Malignant tumors of the lymphatic system

Abstract

The present invention relates to satraplatin for the treatment of malignancies of lymphoid tissues in mammals, preferably humans, in particular malignancies of lymphoid tissues with primary or secondary central nervous system (CNS) involvement (such as primary diffuse large B-cell lymphoma of the CNS).

Description

[Technical Field]

[0001] The present invention relates to satraplatin for the treatment of malignancies of lymphoid tissues in mammals, preferably humans, in particular malignancies of lymphoid tissues with primary or secondary central nervous system (CNS) involvement (such as primary diffuse large B-cell lymphoma of the CNS). [Background technology]

[0002] Malignant tumors of lymphoid tissues are lymphoid tumors derived from lymphocyte cell lines. Lymphocyte cell lines produce B, T, NK, and plasma cells. Well-characterized lymphoid tumors include lymphoma and multiple myeloma. Lymphoma is a tumor arising from lymphocytes in lymph nodes located throughout the body. Lymphocytes form and mature in lymphoid organs, but their physiological role is to circulate in the blood and various organs in the body to find and kill foreign antigens. Because neoplastic lymphocytes retain this ability to circulate throughout the body, lymphomas generally spread throughout the body after onset and exist far from the primary site. Multiple myeloma affects plasma cells that accumulate in the bone marrow and often affects several body parts (e.g., the spine, skull, pelvis, and ribs). Therefore, malignant tumors of lymphoid tissues can spread via blood and / or lymphatic vessels from lymph nodes to both other lymph nodes or lymphoid organs (such as bone marrow and spleen) and extralymphatic organs (such as skin, lungs, central nervous system, stomach, kidneys, liver, and the like) (Vardiman JW et al. Blood (2009) 114:1787-1797). The WHO Classification of Hematopoietic and Lymphoid Tumors and Related Monographs, first published in 2001 and most recently revised in 2016, describes established guidelines for the diagnosis of malignant lymphoma and multiple myeloma. The WHO classification focuses on cell lineage and divides lymphoid tumors into the following groups: (i) mature B-cell lymphoid neoplasms, (ii) mature T-cell and NK-cell neoplasms, (iii) Hodgkin lymphoma, (iv) post-transplant lymphoproliferative disorders (PTLD), and (v) histiocytic and dendritic cell neoplasms (Swerdlow SH et al. Blood (2016) 127:2375-2390). Lymphoma and multiple myeloma are mostly incurable diseases requiring long-term, sometimes permanent, treatment.

[0003] The central nervous system (CNS) is an immunologically privileged site separated from the blood circulation by the blood-brain barrier. Therefore, lymphomas with CNS symptoms (e.g., primary or secondary CNS lymphomas) are some of the most difficult and rare cancers to treat. Primary central nervous system lymphoma (PCNSL), an aggressive non-Hodgkin's lymphoma limited to the CNS (e.g., brain, spine, eye, and leptomeninges) without evidence of systemic metastasis (Grommes C and DeAngelis LM J Clin Oncol (2017) 35:2410-2418), can only be cured in some young / fit patients who receive extensive (immuno)chemotherapy (Mendez JS et al. Neuro Oncol (2018) 20:687-694; Houillier C et al. Neurology (2020) 94:1027-1039). More than 70% of all patients experience a relapse within two years and die within 6 to 9 months of relapse. Furthermore, the incidence of CNS lymphoma is increasing worldwide, especially among older patients (Shiels MS et al. Br J Haematol (2016) 174:417-424). Therefore, there is a high unmet medical need for treatment of malignant tumors of the lymphatic tissue with CNS symptoms, especially primary CNS lymphoma.

[0004] Platinum-based compounds are central to cancer chemotherapy. Since their initial discovery, platinum compounds have emerged as important agents for the treatment of several human malignancies, including lung, head and neck, and cervical cancer. There are three platinum compounds primarily used in current cancer treatment: cisplatin, carboplatin, and oxaliplatin. As presented in the Physicians' Cancer Chemotherapy Drug Manual (Edward Chu; Vincent T. DeVita Jr.; Goyena R, Fallis A. Physicians' Cancer Chemotherapy Drug Manual, 2019), they all belong to the same class of platinum salts, but their efficacy, therapeutic uses, pharmacokinetics, adverse effect profiles, and routes of administration differ considerably.

[0005] Cisplatin is a cornerstone drug in cancer treatment. However, its use is usually limited due to severe, dose-limiting adverse effects, such as neurotoxicity, ototoxicity, and nephrotoxicity. Furthermore, cisplatin must be administered intravenously (Bhargava A and Vaishampayan UN Expert Opin Investig Drugs (2009) 18:1787-1797; Akshintala S et al. Pediatr Blood Cancer (2015) 62:603-610). These disadvantages limit the use of cisplatin to certain patient populations and disease indications.

[0006] There is a serious need for new treatment options for cancer patients, such as those with lymphoid malignancies (e.g., lymphoma or multiple myeloma). Summary of the Invention

[0007] Satraplatin has been developed and emerged as an oral platinum analogue with an improved toxicity profile compared to cisplatin. Despite significant efforts and numerous clinical trials, it has not yet been approved by the FDA (Choy H, Park C, Yao M Clin Cancer Res (2008) 14:1633-1638; Bhargava A and Vaishampayan UN Expert Opin Investig Drugs (2009) 18:1787-1797).

[0008] The inventors have completed pathway analyses that confirm differences in pathway activation and utilization between satraplatin and cisplatin (see Examples section below; also see Figure 7). These data clearly demonstrate that distinct pathways with differentially expressed genes contribute to the cellular sensitivity (and therefore therapeutic efficacy) associated with each of these platinum compounds.

[0009] Despite this, the inventors have surprisingly shown that satraplatin can be effectively used as a substitute for cisplatin to induce cell death in cell lines of lymphoid origin. The data presented herein not only demonstrate that satraplatin is at least equivalent to cisplatin in killing lymphoma and multiple myeloma cell lines in vitro (none of the cell lines tested exhibited resistance to satraplatin), but also demonstrate that satraplatin was effective in killing genetically heterogeneous lymphoma cell lines, including cell lines resembling primary or secondary CNS lymphomas. The inventors have thus discovered a new means of treating lymphoid tumors. In general, it is also effective in lymphomas with primary or secondary CNS symptoms, which have previously been difficult to treat.

[0010] Thus, in a first aspect, the present invention provides satraplatin for treating malignancies of lymphoid tissue in a mammal, preferably a human, while in a further aspect, the present invention provides satraplatin for treating malignancies of lymphoid tissue in a mammal, preferably a human, wherein the malignancy is a malignancy of lymphoid tissue with primary or secondary central nervous system (CNS) symptoms, preferably wherein the malignancy is primary central nervous system (CNS) DLBCL. The present invention, and particularly this aspect thereof, is further supported by the properties of satraplatin, which is orally bioavailable and lipophilic with clinically proven significant CNS penetration and sufficient blood-brain barrier penetration.

[0011] In another aspect, the present invention provides satraplatin for the treatment of malignancies of lymphoid tissue in a mammal, preferably a human, wherein said treatment comprises administering a therapeutically effective amount of satraplatin to said mammal, preferably said human.

[0012] In another aspect, the present invention provides a method for treating malignancies of lymphoid tissue in a mammal, preferably a human, said method comprising administering a therapeutically effective amount of satraplatin to said mammal, preferably said human.

[0013] In a further aspect, the present invention provides the use of satraplatin in the manufacture of a medicament for the treatment of malignancies of lymphoid tissue in a mammal, preferably a human.

[0014] In yet another embodiment, the present invention provides an article of manufacture for treating malignancies of lymphoid tissue in a mammal, preferably a human, comprising satraplatin and instructions for use.

[0015] In one embodiment, the present invention provides satraplatin for treating lymphoid tumors in a mammal.

[0016] Suitably, the mammal may be a human.

[0017] Preferably, the lymphoid tumor may be a mature B-cell tumor or a mature T-cell tumor.

[0018] Suitably, the mature B cell tumour or mature T cell tumour may be a lymphoma, and optionally the lymphoma may be a lymphoma associated with CNS symptoms, such as a primary or secondary CNS lymphoma.

[0019] Preferably, the mature B-cell tumor or the mature T-cell tumor is selected from the group consisting of plasma cell myeloma (multiple myeloma), mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL NOS, germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, secondary CNS lymphoma (SCNSL), peripheral T-cell lymphoma (PCTL), cutaneous T-cell lymphoma (CTCL), Sézary syndrome, anaplastic large T-cell lymphoma (ALCL) and ALK.+ Anaplastic large T-cell lymphoma (ALK) + ALCL).

[0020] Preferably, the lymphoid tumor may be a mature B-cell tumor.

[0021] Suitably, the mature B-cell neoplasm may be selected from the group consisting of plasma cell myeloma (multiple myeloma), mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBL NOS, germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL and secondary CNS lymphoma (SCNSL).

[0022] Suitably, the mature B-cell neoplasm may be selected from the group consisting of plasma cell myeloma (multiple myeloma), primary central nervous system (CNS) DLBCL and secondary CNS lymphoma (SCNSL).

[0023] Preferably, the lymphoid tumor may be a tumor with primary or secondary central nervous system (CNS) symptoms.

[0024] Suitably, the lymphoid tumor may be secondary CNS lymphoma (SCNSL).

[0025] Suitably, the lymphoid tumor may be a primary central nervous system (CNS) DLBCL.

[0026] Preferably, the lymphoid tumor may be a mature T-cell tumor.

[0027] Preferably, the mature T cell tumor is peripheral T cell lymphoma (PTCL), PTCL NOS, anaplastic large T cell lymphoma (ALCL), ALK. + Anaplastic large T-cell lymphoma (ALK) +ALCL), cutaneous T-cell lymphoma (CTCL), Sezary syndrome, and primary cutaneous CD30+ T-cell lymphoproliferative dysplasia.

[0028] Suitably, the mature T-cell neoplasm may be cutaneous T-cell lymphoma (CTCL).

[0029] Preferably, the satraplatin may be formulated for oral administration.

[0030] Preferably, the satraplatin is administered at a concentration of 60 to 140 mg / m 2 Orally administered on days 1 to 5 every 35 days (po day 1 to 5 q35days), preferably 80 mg / m 2 It may be administered orally on days 1–5 of every 35 days (po day 1–5 q35days).

[0031] Alternatively, the satraplatin is administered at a concentration of 60 to 80 mg / m 2 It may be administered orally on days 1–5 of every 28 days (po day 1–5 q28days).

[0032] Preferably, the treatment may result in the death or inhibition of proliferation of tumor cells.

[0033] Preferably, the satraplatin may be administered together with one or more additional therapeutic agents.

[0034] Preferably, the one or more additional therapeutic agents may be co-administered.

[0035] Preferably, the lymphoid tumor may be diffuse large B-cell lymphoma (DLBCL) of the C5 type or MCD subtype.

[0036] Suitably, the lymphoid tumor may be a C5 type or MCD DLBCL with primary or secondary central nervous system (CNS) symptoms.

[0037] Preferably, the mammal may be a human with concordant MYD88L265P and CD79B mutations.

[0038] Suitably, the human may further have ETV6, PIM1, GRHPR, TBL1XR1 and PRDM1 mutations.

[0039] Further aspects and embodiments of the present invention will become apparent as the description continues. [Brief explanation of the drawings]

[0040] [Figure 1-1] FIG. 1A-1G: The effect of satraplatin on cell viability (e.g., IC50) compared to cisplatin in B-cell lymphoma cell lines, including Burkitt's lymphoma cell lines: Raji (FIG. 1A), Daudi (FIG. 1B), Ramos (FIG. 1C), CA46 (FIG. 1D), ST486 (FIG. 1E), MC / CAR (FIG. 1F), and P3HR-1 (FIG. 1G), was measured after 72 hours of incubation at different concentrations, ranging from 10 nM to 100 μM. [Figure 1-2] FIG. 1A-1G: The effect of satraplatin on cell viability (e.g., IC50) compared to cisplatin in B-cell lymphoma cell lines, including Burkitt's lymphoma cell lines: Raji (FIG. 1A), Daudi (FIG. 1B), Ramos (FIG. 1C), CA46 (FIG. 1D), ST486 (FIG. 1E), MC / CAR (FIG. 1F), and P3HR-1 (FIG. 1G), was measured after 72 hours of incubation at different concentrations, ranging from 10 nM to 100 μM. [Figure 1-3]FIG. 1A-1G: The effect of satraplatin on cell viability (e.g., IC50) compared to cisplatin in B-cell lymphoma cell lines, including Burkitt's lymphoma cell lines: Raji (FIG. 1A), Daudi (FIG. 1B), Ramos (FIG. 1C), CA46 (FIG. 1D), ST486 (FIG. 1E), MC / CAR (FIG. 1F), and P3HR-1 (FIG. 1G), was measured after 72 hours of incubation at different concentrations, ranging from 10 nM to 100 μM. [Figure 1-4] FIG. 1A-1G: The effect of satraplatin on cell viability (e.g., IC50) compared to cisplatin in B-cell lymphoma cell lines, including Burkitt's lymphoma cell lines: Raji (FIG. 1A), Daudi (FIG. 1B), Ramos (FIG. 1C), CA46 (FIG. 1D), ST486 (FIG. 1E), MC / CAR (FIG. 1F), and P3HR-1 (FIG. 1G), was measured after 72 hours of incubation at different concentrations, ranging from 10 nM to 100 μM. [Figure 2] FIG. 2A-2C: The effect of satraplatin on cell viability (e.g., IC50) compared to cisplatin in B-cell lymphoma cell lines, including mantle cell lymphoma cell lines JeKo-1 (FIG. 2A), GRANTA-519 (FIG. 2B), and Z-138 (FIG. 2C), was measured after 72 hours of incubation at different concentrations, ranging from 10 nM to 100 μM. [Figure 3-1]FIG. 3A-3P: Effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations from 10 nM to 100 μM (DLBCL subtype cell lines: SU-DHL-8 (FIG. 3A), Pfeiffer (FIG. 3B), DOHH-2 (FIG. 3C), WSU-DLCL2 (FIG. 3D), HBL-1 (FIG. 3E), SU-DHL-4 (FIG. 3F), SU-DH The IC50 values ​​were measured in B-cell lymphoma cell lines such as L-5 (FIG. 3G), SU-DHL-6 (FIG. 3H), KARPAS-422 (FIG. 3I), OCI-LY-19 (FIG. 3J), OCI-LY-3 (FIG. 3K), OCI-LY-7 (FIG. 3L), WSU-NHL (FIG. 3M), Toledo (FIG. 3N), AK / KAW (FIG. 3O), and U-2932 (FIG. 3P). [Figure 3-2] FIG. 3A-3P: Effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations from 10 nM to 100 μM (DLBCL subtype cell lines: SU-DHL-8 (FIG. 3A), Pfeiffer (FIG. 3B), DOHH-2 (FIG. 3C), WSU-DLCL2 (FIG. 3D), HBL-1 (FIG. 3E), SU-DHL-4 (FIG. 3F), SU-DH The IC50 values ​​were measured in B-cell lymphoma cell lines such as L-5 (FIG. 3G), SU-DHL-6 (FIG. 3H), KARPAS-422 (FIG. 3I), OCI-LY-19 (FIG. 3J), OCI-LY-3 (FIG. 3K), OCI-LY-7 (FIG. 3L), WSU-NHL (FIG. 3M), Toledo (FIG. 3N), AK / KAW (FIG. 3O), and U-2932 (FIG. 3P). [Figure 3-3]FIG. 3A-3P: Effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations from 10 nM to 100 μM (DLBCL subtype cell lines: SU-DHL-8 (FIG. 3A), Pfeiffer (FIG. 3B), DOHH-2 (FIG. 3C), WSU-DLCL2 (FIG. 3D), HBL-1 (FIG. 3E), SU-DHL-4 (FIG. 3F), SU-DH The IC50 values ​​were measured in B-cell lymphoma cell lines such as L-5 (FIG. 3G), SU-DHL-6 (FIG. 3H), KARPAS-422 (FIG. 3I), OCI-LY-19 (FIG. 3J), OCI-LY-3 (FIG. 3K), OCI-LY-7 (FIG. 3L), WSU-NHL (FIG. 3M), Toledo (FIG. 3N), AK / KAW (FIG. 3O), and U-2932 (FIG. 3P). [Figure 3-4] FIG. 3A-3P: Effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations from 10 nM to 100 μM (DLBCL subtype cell lines: SU-DHL-8 (FIG. 3A), Pfeiffer (FIG. 3B), DOHH-2 (FIG. 3C), WSU-DLCL2 (FIG. 3D), HBL-1 (FIG. 3E), SU-DHL-4 (FIG. 3F), SU-DH The IC50 values ​​were measured in B-cell lymphoma cell lines such as L-5 (FIG. 3G), SU-DHL-6 (FIG. 3H), KARPAS-422 (FIG. 3I), OCI-LY-19 (FIG. 3J), OCI-LY-3 (FIG. 3K), OCI-LY-7 (FIG. 3L), WSU-NHL (FIG. 3M), Toledo (FIG. 3N), AK / KAW (FIG. 3O), and U-2932 (FIG. 3P). [Figure 3-5]FIG. 3A-3P: Effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations from 10 nM to 100 μM (DLBCL subtype cell lines: SU-DHL-8 (FIG. 3A), Pfeiffer (FIG. 3B), DOHH-2 (FIG. 3C), WSU-DLCL2 (FIG. 3D), HBL-1 (FIG. 3E), SU-DHL-4 (FIG. 3F), SU-DH The IC50 values ​​were measured in B-cell lymphoma cell lines such as L-5 (FIG. 3G), SU-DHL-6 (FIG. 3H), KARPAS-422 (FIG. 3I), OCI-LY-19 (FIG. 3J), OCI-LY-3 (FIG. 3K), OCI-LY-7 (FIG. 3L), WSU-NHL (FIG. 3M), Toledo (FIG. 3N), AK / KAW (FIG. 3O), and U-2932 (FIG. 3P). [Figure 3-6] FIG. 3A-3P: Effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations from 10 nM to 100 μM (DLBCL subtype cell lines: SU-DHL-8 (FIG. 3A), Pfeiffer (FIG. 3B), DOHH-2 (FIG. 3C), WSU-DLCL2 (FIG. 3D), HBL-1 (FIG. 3E), SU-DHL-4 (FIG. 3F), SU-DH The IC50 values ​​were measured in B-cell lymphoma cell lines such as L-5 (FIG. 3G), SU-DHL-6 (FIG. 3H), KARPAS-422 (FIG. 3I), OCI-LY-19 (FIG. 3J), OCI-LY-3 (FIG. 3K), OCI-LY-7 (FIG. 3L), WSU-NHL (FIG. 3M), Toledo (FIG. 3N), AK / KAW (FIG. 3O), and U-2932 (FIG. 3P). [Figure 4-1] FIG. 4A-4D: The effect of satraplatin on cell viability (e.g., IC50) compared to cisplatin in T-cell lymphoma cell lines: HuT 78 (FIG. 4A), KARPAS-299 (FIG. 4B), L-82 (FIG. 4C), and SU-DHL-1 (FIG. 4D) after 72 hours of incubation at different concentrations ranging from 10 nM to 100 μM was measured. [Figure 4-2] FIG. 4A-4D: The effect of satraplatin on cell viability (e.g., IC50) compared to cisplatin in T-cell lymphoma cell lines: HuT 78 (FIG. 4A), KARPAS-299 (FIG. 4B), L-82 (FIG. 4C), and SU-DHL-1 (FIG. 4D) after 72 hours of incubation at different concentrations ranging from 10 nM to 100 μM was measured. [Figure 5-1] FIG. 5A-5K: The effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations ranging from 10 nM to 100 μM was measured (IC50s in the following multiple myeloma cell lines: EJM (FIG. 5A), MM.1S (FIG. 5B), L-363 (FIG. 5C), AMO-1 (FIG. 5D), MM.1R (FIG. 5E), KMS-11 (FIG. 5F), U266B1 (FIG. 5G), NCI-H929 (FIG. 5H), OPM2 (FIG. 5I), MOLP8 (FIG. 5J), and LP-1 (FIG. 5K). [Figure 5-2] FIG. 5A-5K: The effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations ranging from 10 nM to 100 μM was measured (IC50s in the following multiple myeloma cell lines: EJM (FIG. 5A), MM.1S (FIG. 5B), L-363 (FIG. 5C), AMO-1 (FIG. 5D), MM.1R (FIG. 5E), KMS-11 (FIG. 5F), U266B1 (FIG. 5G), NCI-H929 (FIG. 5H), OPM2 (FIG. 5I), MOLP8 (FIG. 5J), and LP-1 (FIG. 5K). [Figure 5-3]FIG. 5A-5K: The effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations ranging from 10 nM to 100 μM was measured (IC50s in the following multiple myeloma cell lines: EJM (FIG. 5A), MM.1S (FIG. 5B), L-363 (FIG. 5C), AMO-1 (FIG. 5D), MM.1R (FIG. 5E), KMS-11 (FIG. 5F), U266B1 (FIG. 5G), NCI-H929 (FIG. 5H), OPM2 (FIG. 5I), MOLP8 (FIG. 5J), and LP-1 (FIG. 5K). [Figure 5-4] FIG. 5A-5K: The effect of satraplatin on cell viability compared to cisplatin after 72 hours of incubation at different concentrations ranging from 10 nM to 100 μM was measured (IC50s in the following multiple myeloma cell lines: EJM (FIG. 5A), MM.1S (FIG. 5B), L-363 (FIG. 5C), AMO-1 (FIG. 5D), MM.1R (FIG. 5E), KMS-11 (FIG. 5F), U266B1 (FIG. 5G), NCI-H929 (FIG. 5H), OPM2 (FIG. 5I), MOLP8 (FIG. 5J), and LP-1 (FIG. 5K). [Figure 6] Relative sensitivity of various cell lines to satraplatin [Figure 7] Genes up-regulated in platinum-sensitive cell lines (cutoff: FC>2 & p-value<0.01) DETAILED DESCRIPTION OF THE INVENTION

[0041] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The embodiments, preferred embodiments, and highly preferred embodiments described and disclosed herein should apply to all aspects and other embodiments, preferred embodiments, and highly preferred embodiments, whether or not explicitly recited or their repetition is avoided for the sake of brevity.

[0042] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., at least one) of the grammatical object of the article. As used herein, the word "or" should be understood to mean "and / or" unless the context clearly dictates otherwise. As used herein, the words "comprise," "comprising," "include," "including," and "includes" are intended to specify the presence of stated features, integers, components, or steps, but do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.

[0043] The present invention demonstrates that satraplatin is at least equivalent to cisplatin in killing lymphoma and multiple myeloma cell lines in vitro. Furthermore, none of the cell lines tested exhibited resistance to satraplatin. Furthermore, the present invention demonstrates that satraplatin was also effective in killing genetically heterogeneous lymphoma cell lines, including cell lines resembling primary or secondary CNS lymphomas. Therefore, further considering that satraplatin is orally bioavailable and therefore convenient for patients and clinical use, has a favorable toxicity profile, and is lipophilic with clinically proven significant CNS penetration (Bhargava A and Vaishampayan UN Expert Opin Investig Drugs (2009) 18:1787-1797), the inventors now propose and envision the use of satraplatin in the treatment of patients with malignancies of the lymphoid tissue, particularly human patients with malignancies of the lymphoid tissue associated with primary or secondary central nervous system (CNS) symptoms (such as, highly preferably, human patients with primary CNS lymphoma (PCNSL)).

[0044] Thus, in a first aspect, the present invention provides satraplatin for the treatment of malignancies of lymphoid tissue in mammals, preferably humans, and in particular for the treatment of patients, preferably human patients, with primary CNS lymphoma (PCNSL).

[0045] Satraplatin: Satraplatin (INN), also known as JM-216, or bis(acetato)amminedichloro(cyclohexylamine)platinum(IV), is a member of a group of platinum(IV) compounds absorbed by the oral route. The lipophilicity of these compounds, and therefore their absorption, appears to be determined primarily by the nature of the axial ligand, acetate. Unlike cisplatin and carboplatin, which are square-planar platinum(II) complexes, satraplatin is an octahedral platinum(IV) compound. The molecular formula of satraplatin is C 10 H 22 N2Cl2O4Pt. Its molecular weight is 500.29 Da. Satraplatin can be synthesized according to the methods disclosed in U.S. Patent Nos. 5,072,011 and 5,244,919, or by appropriate modification of the method disclosed in U.S. Patent No. 6,518,428. Its chemical structure is: [ka] is.

[0046] Blood cells mature through several intermediate stages: stem cells differentiate into cells of either the lymphoid or myeloid lineages, resulting in distinct clinical manifestations, clinical courses, molecular characteristics, and pharmacological effects.

[0047] The term "lymphoid cells" refers to differentiated (or mature) lymphocytes (such as T cells and B cells), NK cells, and plasma cells. The term "lymphoid tissue" refers to tissue of the lymphatic system (e.g., lymph nodes, spleen, tonsils, or thymus tissue) that contains lymphoid cells.

[0048] Continuing new findings led to the 2016 revision of the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, which distinguished between hematopoietic tumors (e.g., myeloid tumors and acute leukemia) and lymphoid tumors (e.g., lymphoma and multiple myeloma), defining these malignancies as separate entities. Each change by the WHO is published in two separate, highly cited reviews: one for "lymphoid neoplasms" and one for "myeloid neoplasms and acute leukemias" (Lymphoid neoplasms: Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127(20):2375-90; Myeloid neoplasms and acute leukemia: Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127(20):2391-405).

[0049] Lymphoid tissue malignancies: The term "lymphoid tissue malignancies" refers to cancers or hyperproliferative disorders arising during hematopoietic development involving cells such as lymphocytes, natural killer cells, and plasma cells. Thus, the term encompasses abnormal proliferation of lymphoid cells (i.e., differentiated (or mature) lymphocytes (such as T cells and B cells), NK cells, and / or plasma cells) or lymphoid tissues (e.g., lymph nodes, spleen, tonsils, or thymus tissues, which contain lymphoid cells). Abnormal proliferation of cells or tissues is also referred to herein as "tumors." Malignant tumors of lymphoid cells or lymphoid tissues may therefore also be referred to herein as "lymphoid tumors." The terms "lymphoid tissue malignancies" and "lymphoid tumors" are used interchangeably herein unless the context clearly dictates otherwise.

[0050] Lymphoid tumors include T-cell tumors, B-cell tumors, NK-cell tumors, and plasma cell tumors. Lymphoid tumors include mature T-cell tumors, mature B-cell tumors, and mature NK tumors, which are listed below. The lymphoid tumors listed here are well known to those skilled in the art. They are classified according to the 2016 World Health Organization (WHO) classification of lymphoid tumors, which is briefly described above (Swerdlow SH et al. Blood (2016) 127:2375-2390). The terms "malignant tumor of lymphoid tissue" and "lymphoid tumor" are used herein in accordance with the WHO classification. As will be apparent to those skilled in the art, the term "lymphoid tumor" encompasses lymphoid malignancies such as lymphomas (e.g., T-cell lymphoma or B-cell lymphoma) and multiple myeloma (plasma cell myeloma of B-cell origin). It does not encompass myeloid tumors or acute leukemia.

[0051] Specific malignancies according to the present invention, as well as preferred malignancies, are named herein according to the terminology used in the WHO classification. Thus, specific malignancies include: I. Mature B-cell neoplasms Small lymphocytic lymphoma Monoclonal B-cell lymphocytosis Splenic marginal zone lymphoma Lymphoplasmacytic lymphoma Waldenström macroglobulinemia IgM monoclonal gammopathy of undetermined significance (MGUS) μ heavy chain disease gamma heavy chain disease alpha heavy chain disease IgG / A monoclonal gammopathy of undetermined significance (MGUS) Plasma cell myeloma (multiple myeloma; these terms are used interchangeably herein) Solitary plasmacytoma of bone Extraskeletal plasmacytoma Monoclonal immunoglobulin deposition diseases Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Nodal marginal zone lymphoma follicular lymphoma In situ follicular tumor Duodenal follicular lymphoma Pediatric follicular lymphoma Primary cutaneous follicle center lymphoma Mantle cell lymphoma In situ mantle cell tumor Diffuse large B-cell lymphoma (DLBCL), not otherwise specified ·Germinal center B cell type ·Activated B cell type T-cell / histiocytic-rich large B-cell lymphoma Primary central nervous system (CNS) DLBCL Primary cutaneous DLBCL / lower limb type EBV+ DLBCL・Non-specific type Chronic inflammation-associated DLBCL Lymphomatoid granulomatosis Primary mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma ALK+ large B-cell lymphoma Plasmablastic lymphoma Primary body cavity lymphoma Burkitt lymphoma High-grade B-cell lymphoma High-grade B-cell lymphoma, not otherwise specified B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma II. Mature T-cell and NK-cell neoplasms Pediatric systemic EBV+ T-cell lymphoma Variola vacciniforme-like lymphoproliferative disorder Adult T-cell lymphoma Extranodal NK / T cell lymphoma / nasal type Enteropathy-associated T-cell lymphoma Monomorphic epitheliotropic intestinal T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma mycosis fungoides Sézary syndrome Primary cutaneous CD30+ T-cell lymphoproliferative disorder Lymphomatoid papulosis Primary cutaneous anaplastic large cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Peripheral T-cell lymphoma (PTCL) ·Peripheral T-cell lymphoma (PTCL) ·Unspecified type ·Angioimmunoblastic T-cell lymphoma Anaplastic large cell lymphoma ALK-positive (ALK + ALCL) Anaplastic large cell lymphoma ALK-negative type (ALK - ALCL) III. Hodgkin lymphoma Nodular lymphocyte-predominant Hodgkin lymphoma Classical Hodgkin lymphoma Nodular sclerosing classical Hodgkin lymphoma Lymphocyte-rich classical Hodgkin lymphoma Mixed-cellularity classical Hodgkin lymphoma Lymphocytopenic classical Hodgkin lymphoma IV. Post-transplant lymphoproliferative disorder (PTLD) Plasma cell hyperplasia (PTLD) Infectious mononucleosis-like PTLD Flowering follicular hyperplasia PTLD Polymorphic PTLD Monomorphic PTLD (B-cell and T / NK-cell types) Classical Hodgkin lymphoma-type PTLD V. Histiocytic and dendritic cell neoplasms Histiocytic sarcoma Langerhans cell histiocytosis Langerhans cell sarcoma Indeterminate dendritic cell tumor Interdigitating cell sarcoma Follicular dendritic cell sarcoma Fibroblastic reticular cell tumor Disseminated juvenile xanthogranuloma Erdheim-Chester disease

[0052] Mature B-cell tumors (such as B-cell lymphomas and multiple myeloma affecting plasma cells from the B-cell lineage) and mature T-cell tumors (such as T-cell lymphomas) are of particular relevance to the present invention. The present invention is particularly relevant to lymphomas (e.g., T-cell lymphomas and B-cell lymphomas). The present invention is also particularly relevant to lymphoid tumors with primary or secondary central nervous system (CNS) symptoms, such as primary CNS lymphoma (PCNSL).

[0053] The term "lymphoma" refers to a lymphatic tumor or cancer in which pathological cells (e.g., T cells, B cells, or NK cells) tend to aggregate in lymphatic tissue and form masses, or tumors. The term "multiple myeloma" refers to a lymphatic tumor or cancer in which pathological cells (plasma cells) tend to aggregate in the bone marrow and form masses, or tumors. The term "leukemia" refers to a hematopoietic tumor in which pathological cells circulate in the blood and bone marrow.

[0054] Lymphatic tumors may also be referred to herein as lymphatic cancers. The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals, preferably humans, that is generally characterized by an unregulated increase in cell number (generally referred to herein as cell proliferation), which may result from an abnormal increase in cell proliferation, an abnormal decrease in cell death, or an imbalance in the amount of cell proliferation and cell death.

[0055] The term "hyperproliferative" refers to a disease associated with some degree of abnormal cell proliferation. In one embodiment, the hyperproliferative disease is cancer.

[0056] CNS lymphoma can occur either as a condition solely in the CNS (known as primary CNS lymphoma (PCNSL)) or as a secondary condition to a systemic lymphoma that has spread to the central nervous system (known as secondary CNS lymphoma (SCNSL)).

[0057] Primary CNS lymphoma (PCNSL): As used herein, the term "primary CNS lymphoma (PCNSL)" refers to a diffuse large B-cell lymphoma-type malignant lymphoma confined to the CNS. Most PCNSL is diffuse large B-cell lymphoma (DLBCL; 90%) and shares characteristics with systemic DLBCL, but PCNSL remains a WHO-endemic entity. The terms "primary CNS lymphoma (PCNSL)" and "primary central nervous system (CNS) DLBCL" are used interchangeably herein (Swerdlow SH et al. Blood (2016) 127:2375-2390; Deckert M et al. Acta Neuropathol (2014) 127:175-188).

[0058] Secondary CNS lymphoma (SCNSL): The term "secondary CNS lymphoma (SCNSL)" refers to lymphoma that originates outside the CNS and spreads to the central nervous system (as opposed to primary CNS lymphoma). It can be a low- or intermediate-grade lymphoma and can be an isolated recurrence or part of a systemic disease at the time of presentation. (Tomita N., Kodama F., Kanamori H., Motomura S., Ishigatsubo. Secondary central nervous system lymphoma. Int J Hematol. 2006;84:128-135).

[0059] The terms "treating" and "treatment" refer to both therapeutic measures and prophylactic or preventative measures, where the goal is to prevent or slow (reduce) an undesired physiological change or disorder, such as, for example, cancer growth, development, or metastasis. Those in need of treatment include those already with the disorder as well as those prone to the disorder or those with the disorder to be prevented. For purposes of this invention, beneficial or desired results include, but are not limited to, alleviation of symptoms, reduction in extent of disease, stabilization of the disease state (i.e., not worsening), delay or slowing of disease progression, improvement or palliation of the disease state, and remission (whether partial or complete), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0060] The term "therapeutically effective amount" refers to an amount of satraplatin that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorate, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of malignant tumors of the present invention, a therapeutically effective amount of satraplatin reduces the number of cancer cells; reduces tumor size; inhibits (i.e., slows to some extent, and preferably stops) cancer cell invasion into peripheral organs; inhibits (i.e., slows to some extent, and preferably stops) tumor metastasis; inhibits tumor growth to some extent; and / or relieves to some extent one or more symptoms associated with cancer. To the extent satraplatin may prevent growth and / or kill existing cancer cells, it may be cytostatic and / or cytotoxic, generally and preferably as judged by determining the time to progression (TTP) and / or response rate (RR).

[0061] A "mammal" for the treatment of malignant tumors and alleviation of symptoms according to the present invention refers to any animal classified as a mammal, including humans, domestic and farm animals, as well as zoo animals, sport animals, or pet animals (e.g., dogs, cats, cows, horses, sheep, pigs, goats, rabbits, etc., preferably humans, dogs, cats, and horses). More preferably, the mammal is a human. In a first aspect, the present invention provides satraplatin for treating malignant tumors of lymphoid tissue in a mammal, preferably a human. Accordingly, the present invention provides satraplatin for treating lymphoid tumors in a mammal, preferably a human. Therefore, the present invention provides satraplatin for treating lymphoma in a mammal, preferably a human, wherein the treatment comprises administering a therapeutically effective amount of satraplatin to the mammal, preferably the human. Therefore, in a preferred embodiment, the mammal is a human, a dog, a cat, or a horse. In a further highly preferred embodiment, the mammal is a human.

[0062] In a preferred embodiment, the malignant tumor is a lymphoid tumor.

[0063] In a preferred embodiment, the malignant tumor is selected from the group consisting of: (i) mature B-cell tumors, (ii) mature T-cell or NK-cell tumors, (iii) Hodgkin's lymphoma, (iv) post-transplant lymphoproliferative disorder (PTLD), and (v) histiocytic or dendritic cell tumors.

[0064] In another preferred embodiment, the malignant tumor is selected from the group consisting of a mature B-cell tumor, a mature T-cell tumor, and a NK-cell tumor.

[0065] In another preferred embodiment, the mature B-cell neoplasm, the mature T-cell neoplasm, or the NK-cell neoplasm is selected from the group consisting of small lymphocytic lymphoma, monoclonal B-cell lymphocytosis, splenic marginal zone lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, IgM monoclonal gammopathy of undetermined significance (MGUS), μ heavy chain disease, γ heavy chain disease, α heavy chain disease, IgG / A monoclonal gammopathy of undetermined significance (MGUS), plasma cell myeloma (multiple myeloma), solitary plasmacytoma of bone, extraskeletal plasmacytoma, monoclonal immunoglobulin deposition disease, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, follicular lymphoma, in Follicular neoplasm in situ, duodenal follicular lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, mantle cell lymphoma, mantle cell tumor in situ, diffuse large B-cell lymphoma (DLBCL) - not otherwise specified (NOS), germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, T-cell / histiocytocyte-rich large B-cell lymphoma, primary central nervous system (CNS) DLBCL, primary cutaneous DLBCL - leg type, Epstein-Barr virus (EBV)+ DLBCL, secondary CNS lymphoma (SCNSL), chronic inflammation-associated DLBCL, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary body cavity effusion lymphoma, Burkitt lymphoma, high-grade B-cell lymphoma, pediatric systemic EBV+ T-cell lymphoma, variola bullosa-like lymphoproliferative dysplasia, adult T-cell lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosis fungoides, Sézary syndrome, primary cutaneous CD30+ T cell lymphoproliferative disorder, lymphomatoid papulopathy, primary cutaneous anaplastic large cell lymphoma, cutaneous T cell lymphoma (CTCL), primary cutaneous γδ T cell lymphoma, peripheral T cell lymphoma (PTCL) NOS, angioimmunoblastic T cell lymphoma, anaplastic large cell lymphoma / ALK positive type (ALK) + ALCL), and anaplastic large cell lymphoma ALK-negative (ALK -ALCL).

[0066] In another preferred embodiment, the lymphoid malignancies do not include T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-cell leukemia, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, or hairy cell leukemia.

[0067] In another preferred embodiment, the mature B-cell neoplasm, the mature T-cell neoplasm, or the NK-cell neoplasm is selected from the group consisting of plasma cell myeloma (multiple myeloma), follicular lymphoma, follicular neoplasm in situ, duodenal follicular lymphoma, mantle cell lymphoma, mantle cell neoplasm in situ, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL) NOS, germinal center B-cell DLBCL NOS, activated B-cell DLBCL NOS, primary central nervous system (CNS) DLBCL, secondary CNS lymphoma (SCNSL), peripheral T-cell lymphoma (PTCL) not otherwise specified, and ALK. + Anaplastic large T-cell lymphoma (ALK) + ALCL) and cutaneous T-cell lymphoma (CTCL).

[0068] In another preferred embodiment, the mature B-cell neoplasm, the mature T-cell neoplasm, or the NK-cell neoplasm is selected from the group consisting of follicular lymphoma, follicular neoplasm in situ, duodenal follicular lymphoma, mantle cell lymphoma, mantle cell neoplasm in situ, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) NOS, germinal center B-cell DLBCL NOS, activated B-cell DLBCL NOS, primary central nervous system (CNS) DLBCL, secondary CNS lymphoma (SCNSL), peripheral T-cell lymphoma (PTCL) not otherwise specified, and ALK. + Anaplastic large T-cell lymphoma (ALK) + ALCL) and cutaneous T-cell lymphoma (CTCL).

[0069] In another preferred embodiment, the malignant tumor is a mature B-cell tumor or a mature T-cell tumor.

[0070] In another highly preferred embodiment, the mature B-cell neoplasm or the mature T-cell neoplasm is selected from the group consisting of Burkitt's lymphoma, plasma cell myeloma (multiple myeloma), mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, secondary CNS lymphoma (SCNSL), peripheral T-cell lymphoma (PTCL), PTCL NOS, anaplastic large T-cell lymphoma (ALCL), ALK + Anaplastic large T-cell lymphoma (ALK) + In one example, the peripheral T-cell lymphoma (PTCL) may be a PTCL NOS. For example, the PTCL NOS may be an anaplastic large T-cell lymphoma (ALCL) or an ALK NOS. + Anaplastic large T-cell lymphoma (ALK) + In another example, the cutaneous T-cell lymphoma (CTCL) may be Sézary syndrome.

[0071] In one example, the mature B-cell neoplasm or the mature T-cell neoplasm is Burkitt's lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, secondary CNS lymphoma (SCNSL), peripheral T-cell lymphoma (PTCL), PTCL NOS, anaplastic large T-cell lymphoma (ALCL), ALK + Anaplastic large T-cell lymphoma (ALK) +In one example, the peripheral T-cell lymphoma (PTCL) may be a PTCL NOS. For example, the PTCL NOS may be an anaplastic large T-cell lymphoma (ALCL) or an ALK NOS. + Anaplastic large T-cell lymphoma (ALK) + In another embodiment, the cutaneous T-cell lymphoma (CTCL) may be Sézary syndrome. In another preferred embodiment, the malignant tumor is a mature B-cell tumor. In one embodiment, the mature B-cell tumor is lymphoma or multiple myeloma. In a specific embodiment, the mature B-cell tumor is lymphoma.

[0072] In another preferred embodiment, the malignant tumor is selected from the group consisting of small lymphocytic lymphoma, monoclonal B-cell lymphocytosis, splenic marginal zone lymphoma, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia, IgM monoclonal gammopathy of undetermined significance (MGUS), μ heavy chain disease, gamma heavy chain disease, alpha heavy chain disease, IgG / A monoclonal gammopathy of undetermined significance (MGUS), plasma cell myeloma (multiple myeloma), solitary plasmacytoma of bone, extraskeletal plasmacytoma, monoclonal immunoglobulin deposition disease, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, follicular lymphoma, in situ follicular tumor, duodenal follicular lymphoma, childhood follicular lymphoma, primary cutaneous follicle center lymphoma, mantle cell lymphoma, in The mature B-cell neoplasm is selected from the group consisting of mantle cell tumor in situ, diffuse large B-cell lymphoma (DLBCL) NOS, germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, T-cell / histiocytocyte-rich large B-cell lymphoma, primary central nervous system (CNS) DLBCL, primary cutaneous DLBCL - leg type, Epstein-Barr virus (EBV)+ DLBCL NOS, secondary CNS lymphoma (SCNSL), chronic inflammation-associated DLBCL, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary body cavity effusion lymphoma, Burkitt lymphoma, and high-grade B-cell lymphoma.

[0073] In another preferred embodiment, the mature B-cell neoplasm does not include chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, or hairy cell leukemia.

[0074] In another highly preferred embodiment, the malignant tumor is a mature B-cell neoplasm selected from the group consisting of plasma cell myeloma (multiple myeloma), follicular lymphoma, follicular neoplasm in situ, duodenal follicular lymphoma, mantle cell lymphoma, mantle cell tumor in situ, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) NOS, germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, and secondary CNS lymphoma (SCNSL).

[0075] In another highly preferred embodiment, the malignant tumor is a mature B-cell neoplasm selected from the group consisting of follicular lymphoma, follicular neoplasm in situ, duodenal follicular lymphoma, mantle cell lymphoma, mantle cell neoplasm in situ, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL) NOS, germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, and secondary CNS lymphoma (SCNSL).

[0076] In another highly preferred embodiment, the mature B-cell neoplasm is selected from the group consisting of Burkitt's lymphoma, plasma cell myeloma (multiple myeloma), mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, and secondary CNS lymphoma (SCNSL).

[0077] In another example, the mature B-cell neoplasm is selected from the group consisting of Burkitt lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, and secondary CNS lymphoma (SCNSL).

[0078] In a further highly preferred embodiment, the mature B cell neoplasm is a follicular lymphoma, an in situ follicular tumor, or a duodenal follicular lymphoma. In a further preferred embodiment, the mature B cell neoplasm is a follicular lymphoma, wherein preferably the follicular lymphoma is an in situ follicular tumor or a duodenal follicular lymphoma. In a further highly preferred embodiment, the mature B cell neoplasm is a mantle cell lymphoma or an in situ mantle cell tumor. In a further highly preferred embodiment, the mature B cell neoplasm is a mantle cell lymphoma, wherein the mantle cell lymphoma is an in situ mantle cell tumor. In a further highly preferred embodiment, the mature B cell neoplasm is a mantle cell lymphoma. In a further highly preferred embodiment, the mature B cell tumor is diffuse large B cell lymphoma (DLBCL) NOS, germinal center B cell (GCB) DLBCL NOS, or activated B cell (ABC) DLBCL NOS. In a further highly preferred embodiment, the mature B cell tumor is diffuse large B cell lymphoma (DLBCL) NOS, wherein the diffuse large B cell lymphoma (DLBCL) NOS is germinal center B cell (GCB) DLBCL NOS or activated B cell (ABC) DLBCL NOS. In a further highly preferred embodiment, the mature B cell tumor is diffuse large B cell lymphoma (DLBCL) NOS. In a further highly preferred embodiment, the mature B cell tumor is germinal center B cell (GBC) diffuse large B cell lymphoma (DLBCL) NOS. In a further highly preferred embodiment, the mature B cell neoplasm is activated B cell (ABC) diffuse large B cell lymphoma (DLBCL) NOS. In a further highly preferred embodiment, the mature B cell neoplasm is primary central nervous system (CNS) DLBCL. In a further highly preferred embodiment, the mature B cell neoplasm is Burkitt's lymphoma.

[0079] In a highly preferred embodiment, the mature B cell neoplasm is selected from the group consisting of plasma cell myeloma (multiple myeloma), primary central nervous system (CNS) DLBCL, and secondary CNS lymphoma (SCNSL). In a highly preferred embodiment, the mature B cell neoplasm is plasma cell myeloma (multiple myeloma).

[0080] In a highly preferred embodiment, said mature B-cell neoplasm is selected from the group consisting of primary central nervous system (CNS) DLBCL and secondary CNS lymphoma (SCNSL).

[0081] In a highly preferred embodiment, the mature B cell neoplasm is a primary CNS lymphoma (PCNSL) or a secondary CNS lymphoma (SCNSL).

[0082] Both PCNSL and SCNSL are treated differently from standard DLBCL and require high-dose methotrexate (HD-MTX) when possible. However, many CNS lymphoma patients are ineligible for HD-MTX treatment or will relapse without receiving standard treatment in subsequent lines. For these patients in particular, the present invention offers satraplatin as an ideal candidate for treatment, worthy of testing in prospective clinical trials.

[0083] In a further highly preferred embodiment, the mature B cell neoplasm is a secondary CNS lymphoma (SCNSL). In a further highly preferred embodiment, the mature B cell neoplasm is a primary CNS lymphoma (PCNSL).

[0084] In another preferred embodiment, the malignancy is lymphoma or multiple myeloma with primary or secondary CNS manifestations.

[0085] In another preferred embodiment, the malignancy is a lymphoma with primary or secondary CNS manifestations.

[0086] In another preferred embodiment, the malignant tumor is a mature T-cell tumor or an NK-cell tumor. In a preferred embodiment, the mature T-cell neoplasm or the NK-cell neoplasm is selected from the group consisting of pediatric systemic EBV+ T-cell lymphoma, variola bullosa-like lymphoproliferative dysplasia, adult T-cell lymphoma, extranodal NK / T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, hepatosplenic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, cutaneous T-cell lymphoma (CTCL), mycosis fungoides, Sézary syndrome, primary cutaneous CD30+ T-cell lymphoproliferative dysplasia, lymphomatoid papulosis, primary cutaneous anaplastic large cell lymphoma, primary cutaneous gamma delta T-cell lymphoma, peripheral T-cell lymphoma (PTCL), PTCL NOS, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma (ALCL), anaplastic large cell lymphoma, ALK-positive type (ALK + ALCL), and anaplastic large cell lymphoma ALK-negative (ALK - ALCL).

[0087] In another preferred embodiment, the mature T-cell or NK-cell neoplasm does not include T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, aggressive NK-cell leukemia, or adult T-cell leukemia. In a highly preferred embodiment, the mature T-cell or NK-cell neoplasm is a peripheral T-cell lymphoma (PTCL).

[0088] In another preferred embodiment, the malignant tumor is a mature T-cell tumor.

[0089] In another highly preferred embodiment, the mature T-cell neoplasm is peripheral T-cell lymphoma (PTCL), PTCL NOS, anaplastic large T-cell lymphoma (ALCL), ALK + Anaplastic large T-cell lymphoma (ALK) + ALCL), cutaneous T-cell lymphoma (CTCL), mycosis fungoides, Sezary syndrome and primary cutaneous CD30+ T-cell lymphoproliferative dysplasia.

[0090] In a preferred embodiment, the mature T-cell neoplasm is peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), mycosis fungoides, Sézary syndrome or primary cutaneous CD30+ T-cell lymphoproliferative dysplasia.

[0091] In another highly preferred embodiment, the mature T-cell neoplasm is peripheral T-cell lymphoma (PTCL), PTCL NOS, anaplastic large T-cell lymphoma (ALCL), ALK + Anaplastic large T-cell lymphoma (ALK) + ALCL), cutaneous T-cell lymphoma (CTCL), Sézary syndrome, and primary cutaneous CD30+ T-cell lymphoproliferative dysplasia.

[0092] In a highly preferred embodiment, the mature T-cell neoplasm is a peripheral T-cell lymphoma (PTCL), such as PTCL NOS or anaplastic large cell lymphoma (ALCL), anaplastic large cell lymphoma-ALK negative (ALK - ALCL) or anaplastic large cell lymphoma ALK-positive (ALK + ALCL).

[0093] In a further highly preferred embodiment, the mature T cell neoplasm is a peripheral T cell lymphoma (PTCL). In a further highly preferred embodiment, the mature T cell neoplasm is a peripheral T cell lymphoma (PTCL) NOS. In a further highly preferred embodiment, the mature T cell neoplasm is a peripheral T cell lymphoma (PTCL) or a PTCL NOS. In a further highly preferred embodiment, the mature T cell neoplasm is an anaplastic large T cell lymphoma (ALCL). In a further highly preferred embodiment, the mature T cell neoplasm is an ALK + Anaplastic large T-cell lymphoma (ALK) + In a further highly preferred embodiment, the mature T-cell neoplasm is ALK. - Anaplastic large T-cell lymphoma (ALK) -In a further highly preferred embodiment, the mature T cell neoplasm is cutaneous T-cell lymphoma (CTCL), wherein preferably the CTCL is Sézary syndrome or primary cutaneous CD30+ T-cell lymphoproliferative disorder. In a further highly preferred embodiment, the mature T cell neoplasm is Sézary syndrome. In a further highly preferred embodiment, the mature T cell neoplasm is mycosis fungoides. In a further highly preferred embodiment, the mature T cell neoplasm is primary cutaneous CD30+ T-cell lymphoproliferative disorder.

[0094] In another highly preferred embodiment, the malignant tumor is a primary cutaneous lymphoma, generally and preferably as defined by the WHO-EORTC classification (Willemze R., et al., Blood 2019;133(16):1703-1714), wherein even more preferably, the malignant tumor is a primary cutaneous T-cell lymphoma (CTCL), generally and preferably as defined by the WHO-EORTC classification (Willemze R., et al., Blood 2019;133(16):1703-1714).

[0095] In another preferred embodiment, the malignant tumor is Hodgkin's lymphoma, which is selected from the group consisting of nodular lymphocyte-predominant Hodgkin's lymphoma, classical Hodgkin's lymphoma, nodular sclerosing classical Hodgkin's lymphoma, lymphocyte-rich classical Hodgkin's lymphoma, mixed cytology classical Hodgkin's lymphoma, and lymphocyte-depleted classical Hodgkin's lymphoma.

[0096] In another preferred embodiment, the malignant tumor is post-transplant lymphoproliferative disorder (PTLD), which is selected from the group consisting of plasma cell hyperplasia PTLD, infectious mononucleosis-like PTLD, flowering follicular hyperplasia PTLD, polymorphic PTLD, and monomorphic PTLD (B cell type and T / NK cell type).

[0097] In another preferred embodiment, the malignant tumor is a histiocytic or dendritic cell tumor, and the histiocytic or dendritic cell tumor is selected from the group consisting of histiocytic sarcoma, Langerhans cell histiocytosis, Langerhans cell sarcoma, indeterminate dendritic cell tumor, interdigitating cell sarcoma, follicular dendritic cell sarcoma, fibroblastic reticulocellular tumor, disseminated juvenile xanthogranuloma, and Erdheim-Chester disease.

[0098] For use in therapy, satraplatin is generally and preferably suitably formulated in a pharmaceutical preparation for oral administration. Thus, in another preferred embodiment, said satraplatin is administered orally.

[0099] Those skilled in the art will further recognize and know the expected dosages and administration schedules. It is understood that the appropriate dosage and administration schedule depends on a number of factors known to those skilled in the art, such as physicians. Representative dosages include milligram or microgram amounts of satraplatin per kilogram of body weight of an animal, preferably a human subject, for example, from about 1 microgram per kilogram to about 500 milligrams per kilogram, from about 100 micrograms per kilogram to about 50 milligrams per kilogram, or from about milligrams per kilogram to about 5 milligrams per kilogram. Thus, further suggested, but not limited to, a dosage of satraplatin administered to an animal, preferably a human, more preferably a human weighing 70 kg, may be 0.05 to 2000 mg, preferably 0.1 mg to 1000 mg, of satraplatin per unit dose. The unit dose may be administered, for example, one, two, three, or more times per day. The unit dose may be administered 1 to 7 times per week, for example, 1, 2 or more times per day. It will be understood that it may be necessary to vary the dose routinely depending on the age and weight of the animal or human and the severity of the malignancy to be treated.

[0100] Those skilled in the art will further appreciate that dosages can also be calculated based on body surface area. A 70 kg person has a body surface area of ​​approximately 1.8 square meters, and dosages include milligram or microgram amounts of satraplatin per animal or human body surface area, e.g., from about 50 micrograms per square meter to about 15 grams per square meter, from about 5 milligrams per square meter to about 1.5 grams per square meter, or from about 50 milligrams per square meter to about 150 milligrams per square meter. The exact dosage will ultimately be at the discretion of the attending physician. A typical and preferred dosing regimen is 80 mg / m 2 Oral administration of 100 mg / m on days 1-5 every 35 days (po day 1-5 q35days) 2 Oral administration of 120 mg / m on days 1–5 every 35 days (po day 1–5 q35days) 2 Oral administration of 140 mg / m on days 1 to 5 every 35 days (po day 1 to 5 q35days) 2 Oral administration on days 1-5 every 35 days or 120 days (po day 1-5 q35days), but in combination therapy, 20 mg / m daily 2 or 40 mg / m 2 In a further preferred embodiment, the satraplatin is administered at a dose of 80 mg / m 2 It is administered orally on days 1-5 every 35 days (po day 1-5 q35days).

[0101] In another embodiment, a typical and preferred dosing regimen is 60-80 mg / m 2 Oral administration of 60 mg / m on days 1–5 every 28 days (po day 1–5 q28 days). 2 orally on days 1–5 every 28 days (po day 1–5 q28days) or 70 mg / m 2 orally on days 1–5 every 28 days (po day 1–5 q28days) or 80 mg / m 2A dosing regimen of oral administration of satraplatin on days 1-5 every 28 days (po day 1-5 q28 days) may be preferred. Suitable dosing regimens are known in the art and can be found, for example, in Srivandana Akshintala et al., Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors. Pediatr Blood Cancer. 2015 Apr;62(4):603-610.

[0102] In another preferred embodiment, the treatment results in the death or inhibition of proliferation of tumor cells.

[0103] In another preferred embodiment, the uses and methods are further characterized by administering one or more additional therapeutic agents to the mammal, preferably the human. In a further preferred embodiment, the satraplatin and the one or more additional therapeutic agents are co-administered to the mammal, preferably the human. Preferably, the co-administration of the satraplatin and the one or more additional therapeutic agents is on different schedules (e.g., generally and preferably at different time intervals).

[0104] The additional therapeutic agent is known to those skilled in the art and preferably includes an immune checkpoint inhibitor independently selected from agents that inhibit cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), 4-1BB / 4-1BBL, OX40 / OX-40L, GITR / GITR-L, T-cell immunoglobulin domain, mucin domain 3 (TIM-3), or lymphocyte activation gene-3 (LAG-3). In a preferred embodiment, the immune checkpoint inhibitor is an antibody. Immune checkpoint inhibitor antibodies are known and include nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab. [Example]

[0105] Cisplatin is a long-term standard chemotherapy drug used to treat a variety of malignancies and is part of numerous combination therapy protocols, including those for lymphoma and multiple myeloma. Its use in these indications is often limited by either pre-existing patient-specific pathologies or cisplatin-induced pathologies (e.g., neurotoxicity and nephrotoxicity), as well as its inefficient crossing of the blood-brain barrier. Therefore, many patients are unable to utilize the full therapeutic potential of cisplatin.

[0106] The inventors are investigating satraplatin as an alternative to cisplatin, an orally available platinum compound that has not been associated with or associated with nephrotoxicity or neurotoxicity in clinical trials.

[0107] The inventors first completed a pathway analysis to identify differences in pathway activation and utilization between satraplatin and cisplatin. They performed univariate analyses of gene expression, mutation, and copy number levels in 66 cell lines and correlated them with the efficacy of cisplatin and / or satraplatin. They found that gene expression significantly correlated with drug response. To identify common and unique molecular features for the two compounds, they overlaid the gene expression correlation results for cell line sensitivity to satraplatin and cisplatin. By combining the identified differentially expressed (DE) genes in cell lines sensitive to satraplatin and cisplatin, they found 24 genes that were commonly upregulated in sensitive cell lines (Figure 7). However, the majority of genes were differentially expressed: 104 unique genes for satraplatin and 60 unique genes for cisplatin, respectively. These data support the distinct activity profiles of these compounds. Due to the complexity of these agents, the efficacy of satraplatin in lymphoid tumors cannot be predicted based on existing data on platinum compounds (e.g., cisplatin). These data clearly reveal that different pathways with differentially expressed genes are involved.

[0108] The inventors next analyzed the cell-killing potential of satraplatin compared to cisplatin in several different lymphoma and multiple myeloma cell lines.

[0109] Tumor cell line studies are useful tools for characterizing cancer signaling pathways, drug sensitivity profiles, cell proliferation and differentiation dynamics, and other important aspects of tumor development and treatment. They provide a sustainable and readily available cancer model for various oncology studies. Cell culture experiments are also paving the way for the development and application of new anticancer drugs.

[0110] Example 1 Effect of satraplatin on the viability of selected cancer cell lines The effect of satraplatin compared to cisplatin on cell viability of 41 selected cancer cell lines was investigated, where the 50% inhibitory concentrations (IC50) in the cancer cell lines were determined using the CellTiter-Glo® (CTG) luminescent cell viability assay after 72 hours of incubation with different concentrations of the two drugs, ranging from 10 nM to 100 μM.

[0111] material and method Cell lines and reagents The cell lines listed in Table 1 were used. All cell lines were cultured in culture medium supplemented with 10–15% FBS at 37°C, 5% CO2, and 95% humidity. Cell viability was measured using the CTG Luminescent Cell Viability Assay according to standard procedures. Satraplatin was purchased from MedChemExpress (China), and cisplatin was purchased from Qilu Pharm (China). 1 mM solutions of both drugs were prepared for storage at -20°C as previously described (Wosikowski K et al., Cancer Chemother Pharmacol (2007) 60(4):589–600). [Table 1] [Table 2] [Table 3]

[0112] Determination of half maximal inhibitory concentration (IC50) Cells were harvested during the logarithmic growth phase and counted using a Count-star. The cell concentration in each culture medium was 4.44 × 10 4 The final cell density was then adjusted to 4 x 10 cells / mL. 390 μL of the cell suspension was added to two 96-well plates (Plates A and B) in triplicate, ensuring cells / well. After 24 h, 10x solutions of cisplatin and satraplatin, starting at 100 μM, were serially diluted 3.16-fold with culture medium to achieve nine dose levels and placed in separate plates. Next, 10 μL (10x) of either satraplatin or cisplatin was transferred to each well of Plate B (triplicate for each drug concentration). Test Plate B was incubated in a humidified incubator at 37°C and 5% CO2 for 72 h and then measured by the CTG assay. For this purpose, the plate was equilibrated at RT for approximately 30 min. Next, 50 μL of CTG reagent was added to each well. The contents were mixed on an orbital shaker for 5 min to induce cell lysis, and the plate was incubated at RT for 20 min to stabilize the luminescence signal. Luminescence was recorded using an EnVision Multi Label Reader.

[0113] Data analysis Data were visualized using GraphPad Prism 5.0. To calculate absolute IC50s (EC50s), dose-response curves were fitted using a nonlinear regression model with a sigmoidal dose-response. The formula for viability was: Viability (%) = (LumTest article - LumMedium control) / (LumNon-treated - LumMedium control) × 100%. Absolute IC50s (EC50s) were calculated according to the dose-response curves generated by GraphPad Prism 5.0. Standard deviations were calculated for each dose level and each cell line and are represented by bars.

[0114] result To provide evidence for the efficacy of satraplatin, a large number of different human lymphoma and myeloma cell lines were used and their susceptibility to killing by satraplatin was tested as described, with cisplatin as a control. Killing of lymphoma cell lines was highly effective (Figures 1-6), with IC50 values ​​at or even below low micromolar concentrations.

[0115] The data presented herein demonstrate that satraplatin kills lymphoma cancer cells in a dose-dependent manner similar to or superior to cisplatin.

[0116] For example, the data show that satraplatin was at least equivalent to cisplatin in inducing cell death in cell lines representative of B-cell lymphomas, particularly Burkitt's lymphoma (FIGS. 1A to 1G), mantle cell lymphoma (FIGS. 2A to 2C), and DLBCL (FIGS. 3A to 3P).

[0117] Satraplatin is a therapeutic agent for T-cell lymphoma, particularly anaplastic large cell lymphoma (ALK)-positive (ALK + It was also at least equivalent to cisplatin in inducing cell death in cell lines representative of ALCL (FIGS. 4A to 4D).

[0118] Finally, satraplatin was also shown to be at least equivalent to cisplatin in inducing cell death in cell lines representative of multiple myeloma (FIGS. 5A to 5L).

[0119] All cells described herein are sensitive to satraplatin. However, as shown in Figure 6, the level of sensitivity varied among cell lines. As shown therein, certain cell lines were particularly sensitive to satraplatin treatment. These cell lines represent mature B-cell tumors (e.g., DLBCL (DOHH2, OCI Ly19, SUDHL5, OCI Ly3, Toledo cell lines), mantle cell lymphoma (Z138 cell line), Burkitt lymphoma (Daudi cell line)) and mature T-cell tumors (e.g., ALK+ ALCL (SUDHL1 cell line), CTCL (HuT78 cell line)). Satraplatin may therefore be particularly useful in treating DLBCL, mantle cell lymphoma, Burkitt lymphoma, CTCL, and ALK+ ALCL.

[0120] The cell lines used herein represent a broader group of malignancies. As just one example, the HUT 78 cell line was derived from a patient with the most aggressive form of cutaneous T-cell lymphoma (Sézary syndrome). Surprisingly, satraplatin demonstrated the highest efficacy in this cell line measured in the experiments described herein (IC50 0.3 μM). Exceptional activity was also observed in other aggressive T-cell lines arising in cutaneous variants (e.g., PCALCL - primary cutaneous anaplastic large cell lymphoma). SU-DHL1, with an IC of 0.3 μM (anaplastic T-cell lymphoma), is a good example. The data obtained for HUT 78 are therefore representative of the efficacy expected when satraplatin is used across the entire spectrum of cutaneous T-cell lymphoma.

[0121] The in vitro data presented herein are predictive of the efficacy of satraplatin treatment in vivo. Satraplatin has been extensively tested in various solid tumor cell lines in the past (Wosikowski K, Lamphere L, Unteregger G, et al. Preclinical antitumor activity of the oral platinum analog satraplatin. Cancer Chemother Pharmacol 2007;60(4):589-600). For example, studies in nude mice bearing human prostate tumor xenografts (Sova P, Mistr A, Kroutil A, Zak F, Pouckova P, Zadinova M. Comparative antitumor efficacy of two orally administered platinum(IV) drugs in nude mice bearing human tumor xenografts. Anticancer Drugs 2006;17(2):201-6) strongly confirmed the compound's efficacy in an in vivo model. Based on these studies, clinical development for prostate cancer was pursued. Clinical development of the drug was subsequently initiated in metastatic prostate cancer. In the SPARC trial, 25% of patients treated with satraplatin had an adequate PSA response (≥50% reduction) (Sternberg CN, Petrylak DP, Sartor O, et al. Multinational, double-blind, phase III study of prednisone and either satraplatin or placebo in patients with castrate-refractory prostate cancer progressing after prior chemotherapy: The SPARC trial. J Clin Oncol 2009;27(32):5431-8). This confirmed the putative efficacy already demonstrated in previous in vitro studies.For satraplatin, in vitro studies therefore provide sufficient evidence of efficacy in humans, and in vitro efficacy can therefore be used as a predictive marker of expected in vivo efficacy.

[0122] Example 2 Mutation pattern of cell line OCI Ly-3 As previously mentioned, DLBCL cell lines were highly sensitive to both cisplatin and satraplatin, with C50 values ​​at low micromolar concentrations or even lower molar doses. Furthermore, satraplatin was significantly superior to cisplatin in killing DLBCL cell lines (e.g., OCI-LY7 cells) and, importantly, satraplatin also highly efficiently killed the cell line OCI-LY3 (FIG. 3K).

[0123] The efficacy of this assay for the OCI Ly-3 cell line is particularly significant. This cell line has been sequenced twice by different laboratories, with an estimated 2-year difference in culture time between samples. Despite this, the same mutations were found, and no differential mutations were detected. OCI Ly-3 showed the highest consistency in the comparative analysis. Mutations found were MYD88, PIM1, CD79B, CARD11, and PRDM1 (Table 2). These mutations resemble the genetic landscape of Cluster 5 DLBCL lymphoma, which represents PCSNL, recently described by Chapuy et al. (Chapuy B et al. Nature Medicine, (2018) 24:679-690). Chapuy et al. described the genetic and mutational signatures of newly characterized DLBCL subsets and clusters (C1-C5). Of particular importance is the so-called C5 signature, which includes concordant MYD88L265P / CD79B mutations and additional mutations in ETV6, PIM1, GRHPR, TBL1XR1, and PRDM1. These mutations are typical of primary CNS lymphomas, and they found that 8 of 9 PCNSL patients had this C5 cluster (Fisher's exact test, P<0.001). These data laid the foundation for the acceptance of the C5 gene signature as similar to PCNSL, which was further confirmed by profiling 48 subjects with PCNSL from 2013 to 2018 at MD Anderson Cancer Center in Houston, Texas (Ou, A et al. Neuro-Oncology Advances (2020) 2:1-8).

[0124] Therefore, based on the mutation pattern, OCI Ly-3 is the most accepted PCNSL-like human DLBCL cell line and is well suited for predicting and comparing the efficacy of investigational compounds for the treatment of PCNSL, as shown in Fig. 3K. OCI Ly-3 was killed very efficiently by satraplatin. [Table 4]

[0125] Given the OCI Ly-3 data presented herein, satraplatin is particularly useful for treating diffuse large B-cell lymphoma (DLBCL) of the C5 or MCD subtype. In this context, C5 DLBCL is defined in Chapuy B et al. Nature Medicine, (2018) 24:679-690. Similarly, MCD DLBCL is defined in Wright et al., Cancer Cell, (2020) 37, 551-568. The clinical profiles of C5 and MCD DLBCL are well characterized in the art. Those skilled in the art can therefore easily identify patients suitable for such satraplatin treatment.

[0126] MCD DLBCL tumors are known to metastasize to extranodal sites in 30% of cases, 46% of which arise in sites that can give rise to extranodal primary lymphoma (central nervous system (CNS), vitreoretinal, testicular, and breast). Meanwhile, other DLBCL subtypes metastasize to these sites at significantly lower frequencies. This category of DLBCL is represented by the cell lines OCI-Ly-3 and HBL-1 (Wright et al., 2020). Given the data presented herein, it is therefore clear that satraplatin is particularly useful for the treatment of DLBCL associated with extranodal primary lymphoma manifestations, such as central nervous system (CNS), vitreoretinal, testicular, and / or breast lymphoma. Of particular interest is the use of satraplatin in the treatment of C5 or MCD subtype DLBCL with primary or secondary CNS manifestations.

[0127] As known to those skilled in the art, C5 and MCD DLBCL are primarily defined by MYD88L265P and CD79B mutations. Given the data presented herein, satraplatin is therefore particularly useful for treating lymphoid tumors (e.g., C5 or MCD DLBCL) in humans with concordant MYD88L265P and CD79B mutations. Such mutations and means for detecting such mutations are well known in the art. Those skilled in the art can therefore easily identify such subjects for treatment with satraplatin.

[0128] In association with the C5 signature, concordant MYD88L265P / CD79B mutations, as well as additional mutations in ETV6, PIM1, GRHPR, TBL1XR1, and PRDM1, have been observed. Given the data presented herein, satraplatin is therefore particularly useful for treating C5 DLBCL in humans who have concordant MYD88L265P and CD79B mutations, and optionally, also have ETV6, PIM1, GRHPR, TBL1XR1, and PRDM1 mutations. Such mutations and means for detecting such mutations are well known in the art. Those skilled in the art can therefore easily identify such subjects for treatment with satraplatin.

Claims

1. A therapeutic agent comprising satraplatin for treating a lymphatic tumor in a mammal, wherein the lymphatic tumor is a mature B-cell tumor or a mature T-cell tumor.

2. The method of claim 1 , wherein the mammal is a human.

3. The mature B-cell tumor or the mature T-cell tumor is selected from the group consisting of plasma cell myeloma (multiple myeloma), mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBCL NOS, germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, secondary CNS lymphoma (SCNSL), primary CNS lymphoma (PCNSL), peripheral T-cell lymphoma (PCTL), cutaneous T-cell lymphoma (CTCL), Sezary syndrome, anaplastic large T-cell lymphoma (ALCL), ALK, ＋ Anaplastic large T-cell lymphoma (ALK) ＋ 3. The therapeutic agent of claim 1 or 2, wherein the therapeutic agent is selected from the group consisting of tumors with primary or secondary central nervous system (CNS) symptoms, ...

4. The therapeutic agent according to claim 1 , wherein the lymphatic tumor is a mature B cell tumor.

5. 5. The method of claim 4, wherein the mature B-cell neoplasm is selected from the group consisting of plasma cell myeloma (multiple myeloma), mantle cell lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), DLBL NOS, germinal center B-cell (GCB) DLBCL NOS, activated B-cell (ABC) DLBCL NOS, primary central nervous system (CNS) DLBCL, secondary CNS lymphoma (SCNSL), primary CNS lymphoma (PCNSL), and tumors with primary or secondary central nervous system (CNS) symptoms.

6. The method of claim 4, wherein the mature B cell tumor is primary CNS lymphoma (PCNSL).

7. The therapeutic agent according to any one of claims 1 to 6, wherein the lymphatic tumor is a tumor associated with primary or secondary central nervous system (CNS) symptoms.

8. The therapeutic agent according to any one of claims 1 to 7, wherein the lymphatic tumor is primary CNS lymphoma (PCNSL).

9. The method of any one of claims 1 to 5 and claim 7, wherein the lymphatic tumor is secondary CNS lymphoma (SCNSL).

10. The method of claim 1 , wherein the lymphatic tumor is primary central nervous system (CNS) DLBCL.

11. The therapeutic agent according to claim 1 , wherein the lymphatic tumor is a mature T-cell tumor.

12. The mature T cell tumor is peripheral T cell lymphoma (PTCL), PTCL NOS, anaplastic large T cell lymphoma (ALCL), ALK. ＋ Anaplastic large T-cell lymphoma (ALK) ＋ 12. The therapeutic agent of claim 11, wherein the tumor is selected from the group consisting of cutaneous T-cell lymphoma (CTCL), Sezary syndrome, primary cutaneous CD30+ T-cell lymphoproliferative dysplasia, secondary CNS lymphoma (SCNSL), primary CNS lymphoma (PCNSL), and tumors with primary or secondary central nervous system (CNS) symptoms.

13. The method of claim 11, wherein the mature T-cell tumor is cutaneous T-cell lymphoma (CTCL).

14. The therapeutic agent of any one of claims 1 to 13, which is formulated for oral administration.

15. Satraplatin is administered in the following regimens: a) 60-140mg / m ２ orally on days 1-5 every 35 days (po day 1-5 q35 days); or b) 60-80mg / m ２ Orally administered on days 1-5 every 28 days (po day 1-5 q28 days) The therapeutic agent according to claim 14, which is used so as to be administered intravenously.

16. Satraplatin at 80 mg / m ２ The therapeutic agent according to claim 15, wherein the composition is orally administered on days 1 to 5 of every 35 days (po day 1-5 q35 days).

17. The therapeutic agent of any one of claims 1 to 16, wherein the treatment results in the death or inhibition of proliferation of tumor cells.

18. 18. The therapeutic agent of any one of claims 1 to 17, administered together with one or more additional therapeutic agents.

19. The method of claim 18 , wherein the method is co-administered with one or more additional therapeutic agents.

20. The therapeutic agent according to any one of claims 1 to 10 and claims 14 to 19, wherein the lymphatic tumor is diffuse large B-cell lymphoma (DLBCL) of the C5 type or MCD subtype.

21. The method of claim 20, wherein the lymphoid tumor is DLBCL with primary or secondary central nervous system (CNS) symptoms.

22. The method of claim 20 or 21, wherein the mammal is a human having concordant MYD88L265P and CD79B mutations.

23. The method of claim 22, wherein the human further has ETV6, PIM1, GRHPR, TBL1XR1, and PRDM1 mutations.

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