 1-2 mg / m² 2 Vincristine, preferably about 1.2 to 1.6 mg / m² 2 Vincristine, most preferably about 1.4 mg / m² 2 It contains vincristine, approximately 75-125 mg of prednisone, preferably approximately 100 mg of prednisone.

[0059] According to this disclosure, T-cell non-Hodgkin lymphoma is treated with combination therapy of pralatrexate and COP (cyclophosphamide, vincristine, and prednisone). Accordingly, according to one aspect of this disclosure, a method is provided for the treatment of T-cell non-Hodgkin lymphoma, comprising administering a therapeutically effective dose of combination therapy of pralatrexate and COP (cyclophosphamide, vincristine, and prednisone) to a patient suffering from lymphoma.

[0060] This disclosure provides a clinical trial protocol to evaluate the therapeutic efficacy of combination therapy with pralatrexate and COP for the treatment of peripheral T-cell lymphoma. Compliance with pralatrexate-COP will be greatly improved by removing doxorubicin, the main CHOP component that causes hematological toxicity and mucositis.

[0061] Specific aspects and embodiments of the present invention are described in the following examples, which are provided for illustrative purposes only and should not be construed in any way as limiting the scope of the invention.

[0062] Unless otherwise indicated, the implementation of this invention will utilize the prior arts of molecular biology (including genetic engineering), microbiology, cell physiology, biochemistry, and immunology, and will be within the scope of those skilled in the art. Such techniques are fully described in literature such as, for example, “Molecular Cloning: A Laboratory Manual”, second edition (Sambrook, 1989); “Oligonucleotide Synthesis” (Gait, 1984); “Animal Cell Culture” (Freshney, 1987); “Methods in Enzymology” “Handbook of Experimental Immunology” (Weir, 1996); “Gene Transfer Vectors for Mammalian Cells” (Miller and Calos, 1987); “Current Protocols in Molecular Biology” (Ausubel, 1987); “PCR: The Polymerase Chain Reaction”, (Mullis, 1994); and “Current Protocols in Immunology” (Coligan, 1991), each of which is incorporated herein by reference. [Examples]

[0063] Example 1 1. Dosage determination test This experiment was conducted to identify the optimal dose of pralatrexate for the next trial (Phase III) of multi-agent chemotherapy based on safety and ORR (Objective Response Rate) at 3 months. Initially, a low dose of 20 mg / m² was used. 230 mg / m² used in combination with COP 2 This was compared with COP. Therefore, these two dose levels were randomly administered to 20 patients in addition to COP (pralatrexate-COP). The appropriate dose for Phase III was determined based on safety and treatment compliance. If the two pralatrexate-COP regimens were similar, the regimen using the highest dose was selected. The dose-effect of polyglutamate-pralatrexate, such as DNA hypomethylation or H3-acetylation, was evaluated in this part of the study as a surrogate for PD (pharmacodynamic) drug exposure. The determination of the best regimen was based on several safety and compliance aspects. A lower dose was selected if treatment discontinuation in more than 20% of cases was associated with safety. A further objective of the dose determination study was also to evaluate the safety profile of newly diagnosed PTCL patients treated with pralatrexate-COP compared to CHOP alone.

[0064] The dose-determining trial is a randomized, phase II, open-label, multicenter study in previously untreated patients with PTCL, with CHOP as the control group. COP (cyclophosphamide, vincristine, and prednisone) in the literature refers to the CHOP regimen without doxorubicin (H). In the dose-determining trial, each investigational group has two dose levels compared to the standard CHOP. Treatment is added to either standard CHOP or COP in three groups: Group 1a (pralatrexate-COP) pralatrexate 20 mg / m² 2 Group 1b: Pralatrexate 30 mg / m² 2 Patients were randomized to either group 1 (receiving CHOP alone) or group 2 (receiving CHOP alone). The analysis was performed when 100 patients had received at least one treatment cycle.

[0065] In a trial of a new combination therapy, the inventors found that pralatrexate showed a synergistic effect when used in combination with COP (cyclophosphamide, vincristine / Oncovin, and prednisone) in patients with previously untreated PTCL. The therapy was repeated every 21 days for up to 6 cycles, with doses of 20-30 mg / m² on days 1 and 8. 2 Pralatrexate is administered intravenously as an IV injection over 3-5 minutes, and COP is administered intravenously at a dose of 750 mg / m² on day 1. 2 Cyclophosphamide; 1.4 mg / m² IV on day 1. 2 Vincristine (maximum 2 mg); Prednisone 100 mg orally daily from day 1 (after completion of pralatrexate administration) to day 5, starting within 15 minutes (±5 minutes) after completion of pralatrexate administration on day 1.

[0066] Combination therapy with pralatrexate and COP may be used as a life-saving, cutting-edge treatment for newly diagnosed patients with PTCL, possessing a favorable safety profile.

[0067] 2. Phase III Clinical Trial The objective of this Phase III clinical trial is to compare the progression-free survival (PFS) of newly diagnosed peripheral T-cell lymphoma (PTCL) patients treated with pralatrexate in combination with COP (pralatrexate-COP) for up to six cycles compared to CHOP alone. It is a randomized, controlled, open-label, multicenter trial in patients with previously untreated PTCL. The optimal dose of pralatrexate with COP, determined after completion of the dose-determination trial, will be evaluated in the Phase III clinical trial. In the Phase III clinical trial, 150 patients will be enrolled in each treatment group, and there are two treatment groups as described below. Patients with previously untreated PTCL will be randomized in a balanced manner (1:1) to one of the two treatment groups and treated for up to six cycles.

[0068] Group 1 (Pralatrexate-COP): A cycle repeated every 21 days for up to 6 cycles, with 20-30 mg / m² administered on days 1 and 8. 2 Pralatrexate is administered intravenously as an IV injection over 3-5 minutes, and COP is administered intravenously at a dose of 750 mg / m² on day 1. 2 Cyclophosphamide; 1.4 mg / m² IV on day 1. 2 Vincristine (maximum 2 mg); Prednisone 100 mg orally daily from day 1 (after completion of pralatrexate administration) to day 5, starting within 15 minutes (±5 minutes) after completion of pralatrexate administration on day 1.

[0069] Group 2: (CHOP): A cycle repeated every 21 days for up to 6 cycles, with the following dosages: On day 1, cyclophosphamide 750 mg / m² was administered intravenously. 2 On day 1, doxorubicin 50 mg / m² was administered intravenously. 2 (To reduce the risk of cardiotoxicity, <550 mg / m²) 2 (Limits lifetime accumulation dose) On day 1, vincristine 1.4 mg / m² was administered intravenously. 2 (maximum 2mg) From day 1 (after completion of pralatrexate administration in group 1) to day 5, prednisone 100 mg is administered orally (PO) daily. Combination chemotherapy that should be administered starting on day 1.

[0070] Example 2: Efficacy and Safety Test NCT06072131 (incorporated herein by reference as a whole) describes a phase III, randomized, open-label trial comparing the efficacy and safety of BELEODAQ®-CHOP or FOLOTYN-COP combination therapy to CHOP regimen alone in newly diagnosed patients with peripheral T-cell lymphoma. Briefly, the trial groups, interventions, and treatments are described in Table 1.

[0071] Table 1 [Table 1]

[0072] Progression-free survival is measured from randomization to the first recorded disease progression or death, regardless of which occurred first.

[0073] Other Embodiments From the above description, it is clear that modifications and alterations may be made to the invention described herein in order to adopt it for various uses and conditions. Such embodiments also fall within the scope of the following claims.

[0074] Any description of a variable in this specification that includes a list of elements in any definition of a variable includes the definition of the variable as any single element or a combination (or subcombination) of the listed elements. Any description of an aspect in this specification includes the aspect as any single aspect or as a combination with any other aspect or part thereof. All patents and publications cited herein are incorporated herein by reference to the same extent as each individual patent and publication is explicitly and individually indicated as being incorporated by reference.

Claims

1. A method for treating peripheral T-cell lymphoma (PTCL), comprising administering a combination therapy comprising cyclophosphamide, vincristine, prednisone, and pralatrexate to a subject in need thereof, wherein the combination therapy does not include doxorubicin.

2. The method according to claim 1, wherein the combination therapy comprises cyclophosphamide, vincristine, prednisone, and pralatrexate.

3. The method according to claim 1 or 2, wherein the administration occurs in a 3-week cycle, optionally including drug-free days.

4. The method according to claim 3, wherein the cyclophosphamide, vincristine, prednisone, and pralatrexate are administered independently daily, weekly, or every two weeks for at most two weeks of a three-week cycle, such that the three-week cycle includes one week of rest.

5. The method according to claim 3 or 4, wherein the three-week cycle is repeated at least 1 to 10 times.

6. The method according to claim 5, wherein the three-week cycle is repeated once, twice, three times, four times, five times, six times, seven times, eight times, nine times, or ten times.

7. The method according to any one of claims 1 to 6, wherein the pralatrexate is administered on days 1 and 8 of the treatment cycle.

8. The method according to any one of claims 1 to 6, wherein the cyclophosphamide and / or vinicristine and / or prednisone are administered daily for the duration of the treatment cycle.

9. The method according to the claim, wherein, in the other embodiment, the cyclophosphamide and / or vinicristine and / or prednisone are administered daily over days 1 to 15, 1 to 10, 1 to 8, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 of a treatment cycle.

10. The method described above includes a 21-day treatment cycle, wherein the treatment cycle is: a) At least approximately 10 mg / m² on day 1 and day 8 ２ Administer pralatrexate intravenously at the specified dose; b) At least approximately 700 mg / m² on day 1 ２ Administer cyclophosphamide intravenously at a dose of at least approximately 1 mg / m². ２ Administer vincristine intravenously at the following dose. Here, cyclophosphamide and / or vinicristine may be administered independently, either following or concurrently with the administration of pralatrexate on day 1; and c) Orally administer prednisone at a dose of at least approximately 50 mg on each of days 1 through 5, wherein prednisone may be optionally administered on day 1 following the administration of pralatrexate. The method according to claim 1, including the method described in claim 1.

11. The method according to claim 10, wherein the 21-day cycle is repeated 1 to 6 times.

12. The aforementioned treatment cycle is as follows: a) Approximately 20-30 mg / m² on day 1 and day 8 ２ Administer pralatrexate intravenously at the specified dose; b1) Approximately 700 mg / m² on day 1 ２ ~About 800mg / m ２ Administer cyclophosphamide at the following dose; b2) Approximately 750 mg / m² on day 1 ２ Administer cyclophosphamide intravenously at the specified dose; b3) Administer vincristine intravenously at a dose of about 1 mg / m ２ to about 2 mg / m ２ on the first day; b4) Approximately 1.2 mg / m² on day 1 ２ ~Approx. 1.6mg / m ２ Administer vincristine intravenously at the specified dose; b5) Approximately 1.4 mg / m² on day 1 ２ Administer vincristine intravenously at the specified dose; c1) Administer prednisone at a dose of approximately 50 mg to 150 mg on day 1 following the administration of pralatrexate; c2) Administer prednisone at a dose of approximately 80 mg to 120 mg on day 1 following the administration of pralatrexate; and c3) Administer prednisone orally at a dose of approximately 100 mg on day 1 following the administration of pralatrexate. The method according to claim 10 or 11, comprising at least one of the following.

13. A kit comprising pralatrexate, cyclophosphamide, vincristine, and prednisone, wherein the kit is not provided for doxorubicin.

14. The kit according to claim 13, wherein the pralatrexate is prescribed separately from cyclophosphamide, vincristine, and prednisone.

15. The aforementioned kit contains approximately 20-30 mg / m² ２ A first pharmaceutical composition comprising pralatrexate and a first pharmaceutically acceptable excipient, and / or about 500-1000 mg / m² ２ A second pharmaceutical composition comprising cyclophosphamide and a second pharmaceutically acceptable excipient, and / or about 1-3 mg / m² ２ The kit according to claim 13, comprising a third pharmaceutical composition comprising vinicristine and a third pharmaceutically acceptable excipient, and / or a fourth pharmaceutical composition comprising about 50 to 150 mg of prednisone and a fourth pharmaceutically acceptable excipient.

16. The kit according to claim 15, wherein at least two of the first pharmaceutical composition, the second pharmaceutical composition, the third pharmaceutical composition, and the fourth pharmaceutical composition are the same pharmaceutical composition.

17. The kit according to claim 15 or 16, wherein the first pharmaceutical composition is a composition for intravenous injection.

18. The kit according to any one of claims 15 to 17, wherein the second pharmaceutical composition is a composition for intravenous injection.

19. The kit according to any one of claims 15 to 18, wherein the third pharmaceutical composition is a composition for intravenous injection.

20. The kit according to any one of claims 15 to 19, wherein the fourth pharmaceutical composition is an oral composition.

21. The second composition is present in an amount of approximately 700-800 mg / m². ２ A kit according to any one of claims 15 to 20, comprising cyclophosphamide.

22. The second composition is present in an amount of approximately 750 mg / m². ２ A kit according to any one of claims 15 to 20, comprising cyclophosphamide.

23. The third composition is present in an amount of about 1 to 2 mg / m². ２ A kit according to any one of claims 15 to 22, comprising vinicristine.

24. The third composition is present in an amount of approximately 1.2 to 1.6 mg / m². ２ A kit according to any one of claims 15 to 22, comprising vinicristine.

25. The third composition is present in an amount of approximately 1.4 mg / m². ２ A kit according to any one of claims 15 to 22, comprising vincristine.

26. The kit according to any one of claims 15 to 25, wherein the fourth composition comprises about 75 to 125 mg of prednisone.

27. The kit according to any one of claims 15 to 25, wherein the fourth composition comprises about 100 mg of prednisone.

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