Plinabulin compositions and use thereof

Abstract

To provide plinabulin, compositions containing plinabulin, compositions containing analogs of plinabulin, and the use.SOLUTION: It is found that immunotherapy mediated adverse events can be prevented and / or treated or reduced by administering plinabulin. It is also found that: immunotherapy-related inflammation can be treated by administering plinabulin; and psoriasis and / or inflammation can be treated by administering plinabulin.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to the fields of chemistry and medicine. More specifically, the present application relates to plinabulin, compositions containing plinabulin, and compositions containing analogs of plinabulin, and uses. [Background technology]

[0002] Immunotherapy-related adverse events (IRAEs) are frequent consequences of immunostimulatory antibody therapy. IRAEs can be severe and even life-threatening. IRAEs include autoimmune reactions such as diarrhea, enterocolitis, dermatitis, hypophysitis, panhypopituitarism, rash, pruritus, and other inflammatory reactions. Severe IRAEs can lead to changes in drug dosage, less effective treatment, or even to the discontinuation of cancer treatment. There is a need to develop effective treatments for IRAEs.

[0003] Phosphodiesterases (PDEs) are enzymes that hydrolyze and degrade cAMP. PDE4 is a cAMP phosphodiesterase that is widely expressed in hematopoietic cells (e.g., myeloid hematopoietic cells, lymphoid hematopoietic cells), non-hematopoietic cells (e.g., smooth muscle cells, keratinocytes, endothelial cells), and sensory / memory neurons. Four PDE4 genes (a, b, c, and d) exhibit distinct target and regulatory properties. Each of these genes can produce multiple protein products due to mRNA splicing variants, resulting in approximately 19 different PDE4 proteins classified into either short or long isoform categories. Regulation of cAMP activity is important in numerous biological processes, making it necessary to develop effective PDE4 inhibitors that can be used to treat various diseases. Summary of the Invention

[0004] Some embodiments are directed to the treatment of pancreatitis, pneumonitis, colitis, hepatitis, nephritis and renal insufficiency, hypothyroidism and hyperthyroidism, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, facial and abducens nerve palsy, hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, myasthenic syndrome, hypophysitis, thyroiditis, type 1 diabetes, arthritis, exfoliative dermatitis, bullous pemphigoid, myositis, myasthenia gravis, vasculitis, hemolytic anemia, partial seizures occurring in patients with inflammatory foci within the brain parenchyma, dermatitis, rash, pruritus, meningitis, sarcoidosis, urticaria ... The present invention relates to a method for preventing and / or treating an immunotherapy-mediated adverse event in a subject selected from the group consisting of idiopathies, pericarditis, fatal myocarditis, vasculopathy, temporal arteritis, vasculitis, rheumatic myalgia, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and extraocular myositis, and hemolytic anemia, comprising administering an effective amount of plinabulin to the subject in need thereof.

[0005] Some embodiments relate to methods of treating or ameliorating immunotherapy-mediated pancreatitis in a subject, comprising administering a PD-1 inhibitor and a CTLA-4 inhibitor, the method comprising administering to the subject in need thereof an effective amount of plinabulin.

[0006] Some embodiments relate to a method of treating an inflammatory skin or joint disease in a subject, comprising topically administering to the subject in need thereof an effective amount of plinabulin.

[0007] Some embodiments are directed to the treatment of rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, systemic lupus erythematosus, inflammatory bowel disease, atopic dermatitis, and and a method for treating an inflammatory disease selected from the group consisting of multiple sclerosis, irritable bowel syndrome, inflammatory bowel disease, and allergic dermatitis in a subject, the method comprising administering to the subject in need thereof an effective amount of plinabulin.

[0008] Some embodiments relate to a method of treating chronic obstructive pulmonary disease or asthma in a subject, comprising administering to the subject in need thereof an effective amount of plinabulin via an inhaler.

[0009] Some embodiments relate to a method of treating immunotherapy-induced inflammation in a subject receiving one or more immune checkpoint inhibitors, the method comprising administering to the subject in need thereof an effective amount of plinabulin.

[0010] Some embodiments relate to topical formulations comprising plinabulin at a concentration that is effective to inhibit PDE4 activity without reducing blood vessel growth or density.

[0011] Some embodiments relate to topical formulations comprising plinabulin at a concentration ranging from about 0.1% to about 10% by weight of the total formulation. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the percentage of patients who experienced steroid-related adverse events during treatment with plinabulin. DETAILED DESCRIPTION OF THE INVENTION

[0013] Plinabulin, i.e., (3Z,6Z)-3-benzylidene-6-{[5-(2-methyl-2-propanyl)-1H-imidazol-4-yl]methylene}-2,5-piperazinedione, is a synthetic analog of the natural compound phenylahistine. Plinabulin can be readily prepared according to the methods and procedures detailed in U.S. Patent Nos. 7,064,201 and 7,919,497, the entire contents of which are incorporated herein by reference. In some embodiments, plinabulin can effectively inhibit PED4 activity. Plinabulin includes its pharmaceutically acceptable salts, polymorphs, and solvates, as described herein.

[0014] Plinabulin may be effective in reducing the incidence and severity of IRAEs, and when combined with anti-cancer immunotherapy, it may help achieve more effective and safer treatment. In addition to treating and preventing IRAEs, plinabulin can also enhance immune responses during immunotherapy treatment to achieve synergistic effects. Plinabulin targets cancer cells and reduces tumor size through immune modulation of cancer cells and / or the tumor microenvironment, promoting anti-cancer / anti-tumor immune enhancement, and can act synergistically with immunotherapy. Therefore, plinabulin not only reduces the risk of immunotherapy-related adverse events and improves the safety of the treatment, but also enhances the efficacy of the anti-cancer immunotherapy.

[0015] Phosphodiesterase 4 (PDE4) is a key enzyme in the breakdown of cyclic adenosine monophosphate and is involved in cytokine production in inflammatory cells, angiogenesis, and the functional properties of other cell types such as keratinocytes. Plinabulin inhibits PDE4 activity and can have anti-inflammatory properties. Plinabulin may be effective in treating inflammatory diseases, including immunotherapy-mediated inflammation and other human chronic inflammatory diseases such as psoriasis and psoriatic arthritis. Plinabulin can be used to treat chronic inflammatory diseases, such as inflammatory diseases of the skin and joints.

[0016] definition Unless otherwise defined, all technical and scientific terms used herein are defined in accordance with the principles of the present invention. "Terms and definitions" have the same meaning as commonly understood by one of ordinary skill in the art to which they pertain. All patents, patent applications, patent application publications, and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for a term herein, those in this section prevail unless stated otherwise.

[0017] As used herein, "subject" means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, as well as any other vertebrate or invertebrate.

[0018] The term "mammal" is used in its ordinary biological sense, and thus specifically includes, but is not limited to, primates, including monkeys (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.

[0019] As used herein, "effective amount" or "therapeutically effective amount" means an amount of a therapeutic agent effective to relieve to some extent one or more of the symptoms of a disease or condition or to reduce the likelihood of one or more of those symptoms occurring, including curing the disease or condition.

[0020] As used herein, "treat," "treatment," or "treating" refers to administering a compound or pharmaceutical composition to a subject for prophylactic or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of the disease or condition but who is susceptible to or otherwise at risk for a particular disease or condition, thereby reducing the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who is already suffering from a disease or condition.

[0021] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound and is not biologically or otherwise unsuitable for pharmaceutical use. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups, or groups similar thereto. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable salts can also be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, bases containing sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc., with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. In some embodiments, treatment of a compound disclosed herein with an inorganic base results in the loss of a labile hydrogen from the compound, resulting in Li + , Na + , K. + , Mg 2+ , and Ca 2+ Salt forms are produced containing inorganic cations such as, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and the like. Many such salts are known in the art, as described in WO 87 / 05297, published September 11, 1987, by Johnston et al., which is incorporated herein by reference in its entirety.

[0022] The terms "topical administration" or "administering topically" refer to the application of a pharmaceutical agent to the outer surface of the skin, nails, hair, hands, or feet so that the pharmaceutical agent is distributed over the outer surface and penetrates into the underlying tissue. Topical administration includes application of the composition to intact skin, nails, hair, hands, or feet, or application of the composition to a fresh or open wound resulting from a break in the skin, nails, hair, hands, or feet. Topical administration of a pharmaceutical agent may result in limited distribution of the agent to the skin and surrounding tissues, or the agent may be distributed systemically as the bloodstream removes the agent from the treatment area.

[0023] PD-1 is an important immune checkpoint receptor expressed by activated T cells and activated B cells and mediates immunosuppression. PD-1 is a member of the CD28 receptor family, which also includes CD28, CTLA-4, ICOS, PD-1, and BTLA. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms, and interspecies homologs of hPD-1, and analogs that share at least one epitope with hPD-1.

[0024] Various cell surface glycoprotein ligands for PD-1 have been identified, including PD-L1, PD-L2, PD-L3, and PD-L4, which are expressed on antigen-presenting cells and many human cancers and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, isoforms, and interspecies homologs of hPD-L1, and analogs that share at least one epitope with hPD-L1. As used herein, the term "PD-L2" includes human PD-L2 (hPD-L2), variants, isoforms, and interspecies homologs of hPD-L2, and analogs that share at least one epitope with hPD-L2. As used herein, the term "PD-L3" includes human PD-L3 (hPD-L3), variants, isoforms, and interspecies homologs of hPD-L3, and analogs that share at least one epitope in common with hPD-L3. As used herein, the term "PD-L4" includes human PD-L4 (hPD-L4), variants, isoforms, and interspecies homologs of hPD-L4, and analogs that share at least one epitope in common with hPD-L4.

[0025] CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a protein receptor that functions as an immune checkpoint and downregulates the immune system. CTLA-4 is found on the surface of T cells and is a member of the immunoglobulin (Ig) superfamily; CTLA-4 contains a single extracellular Ig domain. CTLA-4 transcripts have been found in T cell populations with cytotoxic activity, suggesting that CTLA-4 may function in cytolytic responses.

[0026] Treatment method Some embodiments relate to a method of treating or preventing immunotherapy-related adverse events in a subject receiving one or more immune checkpoint inhibitors, comprising administering to the subject in need thereof an effective amount of plinabulin. In some embodiments, the immunotherapy is an anti-cancer immunotherapy. In some embodiments, the subject also receives radiation therapy in addition to the anti-cancer immunotherapy.

[0027] Some embodiments relate to a method of treating or preventing immunotherapy-induced inflammation in a subject receiving one or more immune checkpoint inhibitors, comprising administering to the subject in need thereof an effective amount of plinabulin, wherein in some embodiments the immunotherapy is an anti-cancer immunotherapy.

[0028] Some embodiments relate to a method of treating, preventing, or ameliorating an immunotherapy-mediated adverse event in a subject, comprising administering to the subject in need thereof an effective amount of plinabulin. Immunotherapy-mediated adverse events may include, but are not limited to, adverse events or conditions disclosed in the package inserts for pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab, and tremelimumab, which are incorporated herein by reference in their entireties for this purpose.

[0029] In some embodiments, the immunotherapy-mediated adverse events include pancreatitis, pneumonitis, colitis, hepatitis, nephritis and renal insufficiency, hypothyroidism and hyperthyroidism, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, facial and abducens nerve palsy, hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, myasthenic syndrome, hypophysitis, thyroiditis, type 1 diabetes, arthritis, exfoliative dermatitis, bullous pemphigoid, myositis, myasthenia gravis, vasculitis, hemolytic The immunotherapy-mediated adverse event is selected from the group consisting of anemia, partial seizures occurring in patients with inflammatory foci within the brain parenchyma, dermatitis, rash, pruritus, meningitis, sarcoidosis, pericarditis, fatal myocarditis, vasculopathy, temporal arteritis, vasculitis, rheumatic myalgia, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central neuropathy (encephalitis), myositis, polymyositis, and extraocular myositis, and hemolytic anemia. In some embodiments, the immunotherapy-mediated adverse event is selected from the group consisting of pancreatitis, pneumonitis, colitis, hepatitis, nephritis, renal insufficiency, hypothyroidism, hyperthyroidism, and uveitis. In some embodiments, the immunotherapy-mediated adverse event is pancreatitis. In some embodiments, the immunotherapy is the administration of one or more checkpoint inhibitors.

[0030] In some embodiments, the immunotherapy-related adverse event is selected from fatigue, rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, decreased appetite, back pain, joint pain, upper respiratory tract infection, fever, headache, and abdominal pain.

[0031] In some embodiments, the immunotherapy-related adverse event is selected from the group consisting of pneumonitis, colitis, hepatitis, endocrinopathy, nephritis and renal insufficiency, adverse skin reactions, and encephalitis. In some embodiments, the immunotherapy-related adverse event is selected from infusion reactions, complications of allogeneic hematopoietic stem cell transplantation (HSCT), and embryo-fetal toxicity. Immune-Related Pneumonitis: In some embodiments, the immunotherapy-related adverse event is pneumonitis. In some embodiments, the immunotherapy-related adverse event is colitis. In some embodiments, the immunotherapy-related adverse event is hepatitis. In some embodiments, the immunotherapy-related adverse event is an increase in transaminases or total bilirubin. In some embodiments, the immunotherapy-related adverse event is an endocrinopathy. In some embodiments, the immunotherapy-related adverse event is hypophysitis. In some embodiments, the immunotherapy-related adverse event is adrenal insufficiency. In some embodiments, the immunotherapy-related adverse event is an alteration in thyroid function. In some embodiments, the immunotherapy-related adverse event is hyperglycemia. In some embodiments, the immunotherapy-related adverse event is nephritis and renal insufficiency. In some embodiments, the immunotherapy-related adverse event is an increase in serum creatinine. In some embodiments, the immunotherapy-related adverse event is a skin adverse reaction. In some embodiments, the immunotherapy-related adverse event is a rash. In some embodiments, the immunotherapy-related adverse event is Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis. In some embodiments, the immunotherapy-related adverse event is encephalitis. In some embodiments, the immunotherapy-related adverse event is a change in neurological function. In some embodiments, the adverse event is Grade 2. In some embodiments, the adverse event is Grade 3 or 4. In some embodiments, the adverse event is Grade 3. In some embodiments, the adverse event is Grade 4. In some embodiments, the adverse event is severe or life-threatening.

[0032] Some embodiments are directed to methods of treating, preventing, or ameliorating immunotherapy-mediated pancreatitis in a subject. Some embodiments relate to methods for treating, preventing, or ameliorating immunotherapy-mediated pneumonitis in a subject, comprising administering an effective amount of plinabulin to the subject in need thereof. Some embodiments relate to methods for treating, preventing, or ameliorating immunotherapy-mediated colitis in a subject, comprising administering an effective amount of plinabulin to the subject in need thereof. Some embodiments relate to methods for treating, preventing, or ameliorating immunotherapy-mediated hepatitis in a subject, comprising administering an effective amount of plinabulin to the subject in need thereof. Some embodiments relate to methods for treating, preventing, or ameliorating immunotherapy-mediated endocrine disorders in a subject, comprising administering an effective amount of plinabulin to the subject in need thereof. Some embodiments relate to methods for treating, preventing, or ameliorating immunotherapy-mediated nephritis and renal dysfunction in a subject, comprising administering an effective amount of plinabulin to the subject in need thereof. Some embodiments relate to methods of treating, preventing, or ameliorating immunotherapy-mediated adverse skin reactions in a subject, comprising administering an effective amount of plinabulin to the subject in need thereof. Some embodiments relate to methods of treating, preventing, or ameliorating immunotherapy-mediated encephalitis in a subject, comprising administering an effective amount of plinabulin to the subject in need thereof. In some embodiments, the immunotherapy comprises administering a PD-1 inhibitor and a CTLA-4 inhibitor. In some embodiments, the immunotherapy comprises administering a PD-1 inhibitor. In some embodiments, the immunotherapy comprises administering nivolumab. In some embodiments, the immunotherapy comprises administering pembrolizumab. In some embodiments, the immunotherapy comprises administering nivolumab in combination with ipilimumab.

[0033] In some embodiments, the methods described herein further include identifying patients at risk for having a serious immunotherapy-related adverse event. In some embodiments, identifying patients at risk for having a serious immunotherapy-related adverse event includes evaluating the patient's medical history (and family medical history), general health, autoimmune disease, baseline laboratory values, and radiological tests (mostly chest and abdominal / pelvic computed tomography (CT) scans, and often brain magnetic resonance imaging (MRI)). In some embodiments, identifying patients at risk for having a serious immunotherapy-related adverse event includes identifying patients with a history of or actively being treated for an autoimmune disease. In some embodiments, identifying patients at risk for having a serious immunotherapy-related adverse event includes identifying patients who had an IRAE at the time of prior immunotherapy treatment induction.

[0034] In some embodiments, the methods described herein include identifying a patient with a serious immunotherapy-related adverse event. In some embodiments, the methods described herein include identifying a patient with a Grade 3 or 4 immunotherapy-related adverse event. In some embodiments, identifying a patient with a serious immunotherapy-related adverse event includes a careful and thorough physical examination of the skin, including mucosal areas, an assessment of the patient's overall condition (fever, lymph node enlargement, etc.), and, if necessary, assessing the severity of the skin AE through biological testing, including blood cell counts, liver tests, and kidney tests. In some embodiments, identifying a patient with a serious immunotherapy-related adverse event includes ruling out dermatological events such as drug rash with eosinophilia and systemic symptoms (DRESS), acute febrile neutrophilic dermatosis (Sweet's syndrome), Stevens-Johnson syndrome, or toxic epidermal necrolysis (TEN). In some embodiments, the grade of the IRAE may be assessed using the National Cancer Institute Common Toxicity Criteria, Version 4.0, which is incorporated by reference in its entirety. In some embodiments, the IRAE may be graded using the American Society of Clinical Oncology treatment guidelines, which are incorporated by reference in their entirety. In some embodiments, the IRAE may be graded using the American Society of Clinical Oncology treatment guidelines (Management of Immunotherapy-Induced Toxicity: EMSO Treatment Guidelines: Ann Oncol (2017) Vol. 28(Suppl. 4): pp. 119-142), which are incorporated by reference in their entirety.

[0035] In some embodiments, the Common Terminology Criteria for Adverse Events (CTCAE) classification, which is incorporated by reference in its entirety, may be used to accurately gauge the severity of cutaneous AEs. With regard to maculopapular rash, the most frequent event with checkpoint inhibitor use, the CTCAE 4th edition includes the following classification: Grade 1 is characterized by macules / papules covering less than 10% of the body surface area (BSA) with or without symptoms (e.g., itching, burning, tightness); Grade 2 is characterized by macules / papules covering 10%-30% of the BSA with or without symptoms (e.g., itching, burning, tightness) and limitations in instrumental activities of daily living (ADL); Grade 3 is characterized by macules / papules covering more than 30% of the BSA with or without associated symptoms and limitations in self-care ADL; and Grade 4 is characterized by papulopustular rash covering more than 30% of the BSA and the presence of life-threatening superinfections requiring admission to the intensive care unit (ICU), Stevens-Johnson syndrome, TEN, and bullous dermatitis.

[0036] In some embodiments, identifying patients with serious immunotherapy-related adverse events involves measuring the patient's thyroid-stimulating hormone (TSH), triiodothyronine, and thyroxine (FT3, FT4) levels, and anti-thyroid antibody (Ab) levels. In some embodiments, identifying patients with serious immunotherapy-related adverse events involves monitoring the patient's blood glucose levels to detect the onset of DM. In some embodiments, the methods described herein involve monitoring TFTs during treatment every cycle of orNTFT for 4-6 weeks after the fourth cycle (i.e., the cycle including repeat CT) for anti-CTLA4 (including in combination with anti-PD-1). In some embodiments, the methods described herein involve monitoring TFTs during treatment every cycle for the first 3 months, and then every 2 cycles (if on a biweekly schedule) when anti-PD-1 / anti-PD-L1 is used.

[0037] In some embodiments, identifying patients with serious immunotherapy-related adverse events includes assessing for severe pressure effect symptoms, i.e., severe headache, any visual disturbances, or severe adrenal insufficiency, i.e., hypotension, severe electrolyte abnormalities. In some embodiments, identifying patients with serious immunotherapy-related adverse events includes assessing for moderate symptoms, i.e., headache but no visual disturbances, or fatigue / mood changes but hemodynamically stable and no electrolyte abnormalities. In some embodiments, identifying patients with serious immunotherapy-related adverse events includes following an MRI pituitary protocol, or ruling out brain metastases and considering a formal visual field evaluation (to provide information to licensing authorities as to whether the patient has an abnormality).

[0038] In some embodiments, identifying patients with serious immunotherapy-related adverse events includes assessing management of ICPi-related toxicity, i.e., hepatitis. In some embodiments, the following criteria may be used to accurately measure the severity of adverse events: Grade 1, ALT or AST >ULN to 3xULN; Grade 2, ALT or AST 3-5xULN; Grade 3, ALT or AST 5-20xULN; and Grade 4, ALT or AST >20xULN.

[0039] In some embodiments, identifying patients with severe immunotherapy-related adverse events includes assessing management of ICPi-related toxicities, i.e., diarrhea and colitis. In some embodiments, severe (Grade 3 / 4) adverse events include more than six liquid stools per day above baseline, or if episodes occur within one hour of a meal. In some embodiments, moderate (Grade 2) adverse events include four to six liquid stools per day above baseline, or abdominal pain, or bloody stool, or nausea, or nocturnal episodes. In some embodiments, mild (Grade 1) adverse events include fewer than four liquid stools above baseline.

[0040] In some embodiments, identifying patients with serious immunotherapy-related adverse events includes assessing management of ICPi-related toxicity, i.e., pneumonitis. In some embodiments, mild (Grade 1) adverse events include radiographic changes only. In some embodiments, moderate (Grade 2) adverse events include mild / moderate new symptoms, dyspnea, cough, and chest pain. In some embodiments, severe (Grade 3 / 4) adverse events include severe new symptoms, new / worsening hypoxia, life-threatening dyspnea, and ARDS.

[0041] In some embodiments, the one or more checkpoint inhibitors are selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a PD-L3 inhibitor, a PD-L4 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a KIR inhibitor, and a TIM3 inhibitor. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0042] In some embodiments, a first immune checkpoint inhibitor and a second immune checkpoint inhibitor are administered to the subject, and the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor. In some embodiments, the first and second immune checkpoint inhibitors are independently selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a PD-L3 inhibitor, a PD-L4 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a KIR inhibitor, and a TIM3 inhibitor. In some embodiments, the first checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor, and the second checkpoint inhibitor is a CTLA-4 inhibitor.

[0043] In some embodiments, the immunotherapy is a monotherapy, and the monotherapy comprises administering a single checkpoint inhibitor selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a PD-L3 inhibitor, a PD-L4 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a KIR inhibitor, and a TIM3 inhibitor. In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor.

[0044] In some embodiments, the immunotherapy is a combination therapy, and the combination therapy comprises administering two or more checkpoint inhibitors selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a PD-L3 inhibitor, a PD-L4 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a KIR inhibitor, and a TIM3 inhibitor. In some embodiments, the combination therapy comprises administering a PD-L1 inhibitor and a CTLA-4 inhibitor.

[0045] In some embodiments, the PD-1 or PD-L1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab. In some embodiments, the PD-1 inhibitor is nivolumab or pembrolizumab. In some embodiments, the PD-L1 inhibitor is atezolizumab, durvalumab, or avelumab. In some embodiments, the CTLA-4 inhibitor is ipilimumab or tremelimumab. In some embodiments, the checkpoint inhibitor is pembrolizumab. In some embodiments, the checkpoint inhibitor is nivolumab.

[0046] In some embodiments, the amount of plinabulin used to treat an indication described herein is effective to inhibit PDE4 activity without reducing blood vessel growth or density. It is effective.

[0047] In some embodiments, the immunotherapy is used to treat or prevent melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, microsatellite instability-high (MSI-H cancer), gastric cancer, advanced renal cell carcinoma, metastatic head and neck squamous cell carcinoma (SCCHN), metastatic colorectal cancer, hepatocellular carcinoma (HCC), or microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC). In some embodiments, the immunotherapy is used to treat or prevent melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, microsatellite instability-high (MSI-H cancer), or gastric cancer.

[0048] Some embodiments relate to treatment of an inflammatory disease or condition in a subject, comprising administering plinabulin to the subject in need thereof, with the proviso that the inflammatory disease or condition is not rheumatoid arthritis, rheumatoid arthritis, psoriasis, diabetic retinopathy, neovascular glaucoma, retinopathy of prematurity, macular degeneration, corneal transplant rejection, retrolental fibrosis, skin flushing, capillary proliferation in arteriosclerotic plaques, or osteoporosis.

[0049] In some embodiments, the plinabulin is about 1 to 50 mg / m of body surface area. 2 In some embodiments, the plinabulin is administered at a dose within the range of about 5 to about 50 mg / m of body surface area. 2 In some embodiments, the plinabulin is administered at a dose within the range of about 20 to about 40 mg / m of body surface area. 2 In some embodiments, the plinabulin is administered at a dose within the range of about 15 to about 30 mg / m of body surface area. 2In some embodiments, the plinabulin is administered at a dose within the range of about 0.5 to 1, 0.5 to 2, 0.5 to 3, 0.5 to 4, 0.5 to 5, 0.5 to 6, 0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10, 0.5 to 11, 0.5 to 12, 0.5 to 13, 0.5 to 13.75, 0.5 to 14, 0.5 to 15, 0.5 to 16, 0.5 to 17, 0.5 to 18, 0.5 to 19, 0.5 to 20, 0.5 to 22.5, 0.5 to 25, 0.5 to 27.5, 0.5 to 30, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1-11, 1-12, 1-13, 1-13.75, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22.5, 1-25, 1-27.5, 1-30, 1.5-2, 1.5-3, 1.5-4, 1.5-5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10, 1.5-11, 1.5-12, 1.5-13, 1.5-13.75, 1.5-14, 1.5-15, 1.5-16, 1.5-17, 1.5-18, 1.5-19, 1.5-20, 1.5-22.5, 1.5-25, 1.5-27 .5, 1.5-30, 2.5-2, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-11, 2.5-12, 2.5-13, 2.5-13.75, 2.5-14, 2.5-15, 2.5-16, 2.5-17, 2.5-18, 2.5-19, 2.5-20, 2.5-22.5, 2.5-25, 2.5-27.5, 2.5-30, 2.5-7.5, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-13.75, 3- 14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-22.5, 3-25, 3-27.5, 3-30, 3.5-6.5, 3.5-13.75, 3.5-15, 2.5-17.5, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-13.75, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19, 4-20, 4-22.5, 4-25, 4-27.5, 4-30, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-13.75, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-22.5, 5-25, 5-27.5, 5-30, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-13.75, 6-14, 6-15, 6-1. 6, 6-17, 6-18, 6-19, 6-20, 6-22.5, 6-25, 6-27.5, 6-30, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-13.75, 7-14, 7-15, 7-16, 7-17, 7-18, 7-19, 7-20, 7-22.5, 7-25, 7-27.5, 7-30, 7.5 ~12.5, 7.5~13.5, 7.5~15, 8~9, 8~10, 8~11, 8~12, 8~13, 8~13.75, 8~14, 8~15, 8~16, 8~17, 8~18, 8~19, 8~20, 8~22.5, 8~25, 8~27.5, 8~30, 9~10, 9~11, 9~12, 9~13, 9~13.75, 9~14 , 9~15, 9~16, 9~17, 9~18, 9~19, 9~20, 9~22.5, 9~25, 9~27.5, 9~30, 10~11, 10~12, 10~13, 10~13.75, 10~14, 10~15, 10~16, 10~17, 10~18, 10~19, 10~20, 10~22.5, 10~25, 10~27. 5, 10–30, 11.5–15.5, 12.5–14.5, 7.5–22.5, 8.5–32.5, 9.5–15.5, 15.5–24.5, 5–35, 17.5–22.5, 22.5–32.5, 25–35, 25.5–24.5, 27.5–32.5, 2–20, 2.5–22.5, or 9.5–21.5 mg / m 2In some embodiments, the plinabulin is administered at a dose within the range of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 10 7, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 2 6, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / m 2 In some embodiments, the plinabulin is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 7, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 2 6, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / m 2 In some embodiments, the plinabulin is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5 , 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50mg / m 2In some embodiments, the plinabulin is administered at a dose of greater than about 10, 13.5, 20, or 30 mg / m of body surface area. 2 In some embodiments, the plinabulin is administered at a dose of about 20 mg / m of body surface area. 2 is administered at a dose of

[0050] In some embodiments, the plinabulin dose is about 5 mg to 100 mg or about 10 mg to 80 mg. In some embodiments, the plinabulin dose is about 15 mg to 100 mg or about 20 mg to 80 mg. In some embodiments, the plinabulin dose is administered at a dose within the range of about 15 mg to 60 mg. In some embodiments, the plinabulin dose is about 0.5 mg to 3 mg, 0.5 mg to 2 mg, 0.75 mg to 2 mg, 1 mg to 10 mg, 1.5 mg to 10 mg, 2 mg to 10 mg, 3 mg to 10 mg, 4 mg to 10 mg, 1 mg to 8 mg, 1.5 mg to 8 mg, 2 mg to 8 mg, 3 mg to 8 mg, 4 mg to 8 mg, 1 mg to 6 mg, 1.5 mg to 6 mg, 2 mg to 6 mg, 3 mg to 6 mg, or about 4 mg. In some embodiments, the plinabulin administered is about 2 mg to 6 mg, or 2 mg to 4.5 mg. In some embodiments, the plinabulin administered is about 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg, 5 mg to 26 mg, 5 mg to 28 mg, 5 mg to 30 mg, 5 mg to 32 mg, 5 mg to 34 mg, 5 mg to 36 mg, 5 mg to 38 mg, 5 mg to 40 mg, 5 mg to 42 mg, 5 mg to 44 mg, 5 mg to 46 mg, 5 mg to 48 mg, 5 mg ~50mg, 5mg~52mg, 5mg~54mg, 5mg~56mg, 5mg~58mg, 5mg~60mg, 7mg~7.7mg, 7mg~9mg, 7mg~10mg, 7mg~12mg, 7mg~14mg, 7mg~15mg, 7mg~16mg, 7mg ~18mg, 7mg~20mg, 7mg~22mg, 7mg~24mg, 7mg~26mg, 7mg~28mg, 7mg~30mg, 7mg~32mg, 7mg~34mg, 7mg~36mg, 7mg~38mg, 7mg~40mg, 7mg~42mg, 7mg~ 44mg, 7mg~46mg, 7mg~48mg, 7mg~50mg, 7mg~52mg, 7mg~54mg, 7mg~56mg, 7mg~58mg, 7mg~60mg, 9mg~10mg, 9mg~12mg, 9mg~14mg, 9mg~15mg, 9mg~ 16mg, 9mg~18mg, 9mg~20mg, 9mg~22mg, 9mg~24mg, 9mg~26mg, 9mg~28mg, 9mg~30mg, 9mg~32mg, 9mg~34mg, 9mg~36mg, 9mg~38mg, 9mg~40mg, 9mg~4 2mg, 9mg~44mg, 9mg~46mg, 9mg~48mg, 9mg~50mg, 9mg~52mg, 9mg~54mg, 9mg~56mg, 9mg~58mg, 9mg~60mg, 10mg~12mg, 10mg~14mg, 10mg~15mg, 10 mg~16mg, 10mg~18mg, 10mg~20mg, 10mg~22mg, 10mg~24mg, 10mg~26mg, 10mg~28mg, 10mg~30mg, 10mg~32mg, 10mg~34mg, 10mg~36mg, 10mg~38mg,10mg~40mg、10mg~42mg、10mg~44mg、10mg~46mg、10mg~48mg、10mg~50mg、10mg~52mg、10mg~54mg、10mg~56mg、10mg~58mg、10mg~60mg、12mg~14mg、12mg~15mg、12mg~16mg、12mg~18mg、12mg~20mg、12mg~22mg、12mg~24mg、12mg~26mg、12mg~28mg、12mg~30mg、12mg~32mg、12mg~34mg、12mg~36mg、12mg~38mg、12mg~40mg、12mg~42mg、12mg~44mg、12mg~46mg、12mg~48mg、12mg~50mg、12mg~52mg、12mg~54mg、12mg~56mg、12mg~58mg、12mg~60mg、15mg~16mg、15mg~18mg、15mg~20mg、15mg~22mg、15mg~24mg、15mg~26mg、15mg~28mg、15mg~30mg、15mg~32mg、15mg~34mg、15mg~36mg、15mg~38mg、15mg~40mg、15mg~42mg、15mg~44mg、15mg~46mg、15mg~48mg、15mg~50mg、15mg~52mg、15mg~54mg、15mg~56mg、15mg~58mg、15mg~60mg、17mg~18mg、17mg~20mg、17mg~22mg、17mg~24mg、17mg~26mg、17mg~28mg、17mg~30mg、17mg~32mg、17mg~34mg、17mg~36mg、17mg~38mg、17mg~40mg、17mg~42mg、17mg~44mg、17mg~46mg、17mg~48mg、17mg~50mg、17mg~52mg、17mg~54mg、17mg~56mg、17mg~58mg、17mg~60mg、20mg~22mg、20mg~24mg、20mg~26mg、20mg~28mg、20mg~30mg、20mg~32mg、20mg~34mg、20mg~36mg、20mg~38mg、20mg~40mg、20mg~42mg、20mg~44mg、20mg~46mg、20mg~48mg、20mg~50mg、20mg~52mg、20mg~54mg、20mg~56mg、20mg~58mg、20mg、 ~60mg、22mg~24mg、22mg~26mg、22mg~28mg、22mg~30mg、22mg~32mg、22mg~34mg、22mg~36mg、22mg~38mg、22mg~40mg、22mg~42mg、22mg~44mg、22mg~46mg、22mg~48mg、22mg~50mg、22mg~52mg、22mg~54mg、22mg~56mg、22mg~58mg、22mg~60mg、25mg~26mg、25mg~28mg、25mg~30mg、25mg~32mg、25mg~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg、30mg~36mg、30mg~38mg、30mg~40mg、30mg~42mg、30mg~44mg、30mg~46mg、30mg~48mg、30mg~50mg、30mg~52mg、30mg~54mg、30mg~56mg、30mg~58mg、30mg~60mg、33mg~34mg、33mg~36mg、33mg~38mg、33mg~40mg、33mg~42mg、33mg~44mg、33mg~46mg、33mg~48mg、33mg~50mg、33mg~52mg、33mg~54mg、33mg~56mg、33mg~58mg、33mg~60mg、36mg~38mg、36mg~40mg、36mg~42mg、36mg~44mg、36mg~46mg、36mg~48mg、36mg~50mg、36mg~52mg、36mg~54mg、36mg~56mg、36mg~58mg、36mg~60mg、40mg~42mg、40mg~44mg、40mg~46mg、40mg~48mg、40mg~50mg, 40mg~52mg, 40mg~54mg, 40mg~56mg, 40mg~58mg, 40mg~60mg, 43mg~46mg, 43mg~48mg, 43mg~50mg, 4 3mg~52mg, 43mg~54mg, 43mg~56mg, 43mg~58mg, 42mg~60mg, 45mg~48mg, 45mg~50mg, 45mg~52mg, 45mg~54mg, 45 mg to 56mg, 45mg to 58mg, 45mg to 60mg, 48mg to 50mg, 48mg to 52mg, 48mg to 54mg, 48mg to 56mg, 48mg to 58mg, 48mg to 60mg, 50mg to 52mg, 50mg to 54mg, 50mg to 56mg, 50mg to 58mg, 50mg to 60mg, 52mg to 54mg, 52mg to 56mg, 52mg to 58mg, or 52mg to 60mg. In some embodiments, the plinabulin dose is greater than about 0.5 mg, 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, or about 40 mg. In some embodiments, the plinabulin dose is less than about 1 mg, 1.5 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, or about 50 mg.

[0051] The actual dose of the checkpoint inhibitors described herein will depend on the particular compound and the condition being treated, and selecting an appropriate dose is well within the knowledge of one of ordinary skill in the art. In some embodiments, the methods described herein involve administering a dose of about 0.01 mg / kg to about 250 mg / kg of body weight, about 0.1 mg / kg to about 200 mg / kg of body weight, about 0.25 mg / kg to about 120 mg / kg of body weight, about 0.5 mg / kg to about 70 mg / kg of body weight, about 1.0 mg / kg to about 50 mg / kg of body weight, about 1.0 mg / kg to about 15 mg / kg of body weight, or about 2.0 mg / kg to about 15 mg / kg of body weight. / kg of body weight, about 3.0 mg / kg to about 12 mg / kg of body weight, or about 5.0 mg / kg to about 10 mg / kg of body weight.In some embodiments, the methods described herein provide a method for administering a 0.5 to 1, 0.5 to 2, 0.5 to 3, 0.5 to 4, 0.5 to 5, 0.5 to 6, 0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10, 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 1 to 60, 1 to 70, 1 to 80, 1 to 90, 1 to 100, 2.5 to 5, 2.5 to 10, 2.5 to 20, 2.5 to 30, 2.5 to 40, 2.5 to 50, 2.5 to 60, 2.5 to 70, 2.5 to 80, 2.5 to 90, 2.5~100, 3~5, 3~10, 3~20, 3~30, 3~40, 3~50, 3~60, 3~70, 3~80, 3~90, 3~100, 5~10, 5~20, 5~30, 5~40, 5~50, 5~60, 5~70, 5~80, 5~90, 5~100, 7.5~10, 7.5~20, 7.5~30, 7.5~40, 7.5~50, 7.5~60, 7.5~70, 7.5~80, 7.5~90, 7.5~100, 10~10, 10~20, 10~30, 10~40, 10~50, 10~60, 10~70, 10~80, 10~90, 10~ 100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 5 and administering a checkpoint inhibitor at a dose within the range of 0-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 80-100, 80-150, 80-200, 80-250, 80-300, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 100-150, 100-200, 100-250, 100-300, 100-350, or 100-400 mg / kg.In some embodiments, the checkpoint inhibitors described herein may be administered at a dose of about 0.1, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22.5, 25, 27.5, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg / kg of body weight. In some embodiments, the methods described herein comprise administering a checkpoint inhibitor at a dose of about 3 mg / kg. In some embodiments, the methods described herein comprise administering a checkpoint inhibitor at a dose of about 3 mg / kg every three weeks for a total of four doses.

[0052] In some embodiments, the checkpoint inhibitor is administered in an amount of about 0.5 to 1, 0.5 to 2, 0.5 to 3, 0.5 to 4, 0.5 to 5, 0.5 to 6, 0.5 to 7, 0.5 to 8, 0.5 to 9, 0.5 to 10, 2.5 to 3, 2.5 to 4, 2.5 to 5, 2.5 to 6, 2.5 to 7, 2.5 to 8, 2.5 to 9, 2.5 to 10, 3-10, 5-10, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2.5-10, 2.5-20, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 5-10, 5~20, 5~30, 5~40, 5~50, 5~60, 5~70, 5~80, 5~90, 5~100, 7.5~10, 7.5~20, 7.5~30, 7.5~40, 7.5~50, 7.5~60, 7.5~70, 7.5~80, 7.5~90, 7.5~100, 10~10, 10~20, 10~30, 10~40 , 10~50, 10~60, 10~70, 10~80, 10~90, 10~100, 10~150, 10~200, 20~30, 20~40, 20~50, 20~60, 20~70, 20~80, 20~90, 20~100, 20~150, 20~200, 30~40, 30~50, 30~60, 30~70, 3 0-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 7 0~150, 70~200, 70~250, 70~300, 70~500, 70~750, 70~1000, 70~1500, 70~2000, 70~3000, 80~100, 80~150, 80~200, 80~250, 80~3000, 80~500, 80~750, 80~1000, 80~1500, 80~2000, 80~3000, 90~100, 90~150, 90~200, 90~250, 90~ 300, 90-350, 90-400, 90-500, 90-750, 90-1000, 90-1500, 90-2000, 90-3000, 100-150, 100-200, 100-250, 100-300, 100-350, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 100-1500, 100-2000, 100-2 It is administered in amounts of 500, 100-3000, 100-3500, 100-4000, 200-500, 200-700, 200-1000, 200-1500, 200-2000, 200-2500, 200-3000, 200-3500, 200-4000, 500-1000, 500-1500, 500-2000, 500-2500, 500-3000, 500-3500, or 500-4000 mg.In some embodiments, the checkpoint inhibitor is administered in an amount of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 750, 800, 850, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7500, 7500, 8000, 8500, 9000, 10000, 15 ... , 650, 700, 750, 800, 850, 900, 1000, 1100, 1200, 1250, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or 5000 mg. In some embodiments, the checkpoint inhibitor is administered in an amount of about 25 mg, 50 mg, or 100 mg per dose.

[0053] In some embodiments, the methods described herein involve administering a dose of about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-120, 1-130, 1-140, 1-150, 1-160, 1-170, 1-180, 1-190, 1-210, 1-220, 1-240, 1-250, 1-260, 1-270, 1-280, 1-290, 1-300, 1-310, 1-320, 1-330, 1-340, 1-350, 1-360, 1-370, 1-380, 1-390, 1-410, 1-420, 1-430, 1-440, 1-450, 1-460, 1-470, 1-480, 1-490, 1-510, 1-520, 1-530, 1-540, 1-550, 1-560, 1-570, 1-580, 1-590, 1-610, 1-620, 1 ~80, 1~90, 1~100, 2~3, 2~4, 2~5, 2~6, 2~7, 2~8, 2~9, 2~10, 2~20, 2~30, 2~40, 2~50, 2~60, 2~70, 2~80, 2~90, 2~100, 2.5~3, 2.5~3.5, 2.5~4, 2.5~5, 2.5~6, 2.5~7, 2.5~9, 2.5~10, 3~4, 3~5, 3~6, ​​3~7 , 3~8, 3~9, 3~10, 5~10, 5~20, 5~30, 5~40, 5~50, 5~60, 5~70, 5~80, 5~90, 5~100, 7.5~10, 7.5~20, 7.5~30, 7.5~40, 7.5~50, 7.5~60, 7.5~70, 7.5~80, 7.5~90, 7.5~100, 10~10, 10~20, 10~30, 10~40, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-80, 30-90, 30-100, 30- 150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50-100, 50-150, 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 7 and administering a PD-1 inhibitor at a dose within the range of 0-250, 70-300, 80-100, 80-150, 80-200, 80-250, 80-300, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 100-150, 100-200, 100-250, 100-300, 100-350, or 100-400 mg / kg. In some embodiments, the methods described herein comprise administering the PD-1 inhibitor at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg of body weight. In some embodiments, the PD-1 inhibitor is administered at a dose of about 3 mg / kg. In some embodiments, the PD-1 inhibitor is administered at a dose of about 2 mg / kg.

[0054] In some embodiments, the PD-1 inhibitor has a concentration of about 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 1 to 60, 1 to 70, 1 to 80, 1 to 90, 1 to 100, 1 to 150, 1 to 200, 1 to 250, 1 to 300, 1 to 500, 2.5 to 3, 2.5 to 4, 2.5 to 5, 2.5 to 6, 2.5 to 7, 2.5 to 8, 2.5 to 9, 2.5 to 10, 2.5 to 20, 2.5 to 30, 2.5 to 40, 2.5 to 50, 2.5 to 60, 2.5 to 70, 2.5 to 80, 2.5 to 90, 2.5 to 100, 2.5 ~200, 2.5~250, 2.5~300, 2.5~500, 3~10, 3~20, 3~30, 3~40, 3~50, 3~60, 3~70, 3~80, 3~90, 3~100, 3~200, 3~250, 3~300, 3~500, 5~10, 5~10, 5~20, 5~30, 5~40, 5~50, 5~60, 5~70, 5~80, 5~90, 5~100, 7.5~10, 7.5~20, 7.5~30, 7.5~40, 7.5~50, 7.5~60, 7.5~70, 7.5~80, 7.5~90, 7.5~100、10~10、10~20、10~30、10~40、10~50、10~60、10~70、10~80、10~90、10~100、10~150、10~200、20~30、20~40、20~50、20~60、20~70、20~80、20~90、20~100、20~150、20~200、30~40、30~50、30~60、30~70、30~80、30~90、30~100、30~150、30~200、40~50、40~60、40~70、40~80、40~90、40~100、40~150、40~200、40~300、50~60、50~70、50~80、50~90、50~100、50~150、50~200、50~250、50~300、60~80、60~100、60~150、60~200、70~100、70~150、70~200、70~250、70~300、70~500、70~750、70~1000、70~1500、70~2000、70~3000、80~100、80~150、80~200、80~250、80~300、80~500、80~750、80~1000、80~1500、80~2000、80~3000、90~100、90~150、90~200、90~250、90~300、90~350、90~400、90~500、90~750、90~1000、90~1500、90~2000、90~3000、100~150、100~200、100~250、100~300、100~350、100~400、100~500、100~600、100~700、100~800、100~900、100~1000、100~1500、100~2000、100~2500、100~3000、100~3500、100~4000、200~500、200~700、200~1000、200~1500、200~2000、200~2500、200~3000、200~3500、200~400. In some embodiments, the PD-1 inhibitor is administered in an amount of about 10 to 30, 10 to 50, 10 to 80, 10 to 100, 10 to 125, 10 to 150, 10 to 175, 10 to 200, 10 to 250, 10 to 300, 10 to 400, 20 to 50, 20 to 100, 20 to 125, 20 to 150, 20 to 175, 20 to 200, 20 to 250, 20 to 300, 20 to 400, 30 to 50, 30 to 80, 30 to 100, 30 to 1 It is administered in amounts of 25, 30-150, 30-175, 30-200, 30-250, 30-300, 30-400, 40-50, 40-80, 40-100, 40-125, 40-150, 40-175, 40-200, 40-250, 40-300, 40-400, 50-80, 50-100, 50-125, 50-150, 50-175, 50-200, 50-250, 50-300, or 50-400 mg. In some embodiments, the PD-1 inhibitor (e.g., nivolumab or pembrolizumab) is administered in an amount of about 50-350 mg per dose, about 100-300 mg per dose, or about 150-250 mg per dose. In some embodiments, the PD-1 inhibitor (e.g., nivolumab or pembrolizumab) is administered in an amount of about 200 mg per dose. In some embodiments, the PD-1 inhibitor (e.g., nivolumab or pembrolizumab) is administered in an amount of about 240 mg per dose.

[0055] In some embodiments, the methods described herein provide a method for administering a dose of about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-10 ...100, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-100, 2-1 ~100, 2.5~3, 2.5~3.5, 2.5~4, 2.5~5, 2.5~6, 2.5~7, 2.5~9, 2.5~10, 3~4, 3~5, 3~6, ​​3~7, 3~8, 3~9, 3~10, 5~10, 5~20, 5~30, 5~40, 5~50, 5~60, 5~70, 5~80 , 5~90, 5~100, 7.5~10, 7.5~20, 7.5~30, 7.5~40, 7.5~50, 7.5~60, 7.5~70, 7.5~80, 7.5~90, 7.5~100, 10~10, 10~20, 10~30, 10~40, 10~50, 10~60, 10~70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-60, 30-70, 30-8 0, 30~90, 30~100, 30~150, 30~200, 40~50, 40~60, 40~70, 40~80, 40~90, 40~100, 40~150, 40~200, 40~300, 50~60, 50~70, 50~80, 50~90, 50~100, 50~150, and administering a PD-L1 inhibitor at a dose within the range of 50-200, 50-250, 50-300, 60-80, 60-100, 60-150, 60-200, 70-100, 70-150, 70-200, 70-250, 70-300, 80-100, 80-150, 80-200, 80-250, 80-300, 90-100, 90-150, 90-200, 90-250, 90-300, 90-350, 90-400, 100-150, 100-200, 100-250, 100-300, 100-350, or 100-400 mg / kg.In some embodiments, the methods described herein comprise administering the PD-L1 inhibitor at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg of body weight.

[0056] In some embodiments, the PD-L1 inhibitor (e.g., atezolizumab) is administered in an amount of about 1 to 10, 1 to 20, 1 to 30, 1 to 40, 1 to 50, 1 to 60, 1 to 70, 1 to 80, 1 to 90, 1 to 100, 1 to 150, 1 to 200, 1 to 250, 1 to 300, 1 to 500, 2.5 to 3, 2.5 to 4, 2.5 to 5, 2.5 to 6, 2.5 to 7, 2.5 to 8, 2.5 to 9, 2.5 to 10, 2.5 to 20, 2.5 to 30, 2.5 to 40, 2.5 to 50, 2.5 to 60, 2.5 to 70, 2.5 to 80, 2.5 to 90, 2.5 to 100, 2.5 to 200, 2.5 to 25 0, 2.5~300, 2.5~500, 3~10, 3~20, 3~30, 3~40, 3~50, 3~60, 3~70, 3~80, 3~90, 3~100, 3~200, 3~250, 3~300, 3~500, 5~10, 5~10, 5~20, 5~30, 5~40, 5~50, 5~ 60, 5~70, 5~80, 5~90, 5~100, 7.5~10, 7.5~20, 7.5~30, 7.5~40, 7.5~50, 7.5~60, 7.5~70, 7.5~80, 7.5~90, 7.5~100, 10~10, 10~20, 10~30, 10~40, 10~50, 10-60, 10-70, 10-80, 10-90, 10-100, 10-150, 10-200, 20-30, 20-40, 20-50, 20-60, 20-70, 20-80, 20-90, 20-100, 20-150, 20-200, 30-40, 30-50, 30-6 0, 30-70, 30-80, 30-90, 30-100, 30-150, 30-200, 40-50, 40-60, 40-70, 40-80, 40-90, 40-100, 40-150, 40-200, 40-300, 50-60, 50-70, 50-80, 50-90, 50 ~100, 50~150, 50~200, 50~250, 50~300, 60~80, 60~100, 60~150, 60~200, 70~100, 70~150, 70~200, 70~250, 70~300, 70~500, 70~750, 70~1000, 70~1500, 70~2000, 70~3000, 80~100, 80~150, 80~200, 80~250, 80~300, 80~500, 80~750, 80~1000, 80~1500, 80~2000, 80~3000, 90~100, 90~150, 90~200, 90~250,90~300, 90~350, 90~400, 90~500, 90~750, 90~1000, 90~1500, 90~2000, 90~3000, 100~150, 100~200, 100~250, 100~300, 100~350, 100~400, 100~500, 100~600, 100~700, 100~800, 100~900, 100~1000, 100~1500, 100~2000, 100~ It is administered in amounts of 2500, 100-3000, 100-3500, 100-4000, 200-500, 200-700, 200-1000, 200-1500, 200-2000, 200-2500, 200-3000, 200-3500, 200-4000, 500-1000, 500-1500, 500-2000, 500-2500, 500-3000, 500-3500, or 500-4000 mg. In some embodiments, the PD-L1 inhibitor is administered in an amount of about 500-1500, 600-1500, 700-1500, 800-1500, 900-1500, 1000-1500, or 1100-1300 mg per dose. In some embodiments, the PD-L1 inhibitor is administered in an amount of about 1200 mg per dose.

[0057] In some embodiments, the methods described herein provide a method for administering a dose of about 0.5-1, 0.5-2, 0.5-3, 0.5-4, 0.5-5, 0.5-6, 0.5-7, 0.5-8, 0.5-9, 0.5-10, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-20, 2-30, 2-40, 2-50, 2-60, 2-70, 2-80, 2 ... 40, 2-50, 2-60, 2-70, 2-80, 2-90, 2-100, 2.5-3, 2.5-3.5, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-9, 2.5-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 5-10, 5-20, 5-30, 5-40, 5-50, 5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80 , 7.5~90, 7.5~100, 10~10, 10~20, 10~30, 10~40, 10~50, 10~60, 10~70, 10~80, 10~90, 10~100, 10~150, 10~200, 20~30, 20~40, 20~50, 20~60, 20~70, 20~80, 20~90, 20~100, 20~150, 20~200, 30~40, 30~50, 30~60, 30~70, 30~80, 30 and administering an inhibitor of CTLA-4 (e.g., ipilimumab) at a dose within the ranges of ∼90, 30–100, 30–150, 30–200, 40–50, 40–60, 40–70, 40–80, 40–90, 40–100, 40–150, 40–200, 40–300, 50–60, 50–70, 50–80, 50–90, 50–100, 50–150, 50–200, 50–250, or 50–300 mg / kg. In some embodiments, the methods described herein comprise administering the CTLA-4 inhibitor at a dose of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg of body weight. In some embodiments, the CTLA-4 inhibitor is administered at a dose of about 3 mg / kg. In some embodiments, the CTLA-4 inhibitor is administered at a dose less than 3 mg / kg. In some embodiments, the CTLA-4 inhibitor is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4 mg / kg. In some embodiments, the CTLA-4 inhibitor (e.g., ipilimumab) is administered at a dose of about 3 mg / kg.

[0058] In some embodiments, the CTLA-4 inhibitor has a concentration of about 1-10, 1-20, 1-30, 1-40, 1-50, 1-60, 1-70, 1-80, 1-90, 1-100, 1-150, 1-200, 1-250, 1-300, 1-500, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-20, 2.5-30, 2.5-40, 2.5-50, 2.5-60, 2.5-70, 2.5-80, 2.5-90, 2.5-100, 2.5-300, 2.5-400, 2.5-500, 2.5-600, 2.5-700, 2.5-800, 2.5-900, 2.5-1000, 2.5-1000, 2.5-2 ... 5-200, 2.5-250, 2.5-300, 2.5-500, 3-10, 3-20, 3-30, 3-40, 3-50, 3-60, 3-70, 3-80, 3-90, 3-100, 3-200, 3-250, 3-300, 3-500, 5-10, 5-10, 5-20, 5-30, 5-40, 5-50, 5-60, 5-70, 5-80, 5-90, 5-100, 7.5-10, 7.5-20, 7.5-30, 7.5-40, 7.5-50, 7.5-60, 7.5-70, 7.5-80, 7.5-90, 7.5~100、10~10、10~20、10~30、10~40、10~50、10~60、10~70、10~80、10~90、10~100、10~150、10~200、20~30、20~40、20~50、20~60、20~70、20~80、20~90、20~100、20~150、20~200、30~40、30~50、30~60、30~70、30~80、30~90、30~100、30~150、30~200、40~50、40~60、40~70、40~80、40~90、40~100、40~150、40~200、40~300、50~60、50~70、50~80、50~90、50~100、50~150、50~200、50~250、50~300、60~80、60~100、60~150、60~200、70~100、70~150、70~200、70~250、70~300、70~500、70~750、70~1000、70~1500、70~2000、70~3000、80~100、80~150、80~200、80~250、80~300、80~500、80~750、80~1000、80~1500、80~2000、80~3000、90~100、90~150、90~200、90~250、90~300、90~350、90~400、90~500、90~750、90~1000、90~1500、90~2000、90~3000、100~150、100~200、100~250、100~300、100~350、100~400、100~500、100~600、10. It is administered in amounts of 0-700, 100-800, 100-900, 100-1000, 100-1500, 100-2000, 100-2500, 100-3000, 100-3500, 100-4000, 200-500, 200-700, 200-1000, 200-1500, 200-2000, 200-2500, 200-3000, 200-3500, 200-4000, 500-1000, 500-1500, 500-2000, 500-2500, 500-3000, 500-3500, or 500-4000 mg. In some embodiments, the CTLA-4 inhibitor is administered in an amount of about 10 to 30, 10 to 50, 10 to 80, 10 to 100, 10 to 125, 10 to 150, 10 to 175, 10 to 200, 10 to 250, 10 to 300, 10 to 400, 20 to 50, 20 to 100, 20 to 125, 20 to 150, 20 to 175, 20 to 200, 20 to 250, 20 to 300, 20 to 400, 30 to 50, 30 to 80, 30 to 100, 30 to It is administered in amounts of 125, 30-150, 30-175, 30-200, 30-250, 30-300, 30-400, 40-50, 40-80, 40-100, 40-125, 40-150, 40-175, 40-200, 40-250, 40-300, 40-400, 50-80, 50-100, 50-125, 50-150, 50-175, 50-200, 50-250, 50-300, or 50-400 mg.

[0059] In some embodiments, the use of plinabulin may reduce the incidence of grade 3 / 4 immunotherapy-related adverse events by at least about 1%, 2%, 3%, 4%, 5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, 50%, 52.5%, 55%, 57.5%, 60%, 62.5%, 65%, 67.5%, 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 95%, or 100%. In some embodiments, the use of plinabulin may reduce the incidence of grade 3 / 4 immunotherapy-related adverse events by at least about 5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, 50%, 52.5%, 55%, 57.5%, 60%, 62.5%, 65%, 67.5%, 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 95%, or 100%. In some embodiments, the use of plinabulin may reduce the incidence of grade 3 / 4 immunotherapy-related adverse events by less than about 5%, less than 10%, less than 12.5%, less than 15%, less than 17.5%, less than 20%, less than 22.5%, less than 25%, less than 27.5%, less than 30%, less than 32.5%, less than 35%, less than 37.5%, less than 40%, less than 42.5%, less than 45%, less than 47.5%, less than 50%, less than 52.5%, less than 55%, less than 57.5%, less than 60%, less than 62.5%, less than 65%, less than 67.5%, less than 70%, less than 72.5%, less than 75%, less than 77.5%, less than 80%, less than 82.5%, less than 85%, less than 87.5%, less than 90%, less than 95%, or less than 100%.In some embodiments, the use of plinabulin reduces the incidence of grade 3 / 4 immunotherapy-related adverse events by about 1% to 5%, 1% to 10%, 1% to 15%, 1% to 20%, 1% to 30%, 1% to 40%, 1% to 50%, 2.5% to 10%, 2.5% to 15%, 2.5% to 20%, 2.5% to 30%, 5% to 10%, 5% to 15%, 5% to 20%, 5% to 30%, 5% to 40%, 10% to 40%, 12.5% ​​to 40%, 5% to 50%, 10% to 50% , 12.5% ​​to 50%, 15% to 50%, 17.5% to 50%, 20% to 50%, 25% to 50%, 27.5% to 50%, 30% to 50%, 5% to 60%, 10% to 60%, 12.5% ​​to 60%, 15% to 60%, 17.5% to 60%, 20% to 60%, 25% to 60%, 27.5% to 60%, 30% to 60%, 35% to 60%, 37.5% to 60%, 40% to 60%, 45% to 70%, or 50% to 80%.

[0060] In some embodiments, the use of plinabulin reduces the duration of grade 3 / 4 immunotherapy-related adverse events by about 1%, 2%, 3%, 4%, 5%, 10%, 12.5%, 15%, 17.5%, or %,20%,22.5%,25%,27.5%,30%,32.5%,35%,37.5%,40%,42.5%,45%,47.5%,50%,52.5%,55%,57.5%,60%,62.5%,65%,67.5%,70%,72.5%,75%,77.5%,80%,82.5%,85%,87.5%,90%,95%,10 The decrease may be by 0%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, or 16-fold. In some embodiments, the use of plinabulin reduces the duration of grade 3 / 4 immunotherapy-related adverse events by about more than 1%, more than 2%, more than 3%, more than 4%, more than 5%, more than 10%, more than 12.5%, more than 15%, more than 17.5%, more than 20%, more than 22.5%, more than 25%, more than 27.5%, more than 30%, more than 32.5%, more than 35%, more than 37.5%, more than 40%, more than 42.5%, more than 45%, more than 47.5%, more than 50%, more than 52.5%, more than 55%, more than 57.5%, more than 60%, more than 62.5%, more than 65%, more than 67.5%, more than 70%, more than 72.5%, more than 75% more than 77.5%, more than 80%, more than 82.5%, more than 85%, more than 87.5%, more than 90%, more than 95%, more than 100%, more than 110%, more than 120%, more than 130%, more than 140%, more than 150%, more than 160%, more than 170%, more than 180%, more than 190%, more than 200%, more than 225%, more than 250%, more than 275%, more than 300%, more than 350%, more than 400%, more than 450%, more than 500%, more than 600%, more than 700%, more than 800%, more than 900%, more than 10-fold, more than 11-fold, more than 12-fold, more than 13-fold, more than 14-fold, more than 15-fold, or more than 16-fold.In some embodiments, the use of plinabulin reduces the duration of grade 3 / 4 immunotherapy-related adverse events by about less than 5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5%, 30%, 32.5%, 35%, 37.5%, 40%, 42.5%, 45%, 47.5%, 50%, 52.5%, 55%, 57.5%, 60%, 62.5%, 65%, 67.5%, 70%, 72.5%, 75%, 77.5%, 80%, 90%, 95%, 100%, 105%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 210%, 220%, 230%, 240%, 250%, 260%, 270%, 280%, 290%, 310%, 320%, 330%, 340%, 350%, 360%, 370%, 380%, 390%, 410%, 420%, 450%, 470%, 450%, 470%, 500%, 520%, 550%, 570%, 600%, 620%, 650%, 670%, 700%, 720%, 750%, 770%, 800%, 900%, 105%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 210%, 220%, 230%, 240%, 250%, 260%, %, less than 82.5%, less than 85%, less than 87.5%, less than 90%, less than 95%, less than 100%, less than 110%, less than 120%, less than 130%, less than 140%, less than 150%, less than 160%, less than 170%, less than 180%, less than 190%, less than 200%, less than 225%, less than 250%, less than 275%, less than 300%, less than 350%, less than 400%, less than 450%, less than 500%, less than 600%, less than 700%, less than 800%, less than 900%, less than 10-fold, less than 11-fold, less than 12-fold, less than 13-fold, less than 14-fold, less than 15-fold, or less than 16-fold. In some embodiments, the use of plinabulin may reduce the duration of grade 3 / 4 immunotherapy-related adverse events by a percentage within the range of about 5% to 10%, 5% to 20%, 5% to 30%, 5% to 40%, 5% to 50%, 5% to 60%, 5% to 70%, 5% to 80%, 5% to 100%, 5% to 2-fold, 5% to 5-fold, 5% to 15-fold, 20% to 10-fold, or 50% to 500%.

[0061] Some embodiments relate to a method of treating or preventing an inflammatory skin or joint condition in a subject, comprising topically administering to the subject in need thereof an effective amount of plinabulin.

[0062] In some embodiments, the skin or joint disease is psoriasis. In some embodiments, the skin or joint disease is arthritis. In some embodiments, the skin or joint disease is rheumatoid arthritis. In some embodiments, the skin or joint disease is selected from ankylosing spondylitis, psoriatic arthritis, sarcoidosis, systemic lupus erythematosus, or atopic dermatitis.

[0063] Some embodiments are directed to treating or preventing an inflammatory disease in a subject selected from the group consisting of rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, systemic lupus erythematosus, inflammatory bowel disease, atopic dermatitis, and multiple sclerosis. The present invention relates to a method for treating a disease comprising administering to said subject in need thereof an effective amount of plinabulin.

[0064] In some embodiments, the plinabulin is administered parenterally. In some embodiments, the plinabulin is administered orally. In some embodiments, the plinabulin is administered topically.

[0065] Some embodiments relate to a method of treating or preventing chronic obstructive pulmonary disease or asthma in a subject, comprising administering to the subject in need thereof an effective amount of plinabulin via an inhaler.

[0066] Compositions and Administration The methods described herein may include administering a composition comprising plinabulin. In some embodiments, the compositions described herein may include one or more pharmaceutically acceptable diluents. In some embodiments, the pharmaceutically acceptable diluent may include Corifol® HS15 (polyethylene glycol (15)-hydroxystearate). In some embodiments, the pharmaceutically acceptable diluent may include Corifol® EL, Corifol® RH40, Corifol® P188, Corifol® P407, and Corifol® F-68. In some embodiments, the pharmaceutically acceptable diluent may include propylene glycol. In some embodiments, the pharmaceutically acceptable diluent may include Corifol and propylene glycol. In some embodiments, the pharmaceutically acceptable diluent may include Corifol and propylene glycol, where Corifol is about 40% by weight and propylene glycol is about 60% by weight, based on the total weight of the diluent. In some embodiments, the compositions may further include one or more other pharmaceutically acceptable excipients.

[0067] Some embodiments relate to topical formulations comprising plinabulin at a concentration that is effective to inhibit PDE4 activity without reducing blood vessel growth or density.

[0068] When applied to the skin, nails, hair, hands, or feet, the amount of plinabulin in the topical formulation is sufficient to produce the desired pharmacological result locally at the site of application or systemically as a result of transdermal transport of the active ingredient in the material.

[0069] Some embodiments relate to topical formulations comprising plinabulin at a concentration ranging from about 0.1% to about 10% by weight of the total formulation, including about 0.05% to 0.1%, 0.05% to 0.2%, 0.05% to 0.3%, 0.05% to 0.4%, 0.05% to 0.5%, 0.05% to 1%, 0.05% to 2%, 0.05% to 3%, 0.05% to 4%, 0.05% to 5%, 0.05% to 6%, 0.05% to 7%, 0.05%~8%, 0.05%~9%, 0.05%~10%, 0.1%~0.2%, 0.1%~0.3, 0.1%~0.4%, 0.1%~0.5%, 0.1%~1%, 0.1%~2%, 0.1%~3%, 0.1%~4%, 0.1%~5%, 0.1%~6%, 0.1%~7%, 0.1%~8%, 0.1%~9%, 0.1% ~10%, 0.5%~1%, 0.5%~2%, 0.5%~3%, 0.5%~4%, 0.5%~5%, 0.5%~6%, 0.5%~7%, 0.5%~8%, 0.5%~9%, 0.1%~0.2%, 1%~2%, 1%~3%, 1%~4%, 1%~5%, 1%~6%, 1%~7%, 1%~8%, 1%~9%, 1%~10%, 2%~3 %, 2%~4%, 2%~5%, 2%~6%, 2%~7%, 2%~8%, 2%~9%, 2%~10%, 3%~4%, 3%~5%, 3%~6%, 3%~7%, 3%~8%, 3%~9%, 3%~10%, 4%~5%, 4%~6%, 4%~7%, 4%~8%, 4%~9%, 4%~10%, 5%~6%, 5%~7%, 5%~8%, 5%~ In some embodiments, the concentration of plinabulin is within the range of about 0.5% to 2.5%, 1% to 3%, or 2% to 4% by weight of the total formulation. In some embodiments, plinabulin has a concentration of about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the total formulation. In some embodiments, plinabulin has a concentration of greater than about 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the total formulation. In some embodiments, plinabulin has a concentration of less than about 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the total formulation. In some embodiments, plinabulin has a concentration of about 0.1%, 0.2%, 0.3%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of the total formulation.

[0070] In some embodiments, the topical formulation comprises one or more ingredients selected from white petrolatum, propylene glycol, mono- and diglycerides, paraffin, butylated hydroxytoluene, or edetate calcium disodium. In some embodiments, the topical formulation comprises polyoxyl 15 hydroxystearate.

[0071] The topical formulations may contain a liquid or semisolid vehicle, which may include, but is not limited to, polymers, thickeners, buffers, neutralizing agents, chelating agents, preservatives, surfactants or emulsifiers, antioxidants, waxes or oils, emollients, sunscreens, and a solvent or mixed solvent system. The solvent or mixed solvent system is important to the formulation because it primarily serves to dissolve the drug. The most suitable solvent or mixed solvent system will also maintain clinically relevant levels of the drug in solution despite the addition of a poor solvent to the formulation. The topical compositions useful in the subject invention may be made into various types of products, including, but not limited to, patches, lotions, creams, gels, sticks, sprays, ointments, pastes, foams, mousses, masks, eye ointments, eye or ear drops, impregnated bandages, wipes, cleansers including soaps, body washes and shampoos, and cosmetics such as makeup primers, blushers, lipsticks, and eye shadows, among others. These types of products can include several types of carrier systems, including, but not limited to, particles, nanoparticles, and liposomes. The formulations can be selected to maximize delivery to the desired target area in the body. The formulations can also include various conventional colorants, fragrances, thickeners, preservatives, humectants, emollients, demulsifiers, solubilizing excipients, dispersants, penetration enhancers, plasticizers, preservatives, stabilizers, demulsifiers, humectants, sunscreens, emulsifiers, moisturizers, astringents, deodorants, and the like, which can be added to provide additional benefits, such as improving the feel or appearance of the topical preparation.

[0072] In some embodiments, the formulation is in the form of a lotion, cream, ointment, gel, emulsion, or suspension.

[0073] A topical drench is a preparation that is applied without friction to the surface of the skin, nail, hair, claw, or hoof and is typically a liquid preparation or a semi-liquid preparation with finely divided solids, waxes, or liquids dispersed therein. Topical drenches will typically contain a suspending agent to create a better dispersion, as well as compounds useful for localizing and retaining the active agent on the skin, nail, hair, claw, or hoof, such as methylcellulose, sodium carboxymethylcellulose, and the like.

[0074] Creams containing the active agent for delivery according to the present invention are viscous liquid or semi-solid oil-in-water or water-in-oil emulsions. The cream base is water-washable, and The oil phase generally comprises petrolatum or a fatty alcohol such as cetyl alcohol or stearyl alcohol, and the aqueous phase is usually, but not always, larger in volume than the oil phase and generally contains a humectant.

[0075] Gel formulations can also be used in conjunction with the present invention. As those skilled in the art of topical pharmaceutical formulations will appreciate, gels are semi-solid. Single-phase gels contain organic macromolecules substantially uniformly distributed in a liquid carrier, which is typically aqueous but may be a solvent or solvent mixture. Conventional gelling agents can be used in various embodiments. Exemplary embodiments use cellulose or its derivatives. Exemplary embodiments use hydroxypropyl methylcellulose, such as Methocel E4M. Other gelling agents include methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate, ethylcellulose, methylhydroxyethylcellulose, hydroxyethylcellulose, and cellulose gum. Cellulose-based gelling agents, particularly hydroxymethylcellulose and hydroxypropyl methylcellulose, are also useful in some embodiments. Cross-linked acrylic polymers, including carbopol, may also be used in some embodiments.

[0076] In one embodiment, the formulations of the present invention are sufficiently viscous to form a firm gel, in one embodiment, the viscosity is in the range of 25,000 to 300,000 cps (centipoise) or 75,000 to 200,000 cps based on Brookfield (LV) analysis.

[0077] For ease of preparation, it may be convenient to prepare a first gel composition, herein designated a "Speed ​​Gel," which can be used to add to other components in the formulation of the final composition for topical administration. There are several possible formulations of the Speed ​​Gel. For example, a Speed ​​Gel can be prepared by mixing lecithin organogel (LO), a 1:1 (wt / wt) mixture of lecithin and isopropyl myristate, with LID oil (a 1:1 (wt / wt) mixture of LO and docusate sodium), dissolving additional docusate sodium powder in the mixture, and adding urea water.

[0078] Ointments are semisolid preparations, typically based on petrolatum or other petroleum-based bases. As those skilled in the art will appreciate, the particular ointment base used will provide optimal delivery of the active agent selected for a given formulation, and preferably will also provide other desired characteristics, such as emollient properties. Like other carriers or vehicles, ointment bases should be inert, stable, nonirritating, and nonsensitizing. As explained in Remington, The Science and Practice of Pharmacy, 19th Edition (Easton, PA: Mack Publishing, 1995), pages 1399-1404, ointment bases can be divided into four classes: oleaginous bases, emulsifiable bases, emulsifiable bases, and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, animal fats, and semisolid hydrocarbons derived from petroleum. Examples of oily ointment bases include USP white ointment, USP yellow ointment, USP oleic acid, USP olive oil, USP paraffin, USP petrolatum, USP white petrolatum, USP spermaceti wax, USP synthetic spermaceti, USP glycerin ointment, USP white wax, and USP yellow wax. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin, and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions and include, for example, cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols of various molecular weights. For more information, see Remington's The Science and Please refer again to the Practice of Pharmacy.

[0079] Useful formulations of the present invention also include sprays and aerosols. Sprays provide the active agent in an aqueous and / or alcoholic solution that can be sprayed onto the skin, nail, hair, claw, or hoof for delivery. Such sprays include sprays formulated to provide a concentrated active agent at the site of administration and subsequent delivery; for example, the spray solution may be composed primarily of alcohol or other similar volatile liquids capable of dissolving the drug or active agent. Upon delivery to the skin, nail, hair, claw, or hoof, the carrier evaporates, leaving a concentrated active agent at the administration site. Examples of aerosol technology are disclosed in U.S. Patent Nos. 6,682,716,415, 6,716,417, 6,783,753, 7,029,658, and 7,033,575.

[0080] The topical pharmaceutical compositions may comprise a suitable solid or gel phase carrier, examples of which include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0081] The topical pharmaceutical composition may also contain a suitable emulsifier, which is an agent that enhances or promotes the mixing and suspension of oil-in-water or water-in-oil systems. The emulsifier used in the present invention may consist of a single emulsifier or may be a nonionic, anionic, cationic, or amphoteric surfactant, or a mixture of two or more such surfactants; nonionic or anionic emulsifiers are preferred for use in the present invention. Such surfactants are described in "McCutcheon's Detergents and Emulsifiers," North American Edition, 1980, published by McCutcheon Division of MC Publishing, 175 Rock Road, Glen Rock, New Jersey 07452, USA.

[0082] Examples of useful ionic surfactants include sodium caproate, sodium caprylate, sodium caprate, sodium laurate, sodium myristate, sodium myristoleate, sodium palmitate, sodium palmitate, sodium oleate, sodium ricinoleate, sodium linoleate, sodium linolenate, sodium stearate, sodium lauryl (dodecyl) sulfate, sodium tetradecyl sulfate, sodium lauryl sarcosinate, dioctyl sodium sulfosuccinate, sodium cholate, sodium taurocholate, sodium glycocholate, sodium deoxycholate, sodium taurodeoxycholate, sodium glycodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, sodium taurochenodeoxycholate, sodium glycochenodeoxycholate, sodium cholyl sarcosinate, sodium N-methyltaurocholate, egg yolk phospholipids, hydrogenated soybean lecithin, sodium hydroxybenzoate ... Lecithin, dimyristoyl lecithin, lecithin, hydroxylated lecithin, lysophosphatidylcholine, cardiolipin, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidic acid, phosphatidylglycerol, phosphatidylserine, diethanolamine, phospholipids, polyoxyethylene-10 oleyl ether phosphate, esters of fatty alcohols or fatty alcohol ethoxylates with phosphoric acid or anhydrides, ether carboxylic acids (fatty acid (by oxidation of the terminal OH group of alcohol ethoxylate), succinylated monoglycerides, sodium stearyl fumarate, propylene glycol stearoyl hydrogen succinate, mono- and diacetylated tartaric acid esters of mono- and diglycerides, citric acid esters of mono- and diglycerides, glyceryl lactate esters of fatty acids, acyl lactates, lactyl esters of fatty acids, sodium stearoyl-2-lactylate, sodium stearoyl lactylate, alginates, propylene glycol alginate Counterions include ethoxylated alkyl sulfates, alkylbenzene sulfones, α-olefin sulfonic acids, acyl isethionates, acyltaurates, alkyl glyceryl ether sulfonic acids, sodium octyl sulfosuccinate, sodium undecylenamideo-MEA-sulfosuccinate, hexadecyltriammonium bromide, decyltrimethylammonium bromide, cetyltrimethylammonium bromide, dodecylammonium chloride, alkylbenzyldimethylammonium salts, diisobutylphenoxyethoxydimethylbenzylammonium salts, alkylpyridinium salts, betaine (trialkylglycine), lauryl betaine (N-lauryl-N,N-dimethylglycine), and ethoxylated amines (polyoxyethylene-15 coconut amine). Briefly, typical counterions are listed above. However, it will be understood by those skilled in the art that any biologically acceptable counterion can be used. For example, although the fatty acids are shown as sodium salts, other cationic counterions, such as alkali metal cations or ammonium, can also be used. Formulations of the invention may include one or more of the ionic surfactants listed above.

[0083] Some high molecular weight alcohols include cetearyl alcohol, cetyl alcohol, stearyl alcohol, emulsifying wax, glyceryl monostearate, and oleyl alcohol. Other examples include ethylene glycol distearate, sorbitan tristearate, propylene glycol monostearate, sorbitan monooleate, sorbitan monostearate (SPAN 60), diethyl glycol monolaurate, sorbitan monopalmitate, sucrose dioleate, sucrose stearate (Clodesta F-160), polyoxyethylene lauryl ether (BRIJ 30), polyoxyethylene (2) stearyl ether (BRIJ 72), polyoxyethylene (21) stearyl ether (BRIJ 721), polyoxyethylene monostearate, and polyoxyethylene glycerin. Examples of suitable emulsifiers include polyoxyethylene (20) sorbitan monolaurate (Myrj45), polyoxyethylene (20) sorbitan monolaurate (TWEEN 20, Polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (TWEEN 40, Polysorbate 40), polyoxyethylene (20) sorbitan monostearate (TWEEN 60, Polysorbate 60), polyoxyethylene (20) sorbitan monooleate (TWEEN 80, Polysorbate 80), other nonionic polyoxyalkylene derivatives of partial long-chain fatty acid esters of hexitol anhydrides, and sodium oleate. In an exemplary embodiment, the emulsifier is octyldodecanol. In an exemplary embodiment, xanthan gum or a xanthan gum mixture is used. Cholesterol and cholesterol derivatives may be used in topical emulsions to promote the formation of a water-in-oil emulsion.

[0084] Some suitable nonionic emulsifiers are those having a hydrophilic-lipophilic balance (HLB) of about 3 to 6 for water-in-oil systems and about 8 to 18 for oil-in-water systems, as determined by the method described by Paul L. Lindner in "Emulsions and Emulsions," edited by Kenneth Lissant, Dekker Company, New York, NY, 1974, pp. 188-190. More preferably, one or more nonionic surfactants that produce systems with an HLB of about 8 to about 18 are used in the present invention.

[0085] Examples of such nonionic emulsifiers include, but are not limited to, polyoxyethylene (2) stearyl ether under the trade name "BRIJ72" having an HLB of 4.9, polyoxyethylene (21) stearyl ether under the trade name "BRIJ721" having an HLB of 15.5, polyoxyethylene lauryl ether under the trade name "Brij30" having an HLB of 9.7, emulsifying wax under the trade name "Polawax" having an HLB of 8.0, sorbitan monostearate under the trade name "Span60" having an HLB of 4.7, and sucrose stearate under the trade name "Clodesta F-160" having an HLB of 14.5. All of these materials are commercially available from Ruger Chemicals, Croda, ICI Americas, Spectrum Chemicals, and BASF. When the topical formulations of the present invention contain at least one emulsifier, each emulsifier is present in an amount of about 0.5 to about 2.5% by weight, preferably 0.5 to 2.0% by weight, and more preferably 1.0% or 1.8% by weight. Preferably, the emulsifier comprises a mixture of steareth 21 (about 1.8%) and steareth 2 (about 1.0%).

[0086] The topical pharmaceutical composition may also contain a suitable emollient. Emollients are substances used to prevent or relieve dryness and to protect the skin, nails, hair, claws, or hooves. Useful emollients include, but are not limited to, hydrocarbon oils, waxes, silicones, cetyl alcohol, isopropyl myristate, stearyl alcohol, oleyl alcohol, octylhydroxystearate, glycerin, other fatty alcohols, including short- or medium-chain fatty alcohols having up to 18 carbons in length, medium- or short-chain fatty acid triglycerides, esters such as fatty acid esters, lecithin and related polar compounds such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, lysophosphatidylcholine, lysophosphatidylethanolamine, and sphingomyelin.Other suitable emollients include triglyceride oils such as wheat germ oil, corn oil, sunflower oil, shea butter oil, castor oil, sweet almond oil, macadamia oil, apricot oil, soybean oil, cottonseed oil, alfalfa oil, poppy seed oil, pumpkin seed oil, sesame oil, cucumber oil, rapeseed oil, avocado oil, hazelnut oil, grapeseed oil, blackcurrant oil, evening primrose oil, millet oil, barley oil, quinoa oil, olive oil, rye oil, safflower oil, kukui seed oil, soybean oil, palm oil, passion flower oil, or vegetable oils such as musk rose oil; caprylic / capric triglycerides, such as those sold under the trade names (Croda, Inc., Edison, New Jersey) and CRODAMOL (Croda, Inc., Edison, New Jersey); fatty alcohols such as capryl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, and stearyl alcohol; and fatty esters such as oleyl acetate, isotridecyl benzoate, diisooctyl sebacate, isopropyl myristate, cetyl octanoate, isopropyl palmitate, butyl stearate, hexyl laurate, myristyl myristate, decyl oleate, hexyldecyl dimethyl octanoate, cetyl lactate, myristyl lactate, lanolin acetate, isocetyl stearate, isocetyl isostearate, cholesteryl 12-hydroxystearate, dipentaerythritol fatty acid esters, and isostearyl malate. A wide variety of suitable emollients are known and can be used herein. See, for example, Sagarin, Cosmetics, Science and Technology, 2nd Edition, Vol. 1, pp. 32-43 (1972), both of which are incorporated herein by reference in their entireties, and U.S. Patent No. 4,919,934 to Deckner et al., issued April 24, 1990. These materials are available from Ruger Chemical Co. (Irvington, NJ).

[0087] When the topical formulations of the present invention contain at least one emollient, each emollient is present in an amount of about 0.1-15% by weight, preferably 0.1-3.0% by weight, and more preferably 0.5, 1.0, or 2.5% by weight. Preferably, the emollient is a mixture of cetyl alcohol, isopropyl myristate, and stearyl alcohol in a 1 / 5 / 2 ratio. The emollient may also be a mixture of cetyl alcohol and stearyl alcohol in a 1 / 2 ratio.

[0088] The topical pharmaceutical composition may also include a suitable antioxidant, which is a substance known to inhibit oxidation. Suitable antioxidants for use in accordance with the present invention include butylated hydroxytoluene, ascorbic acid, sodium ascorbate, calcium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenolol, erythorbic acid, guaiac gum, propyl gallate, thiodipropionic acid, thiodipropionate, and the like. Examples of antioxidants include, but are not limited to, tocopherols such as dilauryl acetate, tert-butylhydroquinone, and vitamin E, as well as pharmaceutically acceptable salts and esters of these compounds. Preferably, the antioxidant is butylated hydroxytoluene, butylated hydroxyanisole, propyl benzoate, ascorbic acid, pharmaceutically acceptable salts or esters thereof, or mixtures thereof. Most preferably, the antioxidant is butylated hydroxytoluene. These materials are available from Ruger Chemical Co. (Irvington, NJ). Antioxidants that may be incorporated into the formulations of the present invention include natural antioxidants prepared from plant extracts such as extracts from aloe vera, avocado, chamomile, Echinacea purpurea, ginkgo biloba, ginseng, green tea, scutellaria, jojoba, lavender, lemongrass, licorice, mallow, oat, peppermint, St. John's wort, willow, wintergreen, wheat and wild yam extracts, marine extracts, and mixtures thereof.

[0089] When the topical formulations of the present invention contain at least one antioxidant, the total amount of antioxidant present is from about 0.001 to 0.5% by weight, preferably 0.05 to about 0.5% by weight, more preferably 0.1%.

[0090] The topical pharmaceutical composition may contain a suitable preservative. Preservatives are compounds added to pharmaceutical formulations to act as antimicrobial agents. Preservatives known in the art to be effective and acceptable in parenteral formulations include benzalkonium chloride, benzethonium, chlorhexidine, phenol, m-cresol, benzyl alcohol, methylparaben, propylparaben, and other parabens, chlorobutanol, o-cresol, p-cresol, chlorocresol, phenylmercuric nitrate, thimerosal, benzoic acid, and various mixtures thereof. See, for example, Wallhausser, K.-H., Develop. Biol. Standard, 24:9-28 (1974) (S. Krager, Basel). Preferably, the preservative is selected from methylparaben, propylparaben, and mixtures thereof. These materials are available from Inolex Chemical Co. (Philadelphia, PA) or Spectrum Chemicals.

[0091] When the topical formulations of the present invention contain at least one preservative, the total amount of preservative present is from about 0.01 to about 0.5% by weight, preferably from about 0.1 to 0.5%, and more preferably from about 0.03 to about 0.15%. Preferably, the preservative is a mixture of methylparaben and propylparaben in a 5 / 1 ratio. When alcohol is used as a preservative, the amount is typically 15-20%.

[0092] The topical pharmaceutical composition may contain a suitable chelating agent for forming a complex with metal cations that do not cross the lipid bilayer. Examples of suitable chelating agents include ethylenediaminetetraacetic acid (EDTA), ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 8-amino-2-[(2-amino-5-methylphenoxy)methyl]-6-methoxyquinoline-N,N,N',N'-tetraacetic acid tetrapotassium salt (QUIN-2). The chelating agents are preferably EDTA and citric acid. The chelating agent may include salts of the above, such as edetate disodium. These materials are available from Spectrum Chemicals.

[0093] When the topical formulations of the present invention contain at least one chelating agent, the total amount of chelating agent present is from about 0.005% to 2.0% by weight, preferably from about 0.05% to about 0.5% by weight, and more preferably about 0.1% by weight.

[0094] The topical pharmaceutical composition comprises a pH adjusting agent for adjusting the pH of the formulation to within a pharmaceutically acceptable range. The composition may also contain a suitable neutralizing agent used in the preparation of the composition. Examples of neutralizing agents include, but are not limited to, trolamine, tromethamine, sodium hydroxide, hydrochloric acid, sodium carbonate, citric acid, acetic acid, and their corresponding acids or bases. Such materials are available from Spectrum Chemicals (Gardena, Calif.).

[0095] When the topical formulations of the present invention contain at least one neutralizing agent, the total amount of neutralizing agent present is about 0.1 to about 10% by weight, preferably 0.1 to about 5.0% by weight, and more preferably about 1.0% by weight. The neutralizing agent is generally added in an amount necessary to bring the formulation to the desired pH. In one embodiment, the pH is about 6.0 to about 8.0. In one embodiment, the pH is about 3.0 to about 4.0.

[0096] The topical pharmaceutical composition may also contain a suitable thickening or viscosity-enhancing agent. These components are dispersible compounds that can increase the viscosity of a polymer-containing solution through the interaction of the polymer with the drug. For example, Carbopol ULTREZ 10, polymethyl methacrylate (PMMA), and fumed silica can be used as viscosity-enhancing agents. These materials are available from Noveon Chemicals, Cleveland, Ohio. Other examples of thickening agents include monoglycerides and fatty alcohols, fatty acid esters of alcohols having from about 3 to about 16 carbon atoms. Examples of suitable monoglycerides are glyceryl monostearate and glyceryl monopalmitate. Examples of fatty alcohols are cetyl alcohol and stearyl alcohol. Examples of suitable esters are myristyl stearate and cetyl stearate. The monoglycerides also function as auxiliary emulsifiers. Other emollients or oily substances that can be used include petrolatum, glyceryl monooleate, myristyl alcohol, and isopropyl palmitate. In one embodiment, the thickener is used in combination with an emulsifier.

[0097] When the topical formulations of the present invention contain at least one viscosity-enhancing agent, the total amount of viscosity-enhancing agent(s) present is from about 0.25% to about 5.0% by weight, preferably from about 0.25% to about 1.0% by weight, and more preferably from about 0.4% to about 0.6% by weight.

[0098] The topical pharmaceutical composition may be prepared from starch, for example, natural starch such as corn starch or potato starch, pregelatinized starch such as National 1551 or Amijele®, or sodium starch glycolate such as Promogel® or Explotab®; wood products, microcrystalline cellulose, for example, Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Disintegrants may also be included, including celluloses such as Tia®, and Solka-Floc®, methylcellulose, croscarmellose, or crosslinked celluloses, for example, crosslinked sodium carboxymethylcellulose (Ac-Di-Sol®), crosslinked carboxymethylcellulose, or crosslinked croscarmellose; crosslinked starches such as sodium starch glycolate; crosslinked polymers such as crospovidone; crosslinked polyvinylpyrrolidone; alginates such as alginic acid or salts of alginic acid such as sodium alginate; clays such as Veegum® HV (magnesium aluminum silicate); gums such as agar gum, guar gum, locust bean gum, karaya gum, pectin, or tragacanth gum; sodium starch glycolate; bentonite; natural sponge; surfactants; resins such as cation exchange resins; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination with starch, etc.

[0099] The topical pharmaceutical composition may also include a suitable nail penetration enhancer. Examples of nail penetration enhancers include mercaptan compounds, sulfites and bisulfites, keratolytic agents, and surfactants. Nail penetration enhancers suitable for use in the invention are described in further detail in Malhotra et al., J. Pharm. Sci., Vol. 91, No. 2, p. 312.

[0100] The topical pharmaceutical composition may also include an anti-foaming bleach inhibitor to enhance the elegance of the cream or lotion and reduce the appearance of a white soapy appearance when the cream or lotion is applied to the skin. One example of such a substance is liquid silicone. Other anti-foaming agents include simethicone, polyglycols, and sorbitan sesquioleate.

[0101] The topical pharmaceutical composition may also contain a post-foaming agent. "Post-foaming" refers to a gel that remains a gel when released from its container but produces a foam when spread on the skin. Post-foaming agents include aliphatic hydrocarbons having 4 to 6 carbon atoms, such as butane, pentane, and hexane (especially pentane and isobutene). Other suitable post-foaming agents include partially or fully halogenated hydrocarbons, such as trichlorofluoroethane. Also, mixtures of aliphatic and halogenated hydrocarbon propellants or post-foaming agents can be used. Generally, suitable post-foaming agents are those that have low solubility in water, e.g., less than about 20 cc of gas per 100 grams of water at 1 atmosphere and 20°C.

[0102] The topical pharmaceutical composition may contain one or more suitable solvents. The ability of any solid substance (solute) to dissolve in any liquid substance (solvent) depends on the physical properties of the solute and the solvent. When the solute and solvent have similar physical properties, the solubility of the solute in the solvent is maximized. This gives rise to the classic understanding that "like dissolves like." Solvents can be characterized as nonpolar, lipophilic oils on the one hand, or polar, hydrophilic solvents on the other. Oil-based solvents dissolve other nonpolar substances through van der Waals interactions, while water and other hydrophilic solvents dissolve polar substances through ionic, dipolar, or hydrogen-bonding interactions. A continuum of solvents can be listed, from the least polar solvent, i.e., hydrocarbons such as decane, to the most polar solvent, water. A solute will have maximum solubility in a solvent of equal polarity. Therefore, for a drug with minimal solubility in water, a less polar solvent will improve its solubility in a solvent with approximately the same polarity as the solute achieving maximum solubility. Most drugs have moderate polarity and therefore exhibit maximum solubility in solvents such as propylene glycol or ethanol, which are significantly less polar than water. If the drug has a higher solubility in propylene glycol (e.g., 8% wt / wt) than in water (e.g., 0.1% wt / wt), adding water to propylene glycol will decrease the maximum drug solubility in the solvent mixture compared to pure propylene glycol. Adding a poor solvent to a good solvent will decrease the maximum solubility in the mixture compared to the maximum solubility in the good solvent.

[0103] When a compound is incorporated into a topical formulation, the concentration of the active ingredient in the formulation may be limited by the solubility of the active ingredient in the selected solvent and / or carrier. Non-lipophilic drugs typically exhibit very low solubility in pharmaceutically acceptable solvents and / or carriers. For example, the solubility of some compounds in water is less than 0.00025% (w / w). The solubility of the same compounds in the present invention is less than about 2% (w / w) in either propylene glycol or isopropyl myristate.

[0104] Examples of solubilizing excipients include polyethoxylated fatty acids, PEG fatty acid diesters, mixtures of PEG fatty acid monoesters and diesters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerylated fatty acids, propylene glycol fatty acid esters, propylene glycol ester-glycerol esters and mixtures of monoglycerides and diglycerides, sterols and sterol derivatives, polyethylene glycol Examples of suitable solvents include sorbitan fatty acid esters, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkylphenols, polyoxyethylene-polyoxypropylene block copolymers, sorbitan fatty acid esters, lower alcohol fatty acid esters, ionic surfactants, tocopherol esters, and sterol esters. In one embodiment of the present invention, ethylhexyl hydroxystearate is the solvent used to dissolve the compounds described herein. In one embodiment of the present invention, diethyleneglycol monoethyl ether (DGME) is the solvent used to dissolve the compounds described herein. In one embodiment of the present invention, diethyleneglycol monoethyl ether (DGME) is the solvent used to dissolve the compounds of the present invention. The compounds of the present invention useful in the present formulations are believed to have a solubility in DGME of about 10% (w / w) to about 25% (w / w). In another embodiment, a cosolvent system of DGME and water is used to dissolve the compounds described herein. In another embodiment, a cosolvent system of DGME and water is used to dissolve the compounds of the present invention. The solvent capacity of DGME decreases when water is added. However, the DGME / water cosolvent system can be tailored to maintain a desired active ingredient concentration of about 0.1% to about 5% (w / w). The active ingredient is preferably present in the topical formulation at a concentration of about 0.5% to about 3% (w / w), more preferably about 1% (w / w). Because DGME is less volatile than water, the active agent is more soluble in a cream formulation as the topical formulation evaporates upon application. This increased solubility reduces the likelihood of reduced bioavailability due to precipitation of the drug on the surface of the skin, nail, hair, claw, or hoof.

[0105] In one embodiment, the vehicle is lipophilic, including oily substances such as petrolatum, mineral oil thickened or gelled with polyethylene, high molecular weight paraffin wax, mono- and diglycerides of fatty acids gelled with polyamide complexes of high molecular weight fatty acids or hydroxystearates, propylene glycol isostearate or isostearyl alcohol gelled with high molecular weight fatty acids, and mixtures thereof.

[0106] The pharmaceutical compositions described herein can be made using standard pharmaceutical formulation techniques, such as those disclosed in Remington, The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins (2005), which is incorporated by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising (a) a safe and therapeutically effective amount of plinabulin or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

[0107] In addition to the topical route of administration, some embodiments include administration by any of the other accepted modes of drug administration that serve similar purposes, including, but not limited to, oral, sublingual, buccal, subcutaneous, intravenous, intranasal, intradermal, intraperitoneal, intramuscular, pulmonary, vaginal, rectal, or intraocular administration.

[0108] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants, such as those commonly used in the art, may be included. The reasons for including various ingredients in pharmaceutical compositions are discussed, for example, in Gilman et al. (eds.), (1990) Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8th ed., which is incorporated herein by reference in its entirety. , Pergamon Press.

[0109] Some examples of substances that can serve as pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEEN; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffers.

[0110] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" refers to a composition containing an amount of a compound or composition suitable for administration to an animal, preferably a mammalian, subject in a single dose in accordance with good medical practice. However, preparing a single dosage form or unit dosage form does not imply that the dosage form is to be administered once per day or once per course of treatment. It is contemplated that such dosage forms may be administered once, twice, three times, or more times per day, and may be administered as an infusion or continuous infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), although a single administration is not specifically excluded, or may be administered more than once during a course of treatment. Those skilled in the art will understand that the formulations are not specifically intended for an entire course of treatment, and such determinations are left to those skilled in the therapeutic arts rather than those skilled in the formulation arts.

[0111] Some embodiments include compositions in any of a variety of suitable forms for various routes of administration other than topical, such as oral, sublingual, buccal, nasal, rectal, intradermal, intraocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes. Those skilled in the art will appreciate that oral and nasal compositions include compositions administered by inhalation and prepared using available methodologies. Depending on the particular route of administration desired, various pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropic agents, surfactants, and encapsulating materials. Optional pharmaceutically active substances may be included, provided they do not substantially interfere with the activity of the compound or composition. The amount of carrier used with the compound or composition is sufficient to provide a practical amount of the substance per administration of a unit dose of the compound. Techniques and compositions for forming dosage forms useful in the methods described herein are described in the following references: Modern Pharmaceutics, 4th Edition, Chapters 9 and 10 (Banker & Rhodes, eds., 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms, 8th Edition (2004), all of which are incorporated herein by reference.

[0112] A variety of oral dosage forms are available, including solid dosage forms such as tablets, capsules (e.g., liquid gel capsules and solid gel capsules), granules, and bulk powders. Tablets can be compressible, wet compressible, enteric coated, sugar coated, film coated, or multiple compressed, and contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, and contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavoring agents. do.

[0113] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art. Tablets typically contain conventional pharmaceutically compatible adjuvants such as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmellose; and lubricants such as magnesium stearate, stearic acid, and talc. Lubricants such as silicon dioxide can be used to improve the flow properties of the powder mixture. Coloring agents such as FD&C dyes can be added for aesthetic purposes. Sweeteners and flavoring agents such as aspartame, saccharin, menthol, peppermint, sucrose, and fruit flavors are useful adjuvants for chewable tablets. Capsules typically contain one or more of the solid diluents disclosed above. The selection of carrier components is influenced by secondary considerations such as non-critical taste, cost, and storage stability, and the selection of carrier components can be readily made by one skilled in the art.

[0114] Oral compositions also include liquid solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, Avicel RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as sweeteners, flavoring agents, and coloring agents, as disclosed above.

[0115] Such compositions may be coated by conventional methods, typically with pH- or time-dependent coatings to release the subject composition in the gastrointestinal tract near the desired site of topical application, or at various times to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes, and shellac.

[0116] The compositions described herein may optionally include other pharmaceutical active agents.

[0117] Other compositions useful for achieving systemic delivery of the target compound include sublingual, buccal, and nasal dosage forms. Such compositions typically contain one or more of soluble filler substances such as sucrose, sorbitol, and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. The glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

[0118] Liquid compositions are formulated for ophthalmic use and are formulated to allow administration to the eye. While less than optimal comfort may sometimes be required for formulation reasons (e.g., drug stability), comfort can be maximized whenever possible. If maximizing comfort is not possible, the solution may be formulated so that the solution is tolerable to patients for topical ophthalmic use. Additionally, ophthalmically acceptable solutions may be packaged for single use or may contain preservatives to prevent contamination from multiple uses.

[0119] For ophthalmic applications, solutions or medications are prepared using saline solution as the primary vehicle. Ophthalmic solutions are often prepared in a variety of formulations. Ophthalmic solutions may preferably be maintained at a comfortable pH using an appropriate buffer system. The formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0120] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic formulations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0121] Isotonicity adjusting agents may be added as needed, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable isotonicity adjusting agent.

[0122] A variety of buffers and pH adjusting means may be used as long as the resulting formulation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Buffers therefore include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. The pH of these formulations may be adjusted as needed using acids or bases.

[0123] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0124] Another excipient component that may be included in the ophthalmic formulation is a chelating agent. A useful chelating agent is edetate disodium (EDTA), although other chelating agents may be substituted or used in combination.

[0125] For intravenous administration, the compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or glucose solution. Suitable excipients may be included to achieve the desired pH, including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as glucose, mannitol, and dextran. Further acceptable excipients are described in Powell et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech, 1998, Vol. 52, pp. 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech, 2011, Vol. 65, pp. 287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0126] The compositions for intravenous administration are diluted with sterile water, saline, or dextrose solution shortly before administration. In some embodiments, the composition may be provided to the caregiver in the form of a solid, ready to be reconstituted with a suitable diluent, such as a liquid. In other embodiments, the composition is provided in a solution that is ready for parenteral administration. In yet other embodiments, the composition is provided in a solution that is further diluted prior to administration. In embodiments involving administering a combination of a compound described herein and another agent, the combination may be provided to the caregiver as a mixture, the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0127] The administration period can be a treatment cycle of several weeks, as long as inflammation continues to be controlled and the treatment plan is clinically acceptable. In some embodiments, a single dose of plinabulin or other therapeutic agent can be administered once a week, preferably once on each of days 1 and 8 of a 3-week (21-day) treatment cycle. In some embodiments, a single dose of plinabulin or other therapeutic agent can be administered once a week for 2, 3, 4, 5, 6, 7, or 8 weeks, preferably on day 1 of each week. In some embodiments, a single dose of plinabulin or other therapeutic agent can be administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or daily during a 1-week, 2-week, 3-week, 4-week, or 5-week treatment cycle. The administration can occur on the same day of the week or on different days each week during the treatment cycle.

[0128] In some embodiments, the administration schedule of plinabulin can be the same as the administration schedule of the checkpoint inhibitor. In some embodiments, the administration schedule of plinabulin can be different from the administration schedule of the checkpoint inhibitor. In some embodiments, plinabulin and the checkpoint inhibitor (e.g., nivolumab) are both administered every two weeks (e.g., days 1 and 15 of a 28-day cycle). In some embodiments, the checkpoint inhibitor (e.g., nivolumab) is administered on days 1 and 15 of a 28-day cycle, and plinabulin is administered on days 1, 8, 15, and 22 of a 28-day cycle. In some embodiments, plinabulin and the checkpoint inhibitor (e.g., pembrolizumab) are both administered every three weeks (e.g., days 1 and 22 of a 42-day cycle). In some embodiments, when plinabulin is used in combination with the first and second checkpoint inhibitors, the plinabulin is administered on the same administration days and according to the same schedule as the first checkpoint inhibitor, where the first checkpoint inhibitor (e.g., 1 mg / kg nivolumab) and plinabulin are co-administered once every three weeks for four doses, followed by administration of a second checkpoint inhibitor (e.g., ipilimumab) on the same day, and then co-administering the first checkpoint inhibitor (e.g., 240 mg per dose of nivolumab) and plinabulin every two weeks for two doses without the second checkpoint inhibitor. In some embodiments, plinabulin is administered before the first immune checkpoint inhibitor. In some embodiments, plinabulin is administered a time (e.g., about 30 minutes, 1 hour, 2 hours, or 4 hours) after administration of the first immune checkpoint inhibitor. In some embodiments, plinabulin is administered simultaneously with the first immune checkpoint inhibitor.

[0130] The treatment cycle can be repeated as long as the treatment regimen is clinically approved. In some embodiments, the treatment cycle is repeated n times, where n is an integer ranging from 2 to 30. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.In some embodiments, a new treatment cycle may begin immediately after the completion of a previous treatment cycle. In some embodiments, a new treatment cycle may begin a period of time after the completion of a previous treatment cycle. [Example]

[0129] Example 1 Phosphodiesterase assays, including PDE3 assays, PDE4 assays, and PDE5 assays Plinabulin was tested using enzyme assays. The starting point for the PDE3 and PDE5 assays was human platelets, and the starting point for the PDE4 assay was human U937 cells. The substrate for all three assays was 1.01 μM [.H]cAMP + cAMP. For all three assays, the pre-incubation time was 15 minutes, the incubation time was 20 minutes, and the pre-incubation and incubation temperatures were 25°C. The quantification method was [ 3 Quantification of [H] adenosine was included, and the significance criterion was set at i50% of maximal stimulation or maximal inhibition. The results of the study are shown in Table 1. [Table 1]

[0130] As shown in Table 1, plinabulin exhibited superior inhibitory activity against PDE4 compared to the activities against other PDE3 and PDE5.

[0131] Example 2 Patients were treated with docetaxel and plinabulin (DN) or docetaxel alone (75 mg / m 2 ) (D). Two types of medication cohort studies were conducted. 1) 30 mg / m 2 Medication cohort: Docetaxel and plinabulin 30 mg / m 2 (DN30mg / m 2 Patients were randomized (1:1) to receive either docetaxel alone (Group A) or docetaxel alone (Group B). 2) 20 mg / m 2Medication cohort: Docetaxel and plinabulin 20 mg / m 2 (DN20mg / m 2 Patients were randomized (2:1) to receive either docetaxel alone (Group D) or docetaxel alone (Group B).

[0132] Dosage regimen Patients received treatment on days 1 and 8 of a 3-week cycle. Day 1 treatment was 75 mg / m 2 administered by intravenous infusion (IV) over 1 hour. 2 of docetaxel, followed 2 hours later by intravenous infusion (IV) over 30 minutes (Group D) or placebo (Group B) at 30 mg / m 2 or 20 mg / m 2 On Day 8, treatment consisted of either placebo (Group D) or 30 mg / m plinabulin administered by intravenous infusion (IV) over 30 minutes (Group DN). Oral dexamethasone (16 mg) was administered the day before, the day of, and the day after docetaxel infusion (Day 1). On Day 8, treatment consisted of placebo (Group D) or 30 mg / m plinabulin administered by intravenous infusion (IV) over 30 minutes (Group DN). 2 or 20 mg / m 2 The patients received plinabulin (DN group).

[0133] Patients who experience treatment-emergent drug-related adverse events (excluding alopecia, anorexia, and fatigue) greater than Grade 2 according to the CTCAE (version 3.0) may have treatment delayed until the adverse event has resolved to less than Grade 1. Safety laboratory tests must be performed at the start of each subsequent cycle and before treatment with docetaxel according to the following criteria: AST ≤ 2.5 x ULN, ALT ≤ 2.5 x ULN (or ≤ 1.5 x ULN if alkaline phosphatase ≥ 2.5 x ULN), bilirubin ≤ ULN, hemoglobin ≥ 9 g / dL, and absolute neutrophil count ≥ 1.5 x 10 9 / L or more, and the platelet count is 100 × 10 9 The dose was reduced in patients with recurrent toxic symptoms or certain severe toxic symptoms.

[0134] The initial dose of plinabulin is 30 mg / m 2or 20 mg / m 2 The dose adjustment was The administration depended on the adverse events observed. The administration volume varied based on the assigned dose and the patient's body surface area. The clinical formulation was supplied as a concentrated solution in amber vials containing 80 mg of drug (4 mg / mL) in 20 mL of 40% Solutol® HS-15 / 60% propylene glycol at room temperature. Each vial was single-use. The exact drug concentration (4 mg / mL in the vial) was diluted 1:20 in 5% dextrose in water (D5W) and administered intravenously (IV) to the distal and central sites. The infusion time may be increased as clinically indicated by the provider's instructions. Plinabulin and placebo should be administered within 6 hours of dilution.

[0135] The initial dose of docetaxel was 75 mg / m 2 Dose adjustments depended on observed adverse events. Administration was by 1-hour intravenous (IV) infusion per institutional protocol at the dose prescribed by the study protocol. Oral dexamethasone (16 mg) was administered the day before, the day of, and the day after docetaxel infusion (Day 1). A similar corticosteroid premedication schedule was used according to local institutional practice. For patients already using corticosteroids, the dose of dexamethasone or other corticosteroids was reduced appropriately.

[0136] Baseline Assessments: (within 14 days of treatment initiation, i.e., 14 days prior to treatment through Day 1) Physical examination, vital signs, ECOG performance status, concurrent medication utilization, safety laboratory tests.

[0137] Treatment Phase: Safety assessments (including a complete physical examination) were performed before study drug infusion. Safety assessments (including a complete physical examination) were performed before each subsequent cycle (2+). In addition, the following assessments were performed: blood cell / platelet counts and clinical chemistry with differential were performed up to 72 hours before Day 1 of each cycle, an additional assessment was performed on Cycle Day 1 / 15, and vital signs (heart rate, respiratory rate, blood pressure, and temperature) were recorded immediately before and after each study drug infusion on the day of infusion, and 30 and 60 minutes after the last infusion of Cycle 1. Vitals were recorded before and after each infusion during the physical examination during subsequent cycles.

[0138] Evaluation of response to treatment was performed during the rest period of the second cycle (and approximately every two cycles thereafter).

[0139] Treatment continued until evidence of progressive disease, unacceptable treatment-related adverse events, after which the study was stopped (either by withdrawal of consent or at the investigator's discretion) or the patient was withdrawn from the study.

[0140] Safety assessment: Adverse events spontaneously reported by patients or noted during physical examination, vital signs, ECOG performance status, and laboratory tests. The results of treatment-emergent adverse events (TEAEs) related to dexamethasone are shown in Table 2. Figure 1 shows the percentage of patients who experienced steroid-related effects with plinabulin administration. [Table 2]

[0141] Figure 1 shows that plinabulin causes a dose-dependent increase in steroid (dexamethasone)-related adverse events. 2 The incidence of steroid-related adverse events in patients receiving plinabulin was statistically significant (p = 0.026) compared with patients not receiving plinabulin. This result suggests that the PDE4 inhibitory effect of plinabulin can be translated into a related PDE4 pharmacological effect.

[0142] Example 3 The effect of plinabulin on immune-related AEs with the nivolumab / plinabulin combination was studied. A total of 10 patients have been enrolled to date in two phase 1 trials in patients with NSCLC, with these patients receiving 13.5 mg / m 2 (n=3), or 20 mg / m 2 (n=5), or 30 mg / m 2 Two patients (n=2) received nivolumab (240 mg or 3 mg / kg) in combination with plinabulin. Two patients developed grade 1 or grade 2 IR-AEs that did not require steroid treatment. No grade 3 / 4 IR-AEs were observed. These test results demonstrated that plinabulin is a potent PDE4 inhibitor and exerts "steroid-like" effects clinically. Therefore, plinabulin is a viable alternative to steroids. Preliminary clinical data suggest that the addition of plinabulin to checkpoint inhibitor therapy may prevent IR-AEs.

[0143] In one phase 1 trial, patients were selected only if they met at least the following inclusion criteria: (1) Subjects with histologically or cytologically confirmed metastatic NSCLC whose disease progressed during or after treatment with at least one platinum-containing chemotherapy regimen. (2) Subjects had received at least one prior systemic therapy for metastatic disease. Adjuvant chemotherapy or concurrent chemoradiotherapy for early-stage disease was not considered prior treatment if the patient's disease did not progress within 6 months of completing chemotherapy. (3) Prior chemotherapy must have been completed at least 4 weeks or 5 half-lives (whichever is longer) before administration of the study drug, and all adverse events must have returned to baseline or stabilized. (4) Prior definitive radiation therapy must have been completed at least 4 weeks before administration of the study drug. Prior palliative radiation therapy should have been completed at least 2 weeks before administration of the study drug. Whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and localized radiation to the site of pain or bronchial obstruction were considered palliative. No radiopharmaceuticals (strontium, samarium) were present within 8 weeks prior to study drug administration. (5) Any preceding major surgery must have been completed at least 4 weeks prior to study drug administration. Any preceding minor surgery must have been completed at least 1 week prior to study drug administration, and subjects must have recovered. Percutaneous biopsies should be completed at least 10 days prior to study drug administration. In this study, nivolumab (240 mg) was administered intravenously (IV) to patients on days 1 and 15 until disease progression, and plinabulin was administered at three different doses (13.5 mg / m 2 , 20 mg / m 2 , 30 mg / m 2 ) was administered intravenously (IV) to patients. Plinabulin was administered at 40 mg / m2 in different groups on days 1, 8, and 15 until disease progression. 2 This treatment is repeated every 28 days unless there is progression of the disease or unacceptable toxicity.

[0144] In the other phase 1 trial, patients were selected only if they met at least the following inclusion criteria: (1) Patients must have histologically or cytologically proven stage IIIB or stage IV recurrent or metastatic non-small cell lung cancer (NSCLC). (2) Patients must have received platinum doublet-based treatment (a maximum of two lines of prior systemic therapy for metastatic disease is permitted. Adjuvant chemotherapy or concurrent chemoradiotherapy for early-stage disease is not considered prior treatment if the patient has not progressed within six months of completing the treatment plan. Patients must have a known activating mutation in the epidermal growth factor receptor (EGFR) or a known translocation in anaplastic lymphoma kinase (ALK) or ROS-1. (Patients with advanced disease are eligible if they have progressed or have failed to tolerate a Food and Drug Administration (FDA)-approved targeted therapy.) (3) Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (4) Subjects, including those in the dose-escalation portion of this study, must have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Images must be acquired within 28 days of study enrollment (target lesions may be present in previously irradiated areas if documented (radiographic) disease progression is present in those areas prior to study enrollment). (5) Absolute neutrophil count (ANC) of 1000 / mm 3(6) Platelet count ≥ 75,000 / dL; (7) Hemoglobin ≥ 9g / dL; (8) Total bilirubin ≤ 1.5mg / dL × upper limit of normal (ULN) (excluding subjects with Gilbert's syndrome who may have a total bilirubin ≤ 3.0mg / dL); (9) Serum creatinine ≤ 1.5mg / dL or creatinine clearance ≥ 60mL / min; (10) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal in the absence of hepatic impairment or ≤ 5 times the upper limit of normal in the presence of hepatic impairment. During the study period, patients received plinabulin intravenously (IV) over 30 minutes and nivolumab (3mg / kg) intravenously (IV) over 60 minutes on Days 1 and 15. This treatment is repeated every 28 days unless there is disease progression or unacceptable toxicities. Two doses of plinabulin (20 mg / m 2 and 30 mg / m 2 The percentage of patients experiencing adverse events of grade 3 or higher severity (adverse events were graded using the National Cancer Institute Common Toxicity Criteria, version 4.0) was examined.

[0145] Other embodiments of the present invention include the following. [1] A method for treating or preventing immunotherapy-related adverse events in a subject receiving one or more immune checkpoint inhibitors, the method comprising administering to the subject in need thereof an effective amount of plinabulin. [2] The method according to [1], wherein the one or more checkpoint inhibitors are selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a PD-L3 inhibitor, a PD-L4 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a KIR inhibitor, and a TIM3 inhibitor. [3] The method according to [1] or [2], wherein the immune checkpoint inhibitor is a PD-1 inhibitor. [4] The method according to [1] or [2], wherein the immune checkpoint inhibitor is a PD-L1 inhibitor. [5] The method according to [1] or [2], wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor. [6] The method of [1], wherein the subject is administered a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, and the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor. [7] The method according to [6], wherein the first and second immune checkpoint inhibitors are independently inhibitors selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a PD-L3 inhibitor, a PD-L4 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a KIR inhibitor, and a TIM3 inhibitor. [8] The method according to [7], wherein the first checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor, and the second checkpoint inhibitor is a CTLA-4 inhibitor. [9] The method according to [1], wherein the immunotherapy is a monotherapy comprising administering a single checkpoint inhibitor selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a PD-L3 inhibitor, a PD-L4 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a KIR inhibitor, and a TIM3 inhibitor.

[10] The method according to [9], wherein the checkpoint inhibitor is a PD-1 inhibitor.

[11] The method according to [9], wherein the checkpoint inhibitor is a PD-L1 inhibitor.

[12] The method according to [9], wherein the checkpoint inhibitor is a CTLA-4 inhibitor.

[13] The method according to [1], wherein the immunotherapy is a combination therapy, and the combination therapy comprises administering two or more checkpoint inhibitors selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a PD-L2 inhibitor, a PD-L3 inhibitor, a PD-L4 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a KIR inhibitor, and a TIM3 inhibitor.

[14] The method according to

[13] , wherein the combination therapy comprises administering a PD-1 inhibitor and a CTLA-4 inhibitor.

[15] The method according to

[13] , wherein the combination therapy comprises administering a PD-L1 inhibitor and a CTLA-4 inhibitor.

[16] The method according to any one of

[13] to

[15] , wherein the amount of plinabulin is effective to inhibit PDE4 activity without reducing blood vessel proliferation or density.

[17] The method according to any one of

[13] to

[16] , wherein the amount of plinabulin is within the range of about 1 mg to about 100 mg.

[18] The method according to any one of [1] to

[17] , wherein the immunotherapy-related adverse event is a grade 3 / 4 adverse event.

[19] The method described in any of [1] to

[18] , which comprises identifying a subject at risk of developing a grade 3 / 4 immunotherapy-related adverse event.

[20] The method according to any one of [1] to

[19] , wherein the immunotherapy-related adverse event is selected from the group consisting of pneumonitis, colitis, hepatitis, endocrine disorders, nephritis and renal insufficiency, skin adverse reactions, and encephalitis.

[21] The method described in

[20] , wherein the immunotherapy-related adverse event is pancreatitis, and the immunotherapy comprises administering a PD-1 inhibitor and a CTLA-4 inhibitor.

[22] The method according to any one of [1] to

[20] , wherein the immunotherapy-related adverse event is the immunotherapy-induced inflammation.

[23] The immunotherapy-induced inflammation is characterized by pancreatitis, pneumonitis, colitis, hepatitis, nephritis and renal insufficiency, hypothyroidism and hyperthyroidism, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, facial and abducens nerve palsy, hypophysitis, diabetic ketoacidosis, hypopituitarism, Guillain-Barré syndrome, myasthenic syndrome, hypophysitis, thyroiditis, type 1 diabetes, arthritis, exfoliative dermatitis, bullous pemphigoid, myositis, myasthenia gravis, vasculitis, hemolytic anemia, intracerebral inflammatory disease, and pulmonary embolism.

[22] The method according to

[22] , wherein the symptom is selected from the group consisting of partial seizures, dermatitis, rash, pruritus, meningitis, sarcoidosis, pericarditis, fatal myocarditis, vasculopathy, temporal arteritis, vasculitis, rheumatic myalgia, conjunctivitis, blepharitis, episcleritis, scleritis, iritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, arthritis, autoimmune thyroiditis, neurosensory hypoacusis, autoimmune central nervous system disorders, myositis, polymyositis, and extraocular myositis, and hemolytic anemia occurring in patients with inflammatory foci in the skin.

[24] The method according to any one of [1] to

[23] , further comprising identifying a subject having the immunotherapy-associated adverse event before administering an effective amount of plinabulin to the subject.

[25] The method according to any one of [1] to

[24] , further comprising identifying a subject having a grade 3 / 4 immunotherapy-related adverse event before administering an effective amount of plinabulin to the subject.

[26] The method according to any of [1] to

[25] , wherein the incidence of immunotherapy-related adverse events is reduced by at least 10%.

[27] The method according to any one of [1] to

[26] , wherein the severity of immunotherapy-related adverse events is reduced by at least 10%.

[28] A method for reducing the incidence of immunotherapy-associated adverse events, comprising administering an effective amount of plinabulin to a subject in need thereof who is receiving one or more immune checkpoint inhibitors.

[29] A method for shortening the duration of immunotherapy-associated adverse events, comprising administering an effective amount of plinabulin to a subject in need thereof who is receiving one or more immune checkpoint inhibitors.

[30] The method according to any one of [1] to

[29] , wherein the subject also receives radiation therapy.

[31] A method for treating or preventing an inflammatory skin or joint disease in a subject, comprising topically administering to the subject in need thereof an effective amount of plinabulin.

[32] The method according to

[31] , wherein the skin or joint disease is psoriasis.

[33] The method according to

[31] , wherein the skin or joint disease is arthritis.

[34] The method according to

[31] , wherein the skin or joint disease is rheumatoid arthritis.

[35] The method according to

[31] , wherein the skin or joint disease is selected from ankylosing spondylitis, psoriatic arthritis, sarcoidosis, systemic lupus erythematosus, or atopic dermatitis.

[36] A method for treating or preventing an inflammatory disease in a subject selected from the group consisting of rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, systemic lupus erythematosus, inflammatory bowel disease, atopic dermatitis, and multiple sclerosis, comprising administering an effective amount of plinabulin to the subject in need thereof.

[37] The method according to

[36] , wherein the plinabulin is administered parenterally.

[38] The method according to

[36] , wherein the plinabulin is administered orally.

[39] The method according to

[36] , wherein the plinabulin is administered locally.

[40] A method for treating or preventing chronic obstructive pulmonary disease or asthma in a subject, comprising administering to the subject in need thereof via an inhaler an effective amount of plinabulin.

[41] A topical formulation comprising plinabulin at a concentration effective to inhibit PDE4 activity without reducing blood vessel growth or density.

[42] A topical formulation comprising plinabulin at a concentration ranging from about 0.1% to about 10% by weight of the total formulation.

[43] The formulation according to

[41] or

[42] , wherein the concentration of plinabulin is within the range of about 0.5% to about 5% by weight of the total formulation.

[44] The formulation according to any one of

[41] to

[43] , further comprising one or more excipients.

[45] The formulation according to any one of

[41] to

[44] , further comprising one or more ingredients selected from white petrolatum, propylene glycol, monoglycerides and diglycerides, paraffin, butylated hydroxytoluene, and calcium disodium edetate.

[46] The formulation according to any one of

[41] to

[45] , further comprising polyoxyl 15 hydroxystearate.

[47] The formulation according to any one of

[41] to

[46] , wherein the formulation is in the form of a cream, ointment, gel, emulsion, or suspension.

Claims

1. A topical composition comprising prinabulin for treating or preventing inflammatory skin or joint diseases associated with immune-mediated inflammation, comprising an amount of prinabulin effective for inhibiting PDE4 activity.

2. The composition according to claim 1, wherein the inflammatory skin or joint disease is selected from the group consisting of psoriasis, arthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, systemic lupus erythematosus, and atopic dermatitis.

3. A composition comprising prinabulin for treating or preventing an immune-mediated inflammatory disease, wherein the inflammatory disease is selected from rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, ankylosing spondylitis, psoriatic arthritis, sarcoidosis, systemic lupus erythematosus, inflammatory bowel disease, atopic dermatitis, or multiple sclerosis.

4. The composition according to claim 3, wherein the prinabulin is administered parenterally, orally, or topically.

5. The composition according to claim 1, wherein the composition is a topical formulation, and the topical formulation contains prinabulin at a concentration effective for inhibiting PDE4 activity without causing proliferation or reduction of blood vessel density.

6. The composition according to claim 1 or 5, comprising prenablin at a concentration in the range of 0.1% to 10% based on the total weight of the composition.

7. The composition according to claim 6, wherein the concentration of the prenabulin is in the range of 0.5% to 5% of the total weight of the composition.

8. The composition according to claim 6 or 7, further comprising one or more excipients.

9. White petrolatum, propylene glycol, monoglycerides and diglycerides, paraffin, The composition according to any one of claims 6 to 8, further comprising one or more components selected from butylated hydroxytoluene or calcium disodium edetate.

10. The composition according to any one of claims 6 to 9, further comprising polyoxyl 15-hydroxystearate.

11. The composition according to any one of claims 6 to 10, wherein the composition is in the form of a cream, ointment, gel, emulsion, or suspension.

12. The composition according to any one of claims 1 to 11, wherein the composition is a topical composition for treating or preventing inflammatory skin or joint disease caused as an immunotherapy-related adverse event.

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