Therapy for treating cancer

Abstract

Provided herein are methods of treating and / or managing cancer, comprising administering to a patient Compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof. Additionally, provided herein are methods of treating and / or managing cancer, comprising administering to a patient Compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, in combination with a second active agent selected from the group consisting of an anti-CD20 antibody, an HDAC inhibitor, a proteasome inhibitor, an anti-CD38 antibody, an anti-SLAMF7 antibody, a nuclear export inhibitor, a BCL-2 inhibitor, and an immune checkpoint inhibitor. Also provided herein are combination therapies for treating and / or managing cancer, further comprising dexamethasone as a third active agent.

Description

[0001] This application claims priority to U.S. Provisional Application No. 62 / 942,378, filed December 2, 2019, the entire contents of which are incorporated herein by reference.

[0002] field

[0003] This article provides a therapy for treating and / or managing cancer, comprising administering to a patient 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (“Compound A”) or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex or polymorph thereof. Combination therapies for the treatment and / or management of cancer are also provided, comprising administration to a patient of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (“Compound A”) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs thereof, in combination with a second active agent selected from anti-CD20 antibodies, histone deacetylase (HDAC) inhibitors, proteasome inhibitors, anti-CD38 antibodies, anti-SLAMF7 antibodies, nuclear export inhibitors, BCL-2 inhibitors, and immune checkpoint inhibitors. This document also provides combination therapies for the treatment and / or management of cancer that further comprise dexamethasone as a third active agent.

[0004] background

[0005] Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue. These abnormal cells invade adjacent tissues or spread lymphaticly or hematogenously to local lymph nodes and distant sites (metastasis). Clinical data and molecular biological studies indicate that cancer is a multi-step process that begins with minute precancerous changes and can progress to tumor formation under certain conditions. Tumor lesions can evolve clonally and develop an increased capacity for invasion, growth, metastasis, and heterogeneity, particularly under conditions where tumor cells evade host immune surveillance. (Roitt, I., Brostoff, J. and Kale, D., Immunology, 17.1-17.12 (3rd edition, Mosby, St. Louis, Mo., 1993).

[0006] A variety of cancers are described in detail in the medical literature. Examples include lung cancer, colon cancer, rectal cancer, prostate cancer, breast cancer, brain cancer, and colorectal cancer. With an aging population, the development of new cancers, and the growth of vulnerable groups (such as those infected with HIV or those excessively exposed to sunlight), cancer incidence continues to rise. Therefore, there is a significant need for new methods and compositions that can be used to treat cancer patients.

[0007] Many types of cancer are associated with the formation of new blood vessels, a process called angiogenesis. Several mechanisms involved in tumor-induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion of cytokines with angiogenic properties by tumor cells. Examples of these cytokines include acidic and basic fibroblast growth factors (α, β-FGF), angiopoietin, vascular endothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cells can release angiogenic peptides by producing proteases and subsequently breaking down the extracellular matrix that stores certain cytokines (such as β-FGF). Angiogenesis can also be indirectly induced by recruiting inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (such as TNF-α and β-FGF).

[0008] Blood cancers begin in blood-forming tissues, such as the bone marrow, or in cells of the immune system. Examples of blood cancers include leukemia, lymphoma, and multiple myeloma. Blood cancers are also known as blood cancers.

[0009] Lymphoma is a cancer that originates in the lymphatic system. Lymphoma is characterized by malignant tumors of lymphocytes—B lymphocytes and T lymphocytes (i.e., B cells and T cells). Lymphoma typically begins in a cluster of lymphatic tissue in lymph nodes or organs (including but not limited to the stomach or intestines). In some cases, lymphoma may involve the bone marrow and blood. Lymphoma can spread from one part of the body to other parts.

[0010] Treatment methods for different forms of lymphoma are described, for example, in U.S. Patent No. 7,468,363, the entire contents of which are incorporated herein by reference. These lymphomas include, but are not limited to, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous B-cell lymphoma, activated B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular centrocellular lymphoma, transformed lymphoma, moderately differentiated lymphocytic lymphoma, intermediate lymphocytic lymphoma (ILL), diffuse poorly differentiated lymphocytic lymphoma (PDL), centricellular lymphoma, diffuse small cleaved cell lymphoma (DSCCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (PTCL), and other lymphomas, mantle cell lymphoma, and low-grade follicular lymphoma.

[0011] Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in both men and women in the United States, with an estimated 63,190 new cases and 18,660 deaths in 2007. Jemal A et al., CA Cancer J Clin 2007;57(1):43-66. The probability of developing NHL increases with age, and the incidence of NHL in older adults has steadily increased over the past decade, raising concerns about the aging trend of the U.S. population. Same reference. Clarke CA et al. Cancer 2002;94(7):2015-2023. NHL is a cancer that grows in white blood cells. It is defined as non-Hodgkin lymphoma. NHL can be B-cell, NK-cell, or T-cell lymphoma. There are more than 60 subtypes of NHL, the most common being diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), small lymphocytic lymphoma, double hit lymphoma, primary mediastinal large B-cell lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma (MALT), nodal marginal zone B-cell lymphoma, and lymphoplasmacytic lymphoma. Burkitt lymphoma and primary exudative lymphoma are the most common B-cell lymphomas.

[0012] The most common T-cell lymphomas include anaplastic large cell lymphoma (systemic and cutaneous types), peripheral T-cell lymphoma, angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma / leukemia, and extranodal NK / T-cell lymphoma.

[0013] Diffuse large B-cell lymphoma (DLBCL) accounts for approximately one-third of all non-Hodgkin lymphomas. While some DLBCL patients are cured with conventional chemotherapy, the rest die from the disease. Anticancer drugs may lead to rapid and sustained lymphocyte depletion by directly inducing apoptosis of mature T cells and B cells. See K. Stahnke et al., Blood 2001, 98:3066-3073. Absolute lymphocyte count (ALC) has been shown to be a prognostic factor for follicular non-Hodgkin lymphoma, and recent results suggest that ALC at diagnosis is an important prognostic factor for diffuse large B-cell lymphoma. See D. Kim et al., Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol. 25, No. 18S (Supplement 20 June), 2007:8082.

[0014] Leukemia is a malignant tumor of the blood-forming tissues. Various forms of leukemia are described, for example, in U.S. Patent No. 7,393,862 and U.S. Provisional Patent Application No. 60 / 380,842, filed May 17, 2002, the entire contents of which are incorporated herein by reference. Although viruses have been reported to cause several forms of leukemia in animals, the causes of human leukemia are largely unknown. (The Merck Manual, 944-952 (17th edition, 1999)). Transformation into a malignant tumor typically occurs in a single cell through two or more steps, followed by proliferation and clonal expansion. In some leukemias, specific chromosomal translocations have been identified that exhibit consistent leukemic cell morphology and distinctive clinical features (e.g., translocations 9 and 22 in chronic myeloid leukemia, and translocations 15 and 17 in acute promyelocytic leukemia). Acute leukemia is primarily a population of undifferentiated cells, while chronic leukemia is a more mature cell form.

[0015] Acute leukemia is classified into lymphoblastic (ALL) and non-lymphoblastic (ANLL) types. (The Merck Manual, 946-949, 17th edition, 1999). They can be further subdivided according to the French-American-British (FAB) classification or based on their type and degree of differentiation, through their morphological and cytochemical appearance. The application of specific B-cell and T-cell markers, as well as monoclonal antibodies against bone marrow antigens, is most helpful in classification. ALL is primarily a childhood disease identified through laboratory findings and bone marrow examination. ANLL, also known as acute myelogenous leukemia or acute myeloblastic leukemia (AML), occurs at all ages and is more common in adults; it is a form often associated with radiation as a causative factor.

[0016] Chronic leukemia is described as lymphocytic (CLL) or myelocytic leukemia (CML). (The Merck Manual, 949-952, 17th edition, 1999). CLL is characterized by the presence of mature lymphocytes in the blood, bone marrow, and lymphoid organs. The hallmarks of CLL are persistent absolute lymphocytosis (>5,000 / μL) and an increase in lymphocytes in the bone marrow. Most CLL patients also have clonal expansion of lymphocytes with B-cell characteristics. CLL is a disease of middle-aged and elderly people. In CML, a characteristic feature is the prevalence of granulocytes at all stages of differentiation in the blood, bone marrow, liver, spleen, and other organs. In symptomatic patients at diagnosis, the total white blood cell (WBC) count is typically around 200,000 / μL, but can reach 1,000,000 / μL. CML is relatively easy to diagnose due to the presence of the Philadelphia chromosome.

[0017] In addition to the acute and chronic classifications, tumors are also classified as precursor or peripheral based on the cells that cause the disease. See, for example, U.S. Patent Publication No. 2008 / 0051379, which is incorporated herein by reference in its entirety. Precursor tumors include ALL and lymphoblastic lymphoma and occur in lymphocytes before they differentiate into T cells or B cells. Peripheral tumors are tumors that occur in lymphocytes that have differentiated into T cells or B cells. Such peripheral tumors include, but are not limited to, B-cell CLL, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, mantle cell lymphoma, follicular lymphoma, nodular marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, nodular marginal zone lymphoma, splenic marginal zone lymphoma, hairy cell leukemia, plasmacytoma, diffuse large B-cell lymphoma, and Burkitt lymphoma. In more than 95% of CLL cases, clonal expansion is of the B-cell lineage. See Cancer: Principles & Practice of Oncology (3rd edition) (1989) (pp. 1843-1847). In less than 5% of CLL cases, the tumor cells exhibit a T-cell phenotype. However, despite these classifications, pathological damage to normal blood cell production is a hallmark of all leukemias.

[0018] Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a crucial role in immune function. However, the uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications. Multiple myeloma is the second most common blood malignancy; however, the exact cause of multiple myeloma remains unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M-protein and other immunoglobulins (antibodies), albumin, and β2-microglobulin. M-protein is an abbreviation for monoclonal protein, also known as atypical protein, which is a particularly abnormal protein produced by myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma.

[0019] Skeletal symptoms, including bone pain, are among the most prominent clinical manifestations of multiple myeloma. Malignant plasma cells release osteoclast-stimulating factors (including IL-1, IL-6, and TNF), which cause calcium to leach from the bone, resulting in lytic lesions; hypercalcemia is another symptom. Osteoclast-stimulating factors, also known as cytokines, prevent apoptosis or death of myeloma cells. Fifty percent of patients have radiodetectable myeloma-related skeletal lesions at diagnosis. Other common clinical symptoms of multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal insufficiency.

[0020] Cancer incidence continues to rise due to the aging of the general population, the development of new cancers, and the increase in vulnerable populations (such as people living with HIV / AIDS, the elderly, or those overexposed to sunlight). Therefore, there is a significant need for new methods, treatments, and compositions for treating patients with cancer, including but not limited to those with lymphoma, NHL, multiple myeloma, AML, leukemia, and solid tumors.

[0021] Non-Hodgkin lymphoma (NHL) represents a broad spectrum of tumors originating from normal lymphocytes. The WHO classification of lymphomas is used to define subtypes based on clinical, pathological, phenotypic, and molecular characteristics (Swerdlow, 2016). In North America and Europe, 85–90% of NHL originates from B cells, while 10–15% originates from T cells (Laurent, 2018). NK lymphoma is very rare.

[0022] NHL is the most common blood malignancy, and it is estimated that in 2019, 74,200 new cases of NHL were diagnosed in the United States, and 19,970 people will die from the disease (Siegel 2019).

[0023] Classical Hodgkin lymphoma (cHL) is a B-cell tumor that most commonly involves the cervix and mediastinal region. It accounts for 95% of all Hodgkin lymphoma (HL) cases. Epidemiologically, it is characterized by a bimodal age curve, peaking in the third decade and then peaking again after 60 years. It is estimated that in 2019, 8,110 new cases of HL were diagnosed in the United States, and 1,000 people will die from the disease (Siegel 2019).

[0024] Most patients present with multiple superficial or deep lymph nodes at diagnosis, with or without systemic symptoms. However, since lymphoma can involve any organ, many other presentations are also possible. Initial examination typically includes a precise diagnosis according to the current WHO classification, analysis of disease spread, and assessment of comorbidities. Prognosis and initial management are subtype-specific (Armitage, 2017).

[0025] There is a great need for safe and effective methods to treat, prevent and manage cancer, especially for cancers that are difficult to treat with standard treatments such as surgery, radiotherapy, chemotherapy and hormone therapy, while reducing or avoiding the toxicity and / or side effects associated with conventional therapies.

[0026] Overview

[0027] This article provides methods for treating or managing cancer. In one aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: an amount of about 0.01 mg to about 5 mg / day of a compound, wherein said compound is compound A.

[0028]

[0029] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0030] In another aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: (i) a therapeutically effective amount of a compound combined with (ii) an anti-CD20 antibody, wherein the compound is compound A.

[0031]

[0032] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0033] In one embodiment, the anti-CD20 antibody is obbinutuzumab. In another embodiment, the anti-CD20 antibody is rituximab.

[0034] In another aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: (i) a therapeutically effective amount of a compound combined with (ii) an HDAC inhibitor, wherein the compound is compound A.

[0035]

[0036] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0037] In one implementation, the HDAC inhibitor is citalinosta (ACY-241) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof.

[0038] In another aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: (i) a combination of a therapeutically effective amount of a compound and (ii) a proteasome inhibitor, wherein the compound is compound A.

[0039]

[0040] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0041] In one embodiment, the proteasome inhibitor is marizomib (salinosporamide A) or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex or polymorph thereof.

[0042] In one embodiment, the proteasome inhibitor is bortezomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound or polymorph thereof.

[0043] In one embodiment, the proteasome inhibitor is carfilzomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex or polymorph thereof.

[0044] In one embodiment, the proteasome inhibitor is ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound or polymorph thereof.

[0045] In another aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: (i) a therapeutically effective amount of a compound combined with (ii) an anti-CD38 antibody, wherein the compound is compound A.

[0046]

[0047] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0048] In one implementation, the anti-CD38 antibody is isatuximab.

[0049] In one implementation, the anti-CD38 antibody is daratumumab.

[0050] In another aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: (i) a therapeutically effective amount of a compound combined with (ii) an anti-SLAMF7 antibody, wherein the compound is compound A.

[0051]

[0052] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0053] In one implementation, the anti-SLAMF7 antibody is elotuzumab.

[0054] In another aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: (i) a therapeutically effective amount of a compound combined with (ii) a nuclear translocation inhibitor, wherein the compound is compound A.

[0055]

[0056] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0057] In one implementation, the nuclear transfer inhibitor is selinexor or a geometrical isomer or mixture thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof.

[0058] In another aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: (i) a therapeutically effective amount of a compound combined with (ii) a BCL-2 inhibitor, wherein the compound is compound A.

[0059]

[0060] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0061] In one implementation, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof.

[0062] In another aspect, this article provides methods for treating or managing cancer, including administering to a patient in need of such treatment or management: (i) a therapeutically effective amount of a compound combined with (ii) an immune checkpoint inhibitor, wherein said compound is compound A.

[0063]

[0064] Or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs thereof.

[0065] In one implementation, the immune checkpoint inhibitor is pembrolizumab.

[0066] In one implementation, the immune checkpoint inhibitor is nivolumab.

[0067] In one implementation, the immune checkpoint inhibitor is ipilimumab.

[0068] In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs thereof.

[0069] In some embodiments, the cancer is recurrent or refractory. In some embodiments, the cancer is newly diagnosed.

[0070] In some embodiments, the cancer is non-Hodgkin lymphoma (NHL). In some embodiments, NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), or primary central nervous system lymphoma (PCNSL).

[0071] In some implementations, NHL is relapsed or refractory NHL.

[0072] In some embodiments, the cancer is Hodgkin lymphoma (HL). In some embodiments, HL is classic Hodgkin lymphoma (cHL).

[0073] In some implementations, HL refers to relapsed or refractory HL. Brief description of the attached diagram

[0075] Figure 1 Synergistic antiproliferative activity of example compound AS in combination with bortezomib. PI: proteasome inhibitor; POM: pomalidomide; BORT: bortezomib; CL: combination index.

[0076] Figure 2 Apoptosis induced by example compound AS in combination with the proteasome inhibitors bortezomib or carfilzomib. POM: pomalidomide; BORT: bortezomib; CFZ: carfilzomib.

[0077] Detailed description

[0078] definition

[0079] As used herein, the term "or" should be interpreted as inclusive "or," referring to any one or any combination thereof. Therefore, "A, B, or C" means any one of the following: "A; B; C; A and B; A and C; B and C; A, B, and C." Exceptions to this definition occur only when the combination of elements, functions, steps, or behaviors is inherently mutually exclusive in some way.

[0080] As used herein, and unless otherwise stated, the terms “subject” or “patient” refer to an animal, including but not limited to mammals, including primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. The terms “subject” and “patient” are used interchangeably herein, for example, to refer to a mammalian subject, such as a human subject.

[0081] As used herein, and unless otherwise stated, the terms “treat,” “treating,” and “treatment” mean the eradication or improvement of a disease or condition, or the eradication or improvement of one or more symptoms associated with said disease or condition. In some embodiments, the term refers to minimizing the spread or aggravation of the disease or condition by administering one or more preventive or therapeutic agents to a patient suffering from such disease or condition. In some embodiments, the term refers to the administration of a compound provided herein, with or without other additional active agents, following the onset of symptoms of a particular disease.

[0082] As used herein, and unless otherwise stated, the terms “prevent,” “preventing,” and “prevention” mean the prevention of the onset, recurrence, or spread of a disease or condition or one or more symptoms thereof. In some embodiments, the term refers to the treatment or administration of a compound provided herein prior to the onset of symptoms, with or without other additional active compounds, particularly for patients at risk of the disease or condition provided herein. The term includes the suppression or relief of symptoms of a particular disease. In some embodiments, patients with a family history of the disease are particularly candidates for prevention programs. Furthermore, patients with a history of recurrent symptoms are also potential candidates for prevention. In this respect, the term “prevention” may be used interchangeably with the term “preventive treatment.”

[0083] As used herein, and unless otherwise stated, the terms “manage,” “managing,” and “treatment” refer to the prevention or mitigation of the progression, spread, or worsening of a disease or condition or one or more of its symptoms. Generally, the beneficial effects a patient experiences from preventative and / or therapeutic agents do not lead to a cure for the disease or condition. In this respect, the term “management” includes treating a patient with a specific disease in an attempt to prevent or minimize a relapse of the disease, or to prolong the time the disease remains in remission.

[0084] As used herein, and unless otherwise stated, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment or control of a disease or condition, or sufficient to delay or minimize one or more symptoms associated with a disease or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment or management of a disease or condition. The term "therapeuticly effective amount" may encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0085] Combination therapy or “in combination with” refers to the use of more than one therapeutic agent to treat a specific disease or condition. The term “in combination with” is not intended to imply that the therapeutic agents must be administered simultaneously and / or formulated for delivery together, although such delivery methods are within the scope of this application. The therapeutic agent may be administered concurrently with one or more other therapeutic agents, before their administration (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks prior), or after their administration (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks later). The therapeutic agent in combination therapy may also be administered in an alternating dosing regimen, with or without a rest period (e.g., no therapeutic agent is administered on certain days of the regimen). Administration of a therapeutic agent “in combination” with another therapeutic agent includes, but is not limited to, sequential administration and concomitant administration of the two active agents. Administration). Typically, each therapeutic agent is administered at a dose and / or schedule determined for that specific active agent.

[0086] As used herein, the terms "additional active agent," "active agent," and "active ingredient" refer to pharmacologically active compounds that can be used to treat specific types of cancer and certain diseases and conditions associated with or characterized by undesirable angiogenesis. Active agents can be macromolecules (e.g., proteins) or small molecules (e.g., synthetic inorganic, organometallic, or organic molecules). Examples of macromolecular active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. In some embodiments, the macromolecular active agent is a biomolecule, such as a naturally occurring or artificially prepared protein. Proteins particularly useful in this application include those that stimulate the proliferation of hematopoietic progenitor cells and immune-active hematopoietic cells in vitro and / or in vivo. Others stimulate the division and differentiation of progenitor cells in the erythroid system. Specific proteins include, but are not limited to: interleukins such as IL-2 (including recombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18; interferons such as interferon α-2a, interferon α-2b, interferon α-n1, interferon α-n3, interferon β-Ia, and interferon γ-Ib; GM-CF and GM-CSF; GC-CSF, BCG, cancer antibodies, and EPO. Small molecule active agents can also be used to mitigate side effects associated with the administration of the compounds provided herein. However, as with some macromolecules, many are thought to provide synergistic effects when administered together with the compounds provided herein (e.g., before, after, or simultaneously). Other examples of small molecule active agents include, but are not limited to, anticancer agents, antibiotics, immunosuppressants, and steroids.

[0087] In some embodiments, the active agent is at least one chemotherapeutic agent, at least one anti-inflammatory agent, or at least one immunosuppressant and / or immunomodulator. In one embodiment, such a chemotherapeutic agent may be selected from antimetabolites, such as methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, fludarabine, 5-fluorouracil, dacarbazine, hydroxyurea, asparaginase, gemcitabine, cladribine, and similar active agents. In one embodiment, such a chemotherapeutic agent may be selected from alkylating agents, such as nitrogen mustard, thiotepa, chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C, cisplatin, and other platinum derivatives, such as carboplatin, and similar active agents. In one embodiment, such a chemotherapeutic agent may be selected from antibiotics, such as bleomycin (formerly known as actinomycin), bleomycin, daunorubicin (formerly known as donomycin), idarubicin, sclerosomycin, mitomycin, mitoxantrone, plicamycin, antramycin (AMC), and similar active agents. In one embodiment, such a chemotherapeutic agent may be selected from antimitotic agents, such as taxanes, such as docetaxel and paclitaxel. In one embodiment, such a chemotherapeutic agent may be selected from topoisomerase inhibitors, such as topotecan. In one embodiment, such a chemotherapeutic agent may be selected from growth factor inhibitors, such as ErbB1 (EGFR) inhibitors (e.g., gefitinib). ), cetuximab ( ), Erlotinib ( ), 2F8 (as provided in WO 2002 / 100348) and similar active agents), ErbB2 (Her2 / neu) inhibitors (such as trastuzumab) (and similar active agents). In one embodiment, this growth factor inhibitor may be a farnesyltransferase inhibitor, such as SCH-66336 and R115777. In one embodiment, this growth factor inhibitor may be a vascular endothelial growth factor (VEGF) inhibitor, such as bevacizumab. In one embodiment, such a chemotherapeutic agent can be a tyrosine kinase inhibitor, such as imatinib (Glivec, Gleevec STI571), lapatinib, PTK787 / ZK222584, and similar active agents. In one embodiment, such a chemotherapeutic agent can be a histone deacetylase inhibitor. Examples of such histone deacetylase inhibitors include heterocyclic polar compounds based on hydroxamic acids, such as SAHA (suberoylanilide hydroxamic acid). In one embodiment, such a chemotherapeutic agent can be a p38αMAP kinase inhibitor, such as SCIO-469.

[0088] In another embodiment, the therapy of the present invention further includes administration to a subject in need of at least one inhibitor of angiogenesis, neovascularization and / or other angiogenesis. Examples of such angiogenesis inhibitors include urokinase inhibitors, matrix metalloproteinase inhibitors (such as marimasatal, neovasatal, BAY 12-9566, AG 3340, BMS-275291, and similar active agents), endothelial cell migration and proliferation inhibitors (such as TNP-470, squalamine, 2-methoxyestradiol, comprbetastatins, endostatin, angiostatin, penicillamine, SCH66336 (Schering-Plough Corp, Madison, NJ), R115777 (Janssen Pharmaceutica, Inc, Titusville, NJ), and similar active agents), angiogenic growth factor antagonists (such as ZD6474, SU 6668, antibodies against anti-angiogenic agents and / or their receptors (such as VEGF, bFGF, and angiopoietin-1), Sugen5416, SU... 5402, anti-angiogenic ribosomes (e.g., angiozyme), interferon α (e.g., interferon α2a), suramin and similar active agents), VEGF-R kinase inhibitors and other anti-angiogenic tyrosine kinase inhibitors (e.g., SU011248), endothelial-specific integrin / survival signaling inhibitors (e.g., Vitaxin and similar agents), copper antagonists / chelators (e.g., tetrathiomolybdate, captopril and similar active agents), formamide-triazole (CAI), ABT-627, CM101, interleukin-12 (IL-12), IM862, PNU145156E, and angiogenic-inhibiting nucleotide molecules (e.g., antisense-VEGF-cDNA, cDNA encoding angiostatin, cDNA encoding p53, and cDNA encoding defective VEGF receptor-2) and similar active agents.Other examples of such inhibitors of angiogenesis, neovascularization, and / or other angiogenesis include anti-angiogenic heparin derivatives and related molecules (e.g., heparinase III), temozolomide, NK4, macrophage migration inhibitory factor (MIF), cyclooxygenase-2 inhibitors, hypoxia-inducible factor 1 inhibitors, anti-angiogenic soy isoflavones, oltipraz, fumagillin and its analogues, somatostatin analogues, pentosan polysulfate, tecogalan sodium, dalteparin, tumstatin, thrombospondin, NM-3, cobustatin, canstatin, atorvastatin, antibodies against other related targets (e.g., anti-α-V / β-3 integrin and anti-kininostatin mAbs) and similar active agents.

[0089] In another embodiment, the therapy of the present invention further includes administration of anticancer immunogens, such as cancer antigens / tumor-associated antigens (e.g., epithelial cell adhesion molecule (EpCAM / TACSTD1), mucin 1 (MUC1), carcinoembryonic antigen (CEA), tumor-associated glycoprotein 72 (TAG-72), gp100, Melan-A, MART-1, KDR, RCAS1, MDA7), cancer-associated viral vaccines (e.g., human papillomavirus vaccine), tumor-derived heat shock proteins, and similar active agents. Many other suitable cancer antigens / tumor-associated antigens described in other parts of this document are also included. Tumor-associated antigens and similar molecules known in the art can also or alternatively be used in such implementations. Anticancer immunogenic peptides also include anti-idiotypic “vaccines,” such as BEC2 anti-idiotypic antibodies, mitumomab, CeaVac and related anti-idiotypic antibodies, anti-idiotypic antibodies against MG7, and other anticancer anti-idiotypic antibodies (see, for example, Birebent et al., Vaccine. 21(15), 1601-12(2003), Li et al., Chin Med J (Engl). 114(9), 962-6 (2001), Schmitt et al., Hybridoma. 13(5), 389-96 (1994), Maloney et al., Hybridoma. 4(3), 191-209 (1985), Raychardhuri et al., J Immunol. 137(5), 1743-9 (1986), Pohl et al., Int J Cancer. 50(6), 958-67 (1992), Bohlen et al., Cytokines Mol Ther. 2(4), 231-8 (1996) and Maruyama, J Immunol Methods. 264(1-2), 121-33 (2002). These anti-idiotypic Abs can optionally be conjugated to a vector, which can be a synthetic (typically inert) molecular vector, a protein (e.g., keyhole limpet). Hemocyanin / KLH (see, for example, Ochi et al., Eur J Immunol. 17(11), 1645-8(1987)) or cells (e.g., erythrocytes—see, for example, Wi et al., J Immunol Methods. 122(2), 227-34(1989)). In another embodiment, the therapy of the present invention further includes administration of a bisphosphonate. Examples of potentially suitable bisphosphonates are pamidronate ( ), zoledronic acid ( ), chlorphosphate ( ), risephosphonate ( ), ibandronate ( etidronate () alendronate () ), tiluphosphonate ( Icarodrine (Yamanouchi Pharmaceutical) and minodronate (YM529, Yamanouchi). In another embodiment, the therapy of the present invention further includes administration of a colony-stimulating factor. Examples of suitable colony-stimulating factors are granulocyte colony-stimulating factor (G-CSF), such as filgrastim (G-CSF). ) and polyethylene glycol-modified filgrastim ( ) and granulocyte-macrophage colony-stimulating factor (GM-CSF), such as saxaglastine ( In another embodiment, the therapy of the present invention further includes administration of an erythropoietin agent. Examples of suitable erythropoietin agents are erythropoietin (EPO), such as alpha-epoetin alfa (e.g.) and ) and β-epotene (e.g.) ) and erythropoiesis-stimulating proteins (e.g. In another embodiment, the therapy of the present invention further includes administration of anticancer cancer cell factors, chemokines, or combinations thereof. Examples of suitable cytokines and growth factors include IFNγ, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, IL-24, IL-27, IL-28a, IL-28b, IL-29, KGF, IFNα (e.g., INFα2b), IFNβ, GM-CSF, CD40L, Flt3 ligand, stem cell factors, ancestim, and TNFα. Suitable chemokines may include Glu-Leu-Arg (ELR) negative chemokines, such as IP-10, MCP-3, MIG, and SDF-1α from the human CXC and CC chemokine families. Suitable cytokines include cytokine derivatives, cytokine variants, cytokine fragments, and cytokine fusion proteins. In another embodiment, the therapy of the present invention further includes administration of an active agent that modulates (e.g., enhances or inhibits) the expression or activity of Fcα or Fcγ receptors. Examples of active agents suitable for this use include interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF) such as filgrastim (…). ) and PEGylated filgrastim ( ), and granulocyte-macrophage colony-stimulating factor (GM-CSF) such as saxaglastine ( Interferon-γ (IFN-γ) and tumor necrosis factor (TNF). In another embodiment, the therapy of the present invention further includes administration of a cell cycle control / apoptosis regulator (or “regulator”). The cell cycle control / apoptosis regulator may include the following molecules: (i) a cell cycle control / apoptosis regulator that targets and modulates a cell cycle control / apoptosis regulator, such as CDC-25 (e.g., NSC663284), (ii) a cyclin-dependent kinase that overstimulates the cell cycle (e.g., flavopiridol (L868275, HMR1275), 7-hydroxyastrosporin (UCN-01, KW-2401), and roscovitine (R-roscovitine, CYC202)), and (iii) a telomerase regulator (e.g., BIBR1532, SOT-095, GRN163, and compositions described in, for example, U.S. Patent Nos. 6,440,735 and 6,713,055). Non-limiting examples of molecules that interfere with the apoptosis pathway include TNF-associated apoptosis-inducing ligand (TRAIL) / apoptosis-2 ligand (Apo-2L), active agents that induce NF-κB blockade leading to inhibition of IL-6 production, antibodies that activate the TRAIL receptor, IFN, antisense Bcl-2, and As2O3 (arsenic trioxide). In another embodiment, the therapy of the present invention further includes administration of a hormone modulator, such as an active agent that can be used for anti-androgen and anti-estrogen therapy. Examples of such hormone modulators include tamoxifen, edoxifene, fulvestrant, droloxifen, toremifene, raloxifene, diethylstilbestrol, ethinyl estradiol, anti-androgens (such as flutamide), progestins (such as hydroxyprogesterone caproate, medroxyprogesterone acetate, megace), corticosteroids (such as hydrocortisone, prednisone), luteinizing hormone-releasing hormone (and its analogues and other LHRH agonists such as buserelin and goserelin), aromatase inhibitors (such as anastrozole, cytraden, exemestane), hormone inhibitors (such as octreotide, sandostatin), and similar active agents. In another embodiment, the therapy of the present invention further includes administration of an anti-anergic agent (e.g., a small molecule compound, protein, glycoprotein, or antibody that disrupts tolerance to tumor and cancer antigens). Examples of such compounds are molecules that block CTLA-4 activity, such as MDX-010 (Phan et al., PNAS USA 100,8372 (2003)). In another embodiment, the therapy of the present invention further includes administration of a nucleic acid or vector containing a tumor suppressor gene, such as a replication-deficient adenovirus encoding recombinant wild-type human p53 / SCH58500; an antisense nucleic acid targeting an oncogene, a mutated or dysregulated gene; or a siRNA targeting a mutated or dysregulated gene. Examples of tumor suppressor targets include, for example, BRCA1, RBI, BRCA2, DPC4 (Smad4), MSH2, MLH1, and DCC.

[0090] In another embodiment, the therapy of the present invention further includes administration of anticancer nucleic acids, such as genasense (augmerosen / G3139), LY900003 (ISIS 3521), ISIS 2503, OGX-011 (ISIS 112989), LE-AON / LEraf-AON (liposome-encapsulated c-Raf antisense oligonucleotide / ISIS-5132), MG98, and other antisense nucleic acids targeting PKCα, clusterin, IGFBP, protein kinase A, cyclin DL, or Bcl-2H. In another embodiment, the therapy of the present invention further includes administration of an anticancer repressive RNA molecule (see, for example, Lin et al., Curr Cancer Drug Targets. 1(3), 241-7(2001), Erratum: Curr Cancer Drug Targets. 3(3), 237(2003), Lima et al., Cancer Gene Ther. 11(5), 309-16(2004), Grzmil et al., Int J Oncol. 4(1), 97-105(2004), Collis et al., Int J Radiat Oncol Biol Phys. 57(2Suppl), S144(2003), Yang et al., Oncogene. 22(36), 5694-701(2003), and Zhang et al., Biochem Biophys ResCommun. 303(4), 1169-78(2003)). In another embodiment, the therapy of the present invention further includes administration of a virus, viral protein, etc. Replication-deficient viruses, which are typically capable of replicating in vivo for one or only a few rounds and targeting tumor cells, can be useful components of such compositions and methods. These viral agents may contain nucleic acids encoding or bound to immunostimulants such as GM-CSF and / or IL-2.Natural oncolytic viruses and such recombinant oncolytic viruses (e.g., HSV-1 virus, reoviruses, replication-deficient and replication-sensitive adenoviruses, etc.) can both be useful components of such methods and compositions (see, for example, Shah et al., J Neurooncol. 65(3), 203-26 (2003), Stiles et al., Surgery. 134(2), 357-64 (2003), Sunarmura et al., Pancreas. 28(3), 326-9 (2004), Teshigahara et al., J Surg Oncol. 85(1), 42-7 (2004), Varghese et al., Cancer Gene Ther. 9(12), 967-78 (2002), Wildner et al., Cancer Res. 59(2), 410-3 (1999), Yamanaka, Int J Oncol. 24(4), 919-23 (2004) and Zwiebel et al., Semin Oncol. 28(4), 336-43 (2001). In another embodiment, the therapy of the present invention may further relate to “whole-cell” and “adoptive” immunotherapy methods. For example, such methods may comprise the infusion or re-infusion of immune system cells (e.g., tumor-infiltrating lymphocytes (TILs), such as CD4+ and / or CD8+ T cells (e.g., T cells expanded with tumor-specific antigens and / or genetic enhancement), antibody-expressing B cells or other antibody-producing / presenting cells, dendritic cells (e.g., recombinant dendritic cells expressing anti-cytokines, dendritic cells cultured with DC expansion agents such as GM-CSF and / or Flt3-L, and / or dendritic cells loaded with tumor-associated antigens), anti-tumor NK cells, so-called hybrid cells, or combinations thereof. Cell lysates may also be used in such methods and compositions. Cellular “vaccines” that may be used in clinical trials in these aspects include Canvaxin. TM , APC-8015(Dendreon), HSPPC-96(Antigenics) and Cell lysates. Antigens shed from cancer cells and mixtures thereof (see, for example, Bystryn et al., Clinical Cancer Research, Vol. 7, 1882-1887, July 2001), optionally mixed with an adjuvant such as alum, may also be components of such methods and combinations. In another embodiment, the therapy of the present invention further includes the application of an internal vaccination method. Internal vaccination refers to the induction of tumor or cancer cell death in a patient, such as drug-induced or radiation-induced cell death of tumor cells, which generally leads to the initiation of an immune response against: (i) tumor cells as a whole or (ii) portions of tumor cells, including (a) secreted proteins, glycoproteins, or other products, (b) membrane-associated proteins or glycoproteins or other membrane-associated or membrane-intercalated components, and / or (c) intracellular proteins or other intracellular components. The immune response induced by internal vaccination may be humoral (i.e., antibody-complement mediated) or cell-mediated (e.g., the development and / or increase of endogenous cytotoxic T lymphocytes that recognize internally killed tumor cells or portions thereof). In another embodiment, the therapy of the present invention further includes the administration of complement. Therefore, the use of compositions comprising anti-CD38 antibodies with serum or complement is also within the scope of this invention. In these compositions, complement is located near the anti-CD38 antibody, for example, through conjugation, or may be suitable for simultaneous administration. Alternatively, the anti-CD38 antibody and complement or serum may be administered separately. In another embodiment, the therapy of this invention further includes administration of differentiation inducers, retinoic acid and retinoic acid analogs (e.g., all-trans retinoic acid, 13-cis retinoic acid and similar active agents), vitamin D analogs (e.g., seocalcitol and similar active agents), inhibitors and similar active agents of ErbB3, ErbB4, IGF-1R, insulin receptor, PDGFRα, PDGFRβ, Flk2, Flt4, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, TrkC, c-Met, Ron, Sea, Tie, Tie2, Eph, Ret, Ros, Alk, LTK, PTK7. In another embodiment, the therapy of the present invention further includes administration of cathepsin B, cathepsin D dehydrogenase activity, a modulator or similar active agent of glutathione S-transferases (e.g., glutathione cysteine ​​synthase and lactate dehydrogenase). In another embodiment, the therapy of the present invention further includes administration of estradiol or epirubicin. In another embodiment, the therapy of the present invention further includes administration of Hsp90 inhibitors such as 17-allylaminogeldemycin, antibodies against tumor antigens such as PSA, CA125, KSA, etc., integrins such as integrin B1, VCAM inhibitors, or similar active agents.

[0091] In another embodiment, the therapy of the present invention further includes administration of calcineurin inhibitors (e.g., valspodar, PSC 833, and other MDR-1 or P-glycoprotein inhibitors), TOR inhibitors (e.g., sirolimus, everolimus, and rapamycin), and inhibitors of lymphocyte homing mechanisms (e.g., FTY720), as well as active agents that affect cell signaling, such as adhesion molecule inhibitors (e.g., anti-LFA, etc.). In another embodiment, the therapy of the present invention also includes radiotherapy. Radiotherapy may include radiation or the related administration of radiopharmaceuticals to a patient. The radiation source may be external or internal to the patient being treated (radiotherapy may be, for example, in the form of external beam radiotherapy (EBRT), brachytherapy / BT, or bone-targeted radiotherapy). Radioactive elements that can be used to implement such methods include, for example, radium, cesium-137, iridium-192, americium-241, gold-198, cobalt-57, copper-67, technetium-99, iodide-123, iodide-131, and indium-111. In another embodiment, the therapy of the present invention further includes autologous peripheral stem cell or bone marrow transplantation. In another embodiment, the therapy of the present invention further includes orthopedic surgical intervention. Orthopedic surgical intervention can be used to treat conditions involving CD38-expressing cells, such as multiple myeloma, to help control pain or maintain function or activity. Such interventions can include physical therapy, bone splinting to prevent or treat fractures, or surgery (minor or major) to repair fractures. In another embodiment, the therapy of the present invention further includes delivery of one or more active agents that promote the access of CD38 antibodies or combinations thereof to the interior of a tumor. Such methods can be combined, for example, with the delivery of relaxin, which is capable of relaxing tumors (see, for example, U.S. Patent No. 6,719,977). In one embodiment, the anti-CD38 antibody used in this invention may be bound to a cell-penetrating peptide (CPP). Cell-penetrating peptides and related peptides (such as modified cell-penetrating antibodies) are described in references such as: Zhao et al., J Immunol Methods. 254(1-2), 137-45 (2001); Hong et al., Cancer Res. 60(23), 6551-6 (2000); Lindgren et al., Biochem J. 377(Pt1), 69-76 (2004); Buerger et al., J Cancer Res Clin Oncol. 129(12), 669-75 (2003); Pooga et al., FASEB J. 12(1), 67-77 (1998); and Tseng et al., Mol Pharmacol. 62(4), 864-72 (2002).

[0092] In another embodiment, the therapy of the present invention further includes administration of at least one anti-inflammatory agent. In one embodiment, such an anti-inflammatory agent may be selected from steroid drugs and NSAIDs (non-steroidal anti-inflammatory drugs). In one embodiment, such an anti-inflammatory agent may be selected from aspirin and other salicylates, Cox-2 inhibitors (such as rofecoxib and celecoxib), NSAIDs (such as ibuprofen, fenprofen, naproxen, sulindac, diclofenac, piroxicam, ketoprofen, diflunisal, nabumetone, etodolac, oxaprozin, and indomethacin), anti-IL6R antibodies, anti-IL8 antibodies (e.g., 10F8 as described in WO2004 / 058797), anti-IL15 antibodies, anti-IL15R antibodies, anti-CD4 antibodies, and anti-CD11 antibodies. Antibodies against α (e.g., efalizumab), anti-α-4 / β-1 integrin (VLA4) antibodies (e.g., natalizumab), CTLA4-Ig for the treatment of inflammatory diseases, prednisolone, prednisone, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, hydroxychloroquine, sulfasalazine, pyrimidine synthesis inhibitors (e.g., leflunomide), IL-1 receptor blockers (e.g., anakinra), TNF-α blockers (e.g., etanercept, infliximab, and adalimumab), and similar active agents.

[0093] In another embodiment, the therapy of the present invention further includes administration of at least one immunosuppressant and / or immunomodulator to a subject in need. In one embodiment, such immunosuppressant and / or immunomodulator may be selected from cyclosporine, azathioprine, mycophenolic acid, mycophenolate mofetil, corticosteroids such as prednisone, methotrexate, gold salts, sulfasalazine, antimalarial drugs, buquina, leflunomide, imidazolidin, 15-deoxyguanidine, 6-mercaptopurine, cyclophosphamide, rapamycin, tacrolimus (FK-506), OKT3, antithymocyte globulin, thymopentin, thymosin-α, and similar active agents. In one embodiment, such immunosuppressants and / or immunomodulators may be selected from immunosuppressive antibodies, such as antibodies binding to p75 of the IL-2 receptor, or antibodies binding to, for example, MHC, CD2, CD3, CD4, CD7, CD28, B7, CD40, CD45, IFNγ, TNF-α, IL-4, IL-5, IL-6R, IL-6; IGF, IGFR1, IL-7, IL-8, IL-10, CD11a, or CD58, or antibodies binding to their ligands. In one embodiment, such immunosuppressants and / or immunomodulators may be selected from soluble IL-15Rα, IL-10, B7 molecules (B7-1, B7-2, their variants, and fragments), ICOS and OX40, inhibitors of negative T-cell regulators (e.g., antibodies against CTLA4), and similar active agents. In another embodiment, the therapy of the present invention further includes administration of an anti-C3b(i) antibody.

[0094] In another embodiment, the therapy of the present invention further includes administration of histone deacetylase inhibitors (e.g., phenylbutyrate) and / or DNA repair agents (e.g., DNA repair enzymes and related compositions such as dimericine). In another embodiment, the therapy of the present invention further includes anticancer-directed photodynamic therapy (e.g., anticancer laser therapy – which may optionally be implemented using photosensitizers, see, for example, Zhang et al., J Control Release. 93(2), 141-50 (2003)), anticancer acoustic and shockwave therapy (see, for example, Kambe et al., Hum Cell. 10(1), 87-94 (1997)) and / or anticancer nutraceutical therapy (see, for example, Roudebush et al., Vet Clin North Am Small AnimPract. 34(1), 249-69, viii (2004) and Rafi, Nutrition. 20(1), 78-82 (2004)).

[0095] As used herein, unless otherwise stated, a "preventively effective amount" of a compound is an amount sufficient to prevent a disease or condition or to prevent its recurrence. A preventively effective amount of a compound refers to the amount of a therapeutic agent, alone or in combination with other agents, that provides preventive benefit in the prevention of disease. The term "preventively effective amount" may also encompass amounts that improve overall prevention or enhance the preventive efficacy of another preventive agent.

[0096] As used herein, and unless otherwise stated, the terms “pharmaceuticalally acceptable carrier,” “pharmaceuticalally acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” mean a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. In one embodiment, each component is “pharmaceuticalally acceptable” in the sense of compatibility with other components of the pharmaceutical preparation and is suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th ed.; Rowe et al., Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds., Gower Publishing. Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004).

[0097] As used herein, and unless otherwise stated, the term “tumor” refers to all dysplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. As used herein, “dysplastic” means any form of disordered or unregulated cell growth that leads to abnormal tissue growth, whether malignant or benign. Therefore, “dysplastic cells” include both malignant and benign cells with disordered or unregulated cell growth.

[0098] As used herein, and unless otherwise stated, the term “relapsed” refers to a situation in which a subject or mammal whose cancer has returned after treatment has achieved remission.

[0099] As used herein, unless otherwise stated, “effective patient-oncology response” means any increase in the therapeutic benefit to the patient. An “effective patient-oncology response” may be, for example, a reduction in tumor progression rate of 5%, 10%, 25%, 50%, or 100%. An “effective patient-oncology response” may be, for example, a reduction in physical symptoms of cancer of 5%, 10%, 25%, 50%, or 100%. An “effective patient-oncology response” may also be, for example, an increase in patient response of 5%, 10%, 25%, 50%, 100%, 200%, or more, as determined by any suitable means, such as gene expression, cell count, assay results, etc.

[0100] As used herein, and unless otherwise stated, the term “probability” generally refers to an increased probability of an event. When used in relation to the effectiveness of a patient’s tumor response, the term “probability” generally considers an increased probability that the rate of tumor progression or tumor cell growth will decrease. When used in relation to the effectiveness of a patient’s tumor response, the term “probability” may also generally refer to an increase in indicators (such as mRNA or protein expression) that can demonstrate increased progression of the tumor during treatment.

[0101] As used herein, and unless otherwise stated, the term “prediction” generally means predetermined or informed. When used to “predict” the effectiveness of cancer treatment, for example, the term “prediction” may mean that the likelihood of a cancer treatment outcome can be determined at the start, before treatment begins, or before significant progress has been made during treatment.

[0102] As used herein, and unless otherwise stated, the term “monitoring” generally refers to the regulation, oversight, control, observation, tracking, or surveillance of an activity. For example, the term “monitoring the effectiveness of a compound” refers to tracking the effectiveness of treatment in patients or cancer in tumor cell cultures. Similarly, when used alone or in conjunction with patient adherence in clinical trials, “monitoring” refers to tracking or confirming that a patient is actually taking the immunomodulatory compound being tested as prescribed. For example, monitoring can be performed by tracking the expression of mRNA or protein biomarkers.

[0103] Improvement in cancer or cancer-related disease can be characterized as a complete or partial response. A “complete response” is defined as the absence of clinically detectable disease, with normalization of any previously abnormal radiographic studies, bone marrow and cerebrospinal fluid (CSF) measurements, or abnormal monoclonal protein measurements. A “partial response” is defined as a reduction of at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in all measurable tumor burdens (i.e., the number of malignant cells present in the subject, the measured tumor mass volume, or the number of abnormal monoclonal proteins) in the absence of new lesions. The term “treatment” encompasses both complete and partial responses.

[0104] As used herein, and unless otherwise stated, the term "refractory or resistant" refers to the presence of residual cancer cells in a subject or mammal even after intensive treatment.

[0105] As used herein, and unless otherwise stated, the term "drug resistance" refers to a condition in which a disease does not respond to treatment with one or more drugs. Drug resistance can be inherent, meaning that the disease has never responded to one or more drugs, or it can be acquired, meaning that the disease has ceased to respond to one or more drugs to which the disease had previously responded. In some embodiments, drug resistance is inherent. In some embodiments, drug resistance is acquired.

[0106] As used herein, and unless otherwise stated, when referring to treatment with a compound, the terms “sensitive” and “sensitivity” are relative terms, referring to the degree of effectiveness of the compound in reducing or decreasing the progression of the treated tumor or disease. For example, when used to indicate treatment of cells or tumors associated with a compound, the term “increased sensitivity” means an increase in the effectiveness of tumor treatment by at least 5% or more.

[0107] As used herein, and unless otherwise stated, the terms “determine,” “measure,” “evaluate,” “assess,” and “determine” as used herein generally refer to any form of measurement and include determining the presence or absence of an element. These terms include quantitative and / or qualitative determinations. Assessments can be relative or absolute. “Assessing the presence of…” can include determining the quantity of something present, as well as determining whether it is present or not.

[0108] As used herein, and unless otherwise stated, the term "pharmaceutically acceptable salt" includes non-toxic acid and base addition salts of the compounds referred to by that term. Acceptable non-toxic acid addition salts include those derived from organic and inorganic acids or bases known in the art, including, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, pyric acid, enanthic acid, etc.

[0109] Acidic compounds can form salts with a variety of pharmaceutically acceptable bases. Bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds are those that form non-toxic base addition salts, i.e., salts containing pharmaceutically acceptable cations, such as, but not limited to, alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, or potassium salts. Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), lysine, and procaine.

[0110] As used herein, and unless otherwise stated, the term "solvent" refers to the compound or its salt provided herein, and further includes stoichiometric or non-stoichiometric solvents bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0111] As used herein, and unless otherwise stated, the term "stereoisomeric pure" refers to a composition containing one stereoisomer of a compound and substantially free of other stereoisomers of that compound. For example, a stereoisomeric pure composition of a compound having one chiral center is substantially free of its opposite enantiomers. A stereoisomeric pure composition of a compound having two chiral centers is substantially free of other diastereomers of that compound. In some embodiments, a stereoisomeric pure compound comprises more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound. As used herein and unless otherwise stated, the term "stereoisomer-enriched" means a composition comprising more than about 60% by weight of one stereoisomer of the compound, more than about 70% by weight, or more than about 80% by weight of one stereoisomer of the compound. As used herein and unless otherwise stated, the term "enantiomer-pure" means a composition of stereoisomers of a compound having a chiral center. Similarly, the term "stereoisomer-enriched" means a composition enriched with stereoisomers of a compound having a chiral center.

[0112] As used herein, and unless otherwise stated, the terms “about” or “approximately” refer to an acceptable error in a particular value as determined by one of ordinary skill in the art, depending in part on how the value is measured or determined. In some embodiments, the terms “about” or “approximately” mean within 1, 2, 3, or 4 standard deviations. In some embodiments, the terms “about” or “approximately” mean within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0113] Clinical trial endpoints for cancer approval

[0114] Overall survival (OS) is defined as the time from the first dose to death from any cause, and is measured in the intention-to-treat population. OS should be evaluated in randomized controlled trials. Demonstration of a statistically significant improvement in overall survival can be considered clinically significant if the toxicity profile is acceptable, and usually already supports new drug approval.

[0115] Several endpoints were based on cancer assessment. These endpoints included disease-free survival (DFS), objective response rate (ORR), time to progression (TTP), progression-free survival (PFS), event-free survival (EFS), duration of response (DOR), and time to treatment failure (TTF). Data collection and analysis of these time-related endpoints were based on indirect assessment, calculation, and estimation.

[0116] Typically, “disease-free survival” (DFS) is defined as the time from randomization to cancer recurrence or death from any cause. While overall survival is a routine endpoint in most ancillary settings, DFS can be an important endpoint in cases where survival may be prolonged, making the survival endpoint impractical. DFS can be a substitute for clinical benefit, or it can provide direct evidence of clinical benefit. This determination is based on the magnitude of the effect, its risk-benefit relevance, and the disease context. The definition of DFS can be complex, especially when death is noted in the absence of a prior record of cancer progression. These events can be considered as disease recurrence or as a review event score. Although all methods used for mortality statistical analysis have some limitations, treating all deaths (deaths from all causes) as recurrence can minimize bias. Using this definition may overestimate DFS, especially in patients who die without observation after a long period. Bias can be introduced if the frequency of long-term follow-up is dissimilar between study groups, or if withdrawal is due to toxicity rather than randomization.

[0117] Objective response rate (ORR) is defined as the sum of the percentage of patients achieving a complete and partial response. Response duration is typically measured from the initial response time to the recorded cancer progression. The FDA usually defines ORR as the sum of partial and complete responses. When defined in this way, ORR is a direct measure of the drug's anticancer activity and can be assessed in a single-arm study. If available, standardized criteria should be used to determine the response. Multiple response criteria are considered appropriate (e.g., RECIST criteria) (Therasse et al. (2000) J. Natl. Cancer Inst, 92:205-16). The significance of ORR is assessed by its magnitude and duration, as well as the percentage of patients achieving a complete response (without detectable evidence of cancer).

[0118] "Duration of Response" (DOR) is the time from achieving a response to relapse or disease progression.

[0119] Time to progression (TTP) and progression-free survival (PFS) are primary endpoints for drug approval. TTP is defined as the time from randomization to objective cancer progression; TTP excludes death. PFS is defined as the time from randomization to objective cancer progression or death. Compared to TTP, PFS is the preferred regulatory endpoint. PFS includes death and therefore correlates better with overall survival. PFS assumes that patient death is randomly associated with cancer progression. However, in cases where most deaths are unrelated to cancer, TTP can be an acceptable endpoint.

[0120] As an endpoint supporting drug approval, progression-free survival (PFS) can reflect cancer growth and be assessed before determining survival benefit. Its determination is not confounded by subsequent therapies. For a given sample size, the magnitude of the effect on PFS can be greater than its effect on overall survival. However, formal validation of PFS as a surrogate for survival in many different malignancies can be difficult. Data are sometimes insufficient to allow for a stable assessment of the correlation between the effects on survival and PFS. Cancer trials are often small, and the proven survival benefits of existing drugs are often modest. The role of PFS as an endpoint supporting licensing approval varies across different cancer contexts. Whether an improvement in PFS represents a direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the effect of the new treatment compared to available therapies and the magnitude of the risk-benefit ratio.

[0121] "Event-free survival" (EFS) is the time from the start of a study to the failure of any treatment, including disease progression, discontinuation of treatment for any reason, or death.

[0122] Time to Treatment Failure (TTF) is defined as a composite endpoint, measuring the time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity, and death. TTF is not recommended as a regulatory endpoint for drug approval. TTF cannot adequately distinguish efficacy from these additional variables. Regulatory endpoints should clearly differentiate between drug efficacy and toxicity, patient or physician withdrawal, or patient intolerance.

[0123] In some implementations, the methods provided herein can be used to achieve one or more of these clinical trial endpoints in patients. In some implementations, the methods provided herein can be used to improve one or more of these clinical trial endpoints in patients.

[0124] compound

[0125] In some embodiments, the compound used in the compositions and methods provided herein is 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A); which has the following structure:

[0126]

[0127] Or its enantiomers or mixtures thereof; or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs.

[0128] In one embodiment, the compound is 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione. In one embodiment, the compound is a pharmaceutically acceptable salt of compound A. In one embodiment, the compound is 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione hydrochloride.

[0129] In one embodiment, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS); it has the following structure:

[0130]

[0131] In one embodiment, the compound is a pharmaceutically acceptable salt of compound AS. In another embodiment, the compound is a hydrochloride salt of compound AS.

[0132] In one embodiment, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AR); it has the following structure:

[0133]

[0134] In one embodiment, the compound is a pharmaceutically acceptable salt of compound AR. In one embodiment, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione hydrochloride.

[0135] Compound A can be prepared according to the methods described in U.S. Application Publications US2011-0196150 and US2014-0045843, the entire contents of which are incorporated herein by reference. Based on the teachings of these publications, the compound can also be synthesized according to other methods that are obvious to those skilled in the art.

[0136] The compounds presented in this paper significantly inhibited TNF-α, IL-1β, and other inflammatory cytokines in LPS-stimulated hPBMCs and human whole blood. TNF-α is an inflammatory cytokine produced by macrophages and monocytes during acute inflammation. TNF-α is responsible for various intracellular signaling events. TNF-α may play a pathological role in cancer. Without being limited by theory, one of the biological effects of the immunomodulatory compounds presented in this paper is the reduction of TNF-α synthesis. The immunomodulatory compounds presented in this paper enhance the degradation of TNF-α mRNA. Under these conditions, the compounds presented in this paper also effectively inhibited IL-1β and stimulated IL-10.

[0137] Furthermore, without being limited by any particular theory, the compounds presented in this paper are effective co-stimulators of T cells and increase cell proliferation in a dose-dependent manner under appropriate conditions.

[0138] In some implementations, without being limited by theory, the biological effects of the immunomodulatory compounds provided herein include, but are not limited to, anti-angiogenic and immunomodulatory effects.

[0139] Compound A, as described herein, contains a chiral center and can exist as a mixture of enantiomers, such as racemic mixtures. This application covers the use of the stereoisomeric pure forms of such compounds, as well as the use of mixtures of these forms. For example, mixtures containing equal or unequal amounts of enantiomers of compound A, as described herein, can be used in the methods and compositions provided herein. These isomers can be resolved by asymmetric synthesis or using standard techniques such as chiral columns or chiral resolving agents. See, for example, Jacques, J. et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, SH, et al., Tetrahedron 33:2725 (1977); Eliel, EL, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, SH, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0140] In some embodiments, the compound used in the compositions and methods provided herein is a monoclonal antibody that binds to CD20. In some embodiments, the anti-CD20 antibody is obituzumab. In some embodiments, the anti-CD20 antibody is rituximab.

[0141] In some embodiments, the compound used in the compositions and methods provided herein is an HDAC inhibitor. In some embodiments, the HDAC inhibitor is 2-(N-(2-chlorophenyl)anilino)-N-[7-(hydroxyamino)-7-oxoheptyl]pyrimidine-5-carboxamide; having the following structure:

[0142]

[0143] Or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the HDAC inhibitor is citalin-dustat (ACY-241).

[0144] In some embodiments, the compounds used in the compositions and methods provided herein are proteasome formulations.

[0145] In some embodiments, the proteasome inhibitor is (1R,4R,5S)-4-(2-chloroethyl)-1-[(S)-[(1S)-cyclohexyl-2-en-1-yl]-hydroxymethyl]-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione; which has the following structure:

[0146]

[0147] Or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is marizomib.

[0148] In some embodiments, the proteasome inhibitor is [(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propionyl]amino]butyl]boronic acid; which has the following structure:

[0149]

[0150] Or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is bortezomib.

[0151] In some embodiments, the proteasome inhibitor is (2S)-4-methyl-N-[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methylepoxyethylene-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]-4-phenylbutyryl]amino]pentanamide; which has the following structure:

[0152]

[0153] Or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is carfilzomib.

[0154] In some embodiments, the proteasome inhibitor is [(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid; which has the following structure:

[0155]

[0156] Or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is ixazomib.

[0157] In some embodiments, the compound used in the compositions and methods provided herein is a monoclonal antibody that binds to CD38a. In some embodiments, the anti-CD38 antibody is ixartuximab. In some embodiments, the anti-CD38 antibody is daratumumab.

[0158] In some embodiments, the compound used in the compositions and methods provided herein is a monoclonal antibody that binds to SLAMF7. In some embodiments, the anti-SLAMF7 antibody is ileizumab.

[0159] In some embodiments, the compound used in the compositions and methods provided herein is a nucleotransfer inhibitor. In some embodiments, the nucleotransfer inhibitor is (Z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-N'-pyrazin-2-ylprop-2-enoylhydrazine; having the following structure:

[0160]

[0161] Or, or mixtures thereof, or isomers or geometric isomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the nucleus transport inhibitor is celiniso.

[0162] In some embodiments, the compound used in the compositions and methods provided herein is a BCL-2 inhibitor. In some embodiments, the BCL-2 inhibitor is 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxane-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide; having the following structure:

[0163]

[0164] Or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof. In some embodiments, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound, or polymorph thereof.

[0165] In some embodiments, the compound used in the compositions and methods provided herein is a monoclonal antibody that inhibits immune checkpoints. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, the immune checkpoint inhibitor is nivolumab. In some embodiments, the immune checkpoint inhibitor is ipilimumab.

[0166] In some embodiments, the compound used in the compositions and methods provided herein is (11b,16a)-9-fluoro-11,17,21-trihydroxy-16-methylpregn-1,4-diene-3,20-dione; it has the following structure:

[0167]

[0168] Or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs.

[0169] In one embodiment, the compound is (11b,16a)-9-fluoro-11,17,21-trihydroxy-16-methylpregn-1,4-diene-3,20-dione. In one embodiment, the compound is a pharmaceutically acceptable salt of dexamethasone. In one embodiment, the compound is dexamethasone sodium phosphate.

[0170] Dexamethasone can be prepared according to the methods described in U.S. Patent Nos. 2,990,401 and 3,035,050, the entire contents of which are incorporated herein by reference.

[0171] It should be noted that if there is a difference between the described structure and the given name of that structure, the described structure will be given more weight. Furthermore, if the stereochemistry of a structure or its components is not indicated by, for example, thick or dashed lines, the structure or its components will be interpreted as including all stereoisomers of that structure.

[0172] Treatment methods and compounds used in such methods

[0173] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. This article provides methods for treating and / or managing cancer using 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the method further includes administration of dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0174] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, as part of a combination therapy. This article provides methods for treating and / or managing cancer using 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the method further comprises administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0175] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A) or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with an anti-CD20 antibody. In some embodiments, the method further comprises administering dexamethasone or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. This document provides 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, for use in such methods. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-CD20 antibody is obbituzumab. In some embodiments, the anti-CD20 antibody is rituximab.

[0176] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A) or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with an HDAC inhibitor. In some embodiments, the method further comprises administering dexamethasone or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. This document provides 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, for use in such methods. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the HDAC inhibitor is citalin-dustat or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0177] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A) or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with a proteasome inhibitor. In some embodiments, the method further comprises administering dexamethasone or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. This document provides 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, for use in such methods. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is marizome or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is bortezomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is carfilzomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion compound or polymorph thereof.

[0178] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A) or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with an anti-CD38 antibody. In some embodiments, the method further comprises administering dexamethasone or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. This document provides 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, for use in such methods. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-CD38 antibody is ixartuximab. In some embodiments, the anti-CD38 antibody is daratumumab.

[0179] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A) or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with an anti-SLAMF7 antibody. In some embodiments, the method further comprises administering dexamethasone or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. This document provides 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, for use in such methods. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-SLAMF7 antibody is ileizumab.

[0180] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A) or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with a nucleotransfer inhibitor. In some embodiments, the method further comprises administering dexamethasone or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. This document provides 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, for use in such methods. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the nucleotransfer inhibitor is celiniso or its geometric isomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0181] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A) or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with a BCL-2 inhibitor. In some embodiments, the method further comprises administering dexamethasone or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. This document provides 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, for use in such methods. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the BCL-2 inhibitor is venetoc or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0182] This article provides methods for treating and / or managing cancer, comprising administering to a patient in need of such treatment and / or management a therapeutically or prophylactically effective amount of 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound A) or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with an immune checkpoint inhibitor. In some embodiments, the method further comprises administering dexamethasone or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. This document provides 3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound A) or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, for use in such methods. In some embodiments, the compound is (S)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidine-2,6-dione (compound AS) or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the compound is a hydrochloride salt of compound AS. In some embodiments, the compound is (R)-3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisodihydroindol-2-yl)piperidin-2,6-dione (compound AR) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, the immune checkpoint inhibitor is nivolumab. In some embodiments, the immune checkpoint inhibitor is ipilimumab.

[0183] As used herein, the term "cancer" includes, but is not limited to, tumors arising from the bloodstream. In some embodiments, the term "cancer" includes Karo-type acute medulloblastic leukemia, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, and low-grade follicular lymphoma.

[0184] In some embodiments, the cancer is a hematological tumor. In some embodiments, the hematological tumor is metastatic. In some embodiments, the hematological tumor is drug-resistant. In some embodiments, the cancer is myeloma or lymphoma.

[0185] In some embodiments, the multiple myeloma is a type of multiple myeloma. In some embodiments, the multiple myeloma is a smoldering myeloma, a slow-growing myeloma, an active multiple myeloma, an extramedullary plasmacytoma, a solitary plasmacytoma of the bone, a light chain myeloma, or a non-secreting myeloma. In some embodiments, the multiple myeloma is a relapsed, refractory, or resistant multiple myeloma. In some embodiments, the multiple myeloma is both relapsed and refractory multiple myeloma.

[0186] This article provides methods for treating or managing myeloma, particularly multiple myeloma. In some embodiments, this article provides methods for treating or managing cryptic myeloma, slow-growing myeloma, active multiple myeloma, extramedullary plasmacytoma, solitary plasmacytoma of bone, light chain myeloma, or non-secreting myeloma. In some embodiments, this article provides methods for treating or managing relapsed, refractory, or resistant multiple myeloma. In some embodiments, this article provides methods for treating and managing both relapsed and refractory multiple myeloma.

[0187] In some implementations, the lymphoma is Hodgkin lymphoma, classic Hodgkin lymphoma (cHL), non-Hodgkin lymphoma (NHL), cutaneous B-cell lymphoma, activated B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular central lymphoma, follicular lymphoma (FL), marginal zone lymphoma (MZL), transformed lymphoma, moderately differentiated lymphocytic lymphoma, intermediate lymphocytic lymphoma (ILL), diffuse poorly differentiated lymphocytic lymphoma (PDL), centricell lymphoma, diffuse small cleavage cell lymphoma (DSCCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma, primary central nervous system lymphoma (PCNSL), or low-grade follicular lymphoma.

[0188] In some embodiments, the lymphoma is non-Hodgkin lymphoma (NHL). In some embodiments, the NHL is diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), peripheral T-cell lymphoma (PTCL), or primary central nervous system lymphoma (PCNSL). In some embodiments, the NHL is DLBCL. In some embodiments, the NHL is FL. In some embodiments, the NHL is MZL. In some embodiments, the NHL is MCL. In some embodiments, the NHL is PTCL. In some embodiments, the NHL is PCNSL.

[0189] In some implementations, NHL is relapsed or refractory NHL. In some implementations, NHL is relapsed or refractory DLBCL. In some implementations, NHL is relapsed or refractory FL. In some implementations, NHL is relapsed or refractory MZL. In some implementations, NHL is relapsed or refractory MCL. In some implementations, NHL is relapsed or refractory PTCL. In some implementations, NHL is relapsed or refractory PCNSL. In some implementations, the subject has at least one prior therapy failure.

[0190] In some implementations, NHL is newly diagnosed.

[0191] In some implementations, the lymphoma is Hodgkin lymphoma (HL).

[0192] In some implementations, HL stands for classic Hodgkin lymphoma (cHL).

[0193] In some implementations, HL refers to relapsed or refractory HL.

[0194] In some implementations, HL refers to relapsed or refractory cHL.

[0195] In some implementations, HL is newly diagnosed.

[0196] In some implementations, this document provides methods for treating or managing Hodgkin lymphoma (HL), classic Hodgkin lymphoma (cHL), non-Hodgkin lymphoma (NHL), cutaneous B-cell lymphoma, activated B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular central lymphoma, follicular lymphoma (FL), marginal zone lymphoma (MZL), transformed lymphoma, moderately differentiated lymphocytic lymphoma, intermediate lymphocytic lymphoma (ILL), diffuse poorly differentiated lymphocytic lymphoma (PDL), central cell lymphoma, diffuse small cleaved cell lymphoma (DSCCL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma, primary central nervous system lymphoma (PCNSL), or low-grade follicular lymphoma.

[0197] In some embodiments, this document provides methods for treating or managing NHL. In some embodiments, this document provides methods for treating or managing DLBCL, FL, MZL, MCL, PTCL, or PCNSL. In some embodiments, this document provides methods for treating or managing HL. In some embodiments, this document provides methods for treating or managing cHL.

[0198] In some embodiments, this document provides methods for treating or managing relapsed or refractory cancers. In some embodiments, this document provides methods for treating or managing relapsed or refractory Hodgkin lymphoma (HL), relapsed or refractory classic Hodgkin lymphoma (cHL), relapsed or refractory non-Hodgkin lymphoma (NHL), relapsed or refractory cutaneous B-cell lymphoma, activated B-cell lymphoma, relapsed or refractory diffuse large B-cell lymphoma (DLBCL), relapsed or refractory mantle cell lymphoma (MCL), relapsed or refractory follicular central lymphoma, relapsed or refractory follicular lymphoma (FL), relapsed or refractory marginal zone lymphoma (MZL), and other relapsed or refractory cancers. Methods for treating recurrent or refractory transformed lymphoma, recurrent or refractory moderately differentiated lymphocytic lymphoma, recurrent or refractory intermediate lymphocytic lymphoma (ILL), recurrent or refractory diffuse poorly differentiated lymphocytic lymphoma (PDL), recurrent or refractory central cell lymphoma, recurrent or refractory diffuse small cleavage cell lymphoma (DSCCL), recurrent or refractory peripheral T-cell lymphoma (PTCL), recurrent or refractory cutaneous T-cell lymphoma, recurrent or refractory primary central nervous system lymphoma (PCNSL), or recurrent or refractory low-grade follicular lymphoma.

[0199] In some embodiments, this document provides methods for treating or managing relapsed or refractory NHL. In some embodiments, this document provides methods for treating or managing relapsed or refractory DLBCL, relapsed or refractory FL, relapsed or refractory MZL, relapsed or refractory MCL, relapsed or refractory PTCL, or relapsed or refractory PCNSL. In some embodiments, this document provides methods for treating or managing relapsed or refractory HL. In some embodiments, this document provides methods for treating or managing relapsed or refractory cHL.

[0200] In some embodiments, this document provides methods for treating or managing newly diagnosed NHL. In some embodiments, this document provides methods for treating or managing newly diagnosed DLBCL, newly diagnosed FL, newly diagnosed MZL, newly diagnosed MCL, newly diagnosed PTCL, or newly diagnosed PCNSL. In some embodiments, this document provides methods for treating or managing newly diagnosed HL. In some embodiments, this document provides methods for treating or managing newly diagnosed cHL.

[0201] This article provides methods for treating cancers, such as NHL and HL, that result in improved overall survival in patients. In some embodiments, improved overall survival is observed in patient populations sensitive to treatment with compound A or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the method further includes administration of dexamethasone or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof.

[0202] This document also provides methods for treating cancers, such as NHL and HL, which lead to improved overall patient survival. In some embodiments, improvements in overall survival are observed in patient populations sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof with (ii) an anti-CD20 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the anti-CD20 antibody is obbituzumab. In some embodiments, the anti-CD20 antibody is rituximab.

[0203] This article also provides methods for treating cancers such as NHL and HL that lead to improved overall survival in patients. In some embodiments, improvements in overall survival are observed in patient populations sensitive to treatment with (i) a combination of compound A or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, or (ii) an HDAC inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the HDAC inhibitor is citalindustat (ACY-241) or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0204] This document also provides methods for treating cancers such as NHL and HL that lead to improved overall survival in patients. In some embodiments, improvements in overall survival are observed in patient populations sensitive to treatment using (i) a combination of compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof with (ii) a proteasome inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is marizome or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is bortezomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is carfilzomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0205] This document also provides methods for treating cancers such as NHL and HL that result in improved overall survival in patients. In some embodiments, improvements in overall survival are observed in patient populations sensitive to combination therapy with (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, and (ii) an anti-CD38 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the anti-CD38 antibody is ixartuximab. In some embodiments, the anti-CD38 antibody is daratumumab.

[0206] This document also provides methods for treating cancers such as NHL and HL that lead to improved overall survival in patients. In some embodiments, improvements in overall survival are observed in patient populations sensitive to combination therapy with (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, and (ii) an anti-SLAMF7 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the anti-SLAMF7 antibody is ileuzumab.

[0207] This document also provides methods for treating cancers such as NHL and HL that lead to improved overall survival in patients. In some embodiments, improvements in overall survival are observed in patient populations sensitive to combination therapy with (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, and (ii) a nucleotransfer inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the nucleotransfer inhibitor is celiniso or its geometrical isomers or mixtures of geometrical isomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof.

[0208] This document also provides methods for treating cancers such as NHL and HL that lead to improved overall survival in patients. In some embodiments, improvements in overall survival are observed in patient populations sensitive to combination therapy with (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, and (ii) a BCL-2 inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the BCL-2 inhibitor is venetoclax or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs.

[0209] This document also provides methods for treating cancers such as NHL and HL that result in improved overall survival in patients. In some embodiments, improvements in overall survival are observed in patient populations sensitive to combination therapy with (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, and (ii) an immune checkpoint inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, the immune checkpoint inhibitor is nivolumab. In some embodiments, the immune checkpoint inhibitor is ipilimumab.

[0210] This article also provides methods for treating cancers such as NHL and HL that lead to improved disease-free survival in patients. In some embodiments, improved disease-free survival is observed in patient populations sensitive to treatment with compound A or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the method further comprises administering dexamethasone or its enantiomers or mixtures thereof, or pharmaceutically acceptable solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof.

[0211] This document also provides methods for treating cancers, such as NHL and HL, that lead to improved disease-free survival in patients. In some embodiments, disease-free survival is observed in patient populations sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an anti-CD20 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-CD20 antibody is obbituzumab. In some embodiments, the anti-CD20 antibody is rituximab.

[0212] This document also provides methods for treating cancers such as NHL and HL that lead to improved disease-free survival in patients. In some embodiments, disease-free survival is observed in patient populations sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof with (ii) an HDAC inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the HDAC inhibitor is citalindustat or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0213] This document also provides methods for treating cancers such as NHL and HL that lead to improved disease-free survival in patients. In some embodiments, disease-free survival is observed in patient populations sensitive to treatment with a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof and (ii) a proteasome inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is marizome or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is bortezomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is carfilzomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0214] This document also provides methods for treating cancers such as NHL and HL that lead to improved disease-free survival in patients. In some embodiments, disease-free survival is observed in patient populations sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof with (ii) an anti-CD38 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the anti-CD38 antibody is ixartuximab. In some embodiments, the anti-CD38 antibody is daratumumab.

[0215] This document also provides methods for treating cancers such as NHL and HL that lead to improved disease-free survival in patients. In some embodiments, disease-free survival is observed in patient populations sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an anti-SLAMF7 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-SLAMF7 antibody is ileuzumab.

[0216] This document also provides methods for treating cancers such as NHL and HL that lead to improved disease-free survival in patients. In some embodiments, disease-free survival is observed in patient populations sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, and (ii) a nucleotransfer inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the nucleotransfer inhibitor is celinisosone or its geometrical isomers or mixtures of geometrical isomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof.

[0217] This document also provides methods for treating cancers such as NHL and HL that lead to improved disease-free survival in patients. In some embodiments, disease-free survival is observed in patient populations sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof with (ii) a BCL-2 inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0218] This document also provides methods for treating cancers, such as NHL and HL, that lead to improved disease-free survival in patients. In some embodiments, disease-free survival is observed in patient populations sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an immune checkpoint inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, the immune checkpoint inhibitor is nivolumab. In some embodiments, the immune checkpoint inhibitor is ipilimumab.

[0219] This article provides methods for treating cancers, such as NHL and HL, that lead to improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment with compound A or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the method further comprises administering dexamethasone or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof.

[0220] This document also provides methods for treating cancers, such as NHL and HL, which result in improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an anti-CD20 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-CD20 antibody is obbituzumab. In some embodiments, the anti-CD20 antibody is rituximab.

[0221] This document also provides methods for treating cancers such as NHL and HL, leading to improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment using (i) a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof with (ii) an HDAC inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the HDAC inhibitor is citalindustat or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0222] This document also provides methods for treating cancers, such as NHL and HL, which result in improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment with a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof and (ii) a proteasome inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is marizome or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is bortezomib or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the proteasome inhibitor is carfilzomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0223] This document also provides methods for treating cancers, such as NHL and HL, which result in improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof with (ii) an anti-CD38 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the anti-CD38 antibody is ixartuximab. In some embodiments, the anti-CD38 antibody is daratumumab.

[0224] This document also provides methods for treating cancers such as NHL and HL, leading to improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an anti-SLAMF7 antibody. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-SLAMF7 antibody is ileuzumab.

[0225] This document also provides methods for treating cancers such as NHL and HL, leading to improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof, and (ii) a nucleotransfer inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. In some embodiments, the nucleotransfer inhibitor is celiniso or its geometrical isomers or mixtures of geometrical isomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof.

[0226] This document also provides methods for treating cancers such as NHL and HL that result in improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment with (i) compound A or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, and (ii) a BCL-2 inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the BCL-2 inhibitor is venetoclax or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs.

[0227] This document also provides methods for treating cancers such as NHL and HL, leading to improved objective response rates in patient populations. In some embodiments, the patient population is sensitive to treatment using a combination of (i) compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof with (ii) an immune checkpoint inhibitor. In some embodiments, the methods provided herein further comprise administration of dexamethasone or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, the immune checkpoint inhibitor is nivolumab. In some embodiments, the immune checkpoint inhibitor is ipilimumab.

[0228] In some embodiments, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs are administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs.

[0229] In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with an anti-CD20 antibody, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with obbituzumab, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs with rituximab is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs.

[0230] In some embodiments, compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with an HDAC inhibitor, is administered in combination with dexamethasone, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with sitalindustat, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered in combination with dexamethasone, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0231] In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with a proteasome inhibitor, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with marizome or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with bortezomib or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with carfilzomib or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with ixazomib or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs.

[0232] In some embodiments, compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with anti-CD38 antibody, is administered in combination with dexamethasone, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with ixartuximab, is administered in combination with dexamethasone, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs with daratumumab is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs.

[0233] In some embodiments, compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with anti-SLAMF7 antibody, is administered in combination with dexamethasone, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with ileizumab, is administered in combination with dexamethasone, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0234] In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with a nucleotransfer inhibitor, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with celinisothiazide or its geometric isomers or mixtures of geometric isomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs.

[0235] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with a BCL-2 inhibitor, is administered in combination with dexamethasone, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with venetoclax, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with dexamethasone, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs.

[0236] In some embodiments, compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with an immune checkpoint inhibitor, is administered in combination with dexamethasone, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, compound A, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with pembrolizumab, is administered in combination with dexamethasone, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with nivolumab, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with ipilimumab, is administered in combination with dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs.

[0237] In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, are administered in combination with conventional therapies for the treatment or management of cancer.

[0238] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with an anti-CD20 antibody, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with obbituzumab, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with rituximab, is administered in combination with conventional therapies for the treatment or management of cancer.

[0239] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with an HDAC inhibitor, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with sitalindustat, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with conventional therapies for the treatment or management of cancer.

[0240] In some embodiments, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with a proteasome inhibitor, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with marizomib, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with bortezomib or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, a combination of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, with carfilzomib or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with ixazomib or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, are administered in combination with conventional therapies for the treatment or management of cancer.

[0241] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with an anti-CD38 antibody, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with ixartuximab, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with daratumumab, is administered in combination with conventional therapies for the treatment or management of cancer.

[0242] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with anti-SLAMF7 antibody, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with ileuzumab, is administered in combination with conventional therapies for the treatment or management of cancer.

[0243] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with a nucleus transport inhibitor, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with celinisoxol, or its geometrical isomers or mixtures of geometrical isomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with conventional therapies for the treatment or management of cancer.

[0244] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with a BCL-2 inhibitor, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with venetoclax, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with conventional therapies for the treatment or management of cancer.

[0245] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with an immune checkpoint inhibitor, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with pembrolizumab, is administered in combination with conventional therapies for the treatment or management of cancer. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with nivolumab, is administered in combination with conventional therapies for the treatment or management of cancer. In some implementations, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs are combined with ipilimumab in combination with conventional therapies for the treatment or management of cancer.

[0246] Examples of such conventional treatments include, but are not limited to, surgery, chemotherapy, radiotherapy, hormone therapy, biological therapy, and immunotherapy.

[0247] In some embodiments, the methods provided herein for treating and / or managing cancer can be used in patients who do not respond to standard treatment. In one embodiment, the cancer is recurrent or refractory to conventional therapies.

[0248] In other embodiments, the methods provided herein for treating and / or managing cancer can be used to treat naive patients who are being tested for the first time, i.e., patients who have not yet received treatment.

[0249] In some embodiments, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs are administered in combination or alternately with a therapeutically effective amount of one or more other active agents.

[0250] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with anti-CD20 antibody, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with obbituzumab, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with rituximab, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents.

[0251] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with an HDAC inhibitor, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with citalin-dustat, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents.

[0252] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with a proteasome inhibitor, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with marizomib, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with bortezomib or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, are administered in combination with or alternately with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs, in combination with ixazomib or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds or polymorphs, in combination with or alternating with a therapeutically effective amount of one or more other active agents.

[0253] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with anti-CD38 antibody, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with ixartuximab, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with daratumumab, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents.

[0254] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with anti-SLAMF7 antibody, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with ileuzumab, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents.

[0255] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, are combined with a nucleotransfer inhibitor and administered in combination or alternately with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, are combined with celinisoxol, or its geometrical isomers or mixtures of geometrical isomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, and administered in combination or alternately with a therapeutically effective amount of one or more other active agents.

[0256] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with a BCL-2 inhibitor, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with venetoclax, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents.

[0257] In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with an immune checkpoint inhibitor, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with pembrolizumab, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A, or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, in combination with nivolumab, is administered in combination with or alternates with a therapeutically effective amount of one or more other active agents. In some embodiments, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs are combined with ipilimumab in combination with or alternate with one or more other active agents in a therapeutically effective amount.

[0258] Other active agents include small and large molecules (e.g., proteins and antibodies), examples of which are provided herein, as well as stem cells. Methods or therapies that may be used in conjunction with the administration of the compounds provided herein include, but are not limited to, surgery, blood transfusion, immunotherapy, biotherapy, radiation therapy, and other non-pharmacological therapies currently used to treat and / or manage diseases and conditions associated with or characterized by undesirable angiogenesis.

[0259] In one embodiment, the additional active agent is selected from alkylating agents, adenosine analogs, glucocorticoids, kinase inhibitors, SYK inhibitors, PDE3 inhibitors, PDE7 inhibitors, doxorubicin, chlorambucil, vincristine, bendamustine, forskolin, rituximab, or combinations thereof. In one embodiment, the additional active agent is rituximab. In another embodiment, the additional active agent is prednisone.

[0260] This invention provides methods for treating patients who have previously received cancer treatment but are unresponsive to standard therapies, as well as patients who have not previously received treatment. The invention also includes methods for treating patients regardless of age, although some diseases or conditions are more common in certain age groups. The invention also includes methods for treating patients who have undergone surgery in an attempt to treat the disease or condition in question, as well as patients who have not undergone surgery. Because patients with cancer have different clinical presentations and different clinical outcomes, the treatment given to a patient can vary depending on his / her prognosis. Skilled clinicians can conveniently determine, without excessive experimentation, the specific secondary activator, type of surgery, and type of non-pharmacological standard therapy that can be effectively used to treat an individual patient with cancer.

[0261] This article provides methods for treating patients who have previously received at least two prior lines of treatment for cancer.

[0262] In some embodiments, this document provides methods for treating and / or managing recurrent or refractory cancer in a patient, including administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof. In some embodiments, the methods provided herein further include administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0263] In some embodiments, this document provides methods for treating and / or managing recurrent or refractory cancer in a patient, including administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof, in combination with an anti-CD20 antibody. In some embodiments, the methods provided herein further include administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-CD20 antibody is obbituzumab. In some embodiments, the anti-CD20 antibody is rituximab.

[0264] In some embodiments, this document provides methods for treating and / or managing recurrent or refractory cancer in patients, including administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof, in combination with an HDAC inhibitor. In some embodiments, the methods provided herein further include administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the HDAC inhibitor is citalindustat or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0265] In some embodiments, this document provides methods for treating and / or managing recurrent or refractory cancer in a patient, including administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof, in combination with a proteasome inhibitor. In some embodiments, the methods provided herein further include administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is marizome or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is bortezomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is carfilzomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the proteasome inhibitor is ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0266] In some embodiments, this document provides methods for treating and / or managing recurrent or refractory cancer in patients, including administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof, in combination with an anti-CD38 antibody. In some embodiments, the methods provided herein further comprise administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-CD38 antibody is ixartuximab. In some embodiments, the anti-CD38 antibody is daratumumab.

[0267] In some embodiments, this document provides a method for treating and / or managing recurrent or refractory cancer in a patient, comprising administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof, in combination with an anti-SLAMF7 antibody. In some embodiments, the method provided herein further comprises administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the anti-SLAMF7 antibody is ileizumab.

[0268] In some embodiments, this document provides methods for treating and / or managing recurrent or refractory cancer in patients, including administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof, in combination with a nucleotransfer inhibitor. In some embodiments, the methods provided herein further include administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the nucleotransfer inhibitor is celiniso or its geometrical isomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0269] In some embodiments, this document provides methods for treating and / or managing recurrent or refractory cancer in patients, including administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof, in combination with a BCL-2 inhibitor. In some embodiments, the methods provided herein further comprise administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0270] In some embodiments, this document provides methods for treating and / or managing recurrent or refractory cancer in patients, including administering to a patient with recurrent or refractory cancer a therapeutically effective amount of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, tautomer, or racemic mixture thereof, in combination with an immune checkpoint inhibitor. In some embodiments, the methods provided herein further include administering dexamethasone or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, the immune checkpoint inhibitor is nivolumab. In some embodiments, the immune checkpoint inhibitor is ipilimumab.

[0271] This article provides a method of using compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures for the treatment and / or management of patients with recurrent or refractory cancers.

[0272] In some embodiments, the therapeutic or prophylactic effective amount of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures is approximately 0.005 mg to about 1,000 mg / day, about 0.01 mg to about 500 mg / day, about 0.01 mg to about 250 mg / day, about 0.01 mg to about 100 mg / day, or about... The therapeutic or prophylactic effective doses are approximately 0.1 mg to about 100 mg / day, about 0.5 mg to about 100 mg / day, about 1 mg to about 100 mg / day, about 0.01 mg to about 50 mg / day, about 0.1 mg to about 50 mg / day, about 0.5 mg to about 50 mg / day, about 1 mg to about 50 mg / day, about 0.02 mg to about 25 mg / day, about 0.05 mg to about 10 mg / day, or about 0.1 mg to about 5 mg / day. In some embodiments, the therapeutic or prophylactic effective dose of compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures is about 0.005 mg to about 1,000 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.01 mg to about 500 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.01 mg to about 250 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.01 mg to about 100 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.1 mg to about 100 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.5 mg to about 100 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1 mg to about 100 mg / day.In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.01 mg to about 50 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.1 mg to about 50 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.5 mg to about 50 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1 mg to about 50 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A is about 0.02 mg to about 25 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.05 mg to about 10 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.1 mg to about 5 mg / day.

[0273] In some embodiments, the therapeutic or prophylactic effective amount of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures is about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.3 mg, about 0.35 mg, about 0.4 mg, about 0.45 mg, about 0.5 mg, about 0.55 mg, about 0.6 mg, about 0.65 mg, about 0.7 mg, about 0.75 mg, about 0.8 mg, about 0.85 mg, or about 0.9 mg. g, approximately 0.95 mg, approximately 1 mg, approximately 1.05 mg, approximately 1.1 mg, approximately 1.15 mg, approximately 1.2 mg, approximately 1.25 mg, approximately 1.3 mg, approximately 1.35 mg, approximately 1.4 mg, approximately 1.45 mg, approximately 1.5 mg, approximately 1.55 mg, approximately 1.6 mg, approximately 1.65 mg, approximately 1.7 mg, approximately 1.75 mg, approximately 1.8 mg, approximately 1.85 mg, approximately 1.9 mg, approximately 1.95 mg, approximately 2 mg, approximately 2.05 mg, approximately 2.1 mg, approximately 2.15 mg, approximately 2.2 mg, approximately 2.25 mg, approximately 2.3mg, approximately 2.35mg, approximately 2.4mg, approximately 2.45mg, approximately 2.5mg, approximately 2.55mg, approximately 2.6mg, approximately 2.65mg, approximately 2.7mg, approximately 2.75mg, approximately 2.8mg, approximately 2.85mg, approximately 2.9mg, approximately 2.95mg, approximately 3mg, approximately 3.05mg, approximately 3.1mg, approximately 3.15mg, approximately 3.2mg, approximately 3.25mg, approximately 3.3mg, approximately 3.35mg, approximately 3.4mg, approximately 3.45mg, approximately 3.5mg, approximately 3.55mg, approximately 3.6mg, approximately 3. 65mg, approximately 3.7mg, approximately 3.75mg, approximately 3.8mg, approximately 3.85mg, approximately 3.9mg, approximately 3.95mg, approximately 4mg, approximately 4.05mg, approximately 4.1mg, approximately 4.15mg, approximately 4.2mg, approximately 4.25mg, approximately 4.3mg, approximately 4.35mg, approximately 4.4mg, approximately 4.45mg, approximately 4.5mg, approximately 4.55mg, approximately 4.6mg, approximately 4.65mg, approximately 4.7mg, approximately 4.75mg, approximately 4.8mg, approximately 4.85mg, approximately 4.9mg, approximately 4.95mg, or approximately 5mg / day.

[0274] In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.1 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.15 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.2 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.25 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.3 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.35 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.4 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.45 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.5 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.55 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.6 mg / day.In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.65 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.7 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.75 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.8 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.85 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.9 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 0.95 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1 mg / day.

[0275] In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.05 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.1 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.15 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.2 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.25 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.3 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.35 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.4 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.45 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.5 mg / day. In some embodiments, the therapeutic or preventive effective amount of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures is about 1.55 mg / day.In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.6 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.65 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.7 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.75 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.8 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.85 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.9 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 1.95 mg / day. In some embodiments, the therapeutic or preventive effective dose of compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures is approximately 2 mg / day.

[0276] In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.05 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.1 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.15 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.2 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.25 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.3 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.35 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.4 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.45 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.5 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.55 mg / day.In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.6 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.65 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.7 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.75 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.8 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.85 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.9 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 2.95 mg / day. In some embodiments, the therapeutic or preventative effective dose of compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures is approximately 3 mg / day.

[0277] In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.05 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.1 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.15 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.2 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.25 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.3 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.35 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.4 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.45 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.5 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.55 mg / day.In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.6 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.65 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.7 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.75 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.8 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.85 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.9 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 3.95 mg / day. In some embodiments, the therapeutic or preventive effective amount of compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures is approximately 4 mg / day.

[0278] In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.05 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.1 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.15 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.2 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.25 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.3 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.35 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.4 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is approximately 4.45 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is approximately 4.5 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is approximately 4.55 mg / day.In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.6 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.65 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.7 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.75 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.8 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.85 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.9 mg / day. In some embodiments, the therapeutic or prophylactic effective amount of compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers, or racemic mixtures thereof, is about 4.95 mg / day. In some embodiments, the therapeutic or preventive effective dose of compound A or its enantiomers or mixtures of enantiomers or pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, tautomers or racemic mixtures is approximately 5 mg / day.

[0279] In one embodiment, for the condition described herein, the recommended daily dose of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, is about 0.1 mg to about 5 mg / day, preferably administered as a single dose once daily, or divided into several doses throughout the day. In some embodiments, the dose range is about 1 mg to about 50 mg / day. In other embodiments, the dose range is about 0.5 to about 5 mg / day. Specific doses / day include 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.55 mg, 0.6 mg, 0.65 mg, 0.7 mg, 0.75 mg, 0.8 mg, 0.85 mg, 0.9 mg, 0.95 mg, 1 mg, 1.05 mg, 1.1 mg, 1.15 mg, 1.2 mg, and 1.25 mg. , 1.3mg, 1.35mg, 1.4mg, 1.45mg, 1.5mg, 1.55mg, 1.6mg, 1.65mg, 1.7mg, 1.75mg, 1.8mg, 1.85mg, 1 .9mg, 1.95mg, 2mg, 2.05mg, 2.1mg, 2.15mg, 2.2mg, 2.25mg, 2.3mg, 2.35mg, 2.4mg, 2.45mg, 2.5mg, 2.55mg, 2.6mg, 2.65mg, 2.7mg, 2.75mg, 2.8mg, 2.85mg, 2.9mg, 2.95mg, 3mg, 3.05mg, 3.1mg, 3.15 mg, 3.2mg, 3.25mg, 3.3mg, 3.35mg, 3.4mg, 3.45mg, 3.5mg, 3.55mg, 3.6mg, 3.65mg, 3.7mg, 3.75mg, 3.8 mg, 3.85 mg, 3.9 mg, 3.95 mg, 4 mg, 4.05 mg, 4.1 mg, 4.15 mg, 4.2 mg, 4.25 mg, 4.3 mg, 4.35 mg, 4.4 mg, 4.45 mg, 4.5 mg, 4.55 mg, 4.6 mg, 4.65 mg, 4.7 mg, 4.75 mg, 4.8 mg, 4.85 mg, 4.9 mg, 4.95 mg, or 5 mg / day. In some embodiments, a specific dose / day is 0.15 mg, 0.3 mg, 0.45 mg, 0.6 mg, 0.75 mg, 0.9 mg, 1 mg, 0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, or 1.9 mg / day.

[0280] In some embodiments, the anti-CD20 antibody is administered at a therapeutically effective amount. In some embodiments, the anti-CD20 antibody is obbituzumab. In some embodiments, obbituzumab is administered intravenously (e.g., by intravenous infusion) or subcutaneously. In some embodiments, obbituzumab is administered at a therapeutically effective amount. In some embodiments, obbituzumab is administered by intravenous infusion. In some embodiments, obbituzumab is administered at a dose of approximately 1000 mg / day. In some embodiments, obbituzumab is administered once every 7 days or once every 4 weeks. In some embodiments, obbituzumab is administered according to locally approved labels or pharmacy manuals for preparation, administration, and storage information.

[0281] In some embodiments, anti-CD20 is rituximab. In some embodiments, rituximab is administered at a therapeutically effective dose. In some embodiments, rituximab is administered intravenously. In some embodiments, at approximately 375 mg / m²... 2 Rituximab is administered at a dose of approximately 1400 mg / day. In some embodiments, rituximab is administered via subcutaneous infusion. In some embodiments, rituximab is administered at a dose of approximately 1400 mg / day. In some embodiments, rituximab is administered once every 7 days or once every 4 weeks. In some embodiments, rituximab is administered according to the label or pharmacy manual approved locally for preparation, administration, and storage information.

[0282] In some embodiments, the HDAC inhibitor is administered in a therapeutically effective amount. In some embodiments, the HDAC inhibitor is citalin-dustat or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, citalin-dustat or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof is administered according to locally approved labeling or pharmacy manuals for preparation, administration, and storage information.

[0283] In some embodiments, a proteasome inhibitor is administered in a therapeutically effective amount. In some embodiments, the proteasome inhibitor is marizome or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, marizome, its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof is administered according to locally approved labeling or pharmacy manuals for preparation, administration, and storage information.

[0284] In some embodiments, the proteasome inhibitor is bortezomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, at a dose of 1.3 mg / m²... 2 Bortezomib or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, may be administered in appropriate amounts. In some embodiments, bortezomib or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, may be administered via rapid intravenous concentration or subcutaneous injection. In some embodiments, bortezomib or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, may be administered once or twice weekly. In some embodiments, bortezomib or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, may be administered according to locally approved labels or pharmacy manuals for preparation, administration, and storage information.

[0285] In some embodiments, the proteasome inhibitor is carfilzomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, it is administered at a dose of 20 / 70 mg / m² once weekly. 2 20 / 56 mg / m² twice a week 2 Or 20 / 27 mg / m² twice a week 2 Carfilzomib or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, may be administered in appropriate amounts. In some embodiments, carfilzomib or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, may be administered by intravenous infusion. In some embodiments, carfilzomib or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, may be administered according to locally approved labels or pharmacy manuals for preparation, administration, and storage information.

[0286] In some embodiments, the proteasome inhibitor is ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered in doses of 4 mg, 3 mg, or 2.3 mg. In some embodiments, ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered orally. In some embodiments, ixazomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered once weekly on days 1, 8, and 15 of a 28-day treatment cycle. In some implementations, ixazomib or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, are administered according to locally approved labels or pharmacy manuals for preparation, administration, and storage information.

[0287] In some embodiments, the anti-CD38 antibody is administered at a therapeutically effective amount. In some embodiments, the anti-CD38 antibody is ixartuximab. In some embodiments, ixartuximab is administered according to locally approved labels or pharmacy manuals for preparation, administration, and storage information.

[0288] In some embodiments, the anti-CD38 antibody is daratumumab. In some embodiments, daratumumab is administered at a dose of 16 mg / kg body weight. In some embodiments, daratumumab is administered weekly, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, daratumumab is administered via intravenous infusion. In some embodiments, daratumumab is administered according to locally approved labels or pharmacy manuals for preparation, administration, and storage information.

[0289] In some embodiments, the anti-SLAMF7 antibody is administered at a therapeutically effective dose. In some embodiments, the anti-SLAMF7 antibody is evolizumab. In some embodiments, evolizumab is administered weekly for the first two 28-day cycles and thereafter every two weeks until disease progression or unacceptable toxicity occurs, at a dose of 10 mg / kg. In some embodiments, evolizumab is administered intravenously. In some embodiments, evolizumab is administered according to the locally approved label or pharmacy manual for preparation, administration, and storage information.

[0290] In some embodiments, a nuclear transport inhibitor is administered in a therapeutically effective amount. In some embodiments, the nuclear transport inhibitor is celinisosole or a geometrical isomer or mixture of geometrical isomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, celinisosole or a geometrical isomer or mixture of geometrical isomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof is administered at a dose of 80 mg on days 1 and 3 of each week. In some embodiments, celinisosole or a geometrical isomer or mixture of geometrical isomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof is administered orally. In some embodiments, celinisosole or a geometrical isomer or mixture of geometrical isomers, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof is administered according to locally approved labels or pharmacy manuals for preparation, administration, and storage information.

[0291] In some embodiments, a BCL-2 inhibitor is administered at a therapeutically effective dose. In some embodiments, the BCL-2 inhibitor is venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof is administered at a dose of 20 mg once daily for 7 days, followed by a weekly escalation to a daily dose of 400 mg. In some embodiments, venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof is administered orally. In some embodiments, venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof is administered according to the locally approved label or pharmacy manual for preparation, administration, and storage information.

[0292] In some embodiments, the immune checkpoint inhibitor is administered at a therapeutically effective dose. In some embodiments, the immune checkpoint inhibitor is pembrolizumab. In some embodiments, pembrolizumab is administered at a dose of 2 mg / kg every 3 weeks. In some embodiments, pembrolizumab is administered by intravenous infusion. In some embodiments, pembrolizumab is administered according to the locally approved label or pharmacy manual for preparation, administration, and storage information.

[0293] In some implementations, the immune checkpoint inhibitor is nivolumab. In some implementations, nivolumab is administered at a dose of 3 mg / kg every 2 weeks. In some implementations, nivolumab is administered by intravenous infusion. In some implementations, nivolumab is administered according to the locally approved label or pharmacy manual for preparation, administration, and storage information.

[0294] In some embodiments, the immune checkpoint inhibitor is ipilimumab. In some embodiments, ipilimumab is administered at a dose of 3 mg / kg every 3 weeks. In some embodiments, ipilimumab is administered a total of 4 doses. In some embodiments, ipilimumab is administered by intravenous infusion. In some embodiments, ipilimumab is administered according to the locally approved label or pharmacy manual for preparation, administration, and storage information.

[0295] In some embodiments, dexamethasone or its enantiomers or mixtures of enantiomers, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof are administered in a therapeutically effective amount. In some embodiments, the therapeutic or prophylactic effective amount of dexamethasone is about 0.5 mg to about 2,000 mg / day, about 1 mg to about 1,000 mg / day, about 1 mg to about 500 mg / day, about 1 mg to about 250 mg / day, about 5 mg to about 250 mg / day, about 7.5 mg to about 250 mg / day, about 10 mg to about 250 mg / day, about 20 mg to about 250 mg / day, about 20 mg to about 200 mg / day, about 1 mg to about 100 mg / day, about 1 mg to about 50 mg / day, about 0.5 mg to about 25 mg / day, or about 0.5 mg to about 10 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 0.5 mg to about 2,000 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 1 mg to about 1,000 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 1 mg to about 500 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 1 mg to about 250 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 5 mg to about 250 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 7.5 mg to about 250 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 10 mg to about 250 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 20 mg to about 250 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 20 mg to about 200 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 1 mg to about 100 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 1 mg to about 50 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 0.5 mg to about 25 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 0.5 mg to about 10 mg / day.

[0296] In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 0.5, about 1, about 2, about 5, about 10, about 15, about 20, about 25, about 30, about 40, about 45, about 50, about 60, about 70, about 80, about 90, about 100, about 150, or about 200 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 0.5 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 1 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 2 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 5 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 10 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 15 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is about 20 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 25 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 30 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 40 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 45 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 50 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 60 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 70 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 80 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 90 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 100 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 150 mg / day. In some embodiments, the therapeutic or preventative effective amount of dexamethasone is approximately 200 mg / day.

[0297] In one embodiment, for the condition described herein, the recommended daily dose of dexamethasone or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs is from about 0.5 mg to about 100 mg per day, preferably as a single dose once daily, or divided into several doses throughout the day. In some embodiments, the dose range is from about 1 mg to about 100 mg per day. In other embodiments, the dose range is from about 0.5 mg to about 20 mg per day. Specific dosages include 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg / day.

[0298] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0299] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with an anti-CD20 antibody. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with obbituzumab. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with rituximab. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0300] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs in combination with an HDAC inhibitor. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs in combination with sitalindustat or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0301] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with a proteasome inhibitor. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with marizomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with bortezomib or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, in combination with carfilzomib or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs, together with ixazomib or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0302] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with an anti-CD38 antibody. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with ixartuximab. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with daratumumab. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0303] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with anti-SLAMF7 antibody. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with ileizumab. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0304] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with a nucleotransfer inhibitor. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, in combination with celiniso or its geometric isomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0305] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs in combination with a BCL-2 inhibitor. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs in combination with venetoclax or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0306] In some embodiments, patients to be treated with one of the methods provided herein have not been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with an immune checkpoint inhibitor. In some embodiments, patients to be treated with one of the methods provided herein have already been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with pembrolizumab. In some embodiments, patients to be treated with one of the methods provided herein have already been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs in combination with nivolumab. In some embodiments, patients to be treated with one of the methods provided herein have been treated with anticancer therapy prior to administration of compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs in combination with ipilimumab. In some embodiments, patients to be treated with one of the methods provided herein have developed resistance to said anticancer therapy.

[0307] The methods presented in this article include treating patients regardless of age, although some diseases or conditions are more common in certain age groups. This article further provides methods for treating patients who have undergone surgery in an attempt to treat the disease or condition in question, as well as patients who have not undergone surgery. Because subjects with cancer have different clinical presentations and outcomes, the treatment given to a particular subject can vary depending on his / her prognosis. Skilled clinicians can readily determine, without excessive experimentation, the specific secondary activator, type of surgery, and type of standard nonpharmacological therapy that can be effectively used to treat an individual subject with cancer.

[0308] Compound A or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, may be administered orally, parenterally (e.g., intramuscular, intraperitoneally, intravenously, CIV, intracranial, subcutaneously), by inhalation, nasal, vaginal, rectal, sublingual, or local (e.g., transdermal or local) routes of administration. Compound A or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, may be formulated alone or with pharmaceutically acceptable excipients, carriers, adjuvants, or mediators suitable for each route of administration in appropriate dosage units.

[0309] In one embodiment, compound A is administered orally as an enantiomer or mixture of enantiomers, or as a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In another embodiment, compound A is administered parenterally as an enantiomer or mixture of enantiomers, or as a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In yet another embodiment, compound A is administered intravenously as an enantiomer or mixture of enantiomers, or as a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof.

[0310] Compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be delivered as a single dose, such as a single bolus, or an oral tablet or pill; or as a time-dependent dose, such as a continuous infusion over time or a fractionated bolus over time. If necessary, compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered, for example, until the patient experiences disease stabilization or resolution, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0311] If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with anti-CD20 antibodies, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with rituximab, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with rituximab, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0312] If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with an HDAC inhibitor, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with citalindustat or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0313] If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with a proteasome inhibitor, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with marizomib or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs may be repeatedly administered in combination with bortezomib or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, for example, until the patient experiences disease stabilization or resolution, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs may be repeatedly administered in combination with carfilzomib or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs, for example, until the patient experiences disease stabilization or resolution, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs may be repeatedly administered in combination with ixazomib or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs, for example, until the patient experiences disease stabilization or resolution, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0314] If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with anti-CD38 antibody, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with idoxurumab, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with daratumumab, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0315] If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with anti-SLAMF7 antibody, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with ileuzumab, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0316] If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with nucleus transport inhibitors, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with celiniso or its geometrical isomers or mixtures of geometrical isomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0317] If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with a BCL-2 inhibitor, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with venetoclax or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0318] If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with an immune checkpoint inhibitor, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with pembrolizumab, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, may be repeatedly administered in combination with nivolumab, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity. If necessary, compound A or its enantiomers or mixtures of enantiomers or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs may be repeatedly administered in combination with ipilimumab, for example, until the patient experiences disease stabilization or regression, or until the patient experiences disease exacerbation or unacceptable toxicity.

[0319] For example, stable disease in solid tumors typically means that the vertical diameter of the measurable lesion has not increased by 25% or more compared to the last measurement. Response Evaluation Criteria in Solid Tumors (RECIST) Guidelines, Journal of the National Cancer Institute 92(3):205-216 (2000). Stable disease or its absence is determined by methods known in the art, such as assessment of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scans, and other generally accepted assessment modalities.

[0320] Compound A, or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes or polymorphs thereof, anti-CD20 antibodies, HDAC inhibitors, proteasome inhibitors, anti-CD38 antibodies, anti-SLAMF7 antibodies, nuclear transport inhibitors, BCL-2 inhibitors, or immune checkpoint inhibitors, may be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID), three times daily (TID), and four times daily (QID). Furthermore, administration may be continuous (i.e., daily for several consecutive days, or daily) or intermittent, for example, in cycles (i.e., including drug-free rest periods of several days, weeks, or months).

[0321] As used herein, the term "daily" means the administration of a therapeutic compound, such as compound A, once or more daily, for a period of time. The term "continuous" is intended to mean the uninterrupted administration of a therapeutic compound, such as compound A, daily for at least 10 days to 52 weeks. The terms "intermittent" or "intermittently" as used herein are intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of compound A may be administered 1–6 days per week, in cycles (e.g., daily administration for 2–8 weeks followed by a rest period of up to 1 week), or every other day. The term "cycle" as used herein is intended to mean the daily or continuous administration of a therapeutic compound, such as compound A, with rest periods.

[0322] In some implementations, the dosing frequency ranges from about a daily dose to about a monthly dose. In some implementations, administration is once daily, twice daily, three times daily, four times daily, every other day, twice weekly, once weekly, once every two weeks, once every three weeks, or once every four weeks.

[0323] In one embodiment, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered once daily. In another embodiment, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered twice daily. In yet another embodiment, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered three times daily. In yet another embodiment, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered four times daily.

[0324] In some embodiments, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered once daily for one to six months, one to three months, one to four weeks, one to three weeks, or one to two weeks. In some embodiments, compound A, or its pharmaceutically acceptable salt or solvate thereof, is administered once daily for one week, two weeks, three weeks, or four weeks. In one embodiment, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered once daily for one week. In another embodiment, compound A, or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered once daily for two weeks. In yet another embodiment, compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered once daily for 3 weeks. In yet another embodiment, compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, is administered once daily for 4 weeks.

[0325] In some embodiments, compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, are administered once daily for 21 days in each 28-day cycle, followed by a 7-day rest period. In some embodiments, compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, are administered for one cycle. In some embodiments, compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, are administered for two cycles. In some embodiments, compound A, or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs thereof, are administered for three cycles. In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, are administered for four cycles. In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, are administered for seven or more cycles.

[0326] In some embodiments, compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, are administered simultaneously with, before (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks prior) or after (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks, or 16 weeks later). In some embodiments, the additional active agent is selected from anti-CD20 antibodies, HDAC inhibitors, proteasome inhibitors, anti-CD38 antibodies, anti-SLAMF7 antibodies, nuclear translocation inhibitors, BCL-2 inhibitors, and immune checkpoint inhibitors. In some embodiments, the combined administration of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, with one or more additional active agents may also be administered according to an alternating dosing regimen, wherein a rest period may or may not be present (e.g., the therapeutic agent is not administered on certain dates of the regimen). In some embodiments, the administration of compound A or its enantiomers or mixtures of enantiomers, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, with one or more additional active agents includes, but is not limited to, sequential administration and concomitant administration.

[0327] This document also provides compound A for use in any of the methods provided herein. This document also provides compound A in combination with the second active agent provided herein, for use in any of the methods provided herein.

[0328] Pharmaceutical compositions and dosage forms

[0329] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In another embodiment, the pharmaceutical composition and dosage form further comprises one or more excipients.

[0330] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an anti-CD20 antibody. In another embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) oxbituzumab. In yet another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients.

[0331] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an HDAC inhibitor. In another embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) a combination of sitalindustat or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In yet another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients.

[0332] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) a proteasome inhibitor. In another embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) marizomib or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In yet another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients. In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) bortezomib or an enantiomer or mixture of enantiomers thereof, or a combination thereof that is pharmaceutically acceptable. In another embodiment, the pharmaceutical composition and dosage form further comprises one or more excipients. In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) carfilzomib or an enantiomer or mixture of enantiomers thereof, or a combination thereof that is pharmaceutically acceptable. In another embodiment, the pharmaceutical composition and dosage form further comprises one or more excipients. In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) ixazomib or an enantiomer or mixture of enantiomers thereof, or a combination of a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In another embodiment, the pharmaceutical composition and dosage form further comprises one or more excipients.

[0333] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an anti-CD38 antibody. In another embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) ixartuximab. In another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients. In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) daratumumab. In another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients.

[0334] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an anti-SLAMF7 antibody. In another embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) ileizumab. In yet another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients.

[0335] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) a nucleus transport inhibitor. In another embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) celiniso or a geometrical isomer or mixture of geometrical isomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In yet another embodiment, the pharmaceutical composition and dosage form further comprises one or more excipients.

[0336] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) a BCL-2 inhibitor. In another embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) venetoclax or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In yet another embodiment, the pharmaceutical compositions and dosage forms further comprise one or more excipients.

[0337] In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) an immune checkpoint inhibitor. In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) pembrolizumab. In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) nivolumab. In one embodiment, this document provides pharmaceutical compositions and dosage forms comprising: (i) a combination of (i) compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof, and (ii) ipilimumab. In another embodiment, the pharmaceutical composition and dosage form further comprises one or more excipients.

[0338] In some embodiments, the pharmaceutical compositions and dosage forms provided herein further comprise one or more additional active agents, in amounts that effectively modulate the disease or disease symptoms, including those described herein. Examples of optional additional active agents are provided herein (see, for example, the definitions section).

[0339] In some embodiments, the pharmaceutical compositions provided herein can be administered orally, parenterally, via inhalation spray, topically, rectally, nasally, orally, via vaginally, or through an implanted reservoir, preferably orally or by injection. Oral delivery forms include, but are not limited to, tablets, capsules, capsule-shaped tablets, solutions, suspensions, and syrups, and may also contain multiple particles, beads, powders, or pellets, which may or may not be encapsulated. In one embodiment, the pharmaceutical composition may contain any conventional, non-toxic, pharmaceutically acceptable carrier, adjuvant, or mediator. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to enhance the stability of the formulated compound or its delivery form. The term parenterally as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.

[0340] In some embodiments, the dosage forms of compound A provided herein, or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, are suitable for oral, mucosal (e.g., nasal, sublingual, vaginal, oral, or rectal), parenteral (e.g., subcutaneous, intravenous, rapid concentration, intramuscular, or intra-arterial), topical (e.g., eye drops or other ophthalmic preparations), transdermal, or percutaneous administration to patients. Examples of dosage forms include, but are not limited to: tablets; capsules; capsules, such as soft elastic gelatin capsules; flat capsules; troches; lozenges; dispersions; suppositories; powders; aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage forms suitable for oral or mucosal administration to patients, including suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral administration to patients; eye drops or other ophthalmic preparations suitable for topical administration; and sterile solids (e.g., crystalline or amorphous solids) that can be reconfigured to provide liquid dosage forms suitable for parenteral administration to patients.

[0341] In one implementation scheme, obitucilumab, such as The formulation is as described in the packaging instructions. In one embodiment, rituximab, such as RITUXAN... TM (Anti-CD20 antibody sold under the trademark RITUXAN) is formulated as described in the package insert. In one embodiment, citalin-dustat or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph is formulated as described in the published clinical trial protocol. In one embodiment, marizomib or its enantiomers or mixtures of enantiomers or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph is formulated as described in the published clinical trial protocol. In one embodiment, as... The packaging instructions describe the formulation of bortezomib or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs. In one embodiment, as... The formulation of carfilzomib or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs, as described in the packaging instructions, is indicated. In one embodiment, as... The packaging instructions describe the formulation of ixazomib or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs. In one embodiment, ixazomib is formulated as described in the published clinical trial protocol. In one embodiment, as described... The daratumumab is formulated as described in the packaging instructions. In one embodiment, such as EMPLICITI... TM The instructions for use describe the formulation of ileizumab (SLAMF7-targeted immunostimulatory antibody sold under the EMPLICITI trademark). In one embodiment, such as XPOVIO... TM The instructions for use describe the formulation of celinizol or its geometric isomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs (nuclear transport inhibitors sold under the trademark XPOVIO). In one embodiment, such as VENCLEXTA TM The instructions for use describe the formulation of venetoclax or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs (BCL-2 inhibitors sold under the trademark VENCLEXTA). In one embodiment, as follows: The pembrolizumab is formulated as described in the packaging instructions. In one embodiment, as follows: The nivolumab is formulated as described in the packaging instructions. In one embodiment, such as YERVOY... TM Nivolumab (human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody sold under the YERVOY trademark) is formulated as described in the package insert.

[0342] Whether a particular excipient is suitable for inclusion in the pharmaceutical compositions or dosage forms provided herein depends on a variety of factors, including but not limited to the route of administration. For example, oral dosage forms such as tablets may contain excipients that are not suitable for parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredient in the dosage form. For example, the degradation of some active ingredients can be accelerated by some excipients such as lactose or by exposure to water. Active ingredients containing primary or secondary amines are particularly susceptible to this accelerated degradation. Therefore, this document covers pharmaceutical compositions and dosage forms containing very little (if any) lactose. As used herein, the term “lactose-free” means that the amount of lactose present (if any) is insufficient to significantly increase the degradation rate of the active ingredient.

[0343] The lactose-free compositions described herein may contain excipients such as those listed in United States Pharmacopeia (USP) 25-NF 20 (2002). In some embodiments, the lactose-free compositions contain pharmaceutically compatible and pharmaceutically acceptable amounts of active ingredients, binders / fillers, and lubricants. In some embodiments, the lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0344] This article also includes anhydrous pharmaceutical compositions and dosage forms containing active ingredients, as water can promote the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the pharmaceutical industry as a means of simulating long-term storage in order to determine, for example, shelf life or the stability of the formulation over time. See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2nd ed., Marcel Dekker, NY, 1995, pp. 379-80. In fact, water and heat accelerate the decomposition of some compounds. Therefore, the effect of water on formulations can be very important, as they are typically exposed to moisture and / or humidity during the manufacture, handling, packaging, storage, transportation, and use of the formulation.

[0345] The anhydrous pharmaceutical compositions and dosage forms provided herein can be prepared using anhydrous or low-moisture components and low-moisture or low-humidity conditions. Pharmaceutical compositions and dosage forms containing lactose and at least one active ingredient comprising a primary or secondary amine are preferably anhydrous if they are expected to come into significant contact with moisture and / or humidity during manufacturing, packaging, and / or storage.

[0346] Anhydrous pharmaceutical compositions should be prepared and stored in a manner that preserves their anhydrous properties. Therefore, in some embodiments, this document provides for packaging anhydrous compositions using materials that prevent exposure to water, so that they can be included in suitable prescription kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foil, plastic, unit-dose containers (e.g., vials), blister packs, and strip packs.

[0347] This document includes pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate of degradation of the active ingredient. Such compounds, referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0348] 1. Oral dosage form

[0349] In some embodiments, the pharmaceutical compositions suitable for oral administration described herein are formulated into discrete dosage forms, examples of which include, but are not limited to, tablets (e.g., chewable tablets), capsule tablets, capsules, and liquids (e.g., flavored syrups). These dosage forms contain a predetermined amount of the active ingredient and can be prepared by some known pharmaceutical methods. See generally Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing, Easton PA (1990).

[0350] In some embodiments, the oral dosage forms provided herein are prepared according to conventional pharmaceutical mixing techniques by mixing the active ingredient with at least one excipient into a close mixture. The excipient can take many forms, depending on the desired formulation for administration. For example, excipients suitable for oral liquid or aerosol dosage forms include, but are not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents. Examples of excipients suitable for solid oral dosage forms (e.g., powders, tablets, capsules, and pouches) include, but are not limited to, starch, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrants.

[0351] Because of their ease of administration, tablets and capsules represent the most advantageous form of oral dosage unit, in which case solid excipients are used. Tablets can be coated using standard aqueous or non-aqueous techniques if desired. Such dosage forms can be prepared using several known pharmaceutical methods. In some embodiments, pharmaceutical compositions and dosage forms are prepared by uniformly and tightly mixing the active ingredient with a liquid carrier, a finely dispersed solid carrier, or both, and then shaping the product into the desired form if necessary.

[0352] In some embodiments, tablets are prepared by compression or molding. In some embodiments, compressed tablets are prepared by compressing the active ingredient, optionally mixed with excipients, in a free-flowing form (e.g., powder or granules) in a suitable machine. In some embodiments, molded tablets are prepared by molding a mixture of powdered compounds wetted with an inert liquid diluent in a suitable machine.

[0353] Examples of excipients that may be used in the oral dosage forms provided herein include, but are not limited to, binders, fillers, disintegrants, and lubricants. Binders suitable for the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth gum, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pregelatinized starch, hydroxypropyl methylcellulose (e.g., numbers 2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

[0354] Suitable forms of microcrystalline cellulose include, but are not limited to, AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA), and mixtures thereof. Specific binders include mixtures of microcrystalline cellulose and sodium carboxymethyl cellulose (e.g., Avicel RC-581). Suitable anhydrous or low-moisture excipients or additives include AVICEL-PH-103. TM And Starch1500LM.

[0355] Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, glucose dextrorates, kaolin, mannitol, silica, sorbitol, starch, pregelatinized starch, and mixtures thereof. In some embodiments, the binder or filler in the pharmaceutical compositions provided herein is present at about 50 to about 99% by weight of the pharmaceutical composition or dosage form.

[0356] A disintegrant is used in the compositions provided herein to provide the ability of the tablets to disintegrate upon exposure to an aqueous environment. Tablets containing too much disintegrant may disintegrate during storage, while tablets containing too little disintegrant may disintegrate at an undesirable rate or under undesirable storage conditions. Therefore, a sufficient amount of disintegrant should be used, neither too much nor too little, to adversely alter the release of the active ingredient to form the solid oral dosage form provided herein. The amount of disintegrant used varies depending on the type of formulation. In some embodiments, the pharmaceutical compositions provided herein comprise about 0.5 to about 15% by weight or about 1 to about 5% by weight of disintegrant.

[0357] Disintegrants suitable for use in the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilinpotassium, sodium glycolate starch, potato or cassava starch, other starches, pregelatinized starches, other starches, clays, other alginates, other celluloses, gums, and mixtures thereof.

[0358] Lubricants suitable for the pharmaceutical compositions and dosage forms provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, and mixtures thereof. Other lubricants include, but are not limited to, syloid silica gel (AEROSIL 200, WRGrace Co., Baltimore, MD), synthetic silica condensed aerosol (Degussa Co. of Plano, TX), CAB-O-SIL (pyrogenic silicon dioxide, Degussa Co. of Plano, TX), and mixtures thereof. In some embodiments, if used, the lubricant is used in an amount less than about 1% by weight of the pharmaceutical composition or dosage form in which it is incorporated.

[0359] In some embodiments, this document provides a solid oral dosage form comprising compound A or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex or polymorph thereof; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin.

[0360] In some embodiments, this document provides a solid oral dosage form comprising compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex or polymorph thereof; and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica and gelatin.

[0361] In some embodiments, this document provides a solid oral dosage form comprising a hydrochloride salt of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof; and one or more excipients selected from anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

[0362] In some embodiments, this document provides a solid oral dosage form comprising a hydrochloride salt of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof; and anhydrous lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, and gelatin.

[0363] 2. Delayed-release formulation

[0364] In some embodiments, the active ingredients provided herein are administered via controlled release or via a delivery device. Examples include, but are not limited to, U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which is incorporated herein by reference in its entirety. In some embodiments, such dosage forms are used to provide a slow or controlled release of one or more active ingredients, using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, permeable systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations thereof to provide different proportions of desired release profiles. This article covers single-unit dosage forms suitable for oral administration, including but not limited to tablets, capsules, soft capsules, and capsule-shaped tablets suitable for controlled release.

[0365] All controlled-release pharmaceutical products share the common goal of improving drug therapy beyond what their non-controlled-release counterparts achieve. Ideally, the use of optimally designed controlled-release formulations in medical treatment is characterized by the use of the least amount of drug substance to cure or control the condition in the shortest possible time. The advantages of controlled-release formulations include prolonged drug activity, reduced dosing frequency, and increased patient compliance. Furthermore, controlled-release formulations can be used to influence the time of onset of action or other characteristics, such as drug blood levels, and thus can affect the occurrence of side effects (e.g., adverse reactions).

[0366] Most controlled-release formulations are designed to initially release a certain amount of drug (active ingredient), which rapidly produces the desired therapeutic effect, and then gradually and continuously release additional amounts of drug to maintain that level of therapeutic or preventative effect over an extended period of time. To maintain this constant drug level in the body, the drug must be released from the dosage form at a rate that replaces the amount of drug metabolized and excreted from the body. The controlled release of the active ingredient can be stimulated by a variety of conditions, including but not limited to pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0367] 3. Parenteral dosage form

[0368] Parenteral dosage forms can be administered to patients via a variety of routes, including but not limited to subcutaneous, intravenous (including rapid concentration), intramuscular, and intra-arterial administration. Because their administration typically bypasses the patient's natural defenses against contaminants, parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to the patient. Examples of parenteral dosage forms include, but are not limited to, solutions prepared for injection, dried products prepared for dissolution or suspension in pharmaceutically acceptable injectable media, suspensions prepared for injection, and emulsions.

[0369] Suitable media for providing the parenteral dosage forms described herein include, but are not limited to: USP water for injection; aqueous media, such as, but not limited to, sodium chloride injection, Ringer's solution, glucose injection, glucose and sodium chloride injection, and lactated Ringer's solution; water-miscible media, such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous media, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0370] Compounds that increase the solubility of one or more active ingredients provided herein may also be incorporated into the parenteral dosage forms provided herein. For example, cyclodextrins and their derivatives may be used to increase the solubility of compound A or its enantiomers or mixtures thereof, or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion complexes, or polymorphs. See, for example, U.S. Patent No. 5,134,127, which is incorporated herein by reference in its entirety.

[0371] 4. Topical and mucosal formulations

[0372] The topical and mucosal dosage forms described herein include, but are not limited to, sprays, aerosols, solutions, emulsions, suspensions, eye drops, or other ophthalmic preparations, or other forms known to those skilled in the art. See, for example, Remington's Pharmaceutical Sciences, 16th and 18th editions, Mack Publishing, Easton PA (1980 & 1990); and Introduction to Pharmaceutical Dosage Forms, 4th edition, Lea & Febbiger, Philadelphia (1985). Dosage forms suitable for treating oral mucosal tissues can be formulated as mouthwashes or oral gels.

[0373] Suitable excipients (e.g., carriers and diluents) and other materials that may be used to provide the topical and mucosal dosage forms included herein depend on the specific tissue to which a given pharmaceutical composition or dosage form is applied. In fact, in some embodiments, excipients include, but are not limited to, water, acetone, ethanol, ethylene glycol, propylene glycol, butyl-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures thereof to form a non-toxic and pharmaceutically acceptable solution, emulsion, or gel. Humectants or moisturizers may also be added to the pharmaceutical composition and dosage form if desired. Further examples of such ingredients can be found, for example, in Remington's Pharmaceutical Sciences, 16th and 18th editions, Mack Publishing, Easton PA (1980 & 1990).

[0374] The pH of a pharmaceutical composition or dosage form can also be adjusted to improve the delivery of one or more active ingredients. Similarly, the polarity, ionic strength, or tonicity of the solvent carrier can be adjusted to improve delivery. Compounds such as stearates can also be added to a pharmaceutical composition or dosage form to advantageously alter the hydrophilicity or lipophilicity of one or more active ingredients, thereby improving delivery. In this regard, stearates can be used as lipid carriers for formulations, as emulsifiers or surfactants, and as delivery enhancers or penetration enhancers. Different salts, hydrates, or solvates of the active ingredient can be used to further modify the properties of the resulting composition.

[0375] 5. Reagent kit

[0376] In some embodiments, the active ingredients provided herein are not administered to patients simultaneously or via the same route of administration. Therefore, this document covers kits that, when used by a physician, can simplify the administration of appropriate amounts of the active ingredients to the patient.

[0377] In some embodiments, the kits provided herein comprise a dosage form of compound A or its enantiomers or mixtures thereof, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, inclusion complex, or polymorph thereof. In some embodiments, the kits provided herein also comprise an anti-CD20 antibody, an HDAC inhibitor, a proteasome inhibitor, an anti-CD38 antibody, an anti-SLAMF7 antibody, a nuclear translocation inhibitor, a BCL-2 inhibitor, and / or an immune checkpoint inhibitor. In some embodiments, the kits provided herein also comprise ocbituzumab, rituximab, sitalin-dustat, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof; marizomib, or an enantiomer or mixture of enantiomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof; bortezomib, or an enantiomer or mixture of enantiomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof; carfilzomib, or an enantiomer or mixture of enantiomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof; and carfilzomib, or an enantiomer or mixture of enantiomers thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof. Salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs of ixazomib or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof; ixazomib, daratumumab, ileuzumab, celinizol or its geometrical isomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof; venetoclax or its pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof; pembrolizumab, nivolumab, and / or ipilimumab. In some embodiments, the kits provided herein also contain additional active ingredients, including but not limited to those provided herein. In some embodiments, the kits provided herein also contain dexamethasone or its enantiomers or mixtures thereof, or pharmaceutically acceptable salts, solvates, hydrates, cocrystals, inclusion compounds, or polymorphs thereof.

[0378] In some embodiments, the kits provided herein also include a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, infusion bags, patches, and inhalers.

[0379] In some embodiments, the kits provided herein also include cells or blood for transplantation and a pharmaceutically acceptable medium for administering one or more active ingredients. For example, if the active ingredient is provided in solid form and must be reconstituted for parenteral administration, the kit may include a sealed container suitable for the medium, wherein the active ingredient can be dissolved to form a particulate-free sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable media include, but are not limited to: USP water for injection; aqueous media, such as, but not limited to, sodium chloride injection, Ringer's solution, glucose injection, glucose and sodium chloride injection, and lactated Ringer's solution; water-miscible media, such as, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous media, such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate. Example

[0380] Some embodiments of the present invention are illustrated by the following non-limiting examples.

[0381] Example 1: A Phase 1, multicenter, open-label study evaluating the safety, pharmacokinetics, and preliminary efficacy of compound A alone and in combination with rituximab or obbituzumab in subjects with relapsed or refractory non-Hodgkin lymphoma (R / R NHL) and classic Hodgkin lymphoma (cHL).

[0382] I. Research Objectives

[0383] The primary objective of this study was to determine the safety and tolerability of compound A alone and in combination with rituximab or obbituzumab in subjects with R / R NHL and cHL, and to define the maximum tolerated dose (MTD) and / or recommended phase 2 dose (RP2D) of compound A in subjects with R / R NHL and cHL.

[0384] The secondary objective was to characterize the pharmacokinetics (PK) of compound A alone and in combination with rituximab or obbituzumab, and to evaluate the preliminary efficacy of compound A alone and in combination with rituximab or obbituzumab in R / R NHL and cHL.

[0385] The exploratory objective is to associate PK with safety, clinical activity, and pharmacodynamic (PD) biomarkers, and to explore PD biomarkers of compound A activity, and to evaluate the effects of compound A on normal T, B, and NK cells in peripheral blood.

[0386] The study endpoints are shown in Table 1.

[0387] Table 1: Study endpoints.

[0388]

[0389]

[0390] NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events.

[0391] ECOG: Eastern Cooperative Oncology Group.

[0392] ECG: Electrocardiogram

[0393] II. Research Design

[0394] This is a phase 1, multi-group, multicenter study to demonstrate the safety, tolerability, and preliminary efficacy signals of compound A, alone or in combination with rituximab or obbituzumab, in subjects with R / R NHL or cHL.

[0395] Following the dose discovery (DF) phase with three parallel cohorts (DF-A cohort: monotherapy, DF-B cohort: combination with rituximab, DF-C cohort: combination with obbituzumab) was the dose confirmation (DC) phase with five cohorts (DC-A: MCL, monotherapy with compound A; DC-B: PTCL, monotherapy with compound A; DC-C: cHL, monotherapy with compound A; DC-D: aggressive B-cell lymphoma, combination with rituximab; DC-E: aggressive B-cell lymphoma, combination with obbituzumab; DC-F: FL and MZL, combination with obbituzumab).

[0396] A. Dose Discovery Phase (DF)

[0397] The dose discovery period consists of a 21-day study period in which study treatment is administered using an mTPI-2 design with a target toxicity level (TTL) of 0.2, following a 28-day cycle. Dose-limiting toxicities (DLTs) are assessed to determine the mean time to drug response (MTD) during the first treatment cycle in each cohort.

[0398] The DLT is defined as follows:

[0399] ●Hematology DLT

[0400] ○ Any febrile episode of neutropenia;

[0401] Grade 4 neutropenia lasting ≥7 days;

[0402] Grade 4 thrombocytopenia lasting ≥7 days;

[0403] ○ Grade 3 thrombocytopenia with clinically significant bleeding and / or requiring platelet transfusion;

[0404] Grade 4 anemia is not explained by underlying diseases.

[0405] ●Non-hematologic DLT

[0406] ○Except for any non-hematologic toxicity grade ≥3:

[0407] ■ Grade 3-4 infusion-related reactions associated with rituximab or obbituzumab resolved to ≤ Grade 2 within 72 hours of the start of maximum medical intervention.

[0408] ■ Grade 3-4 tumor lysis syndrome, assessed using the Cairo-Bishop grading system, regressed to ≤ Grade 2 within 72 hours of the start of maximum medical intervention.

[0409] ■ Any grade 3-4 event associated with disease progression, including flushing effect

[0410] ○ Any treatment interruption exceeding 2 weeks due to adverse reactions

[0411] Following the initial dose of compound A, all subjects within the same dose level group were treated and observed for at least 28 days (CL). If DL was declared tolerable, DL+1 was initiated. If DL1 was declared intolerable, subjects were added to DL-1 (and eventually to DL-2). The dose levels studied are shown in Table 2. Outside of CL, dose reductions were permitted based on safety assessments at each visit (see below). Dose reductions are shown in Table 3.

[0412] In the monotherapy group (group DF-A), subjects with R / R NHL or cHL received compound A orally at the dose specified at the group dose level on days 1-21 of each 28-day cycle.

[0413] In the combination therapy group (group DF-B), subjects with R / RB cell NHL received compound A orally at the group dose level specified on D1-21 of each 28-day cycle, and on C1D1 at 375 mg / m². 2 Rituximab was administered at the IV dose, followed by a SC infusion of 1400 mg on days 8, 15, and 22 of C1, and then every 28-day cycle from C2 to C5 on day 1, or at 375 mg / m² according to the same schedule. 2 The dose is administered via IV infusion.

[0414] In the combination therapy group (group DF-C), subjects with R / R FL (grades 1-3a), MZL, or invasive NHL received compound A orally at the dose specified at the group dose level on days 1-21 of each 28-day cycle, and received 1000 mg of ocbituzumab via IV infusion weekly on days 1 (D1, 8, 15) and on day 1 of each 28-day cycle (from C2 to 6).

[0415] Dose escalation for monotherapy (group DF-A) and combination therapy (groups DF-B and DF-C) can be performed concurrently with the evaluation of the recommended 21-day dose over a 28-day period. Study treatment continues until disease progression, unacceptable toxicity, or the subject or clinician decides to withdraw consent, except for FL and MZL patients who have received compound A for up to 12 cycles.

[0416] Approximately 66 subjects were treated (22 subjects per group), and the MTD was evaluated during the DF phase; however, the total number of subjects in the DF phase depended on the number of dose levels required to establish the MTD.

[0417] B. Dosage ...

Claims

1. Use of the compound in the preparation of a medicament for the treatment or management of patients with multiple myeloma in combination with a proteasome inhibitor, wherein the compound is compound AS. Compound AS Or its pharmaceutically acceptable salt; The drug comprises 1.0 mg, 1.3 mg, or 1.6 mg of the compound; and The proteasome inhibitor is bortezomib or a pharmaceutically acceptable salt thereof.

2. Use of the composition in the preparation of one or more medicaments for treating or managing multiple myeloma in patients, wherein the composition comprises a compound and a proteasome inhibitor, and wherein the compound is compound AS. Compound AS Or its pharmaceutically acceptable salt; The drug comprises 1.0 mg, 1.3 mg, or 1.6 mg of the compound; and The proteasome inhibitor is bortezomib or a pharmaceutically acceptable salt thereof.

3. The use of claim 1 or 2, wherein the multiple myeloma is a relapsed or refractory multiple myeloma.

4. The use of claim 3, wherein the patient has experienced at least one prior treatment failure.

5. The use of claim 1 or 2, wherein the multiple myeloma is newly diagnosed.

6. The use of claim 1 or 2, wherein the compound is for oral administration.

7. The use of claim 1 or 2, wherein the medicament comprises 1.0 mg of the compound.

8. The use of claim 1 or 2, wherein the bortezomib or a pharmaceutically acceptable salt thereof is used for administration by subcutaneous application.

9. The use of claim 1 or 2, wherein dexamethasone or a pharmaceutically acceptable salt thereof is also administered.

10. The use of claim 9, wherein the drug comprises 10 mg, 20 mg or 40 mg of the dexamethasone or a pharmaceutically acceptable salt thereof.

11. The use of claim 9, wherein the dexamethasone or a pharmaceutically acceptable salt thereof is used for administration by oral administration.

12. The use of claim 1 or 2, wherein the compound is a hydrochloride salt of compound AS.

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