Compositions and methods for reducing chemotherapy-induced neutropenia by administration of plinabulin and g-CSF formulations

Abstract

It is the object of the present invention to provide prinabulin and one or more G-CSF agents for the treatment of chemotherapy-induced neutropenia, stimulation of neutrophil survival, reduction of bone pain induced by G-CSF agents and immunosuppressive effects induced by G-CSF agents.SOLUTION: It has been found that Plinabulin and one or more G-CSF formulations can be provided for treatment of chemotherapy-induced neutropenia, stimulation of neutrophil survival, reduction of bone pain induced by G-CSF formulations and immunosuppressive effects induced by G-CSF formulations, and that docetaxel-induced neutropenia can be reduced by co-administration of Plinabulin and one or more G-CSF compounds.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to a method for reducing or ameliorating neutropenia using plinabulin. [Background technology]

[0002] Myelosuppression is a primary toxicity of many chemotherapy regimens, often with limited application. Both the duration of grade 4 neutropenia and the depth of the neutrophil nadir are associated with severe and fatal infections. As a result, neutropenia prevention is a major goal for oncology practitioners for both safety and cost-effectiveness as well as quality of life.

[0003] Neutropenia is a frequent and potentially fatal complication of cytotoxic myelosuppressive chemotherapy. Studies have shown that patients with neutropenia are more susceptible to infections that often require antibiotic treatment and, in severe cases, require hospitalization. Furthermore, severe neutropenia often necessitates modifications to chemotherapy regimens, thereby compromising the ultimate success of anticancer treatment plans. Summary of the Invention

[0004] Some embodiments relate to methods of treating chemotherapy-induced neutropenia comprising co-administering plinabulin and one or more G-CSF compounds.

[0005] Some embodiments relate to a method for reducing bone pain, comprising administering an effective amount of plinabulin. In some embodiments, the bone pain is induced by a G-CSF formulation. In some embodiments, the bone pain is induced by pegfilgrastim.

[0006] Some embodiments relate to methods of stimulating neutrophil survival comprising co-administering plinabulin and one or more G-CSF compounds.

[0007] Some embodiments relate to a method of treating a patient receiving docetaxel in an amount sufficient to cause neutropenia, the method comprising co-administering plinabulin and one or more G-CSF compounds to reduce or prevent neutropenia in the patient.

[0008] Some embodiments provide a method of treating docetaxel-induced neutropenia in a subject comprising co-administering plinabulin and one or more G-CSF compounds, wherein plinabulin is administered at a dose of about 1 mg / m 2 ~about 50mg / m 2 The present invention relates to a method of administering the compound at a dosage in the range of

[0009] Some embodiments provide a method for treating docetaxel-induced neutropenia in a subject afflicted with advanced breast cancer (e.g., early stage or metastatic breast cancer), comprising identifying the patient as having advanced or metastatic breast cancer; and co-administering plinabulin and one or more G-CSF compounds, wherein plinabulin is administered at a dose of about 1 mg / m 2 ~about 50mg / m 2 The present invention relates to a method of administering the compound at a dosage in the range of

[0010] Some embodiments provide a method of treating docetaxel-induced neutropenia in a subject afflicted with non-small cell lung cancer, comprising identifying the patient as having non-small cell lung cancer; and co-administering plinabulin and one or more G-CSF compounds, wherein plinabulin is administered at a dose of about 1 mg / m 2 ~about 50mg / m 2 The present invention relates to a method of administering the compound at a dosage in the range of

[0011] Some embodiments include a method of treating docetaxel-induced neutropenia in a subject afflicted with hormone-refractory metastatic prostate cancer, comprising identifying the patient as having hormone-refractory metastatic prostate cancer; and co-administering plinabulin and one or more G-CSF compounds, wherein the plinabulin is administered at a dose of about 1 mg / m 2 ~about 50mg / m 2The present invention relates to a method of administering the compound at a dosage in the range of

[0012] Some embodiments provide a method of stimulating neutrophil survival comprising co-administering plinabulin and one or more G-CSF compounds, wherein plinabulin is administered at a dose of about 1 mg / m 2 ~about 50mg / m 2 The present invention relates to a method of administering the compound at a dosage in the range of

[0013] Some embodiments relate to pharmaceutical compositions comprising about 1 mg to about 150 mg, 1 mg to about 100 mg, or about 1 mg to about 40 mg of plinabulin.

[0014] Some embodiments relate to a pharmaceutical composition comprising docetaxel and about 1 mg to about 150 mg, 1 mg to about 100 mg, or about 1 mg to about 40 mg of plinabulin, wherein the docetaxel and plinabulin are provided in two separate sterile containers. [Brief explanation of the drawings]

[0015] [Figure 1] 1 is a graph showing neutrophil count change over time with plinabulin versus pegfilgrastim treatment. [Figure 2] Graph measuring the change in mean neutrophil count (ANC) median during the first 10 days of cycle 1 chemotherapy treatment for patients receiving plinabulin and G-CSF combination or G-CSF formulation alone. [Figure 3] 1 is a bar graph showing the incidence of grade 3 / 4 neutropenia in cycle 1 of TAC treatment for breast cancer patients receiving plinabulin in combination with G-CSF or G-CSF alone. [Figure 4] 1 is a bar graph showing the incidence of bone pain in cycle 1 of TAC treatment for breast cancer patients who received a combination of plinabulin and G-CSF or a G-CSF preparation alone. [Figure 5]1 is a graph showing the duration of bone pain in cycle 1 of TAC treatment for breast cancer patients who received a combination of plinabulin and G-CSF or G-CSF alone. [Figure 6] Graph showing the percentage of patients with neutrophil to lymphocyte ratio (NLR) values ​​greater than 5 in various treatment groups. [Figure 7] Figure 7A shows the percentage of patients with an NLR greater than 5 in plinabulin (20 mg / m2) alone, plinabulin (20 mg / m2) + Neulasta 6 mg, and Neulasta (6 mg). Figure 7B shows the percentage of patients with a monocyte to lymphocyte ratio (LMR) less than 3.2 in plinabulin (20 mg / m2) alone, plinabulin (20 mg / m2) + Neulasta 6 mg, and Neulasta (6 mg). DETAILED DESCRIPTION OF THE INVENTION

[0016] Plinabulin, (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 produced according to the methods and procedures detailed in U.S. Patent Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entireties. In some embodiments, plinabulin can effectively promote antigen uptake and migration of dendritic cells to lymph nodes, where tumor-specific antigens are presented by dendritic cells to primary immune effector cells. Exposure of dendritic cells to plinabulin promotes dendritic cell maturation. It can induce maturation and significantly enhance the ability of primary T cells. In some embodiments, plinabulin can mediate tumor burden reduction through immune modulation of the tumor microenvironment and promote anti-tumor immune enhancement. In some embodiments, substantial therapeutic synergy can be achieved when plinabulin is combined with G-CSF.

[0017] Plinabulin is a small molecule with tumor-inhibiting and immune-enhancing effects. It induces dendritic cell maturation and the production of the cytokines interleukin-1β (IL-1β), IL-6, and IL-12, all of which are important for neutrophil survival. Plinabulin also induces the production of MHC II, CD40, CD80, and CD86, as well as antigen-specific T cell activation. Plinabulin can induce dendritic cell maturation, leading to the release of cytokines interleukin (IL)-1β, IL-6, and IL-12 from monocytes / dendritic cells, which protect neutrophils from apoptosis. In particular, IL-6 may be mediated by the prevention of neutrophil apoptosis, and IL-1β may be mediated by an increase in neutrophil counts. Plinabulin can prevent docetaxel-induced or cyclophosphamide-induced neutropenia through a mechanism of action distinct from that of G-CSF analogs. When used for the treatment of solid tumors, plinabulin has demonstrated protective effects against neutropenia. In a phase 2 (Ph2) trial, the addition of plinabulin to docetaxel (Plin+Doc; n=38) in NSCLC patients (pts) with measurable disease improved mOS by 4.6 months compared with Doc alone. The DOR (a marker of immune response) was approximately 1 year longer with plinabulin plus docetaxel compared with docetaxel alone (P<0.05). Plin exerted immune-enhancing effects (DOR) without an increase in immune-related adverse events (IR-AEs).

[0018] Granulocyte colony-stimulating factor (G-CSF) refers to a compound or factor that stimulates the proliferation, differentiation, commitment, and terminal cell functional activation of granulocytes in animals, including human subjects. The term G-CSF or G-CSF variants includes all naturally occurring variants of G-CSF (with or without leader sequence), G-CSF biosimilars, and G-CSF proteins derived therefrom that have been modified by recombinant DNA techniques, particularly fusion proteins that contain additional polypeptide sequences apart from the G-CSF portion. For example, (1) the half-life of a G-CSF molecule (or, e.g., formulate an oral dosage form) may be increased by adding chemical modifications to the G-CSF molecule, such as, for example, reducing the ability of proteases to act on the G-CSF molecule or adding an enteric coating for oral formulations that acts to alter some characteristic of the G-CSF molecule, such as increasing serum or other half-life or increasing antigenicity; (2) hybrid molecules may be produced, such as by combining G-CSF with part or all of another protein, such as another cytokine or another protein that signals through cells by entry via the G-CSF-G-CSF receptor transport mechanism; or (3) biological activity may be increased, such as, for example, the ability to selectively stimulate neutrophils (compared to unmodified G-CSF molecules). G-CSF includes its derivative, mimetic, variant and chemically modified compound or hybrid described in U.S. Patent No. 5,399,345; U.S. Patent No. 5,416,195; U.S. Patent No. 5,981,551; U.S. Patent No. 6,166,183 and U.S. Patent No. 6,261,550 (these contents are incorporated by reference in their entirety).G-CSF compounds include but are not limited to filgrastim and pegfilgrastim.Examples of G-CSF include, but are not limited to, Neupogen® (Amgen), Tevagrastim® (Teva), Biograstim® (CT Arzneimittel), Ratiograstim® (Ratiopharm GmbH), Zarxio® (Sandoz GmbH), Filgrastim Hexal® (Hexal AG), Neulasta® (Amgen), Granocyte® and Neutrogin® (Chugai), and Neu-up® (Kyowa Hakko), Rolontis® (Spectrum, eflapegrastim), Aiduo (mecapegfilgrastim, Hengrui), Fulphila™ (pegfilgrastim-jmdb, Mylan). G-CSF is often given to treat chemotherapy-induced severe neutropenia. G-CSFs, such as pegfilgrastim, are colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and terminal cell functional activation.

[0019] Febrile neutropenia (FN) was defined as fever (≥38.3°C) and docetaxel-induced neutropenia (absolute neutrophil count [ANC] <0.5 × 10 9Chemotherapy-induced severe neutropenia is a potentially fatal condition characterized by a high blood pressure (1 / L). The risk of severe neutropenia, including FN, can be mitigated by reducing the docetaxel dose or extending the drug administration interval. However, studies have shown that these measures directly correlate with lower long-term survival rates due to the relative reduction in drug administration intensity. Therefore, granulocyte colony-stimulating factors (G-CSFs), such as filgrastim (Neupogen®) or pegfilgrastim (Neulasta®), can be given to treat chemotherapy-induced severe neutropenia, allowing chemotherapy to be administered more effectively. According to these guidelines, the prophylactic use of G-CSF is recommended for patients at significant risk for FN, based on the chemotherapy regimen and the patient's specific risk factors. However, prophylactic use of G-CSF has several significant limitations regarding safety, cost, and convenience of use. Treatment should be administered within 14 days of the start of chemotherapy. Furthermore, G-CSF treatment cannot begin until 24 hours after the last dose of chemotherapy in each treatment cycle and is generally administered once per chemotherapy cycle (requiring an in-treatment baseline complete blood count [CBC] and platelet count). A concern with administering G-CSF on the day of chemotherapy is that increased proliferation of myeloid cells may increase sensitivity to cytotoxic chemotherapy drugs. Because cytotoxic chemotherapy causes the most damage to rapidly proliferating cells, administering an agent that promotes faster proliferation of myeloid cells while chemotherapy is in progress may cause greater toxicity. The duration of G-CSF treatment is intended to attenuate chemotherapy-induced neutropenia and depends on the myelosuppressive potential of the chemotherapy regimen used. Patients must either self-administer the drug or return to a facility for treatment and evaluation, which is often difficult and expensive for the patient.

[0020] Warnings and precautions for pegfilgrastim include splenic rupture, acute respiratory distress syndrome, allergic reactions including anaphylaxis, fatal sickle cell crisis, glomerulonephritis, capillary leak syndrome, and leukocytosis. The most common side effects are bone pain and pain in the extremities, occurring in 31% and 9% of patients, respectively. Additional notable adverse events include acute febrile neutrophilic dermatosis, cutaneous vasculitis, and injection site reactions.

[0021] Plinabulin may be effective in relieving docetaxel-associated severe neutropenia (including FN), has a better safety profile (much less bone pain), and is more convenient for patients by requiring fewer patient visits and potentially reducing the burden on the healthcare system. Most importantly, plinabulin can be given after the docetaxel cycle (e.g., 30 minutes or 1 hour) as opposed to 24 hours after the completion of the cycle (formulated with pegfilgrastim, G-CSF, and its biosimilars).

[0022] Patients with solid tumors who received plinabulin monotherapy treatment (in the absence of chemotherapy) did not experience clinically significant worsening in hematology or chemistry laboratory parameters; however, there was a significantly lower incidence of neutropenia in patients receiving plinabulin plus docetaxel compared with the docetaxel monotherapy treatment group.

[0023] Clinical complications of neutropenia (febrile neutropenia, infection, sepsis, and mortality) Grade 4 neutropenia occurs more frequently than Grade 2 or 3 neutropenia. For regulatory approval, the FDA and health authorities focus on Grade 4 neutropenia data. Grade 4 neutropenia / severe neutropenia is defined as <0.5 × 10 9The absolute neutrophil count is 0.01 / L. In animal model studies, plinabulin has been shown to prevent neutropenia caused by chemotherapy with different mechanisms: docetaxel, cisplatin, adriamycin, cyclophosphamide, topotecan, and gemcitabine. Table 1 shows that plinabulin has many advantages over G-CSF preparations for treating or attenuating neutropenia. [Table 1]

[0024] Compared with docetaxel treatment alone, the addition of plinabulin to docetaxel significantly (p<0.0003) reduced the proportion of patients with grade 4 neutropenia from 33.3% to 4.6% in cycle 1. Data showed that the incidence of grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 x 10) was highest on day 8, the day following docetaxel administration that corresponds to the greatest decrease in neutrophil count. 9 Plinabulin also reduced the clinical sequelae associated with docetaxel-induced neutropenia (sepsis, infection, hospitalization, need for docetaxel dose reduction, and use of G-CSF). Bone pain was reported in 4% of patients receiving plinabulin. Plinabulin has a favorable safety profile; 2 and 20 mg / m 2 Grade 3 transient hypertension was the most notable event, occurring in 20% and 5% of patients receiving plinabulin.

[0025] Plinabulin can be effective for alleviating docetaxel-induced neutropenia. Administered by intravenous infusion on the same day as docetaxel (approximately 30 minutes or 1 hour after administration), plinabulin can be given in a single dose determined for each cycle. Plinabulin is effective, safe (much less bone pain), cost-effective, and potentially a convenient alternative to G-CSF for the prevention of docetaxel-induced neutropenia.

[0026] Plinabulin and G-CSF (e.g., pegfilgrastim or filgrastim) can act synergistically to treat or prevent neutropenia that occurs during chemotherapy. Chemotherapy can include treatment using chemotherapy drugs or radiation therapy. The combination of plinabulin and G-CSF (e.g., pegfilgrastim or filgrastim) can help treat chemotherapy-induced severe neutropenia, maintain the neutrophil count of patients during treatment, and enable more effective chemotherapy. In addition, the administration of plinabulin and G-CSF preparations can help shorten the duration of severe neutropenia and maintain the absolute neutrophil count within the normal range.

[0027] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, those in this section prevail unless otherwise specified.

[0028] As used herein, "subject" means a human or non-human mammal, e.g., a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, e.g., a chicken, as well as other vertebrates or invertebrates.

[0029] The term "mammal" is used in its ordinary biological sense, and thus particularly 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.

[0030] As used herein, "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent that is effective to some extent to alleviate or reduce the likelihood of developing one or more symptoms of a disease or condition, including curing the disease or condition.

[0031] As used herein, "treat," "treatment," or "treating" refers to administering a compound or pharmaceutical composition to a subject for preventative and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to or otherwise at risk for a particular disease or condition, whereby treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who already has, has, or is likely to develop a disease or condition.

[0032] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a compound and is not biologically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts due to the presence of amino and / or carboxylic acid 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 reactive hydrogen from the compound, resulting in the formation of Li + , Na + , K. + , Mg2+ and Ca 2+ Salt forms containing inorganic cations such as are obtained. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87 / 05297, Johnston et al., published September 11, 1987 (incorporated herein by reference in its entirety).

[0033] Treatment method Plinabulin may be effective in remission or treatment of chemotherapy-related (e.g., docetaxel-, TAC-, or TC-related) severe neutropenia (including FN) and has a favorable safety profile. Patients receiving plinabulin treatment experienced less bone pain, fewer hospitalizations, and a lower incidence of grade 4 neutropenia in cycle 1 compared with other treatments (e.g., G-CSF). Additionally, plinabulin treatment resulted in minimal or no febrile neutropenia compared with other treatments (e.g., G-CSF). Patients may enjoy a better quality of life thanks to plinabulin's superior properties.

[0034] For some embodiments, G-CSF can be administered along with plinabulin in the treatment of chemotherapy-induced neutropenia described herein.

[0035] In some embodiments, the chemotherapy includes only docetaxel and no other additional chemotherapeutic agents. In some embodiments, the chemotherapy does not include docetaxel.

[0036] In some embodiments, plinabulin can be co-administered with G-CSF to reduce, ameliorate, or prevent neutropenia induced by chemotherapy or radiation therapy. In some embodiments, plinabulin can be co-administered with G-CSF to stimulate neutrophil production or proliferation. In some embodiments, plinabulin can be co-administered with G-CSF to reduce, ameliorate, or prevent neutropenia caused by docetaxel. Combined with the effect of neutropenia prevention, patients receiving plinabulin may require less G-CSF treatment. Co-administration of plinabulin and G-CSF can act synergistically to continuously maintain a patient's neutrophil count and reduce the risk of stopping chemotherapy due to severe side effects.

[0037] Some embodiments include simultaneous administration of the compositions and / or pharmaceutical compositions described herein with an additional drug. For example, as described above, some embodiments include simultaneous administration of plinabulin and one or more G-CSF formulations. "Co-administration" refers to the administration of two or more drugs in such a way that administration of one or more drugs has a broader effect simultaneously with one or more other drugs, regardless of when or how they are actually administered. In one embodiment, the drugs are administered simultaneously. In one such embodiment, co-administration is achieved by combining the drugs in a single dosage form. In another embodiment, the drugs are administered sequentially. In one embodiment, the drugs are administered by the same route, such as orally or intravenously. In another embodiment, the drugs are administered by different routes, such as one administered orally and another administered intravenously. In some embodiments, the time between administration of one or more agents and administration of one or more co-administered agents can be about 5 minutes, 10 minutes, 20 minutes, 30 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 65 minutes, 70 minutes, 75 minutes, 90 minutes, 2 hours, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days, 21 days, 28 days, or 30 days.In some embodiments, the time between administration of one or more agents and administration of one or more co-administered agents is about 1 minute to 5 minutes, 1 minute to 10 minutes, 1 minute to 20 minutes, 1 minute to 30 minutes, 1 minute to 40 minutes, 1 minute to 50 minutes, 1 minute to 1 hour, 1 minute to 2 hours, 1 minute to 4 hours, 1 minute to 6 hours, 1 minute to 8 hours, 1 minute to 10 hours, 1 minute to 12 hours, 1 minute to 24 hours, 1 minute to 36 hours, 1 minute to 48 hours, 1 minute to 60 hours, 1 minute to 72 hours, 5 minutes to 10 minutes, 5 minutes to 20 minutes, 5 minutes to 30 minutes, 5 minutes to 40 minutes, 5 minutes to 50 minutes, 5 minutes to 1 hour, 5 minutes to 75 minutes, 5 minutes to 2 hours, 5 minutes to 4 hours, 5 minutes to 6 hours, 5 minutes to 8 hours, 5 minutes to 10 hours, 5 minutes to 12 hours, 5 minutes to 24 hours, 5 minutes to 36 hours, 5 minutes to 48 hours, 5 minutes to 60 hours, 5 minutes to 72 hours, 10 minutes to 20 minutes, 10 minutes to 30 minutes, 10 minutes to 40 minutes, 10 minutes to 50 minutes, 10 minutes to 1 hour, 10 minutes to 75 minutes, 10 minutes to 2 hours, 10 minutes to 4 hours, 10 minutes to 6 hours, 10 minutes to 8 hours, 10 minutes to 10 hours, 10 minutes to 12 hours, 10 minutes to 24 hours, 10 minutes to 36 hours, 10 minutes to 48 hours, 10 minutes to 60 hours, 10 minutes to 72 hours, 30 minutes to 40 minutes, 30 minutes to 50 minutes, 30 minutes to 1 hour, 30 minutes to 75 minutes, 30 minutes to 2 hours, 30 minutes to 4 hours, 30 minutes to 6 hours, 30 minutes to 8 hours, 30 minutes to 10 hours, 30 minutes to 12 hours, 30 minutes to 24 hours, 30 minutes to 36 hours, 30 minutes to 48 hours, 30 minutes to 60 hours, 30 minutes to 72 hours, 1 hour to 2 hours, 1 hour to 4 hours, 1 hour to 6 hours, It can range from 1 hour to 8 hours, 1 hour to 10 hours, 1 hour to 12 hours, 1 hour to 24 hours, 1 hour to 36 hours, 1 hour to 48 hours, 1 hour to 60 hours, 1 hour to 72 hours, 6 hours to 8 hours, 6 hours to 10 hours, 6 hours to 12 hours, 6 hours to 24 hours, 6 hours to 36 hours, 6 hours to 48 hours, 6 hours to 60 hours, 6 hours to 72 hours, 12 hours to 24 hours, 12 hours to 36 hours, 12 hours to 48 hours, 12 hours to 60 hours, or 12 hours to 72 hours.

[0038] Patients receiving combination therapy with plinabulin and G-CSF are less likely to require chemotherapy (e.g., docetaxel, TAC, or TC) dose reduction. The safety profile of plinabulin is better than other agents used to treat or ameliorate docetaxel-induced neutropenia (e.g., G-CSF therapy).

[0039] Patients receiving combination therapy with plinabulin and G-CSF may exhibit at least one of the following conditions: 1) Grade 4 neutropenia (absolute neutrophil count [ANC] <0.5 × 10 9 / L); 2) lower incidence of febrile neutropenia (FN) (ANC < 0.5 × 10 9 1) Lower incidence of neutrophil counts (blood counts / L and body temperature ≥ 38.3°C); 2) Higher neutrophil counts during treatment cycles; 3) Lower incidence of confirmed infections in cycles 1-4; 4) Lower incidence of morbidity and shorter hospital stays and mortality due to FN during treatment cycles; 5) Better health-related quality of life; 6) Shorter duration of severe neutropenia; 7) Maintenance of neutrophil counts within the normal range and prevention of neutrophil count overshoot above the normal range. Compared with G-CSF treatment (e.g., pegfilgrastim or filgrastim), plinabulin treatment demonstrated lower frequency of antibiotic use, fewer docetaxel dose delays, dose reductions, and / or dose interruptions, lower incidence, incidence, and severity of adverse events (AEs) / serious adverse events (SAEs), lower incidence, incidence, and severity of bone pain, and better systemic tolerance (physical and safety laboratory tests).

[0040] In some embodiments, treating neutropenia includes reducing the likelihood or incidence of neutropenia, reducing the duration of neutropenia, and / or maintaining a subject's mean neutrophil count within a range acceptable for chemotherapy treatment.

[0041] In some embodiments, plinabulin can be used to reduce the incidence of bone pain episodes. In some embodiments, plinabulin can be used to shorten the duration of bone pain. In some embodiments, bone pain is induced by a G-CSF preparation.

[0042] In some embodiments, plinabulin can be used to reduce the immunosuppressive effects of G-CSF. In some embodiments, the immunosuppressive effects are caused by G-CSF preparations. In some embodiments, plinabulin can be used to reduce the immunosuppressive effects induced by G-CSF preparations during chemotherapy or radiation therapy.

[0043] In some embodiments, plinabulin can be used to reduce the NLR value (the ratio of absolute neutrophil count to absolute lymphocyte count) in patients undergoing chemotherapy. In some embodiments, plinabulin can be used to reduce the NLR value in patients receiving G-CSF preparations during chemotherapy. In some embodiments, the NLR value of the patient can be reduced to 5. In some embodiments, the methods described herein can reduce the incidence of patients with an NLR value greater than 5. An NLR greater than 5 is a negative predictor of poor survival. In some embodiments, the methods described herein can reduce the incidence of patients with an NLR value greater than 5, where the incidence is reduced by at least 10%. In some embodiments, the methods described herein can reduce the incidence of patients with an NLR value greater than 5, where the incidence is reduced by at least 10%, 20%, 30%, 40%, or 50%.

[0044] In some embodiments, plinabulin can be used to reduce the LMR value (absolute lymphocyte count to absolute monocyte count ratio) in patients undergoing chemotherapy. In some embodiments, the patient is also administered a G-CSF preparation. An LMR of less than 3.6 is a negative predictor of poor survival.

[0045] In some embodiments, the methods described herein involve identifying a patient who develops or is at risk of developing bone pain after receiving G-CSF treatment.

[0046] In some embodiments, chemotherapy is selected from the group consisting of methotrexate, vinblastine, doxorubicin, cisplatin, MVAC (methotrexate, vinblastine, doxorubicin and cisplatin), docetaxel, trastuzumab, cyclophosphamide, paclitaxel, dose-dense AC followed by T (i.e., doxorubicin, cyclophosphamide, paclitaxel), TAC (docetaxel, doxorubicin, cyclophosphamide), fluorouracil, bleomycin, etoposide, vincristine, procarbazine, cyclophosphamide, prednisone, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), gemcitabine, ifosfamide, carboplatin, ICE (ifosfamide, carboplatin, etoposide), rituximab, RICE (rituximab, ifosfamide, carboplatin, etoposide), CHOP-14 (cyclophosphamide, doxorubicin, vincristine, prednisone), mesna, novantrone, MINE (mesna, ifosfamide, novantrone, etoposide) , dexamethasone, cytarabine, DHAP (dexamethasone, cisplatin, cytarabine), methylprednisolone, ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine), HyperCVAD and rituximab (cyclophosphamide, vincristine, doxorubicin, dexamethasone, rituximab), dacarbazine, vinblastine, dacarbazine combinations (dacarbazine, cisplatin, vinblastine), dacarbazine combinations with IL-2 and interferon alpha (dacarbazine, cisplatin, vinblastine), IL-2, interferon α), topotecan, MAID (mesna, doxorubicin, ifosfamine, dacarbazine), VeIP (vinblastine, ifosfamide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), TIP (paclitaxel, ifosfamide, cisplatin), gemcitabine, CMF classic (cyclophosphamide, methotrexate, fluorouracil), AC (doxorubicin, cyclophosphamide), FEC (fluorouracil, epirubicin, cyclophosphamide), TC (docetaxel,cyclophosphamide), cisplatin / topotecan, paclitaxel / cisplatin, irinotecan, FOLFOX (fluorouracil, leucovorin, oxaliplatin), irinotecan / cisplatin, epirubicin / cisplatin / 5-fluorouracil, epirubicin / cisplatin / capecitabine, DT-PACE (dexamethasone / thalidomide / cisplatin / doxorubicin / cyclophosphamide / etoposide), ET-PACE and bortezomib, EPOCH (etoposide, prednisone, vincristine, cyclophosphamide), cisplatin / paclitaxel, cisplatin / vinorelbine, cisplatin / docetaxel, cisplatin / etoposide, carboplatin / paclitaxel, carboplatin / docetaxel, FOLFIRINOX (5-FU / leucovorin), GDP (gemcitabine, dexamethasone, cisplatin), GDP and rituximab, FMR (fludarabine, mitoxantrone, rituximab), CHOP and rituximab (cyclophosphamide, doxorubicin, vincristine, prednisone, rituximab), cisplatin / paclitaxel, cisplatin / vinorelbine, cisplatin / docetaxel, cisplatin / etoposide, carboplatin / paclitaxel, carboplatin / docetaxel, FOLFIRINOX (5-FU / leucovorin), In some embodiments, the chemotherapy can independently include one or more agents selected from the group consisting of methotrexate, vinblastine, doxorubicin, cisplatin, etoposide / carboplatin, etoposide / cisplatin. In some embodiments, the chemotherapy can independently include one or more agents selected from the group consisting of methotrexate, vinblastine, doxorubicin, cisplatin, docetaxel, trastuzumab, cyclophosphamide, paclitaxel, fluorouracil, bleomycin, etoposide, vincristine, procarbazine, prednisone, gemcitabine, ifosfamide, carboplatin, methicillin-resistant Staphylococcus aureus ... In some embodiments, the chemotherapy may independently include one or more agents selected from the group consisting of nacarbazine, novantrone, cytarabine, methylprednisolone, rituximab, dacarbazine, vinblastine, topotecan, gemcitabine, irinotecan, epirubicin, 5-fluorouracil, capecitabine, bortezomib, and cabazitaxel. In some embodiments, the chemotherapy does not include a taxane. In some embodiments, the chemotherapy does not include docetaxel alone. In some embodiments, when the chemotherapy includes administering more than one chemotherapeutic agent,At least one of the chemotherapeutic agents is not a taxane. In some embodiments, when the chemotherapy comprises administering more than one chemotherapeutic agent, at least one of the chemotherapeutic agents is not docetaxel. In some embodiments, when the chemotherapy comprises only one chemotherapeutic agent, the chemotherapy is not a taxane. In some embodiments, when the chemotherapy comprises only one chemotherapeutic agent, the chemotherapy is not docetaxel. In some embodiments, the chemotherapy comprises administering docetaxel, doxorubicin, and cyclophosphamide (TAC); docetaxel and cyclophosphamide (TC); doxorubicin and cyclophosphamide (AC); docetaxel and doxorubicin (TA); docetaxel; doxorubicin; or cyclophosphamide. In some embodiments, the chemotherapy comprises administering docetaxel, doxorubicin, and cyclophosphamide (TAC).

[0047] In some embodiments, chemotherapy includes methotrexate, vinblastine, doxorubicin, cisplatin, MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), trastuzumab, cyclophosphamide, dose-dense AC followed by T (i.e., doxorubicin, cyclophosphamide, paclitaxel), fluorouracil, bleomycin, etoposide, vincristine, procarbazine, prednisone, BEACO PP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone), gemcitabine, ifosfamide, carboplatin, ICE (ifosfamide, carboplatin, etoposide), rituximab, RICE (rituximab, ifosfamide, carboplatin, etoposide), CHOP-14 (cyclophosphamide, doxorubicin, vincristine, prednisone), mesna, novantrone, MINE (mesna, ifosfamide) cyclophosphamide, novantrone, etoposide), dexamethasone, cytarabine, DHAP (dexamethasone, cisplatin, cytarabine), methylprednisolone, ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine), HyperCVAD and rituximab (cyclophosphamide, vincristine, doxorubicin, dexamethasone, rituximab), dacarbazine, vinblastine, dacarbazine combination drugs (dacarbazine, cisplatin, vinblastine), The therapy may include one or more agents selected from the group consisting of dacarbazine combination drugs with IL-2 and interferon alpha (dacarbazine, cisplatin, vinblastine, IL-2, interferon alpha), topotecan, MAID (mesna, doxorubicin, ifosfamine, dacarbazine), VeIP (vinblastine, ifosfamide, cisplatin), VIP (etoposide, ifosfamide, cisplatin), and TIP (paclitaxel, ifosfamide, cisplatin).In some embodiments, gemcitabine, CMF classic (cyclophosphamide, methotrexate, fluorouracil), AC (doxorubicin, cyclophosphamide), FEC (fluorouracil, epirubicin, cyclophosphamide), cisplatin / topotecan, paclitaxel / cisplatin, irinotecan, FOLFOX (fluorouracil, leucovorin, oxaliplatin), irinotecan / cisplatin, epirubicin / cisplatin / 5-fluorouracil ... Vincristine / cisplatin / capecitabine, DT-PACE (dexamethasone / thalidomide / cisplatin / doxorubicin / cyclophosphamide / etoposide), ET-PACE and bortezomib, EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), GDP (gemcitabine, dexamethasone, cisplatin), GDP and rituximab, FMR (fludarabine, mitoxantrone, rituximab), CHOP and rituximab (cyclophosphamide) In some embodiments, the chemotherapy is selected from the group consisting of methotrexate, vinblastine, doxorubicin, vincristine, prednisone, rituximab), cisplatin / paclitaxel, cisplatin / vinorelbine, cisplatin / etoposide, carboplatin / paclitaxel, FOLFIRINOX (5-FU / leucovorin, irinotecan, and oxaliplatin), cabazitaxel, etoposide / carboplatin, etoposide / cisplatin. In some embodiments, the chemotherapy is selected from the group consisting of methotrexate, vinblastine, doxorubicin, cisplatin The therapeutic agent may include one or more agents selected from the group consisting of trastuzumab, cyclophosphamide, fluorouracil, bleomycin, etoposide, vincristine, procarbazine, prednisone, gemcitabine, ifosfamide, carboplatin, mesna, novantrone, cytarabine, methylprednisolone, rituximab, dacarbazine, vinblastine, topotecan, gemcitabine, irinotecan, epirubicin, 5-fluorouracil, capecitabine, and bortezomib.

[0048] Some embodiments relate to a method for reducing or preventing chemotherapy-induced neutropenia, the method comprising co-administering plinabulin and one or more G-CSF compounds to a patient undergoing chemotherapy treatment.Some embodiments relate to a method for reducing or preventing docetaxel-induced neutropenia, the method comprising co-administering plinabulin and one or more G-CSF compounds to a patient undergoing docetaxel treatment.

[0049] Chemotherapy such as taxotere, adriamycin, and cyclophosphamide (TAC) and taxotere and cyclophosphamide (TC) can also cause severe neutropenia. TAC has a high risk (>20%) of causing FN. In some embodiments, during TAC chemotherapy, the doxorubicin component is omitted and a TA chemotherapy drug is administered. For example, during TAC chemotherapy, the doxorubicin component may be omitted in cycles 2 to 4 at the investigator's discretion, i.e., TC may be administered instead of TAC. Some embodiments relate to a method for reducing or preventing neutropenia induced by TAC or TC, the method comprising administering plinabulin to a patient undergoing docetaxel treatment. In some embodiments, the chemotherapy includes only TAC and no other additional chemotherapeutic agents. In some embodiments, the chemotherapy includes only TC and no other additional chemotherapeutic agents. In some embodiments, the administration schedule for TAC is as follows: Day 1: Doxorubicin 50 mg / m 2 intravenously, followed by cyclophosphamide 500 mg / m 2 intravenously, followed by docetaxel 75 mg / m after a 1-hour interval 2 In some embodiments, the dosing schedule for TC is: Day 1: Docetaxel 75 mg / m 2 intravenously, followed by cyclophosphamide 600 mg / m 2 Including intravenous.

[0050] Plinabulin is useful for the prevention, treatment, or amelioration of neutropenia resulting from chemotherapy (eg, docetaxel, TAC, or TC).

[0051] Some embodiments are directed to a method of treating a patient receiving docetaxel in an amount sufficient to cause neutropenia, the method comprising administering plinabulin and one or more G-CSF inhibitors. and administering the compound to reduce or prevent neutropenia in a patient.

[0052] Some embodiments relate to a method of treating a patient receiving a chemotherapy drug in an amount sufficient to cause neutropenia, the method comprising co-administering plinabulin and G-CSF to reduce or prevent neutropenia in the patient.

[0053] Some embodiments relate to the co-administration of plinabulin and G-CSF to reduce the degree of neutropenia and the duration of severe neutropenia.

[0054] In some embodiments, the patient is suffering from advanced or metastatic breast cancer, early stage breast cancer, non-small cell lung cancer, or resistant metastatic prostate cancer. In some embodiments, the patient is suffering from head and neck cancer, lung cancer, gastric cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, kidney cancer, bladder cancer, ovarian cancer, cervical cancer, melanoma, glioblastoma, myeloid leukemia, myeloma, lymphoma, or leukemia. In some embodiments, the patient is suffering from renal cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, Hodgkin's lymphoma, or squamous cell carcinoma. In some embodiments, the patient is suffering from breast cancer, colon cancer, rectal cancer, lung cancer, prostate cancer, melanoma, leukemia, ovarian cancer, gastric cancer, renal cell carcinoma, liver cancer, pancreatic cancer, lymphoma, and myeloma. In some embodiments, the patient is suffering from a solid tumor or blood cancer. In some embodiments, the patient is diagnosed with acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), adrenal gland cancer, basal and squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer, brain and spinal cord tumors, breast cancer, cervical cancer, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myelomonocytic leukemia (CMML), colorectal cancer, endometrial cancer, esophageal cancer, eye cancer (ocular melanoma and lymphoma), gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, Hodgkin's lymphoma, Kaposi's sarcoma, renal cancer, laryngeal and hypopharyngeal cancer, leukemia , liver cancer, lung cancer, pulmonary carcinoid tumor, lymphoma, malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, or Wilms' tumor.

[0055] Some embodiments relate to treating chemotherapy (e.g., docetaxel, TAC, or TC)-induced neutropenia in a subject with advanced or metastatic breast cancer, comprising identifying a patient with advanced or metastatic breast cancer; and co-administering a pharmaceutically effective amount of plinabulin and a pharmaceutically effective amount of a G-CSF compound.

[0056] Some embodiments relate to a method for treating chemotherapy (e.g., docetaxel, TAC, or TC)-induced neutropenia in a subject afflicted with non-small cell lung cancer, comprising identifying a patient with non-small cell lung cancer; and co-administering a pharmaceutically effective amount of plinabulin and a pharmaceutically effective amount of a G-CSF compound.

[0057] Some embodiments relate to a method of treating chemotherapy (e.g., docetaxel, TAC, or TC)-induced neutropenia in a subject afflicted with hormone-refractory metastatic prostate cancer, comprising identifying a patient with hormone-refractory metastatic prostate cancer; and co-administering a pharmaceutically effective amount of plinabulin and a pharmaceutically effective amount of a G-CSF compound.

[0058] In some embodiments, the neutropenia is febrile neutropenia. In some embodiments, the neutropenia is drug-induced neutropenia. In some embodiments, the neutropenia is , the neutropenia is taxane-induced neutropenia.

[0059] Some embodiments provide a method of stimulating neutrophil survival comprising co-administering plinabulin and G-CSF, wherein plinabulin is administered at a dose of about 1 mg / m 2 ~about 50mg / m 2 Some embodiments relate to methods of stimulating neutrophil survival comprising co-administering plinabulin and one or more G-CSF compounds.

[0060] In some embodiments, the G-CSF formulation is administered using an on-body injector (e.g., an Onpro® on-body injector). In some embodiments, the G-CSF formulation is administered subcutaneously.

[0061] In some embodiments, the methods described herein further comprise monitoring the patient's absolute neutrophil count. In some embodiments, the methods described herein further comprise monitoring the patient's absolute neutrophil count. 9 / L, approx. 1.0×10 9 / L, or approximately 0.5 × 10 9 If the patient has an absolute neutrophil count that is less than 1 / L, monitoring the patient's absolute neutrophil count and administering a G-CSF preparation.

[0062] In some embodiments, when plinabulin is co-administered with G-CSF to treat neutropenia, patients have an absolute neutrophil count (ANC) of less than 500 neutrophils / mcl or an ANC of less than 1000 neutrophils / mcl and a predicted decrease in neutrophils / mcl of 500 or less over the next 48 hours. In some embodiments, plinabulin is co-administered with G-CSF to treat neutropenia in patients with an ANC of less than 100 neutrophils / mcl. In some embodiments, plinabulin is co-administered with G-CSF to treat neutropenia in patients with an ANC of less than 500 neutrophils / mcl. In some embodiments, plinabulin is co-administered with G-CSF to treat neutropenia in patients with an ANC of less than 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, or 50 neutrophils / mcl. In some embodiments, plinabulin is co-administered with G-CSF to treat neutropenia in patients with an ANC of less than about 1000-100, 900-100, 800-100, 700-100, 600-100, 500-100, 400-100, 300-100, 200-100, 1000-200, 900-200, 800-200, 700-200, 600-200, 500-200, 400-200, 300-200, 1000-30 Treat neutropenia in patients with an ANC in the ranges of 0, 900-300, 800-300, 700-300, 600-300, 500-300, 400-300, 1000-400, 900-400, 800-400, 700-400, 600-400, 500-400, 1000-500, 900-500, 800-500, 700-500, or 600-500 neutrophils / mcl.

[0063] In some embodiments, about 1-50 mg / m of body surface area 2 In some embodiments, plinabulin is administered at a dose ranging from about 20 mg / m of body surface area. 2 In some embodiments, plinabulin is administered at a dose of about 10-30 or about 15-25 mg / m of body surface area. 2In some embodiments, plinabulin is administered at a dose ranging from about 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 11, 1 to 12, 1 to 13, 1 to 13.75, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 22.5, 1 to 25, 1 to 27.5, 1 to 30, 1.5 to 2, 1.5 to 3, 1.5 to 4, 1.5 to 5, 1.5 to 6, 1.5 to 7, 1.5 to 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、6~16、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, t2.5–22.5, or 9.5–21.5 mg / m of body surface area. 2 In some embodiments, plinabulin is administered at a dose ranging from 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, 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, 40mg / body surface area m 2 In some embodiments, 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, 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, 40mg / body surface area m 2In some embodiments, 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. 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, 2 9.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 mg / body surface area m 2 Administered at a dose of >.

[0064] In some embodiments, plinabulin is administered once per treatment cycle. In some embodiments, plinabulin is administered two or more times per treatment cycle. In some embodiments, the treatment cycle is a 21-day treatment cycle.

[0065] In some embodiments, the total dose of plinabulin administered in a 21-day treatment cycle is about 1-50 mg / m of body surface area. 2 In some embodiments, the total dose of plinabulin administered in a 21-day treatment cycle is in the range of about 20 mg / m of body surface area. 2 In some embodiments, the total dose of plinabulin administered in a 21-day treatment cycle is about 10-30 or about 15-25 mg / m of body surface area. 2In some embodiments, the total dose of plinabulin administered in a 21-day treatment cycle is in the range of about 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 11, 1 to 12, 1 to 13, 1 to 13.75, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 22.5, 1 to 25, 1 to 27.5, 1 to 30, 1.5 to 2, 1.5 to 3, 1.5 to 4, 1.5 to 5, 1.5 to 6, 1.5 to 7, 1.5 to 8, 1.5 to 9, 1.5 to 10, 1.5 to 11, 1.5 to 12, 1.5 to 13, 1.5 to 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, 6-16, 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, 12.5~1 4.5, 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, t2.5-22.5, or 9.5-21.5 mg / m of body surface area. 2 In some embodiments, the total dose of plinabulin administered in a 21 day cycle is in 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, 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, 1 6.5, 17, 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, 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 mg / body surface area m 2In some embodiments, the total dose of plinabulin administered in a 21 day cycle is 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, 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, 6.5, 17, 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, 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 mg / body surface area m 2 In some embodiments, the total dose of plinabulin administered in a 21 day cycle is less than 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, 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, 50 mg / body surface area m 2 It's super.

[0066] In some embodiments, when a single dose of plinabulin is administered once per chemotherapy (e.g., docetaxel, TAC, or TC) treatment cycle (e.g., 21 days), the total amount of plinabulin administered per chemotherapy treatment cycle is about 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 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 0.5~14, 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, 6-16, 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, 9-13.7 5, 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 of body surface area. 2 In some embodiments, the total amount of plinabulin administered per chemotherapy treatment cycle is in 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, 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, 6.5, 17, 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, 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 mg / body surface area m 2In some embodiments, the total amount of plinabulin administered per chemotherapy treatment cycle is 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, 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, 103 6.5, 17, 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, 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 mg / body surface area m 2 In some embodiments, the total amount of plinabulin administered per chemotherapy treatment cycle is less than 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, 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, 50 mg / body surface area m 2 In some embodiments, the total amount of plinabulin administered per chemotherapy treatment cycle is greater than about 20 mg / m of body surface area. 2 is.

[0067] In some embodiments, the dose of plinabulin is about 5 mg to 300 mg, 5 mg to 200 mg, 7.5 mg to 200 mg, 10 mg to 100 mg, 15 mg to 100 mg, 20 mg to 100 mg, 30 mg to 100 mg, 40 mg to 100 mg, 10 mg to 80 mg, 15 mg to 80 mg, 20 mg to 80 mg, 30 mg to 80 mg, 40 mg to 80 mg, 10 mg to 60 mg, 15 mg to 60 mg, 20 mg to 60 mg, 30 mg to 60 mg, about 40 mg to 60 mg, 1 mg to 40 mg, 1 mg to 35 mg, 1 mg to 30 mg, 10 mg to 40 mg, 10 mg to 35 mg, or 20 mg to 35 mg. In some embodiments, the amount of plinabulin administered is about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the administered plinabulin 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 to 50 mg, 5 mg to 52 mg, 5 mg to 54 mg, 5 mg to 56 mg, 5 mg to 58 mg, 5 mg to 60 mg, 7 mg to 7.7 mg, 7 mg to 9 mg, 7 mg to 10 mg, 7 mg to 12 mg, 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~42mg、9mg~44mg、9mg~46mg、9mg~48mg、9mg~50mg、9mg~52mg、9mg~54mg、9mg~56mg、9mg~58mg、9mg~60mg、10mg~12mg、10mg~14mg、10mg~15mg、10mg~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, 33m g~50mg, 33mg~52mg, 33mg~54mg, 33mg~56mg, 33mg~58mg, 33mg~60mg, 36mg~38mg, 36mg~40mg, 36mg~4 2mg, 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, 40m g~56mg, 40mg~58mg, 40mg~60mg, 43mg~46mg, 43mg~48mg, 43mg~50mg, 43mg~52mg, 43mg~54mg, 43mg~5 6mg, 43mg~58mg, 42mg~60mg, 45mg~48mg, 45mg~50mg, 45mg~52mg, 45mg~54mg, 45mg~56mg, 45mg~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 dose of plinabulin is about 5 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 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or more than about 200 mg. In some embodiments, the dose of plinabulin is about 5 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 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg,Or less than about 200 mg.

[0068] In some embodiments, the neutropenia is induced by chemotherapy. The administration period can be a multi-week treatment cycle as long as the tumor remains under control and the regimen is clinically tolerated. In some embodiments, the chemotherapy agent and plinabulin can be administered once every three weeks. In some embodiments, the chemotherapy agent and plinabulin can be administered once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, the chemotherapy agent and plinabulin can be administered once a week, preferably on each of days 1 and 8 of a three-week (21-day) treatment cycle. In some embodiments, the chemotherapy agent and plinabulin can be administered once a week, preferably on each of days 1 and 8 of a three-week (21-day) treatment cycle. 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 for one, two, three, four, or five weeks during a treatment cycle. Administration can occur on the same or different days each week during a treatment cycle. In some embodiments, plinabulin is administered before chemotherapy administration. In some embodiments, plinabulin is administered simultaneously with chemotherapy administration. In some embodiments, plinabulin is administered after chemotherapy administration.

[0069] The G-CSF formulations described herein include both short-acting and long-acting G-CSF formulations. In some embodiments, long-acting G-CSF can include both formulations with pegylated or other linkers to achieve a sustained-release effect. In some embodiments, the G-CSF formulation is a short-acting formulation that requires daily administration for up to two weeks or until the ANC reaches a level acceptable to the chemotherapy-treated patient. In some embodiments, the G-CSF formulation is a long-acting formulation that does not require daily administration. In some embodiments, the G-CSF formulation is a long-acting formulation that requires administration once per treatment cycle. In some embodiments, the long-acting G-CSF formulation can be pegfilgrastim, efrapegrastim, or macafilgrastim. In some embodiments, the short-acting G-CSF can be filgrastim. In some embodiments, the G-CSF formulation can be selected from Neupogen® (Amgen), Tevagrastim® (Teva), Biograstim® (CT Arzneimittel), Ratiograstim® (Ratiopharm GmbH)), Zarxio® (Sandoz GmbH), Filgrastim Hexal® (Hexal AG), Neulasta® (Amgen), Granocyte® and Neutrogin® (Chugai), and Neu-up® (Kyowa Hakko), Rolontis® (Spectrum, eflapegrastim), Aiduo (mecapegfilgrastim, Hengrui), Fulphila™ (pegfilgrastim-jmdb, Mylan).

[0070] In some embodiments, during a chemotherapy treatment cycle, the chemotherapy drug is administered only once at the beginning of the treatment cycle, and then plinabulin and G-CSF are co-administered once, twice, three times, four times, five times, or six times during the treatment cycle. In some embodiments, during a chemotherapy treatment cycle, the chemotherapy drug is administered only once at the beginning of the treatment cycle, and then plinabulin and G-CSF are co-administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, during a chemotherapy treatment cycle, the chemotherapy drug is administered only once at the beginning of the treatment cycle, and then plinabulin and G-CSF are co-administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or every day for one, two, three, four, or five week treatment cycles. In some embodiments, during a chemotherapy treatment cycle, the chemotherapy agent is administered only once at the start of the treatment cycle, then plinabulin is administered once per treatment cycle, followed by G-CSF, and the G-CSF formulation can be administered once per treatment cycle if a long-acting G-CSF is used, or multiple times per treatment cycle if a short-acting G-CSF is used. The G-CSF formulation is administered ≥ 24 hours after the chemotherapy agent is administered. In some embodiments, during a chemotherapy treatment cycle, the chemotherapy agent is administered once per treatment cycle, plinabulin, on day 1, then plinabulin, on day 2, followed by G-CSF, on day 3. In some embodiments, the chemotherapy treatment includes more than one chemotherapy agent, and the chemotherapy agent is administered on days 1 and 2 of the treatment cycle, and plinabulin is administered on day 1 after the administration of the first chemotherapy agent, followed by G-CSF on day 3. In some embodiments, the chemotherapy treatment includes more than one chemotherapy agent, and the chemotherapy agent is administered on days 1 and 2 of the treatment cycle, and plinabulin is administered on day 1 after the administration of the first chemotherapy agent, followed by G-CSF, on day 3. In some embodiments, the chemotherapy treatment includes more than one chemotherapy agent, and the chemotherapy agent is administered on day 1, after the administration of the first chemotherapy agent, followed by G-CSF, on day 3. The chemotherapy agents are administered on days 1, 2, and 3 of the first treatment cycle, and plinabulin is administered on day 1 after the first chemotherapy agent is administered, followed by G-CSF on day 4 of every treatment cycle. In some embodiments, the G-CSF formulation can be administered once per treatment cycle when a long-acting G-CSF is used, or multiple times per treatment cycle when a short-acting G-CSF is used. The G-CSF formulation is administered ≥ 24 hours after the chemotherapy agent is administered.

[0071] In some embodiments, neutropenia is induced by docetaxel. The administration period can be a multi-week treatment cycle, as long as the tumor remains under control and the regimen is clinically tolerated. In some embodiments, docetaxel and plinabulin can be administered once every three weeks. In some embodiments, docetaxel and plinabulin can be administered once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, docetaxel and plinabulin can be administered once a week, preferably on days 1 and 8 of a three-week (21-day) treatment cycle. In some embodiments, docetaxel and plinabulin 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 for one, two, three, four, or five weeks of the treatment cycle. Administration can occur on the same or different days each week during the treatment cycle. In some embodiments, plinabulin is administered before administration of docetaxel. In some embodiments, plinabulin is administered simultaneously with administration of docetaxel. In some embodiments, plinabulin is administered after administration of docetaxel.

[0072] In some embodiments, plinabulin and G-CSF can be administered simultaneously after the administration of chemotherapy. When plinabulin and / or G-CSF are administered after the administration of chemotherapy, it means that plinabulin and / or G-CSF are administered after the final chemotherapy agent has been completely administered to the patient. For example, administering plinabulin approximately 30 minutes after the administration of TAC chemotherapy means that administration of plinabulin begins approximately 30 minutes after the administration of the final chemotherapy agent (e.g., docetaxel). In some embodiments, plinabulin is administered approximately 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours after the administration of chemotherapy. In some embodiments, the plinabulin is administered less than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration of the chemotherapy agent. In some embodiments, the plinabulin is administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or more than 24 hours after administration of the chemotherapy agent.In some embodiments, plinabulin is administered about 1 to 5 minutes, 1 to 10 minutes, 1 to 15 minutes, 1 to 20 minutes, 1 to 25 minutes, 1 to 30 minutes, 1 to 45 minutes, 1 to 1 hour, 1 to 75 minutes, 1 to 90 minutes, 1 to 120 minutes, 0.25 to 0.5 hours, 0.25 to 0.75 hours, 15 to 45 minutes, 15 to 75 minutes, 15 to 90 minutes, 15 to 120 minutes, 0.25 to 1 hour, 30 to 45 minutes, 30 to 75 minutes, 30 to 90 minutes, 0.5 hours to 1 hour, 0.5 hours to 2 hours, 0.5 hours to 2.5 hours, 1 hour to 2 hours, 1 hour to 3 hours, or 1 hour to 5 hours after administration of the chemotherapy agent. In some embodiments, plinabulin is administered 30 minutes after administration of the chemotherapy agent. In some embodiments, the plinabulin is administered less than about 1 hour after administration of the chemotherapy agent.

[0073] In some embodiments, plinabulin and G-CSF can be administered after the administration of chemotherapy. When plinabulin and / or G-CSF are administered after the administration of chemotherapy, it means that plinabulin and / or G-CSF are administered after the final chemotherapy agent has been completely administered to the patient. For example, administering plinabulin about 30 minutes after the administration of TAC chemotherapy means that administration of plinabulin begins about 30 minutes after the administration of the final chemotherapy agent (e.g., docetaxel). In some embodiments, plinabulin is administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours after the administration of chemotherapy. In some embodiments, the plinabulin is administered less than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration of the chemotherapy agent. In some embodiments, the plinabulin is administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or more than 24 hours after administration of the chemotherapy agent.In some embodiments, the chemotherapeutic agent is administered within about 1 to 5 minutes, 1 to 10 minutes, 1 to 15 minutes, 1 to 20 minutes, 1 to 25 minutes, 1 to 30 minutes, 1 to 45 minutes, 1 minute to 1 hour, 1 to 75 minutes, 1 to 90 minutes, 1 to 120 minutes, 0.25 hours to 0.5 hours, 0.25 to 0.75 hours, 15 minutes to 45 minutes, 10 minutes to 20 minutes, 10 to 30 minutes, 10 to 40 minutes, 10 to 50 minutes, 15 minutes ... Plinabulin is administered within 75 minutes, 15 minutes to 90 minutes, 15 minutes to 120 minutes, 20 minutes to 30 minutes, 20 minutes to 40 minutes, 20 minutes to 50 minutes, 25 minutes to 35 minutes, 28 minutes to 32 minutes, 0.25 to 1 hour, 30 minutes to 45 minutes, 30 minutes to 75 minutes, 30 minutes to 90 minutes, 0.5 hours to 1 hour, 0.5 hours to 2 hours, 0.5 hours to 2.5 hours, 1 hour to 2 hours, 1 hour to 3 hours, or 1 hour to 5 hours. In some embodiments, plinabulin is administered approximately 30 minutes after administration of the chemotherapy agent. In some embodiments, plinabulin is administered less than about 1 hour after administration of the chemotherapy agent.

[0074] In some embodiments, G-CSF is administered after chemotherapy. In some embodiments, G-CSF (or the first administration of G-CSF if short-acting G-CSF is used) is administered about 5 hours, 10 hours, 12 hours, 15 hours, 20 hours, 24 hours, 30 hours, 36 hours, 41 hours, 48 ​​hours, or 54 hours after chemotherapy. In some embodiments, G-CSF (or the first administration of G-CSF if short-acting G-CSF is used) is administered less than about 24 hours, 30 hours, 36 hours, 42 hours, 48 ​​hours, 54 hours, or 60 hours after chemotherapy. In some embodiments, G-CSF (or the first administration of G-CSF if short-acting G-CSF is used) is administered more than about 10 hours, 12 hours, 15 hours, 20 hours, 24 hours, 30 hours, 36 hours, 41 hours, 48 ​​hours, or 54 hours after chemotherapy. In some embodiments, G-CSF (or, if a short-acting G-CSF is used, the first dose of G-CSF) is administered about 10 to 36 hours, 10 to 48 hours, 10 to 54 hours, 24 to 36 hours, 24 to 48 hours, 24 to 54 hours, or 24 to 60 hours after chemotherapy administration. In some embodiments, G-CSF (or, if a short-acting G-CSF is used, the first dose of G-CSF) is administered at least 24 hours after chemotherapy administration.

[0075] In some embodiments, plinabulin and G-CSF are administered after administration of docetaxel. In some embodiments, plinabulin and G-CSF are administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, or 3.5 hours after administration of docetaxel. Plinabulin is administered 5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In some embodiments, plinabulin is administered less than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after administration of docetaxel. In some embodiments, plinabulin is administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or more than 24 hours after administration of docetaxel. In some embodiments, plinabulin is administered approximately 1 to 5 minutes, 1 to 10 minutes, 1 to 15 minutes, 1 to 20 minutes, 1 to 25 minutes, 1 to 30 minutes, 1 to 45 minutes, 1 to 1 hour, 1 to 75 minutes, 1 to 90 minutes, 1 to 120 minutes, 0.25 to 0.5 hours, 0.25 to 0.75 hours, 15 to 45 minutes, 15 to 75 minutes, 15 to 90 minutes, 15 to 120 minutes, 0.25 to 1 hour, 30 to 45 minutes, 30 to 75 minutes, 30 to 90 minutes, 0.5 to 1 hour, 0.5 to 2 hours, 0.5 to 2.5 hours, 1 to 2 hours, 1 to 3 hours, or 1 to 5 hours after docetaxel administration. In some embodiments, plinabulin is administered 30 minutes after docetaxel administration. In some embodiments, plinabulin is administered less than 1 hour after administration of docetaxel.

[0076] In some embodiments, when plinabulin and G-CSF are co-administered before administration of a chemotherapy agent, plinabulin is administered about 1 to 5 minutes, 1 to 10 minutes, 1 to 15 minutes, 1 to 20 minutes, 1 to 25 minutes, 1 to 30 minutes, 0.25 to 0.5 hours, 0.25 to 0.75 hours, 0.25 to 1 hour, 0.5 to 1 hour, 0.5 to 2 hours, 0.5 to 2.5 hours, 1 to 2 hours, 1 to 3 hours, or 1 to 5 hours before administration of the chemotherapy agent. In some embodiments, plinabulin is administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of the chemotherapy agent. In some embodiments, the plinabulin is administered less than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before administration of the chemotherapy agent. In some embodiments, the plinabulin is administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or more than 24 hours before administration of the chemotherapy agent.

[0077] In some embodiments, when plinabulin and G-CSF are co-administered before administration of docetaxel, plinabulin is administered about 1 to 5 minutes, 1 to 10 minutes, 1 to 15 minutes, 1 to 20 minutes, 1 to 25 minutes, 1 to 30 minutes, 0.25 to 0.5 hours, 0.25 to 0.75 hours, 0.25 to 1 hour, 0.5 to 1 hour, 0.5 to 2 hours, 0.5 to 2.5 hours, 1 to 2 hours, 1 to 3 hours, or 1 to 5 hours before administration of docetaxel. In some embodiments, plinabulin is administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours before administration of docetaxel. In some embodiments, plinabulin is administered less than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours before administration of docetaxel. In some embodiments, plinabulin is administered about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or more than 24 hours before administration of docetaxel.

[0078] In some embodiments, the infusion time of plinabulin is about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours. In some embodiments, the infusion time of plinabulin is less than about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours. In some embodiments, the infusion time of plinabulin is about 1 minute, 5 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 45 minutes, 50 minutes, 1 hour, 75 minutes, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or more than 24 hours. In some embodiments, the infusion time of plinabulin is about 1 to 5 minutes, 1 to 10 minutes, 1 to 15 minutes, 1 to 20 minutes, 1 to 25 minutes, 1 to 30 minutes, 1 to 45 minutes, 1 minute to 1 hour, 1 to 75 minutes, 1 to 90 minutes, 1 to 120 minutes, 0.25 hours to 0.5 hours, 0.25 to 0.75 hours, 15 minutes to 45 minutes, 15 minutes to 75 minutes, 15 minutes to 90 minutes, 15 minutes to 120 minutes, 0.25 to 1 hour, 30 minutes to 45 minutes, 30 minutes to 75 minutes, 30 minutes to 90 minutes, 0.5 hours to 1 hour, 0.5 hours to 2 hours, 0.5 hours to 2.5 hours, 1 hour to 2 hours, 1 hour to 3 hours, or 1 hour to 5 hours. In some embodiments, the infusion time of plinabulin is determined by a single dose (e.g., 5, 10, 20, or 30 mg / m 2 In some embodiments, the infusion time for plinabulin is about 1 hour (e.g., 20, 30, or 30 mg / m 2 super).

[0079] In some embodiments, when plinabulin is co-administered with G-CSF, the treatment schedule comprises administering a chemotherapy agent followed by administration of plinabulin once every three weeks. In some embodiments, the treatment schedule comprises administering a chemotherapy agent followed by administration of plinabulin approximately 30 minutes after administration of the chemotherapy agent, with plinabulin being administered once every three weeks in a treatment cycle. In some embodiments, the treatment schedule comprises administering a chemotherapy agent followed by administration of plinabulin once every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks. In some embodiments, the treatment schedule comprises administering a chemotherapy agent followed by administration of plinabulin twice every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks. In some embodiments, the treatment schedule comprises administering a chemotherapy agent followed by administration of plinabulin once every week in a treatment cycle of one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks. In some embodiments, the treatment schedule comprises administering a chemotherapy agent followed by administering plinabulin twice weekly in a 1-week, 2-week, 3-week, 4-week, 5-week, 6-week, 7-week, or 8-week treatment cycle. In some embodiments, the treatment schedule comprises administering a chemotherapy agent followed by administering plinabulin on days 1, 8, and 15 of a 21-day treatment cycle. In some embodiments, the treatment schedule comprises administering plinabulin after every dose of chemotherapy. In some embodiments, the treatment schedule comprises administering plinabulin after the first dose / cycle of chemotherapy, followed by administering plinabulin following every second, third, fourth, fifth, or sixth dose of chemotherapy. In some embodiments, the treatment schedule comprises administering plinabulin after every other chemotherapy dose. In some embodiments, plinabulin is administered after every second, third, fourth, fifth, or sixth dose of chemotherapy.

[0080] In some embodiments, the first administration of plinabulin or G-CSF is administered as soon as neutropenic onset is suspected or confirmed.

[0081] In some embodiments, when plinabulin is co-administered with G-CSF, the treatment schedule comprises administering a chemotherapy drug (e.g., docetaxel, TAC, or TC), followed by administration of plinabulin once every three weeks. In some embodiments, the treatment schedule comprises administering a chemotherapy drug (e.g., docetaxel, TAC, or TC), followed by administration of plinabulin approximately 30 minutes after administration of the chemotherapy drug, wherein plinabulin is administered once every three weeks in a treatment cycle. In some embodiments, the treatment schedule comprises administering a chemotherapy drug (e.g., docetaxel, TAC, or TC), followed by administration of plinabulin once every one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks. In some embodiments, the treatment schedule comprises administering a chemotherapeutic agent (e.g., docetaxel, TAC, or TC) followed by administering plinabulin twice every week, every two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks. In some embodiments, the treatment schedule comprises administering a chemotherapeutic agent (e.g., docetaxel, TAC, or TC) followed by administering plinabulin once every week for a one-week, two-week, three-week, four-week, five-week, six-week, seven-week, or eight-week treatment cycle. In some embodiments, the treatment schedule comprises administering a chemotherapeutic agent (e.g., docetaxel, TAC, or TC) followed by administering plinabulin twice every week for a one-week, two-week, three-week, four-week, five-week, six-week, seven-week, or eight-week treatment cycle. In some embodiments, the treatment schedule involves administering a chemotherapeutic agent (e.g., docetaxel, TAC, or TC) followed by administering plinabulin on days 1, 8, and 15 of a 21-day treatment cycle. In some embodiments, the treatment schedule involves co-administering plinabulin and G-CSF after every administration of the chemotherapeutic agent (e.g., docetaxel, TAC, or TC).In some embodiments, the treatment schedule comprises co-administration of plinabulin and G-CSF after the first dose of chemotherapy (e.g., docetaxel, TAC, or TC), followed by co-administration of plinabulin and G-CSF following every second, third, fourth, fifth, or sixth dose of chemotherapy. In some embodiments, the treatment schedule comprises co-administration of plinabulin and G-CSF after every other dose of chemotherapy (e.g., docetaxel, TAC, or TC). In some embodiments, plinabulin and / or G-CSF are administered after every second, third, fourth, fifth, or sixth dose of chemotherapy (e.g., docetaxel, TAC, or TC).

[0082] In some embodiments, the treatment schedule comprises administering a chemotherapy agent (e.g., docetaxel, TAC, or TC), followed by co-administration of plinabulin and G-CSF once every three weeks. In some embodiments, the treatment schedule comprises administering a chemotherapy agent (e.g., docetaxel, TAC, or TC), followed by co-administration of plinabulin and G-CSF, where plinabulin is administered once every three weeks in a treatment cycle. In some embodiments, the treatment schedule comprises administering a chemotherapy agent (e.g., docetaxel, TAC, or TC), followed by co-administration of plinabulin and G-CSF once every week, every two weeks, every three weeks, every four weeks, every five weeks, every six weeks, every seven weeks, or every eight weeks. In some embodiments, the treatment schedule comprises administering a chemotherapeutic agent (e.g., docetaxel, TAC, or TC) followed by co-administration of plinabulin and G-CSF twice weekly, every 1 week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks. In some embodiments, the treatment schedule comprises administering a chemotherapeutic agent (e.g., docetaxel, TAC, or TC) followed by co-administration of plinabulin and G-CSF once weekly for a 1-week, 2-week, 3-week, 4-week, 5-week, 6-week, 7-week, or 8-week treatment cycle. In some embodiments, the treatment schedule comprises administering a chemotherapeutic agent (e.g., docetaxel, TAC, or TC) followed by co-administration of plinabulin and G-CSF twice weekly for a 1-week, 2-week, 3-week, 4-week, 5-week, 6-week, 7-week, or 8-week treatment cycle. In some embodiments, the treatment schedule comprises administering a chemotherapeutic agent (e.g., docetaxel, TAC, or TC) followed by co-administration of plinabulin and G-CSF on days 1, 8, and 15 of a 21-day treatment cycle. In some embodiments, the treatment schedule comprises co-administration of plinabulin and G-CSF after every administration of a chemotherapeutic agent (e.g., docetaxel, TAC, or TC).In some embodiments, the treatment schedule comprises simultaneous administration of plinabulin and G-CSF after the first dose of chemotherapy (e.g., docetaxel, TAC, or TC), followed by administration of plinabulin following every second, third, fourth, fifth, or sixth dose of chemotherapy. In some embodiments, the treatment schedule comprises simultaneous administration of plinabulin and G-CSF after every other dose of chemotherapy (e.g., docetaxel, TAC, or TC). In some embodiments, plinabulin and G-CSF are administered after every second, third, fourth, fifth, or sixth dose of chemotherapy (e.g., docetaxel, TAC, or TC).

[0083] In some embodiments, co-administration of plinabulin and G-CSF comprises administering only one dose of G-CSF after administering the first dose of plinabulin, and not administering G-CSF after the second dose of plinabulin per chemotherapy treatment cycle. In some embodiments, co-administration of plinabulin and G-CSF comprises administering one dose of G-CSF after administering each dose of plinabulin. In some embodiments, co-administration of plinabulin and G-CSF comprises administering a single dose of plinabulin followed by daily administration of G-CSF for up to 1 week, 2 weeks, or 3 weeks, or until the patient's ANC returns to a level that allows chemotherapy to be tolerated.

[0084] In some embodiments, the treatment schedule comprises co-administering plinabulin and G-CSF after every cycle of chemotherapy (e.g., docetaxel, TAC, or TC). In some embodiments, the treatment schedule comprises administering plinabulin after the first cycle of chemotherapy (e.g., docetaxel, TAC, or TC), then administering plinabulin following every second, third, fourth, fifth, or sixth cycle of chemotherapy. In some embodiments, the treatment schedule comprises administering plinabulin after every other cycle of chemotherapy (e.g., docetaxel, TAC, or TC). In some embodiments, plinabulin is administered after every second, third, fourth, fifth, or sixth cycle of chemotherapy (e.g., docetaxel, TAC, or TC).

[0085] Treatment cycles can be repeated as long as the regimen is clinically tolerated. In some embodiments, treatment cycles for docetaxel or other chemotherapy are 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 can be administered immediately after completion of the previous treatment cycle. In some embodiments, a new treatment cycle can be administered some time after completion of the previous treatment cycle.

[0086] In some embodiments, co-administration of plinabulin and G-CSF can reduce the incidence of grade 3 and / or 4 neutropenia 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, co-administration of plinabulin and G-CSF can reduce the incidence of grade 3 and / or 4 neutropenia 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, co-administration of plinabulin and G-CSF can reduce the incidence of grade 3 and / or 4 neutropenia by less than 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, co-administration of plinabulin and G-CSF reduces the incidence of Grade 3 and / or 4 neutropenia 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%, 10 ... The reduction can be in the range of 0% 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%.

[0087] In some embodiments, co-administration of plinabulin and G-CSF may be about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% more effective in reducing the incidence of grade 3 and / or 4 neutropenia than the use of G-CSF (e.g., pegfilgrastim). In some embodiments, co-administration of plinabulin and G-CSF may be greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% more effective in reducing the incidence of grade 3 and / or 4 neutropenia than the use of G-CSF (e.g., pegfilgrastim). In some embodiments, co-administration of plinabulin and G-CSF may be less than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% more effective in reducing the incidence of grade 3 and / or 4 neutropenia than the use of G-CSF (e.g., pegfilgrastim). In some embodiments, co-administration of plinabulin and G-CSF may be greater than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% more effective in reducing the incidence of grade 3 and / or 4 neutropenia than the use of G-CSF (e.g., pegfilgrastim).

[0088] In some embodiments, co-administration of plinabulin and G-CSF reduces the duration of severe neutropenia by 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%, The time can be reduced by 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 10x, 11x, 12x, 13x, 14x, 15x, or 16x. In some embodiments, co-administration of plinabulin and G-CSF reduces the duration of severe neutropenia by 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%, The reduction can be 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 10x, 11x, 12x, 13x, 14x, 15x, or greater than 16x.In some embodiments, co-administration of plinabulin and G-CSF reduces the duration of severe neutropenia by 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%. The reduction may be less than 5%, 80%, 82.5%, 85%, 87.5%, 90%, 95%, 100%, 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, co-administration of plinabulin and G-CSF can reduce the duration of severe neutropenia by 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%.

[0089] In some embodiments, co-administration of plinabulin and G-CSF is 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% or more effective in reducing the duration of severe neutropenia compared to G-CSF (e.g., pegfilgrastim). It may be 5%, 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 10x, 11x, 12x, 13x, 14x, 15x, or 16x more effective. In some embodiments, co-administration of plinabulin and G-CSF is more effective than G-CSF (e.g., pegfilgrastim) in reducing the duration of severe neutropenia by 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%, It can be 70%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, 10x, 11x, 12x, 13x, 14x, 15x, or 16x more effective.In some embodiments, co-administration of plinabulin and G-CSF is more effective than G-CSF (e.g., pegfilgrastim) in shortening the duration of severe neutropenia by 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%, 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%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 142%, 143%, 145%, 146%, It may be 0%, 72.5%, 75%, 77.5%, 80%, 82.5%, 85%, 87.5%, 90%, 95%, 100%, 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 less effective. In some embodiments, co-administration of plinabulin and G-CSF can be in the range of about 5% to 15 times, 20% to 10 times, or 50% to 500% more effective than G-CSF (e.g., pegfilgrastim) in shortening the duration of severe neutropenia.

[0090] Plinabulin and G-CSF can be co-administered after chemotherapy to treat or ameliorate neutropenia. In some embodiments, a single dose of G-CSF (e.g., pegfilgrastim or efrapegrastim, or other long-acting G-CSF) is about 10 mg, about 0.3 mg to about 6 mg, about 0.1 mg to about 6 mg, 0.1 mg to about 7 mg, 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 6 mg, or about 0. 5mg to about 5mg, about 0.5mg to about 4mg, about 0.5mg to about 3mg, 1mg to about 100mg, about 1mg to about 50mg, about 1mg to about 25mg, about 1mg to about 15mg, about 1mg ~10mg, 1mg~8mg, 1mg~7mg, 1mg~6mg, 1mg~5mg, 1mg~4mg, 1mg~3mg, 2mg~50mg, 2m g ~ about 25mg, about 2mg - about 15mg, about 2mg - about 10mg, about 2mg - about 10mg, about 2mg - about 8mg, about 2mg - about 7mg, about 2mg - about 6mg, about 2mg - about 5mg, Approximately 2mg to approximately 4mg, approximately 2mg to approximately 3mg, approximately 3mg to approximately 50mg, approximately 3mg to approximately 25mg, approximately 3mg to approximately 15mg, approximately 3mg to approximately 10mg, approximately 3mg to approximately 10mg, approximately 3mg to approximately The dose may be in the range of about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 50 mg, about 4 mg to about 25 mg, about 4 mg to about 15 mg, about 4 mg to about 10 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 25 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, or about 5 mg to about 8 mg.In some embodiments, a single dose of G-CSF (e.g., pegfilgrastim or efrapegrastim, or other long-acting G-CSF) may be 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 3 mg, 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 2 mg to about 50 mg, about 2 mg to about 25 mg, about 2 mg to about 15 mg, or about 2 mg to about 10 mg. The amount may be the same as that of filgrastim, in the range of about 2 mg to about 10 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 50 mg, about 3 mg to about 25 mg, about 3 mg to about 15 mg, about 3 mg to about 10 mg, about 3 mg to about 10 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 50 mg, about 4 mg to about 25 mg, about 4 mg to about 15 mg, about 4 mg to about 10 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 25 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, or about 5 mg to about 8 mg. In some embodiments, a single dose of G-CSF (e.g., pegfilgrastim or efrapegrastim, or other long-acting G-CSF) can be about 3 mg to about 10 mg, or about 4 mg to about 8 mg, or the same amount as filgrastim in the ranges described herein. In some embodiments, a single dose of G-CSF (e.g., pegfilgrastim or efrapegrastim, or other long-acting G-CSF) can be about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or more than about 10 mg.In some embodiments, a single dose of G-CSF (e.g., pegfilgrastim or efrapegrastim, or other long-acting G-CSF) can be about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12.5 mg, or less than about 15 mg. In some embodiments, a single dose of G-CSF (e.g., pegfilgrastim or efrapegrastim, or other long-acting G-CSF) can be about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, a single dose of G-CSF (eg, pegfilgrastim or efrapegrastim, or other long-acting G-CSF) may be about 6 mg.

[0091] In some embodiments, the total dose of G-CSF (e.g., pegfilgrastim or efrapegrastim, or other long-acting G-CSF) administered in a 21-day treatment cycle is from 0.1 mg to about 10 mg, from about 0.3 mg to about 6 mg, from about 0.1 mg to about 6 mg, from 0.1 mg to about 7 mg, from 0.5 mg to about 10 mg, from about 0.5 mg to about 8 mg, from about 0.5 mg to about 7 mg, mg, about 0.5mg to about 6mg, about 0.5mg to about 5mg, about 0.5mg to about 4mg, about 0.5mg to about 3mg, 1mg to about 100mg, about 1mg to about 50mg, about 1mg to about 25mg, Approximately 1 mg to approximately 15 mg, approximately 1 mg to approximately 10 mg, approximately 1 mg to approximately 8 mg, approximately 1 mg to approximately 7 mg, approximately 1 mg to approximately 6 mg, approximately 1 mg to approximately 5 mg, approximately 1 mg to approximately 4 mg, approximately 1 mg to approximately 3 mg, approximately 2 mg ~ about 50mg, about 2mg - about 25mg, about 2mg - about 15mg, about 2mg - about 10mg, about 2mg - about 10mg, about 2mg - about 8mg, about 2mg - about 7mg, about 2mg - about 6mg, about 2mg to about 5mg, about 2mg to about 4mg, about 2mg to about 3mg, about 3mg to about 50mg, about 3mg to about 25mg, about 3mg to about 15mg, about 3mg to about 10mg, about 3mg to about 10mg, The dose may be in the range of about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 50 mg, about 4 mg to about 25 mg, about 4 mg to about 15 mg, about 4 mg to about 10 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 25 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, or about 5 mg to about 8 mg.In some embodiments, the total dose of G-CSF (e.g., pegfilgrastim or efrapegrastim, or other long-acting G-CSF) per 21-day cycle is 0.5 mg to about 10 mg, about 0.5 mg to about 8 mg, about 0.5 mg to about 7 mg, about 0.5 mg to about 6 mg, about 0.5 mg to about 5 mg, about 0.5 mg to about 4 mg, about 0.5 mg to about 3 mg, 1 mg to about 100 mg, about 1 mg to about 50 mg, about 1 mg to about 25 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 2 mg to about 50 mg, about 2 mg to about 25 mg, about 2 mg to about 15 mg, or about 2 mg to about 25 mg. g ~ about 10mg, about 2mg - about 10mg, about 2mg - about 8mg, about 2mg - about 7mg, about 2mg - about 6mg, about 2mg - about 5mg, about 2mg - about 4mg, about 2mg - about 3mg , about 3 mg to about 50 mg, about 3 mg to about 25 mg, about 3 mg to about 15 mg, about 3 mg to about 10 mg, about 3 mg to about 10 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 m The total dose of G-CSF (e.g., pegfilgrastim, efrapegrastim, or other long-acting G-CSF) administered per 21-day cycle may be the same as the amount of filgrastim, ranging from about 3 mg to about 10 mg, or about 4 mg to about 8 mg, or from about 3 mg to about 5 mg, or from about 3 mg to about 4 mg, or from about 4 mg to about 50 mg, or from about 4 mg to about 25 mg, or from about 4 mg to about 15 mg, or from about 5 mg to about 10 mg, or from about 5 mg to about 8 mg, or from about 3 mg to about 10 mg, or from about 4 mg to about 8 mg, or from about 5 ... In some embodiments, the total dose of G-CSF (e.g., pegfilgrastim, efrapegrastim, or other long-acting G-CSF) per 21-day cycle can be about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or more than about 10 mg.In some embodiments, the total dose of G-CSF (e.g., pegfilgrastim, efrapegrastim, or other long-acting G-CSF) per 21-day cycle can be less than about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 12.5 mg, or about 15 mg. In some embodiments, the total dose of G-CSF (e.g., pegfilgrastim, efrapegrastim, or other long-acting G-CSF) per 21-day cycle can be about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, or about 10 mg. In some embodiments, the total dose of G-CSF (e.g., pegfilgrastim, efrapegrastim, or other long-acting G-CSF) per 21-day cycle can be about 6 mg.

[0092] In some embodiments, G-CSF (e.g., filgrastim or other short-acting G-CSF) can be administered in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 μg / kg / day. In some embodiments, G-CSF (e.g., filgrastim or other short-acting G-CSF) can be administered in an amount greater than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 μg / kg / day. In some embodiments, G-CSF (e.g., filgrastim or other short-acting G-CSF) can be administered in an amount of less than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, or 50 μg / kg / day. In some embodiments, G-CSF (e.g., filgrastim or other short-acting G-CSF) can be administered in an amount of about 1 to 5, 1 to 10, 1 to 15, 1 to 20, 1 to 30, 2.5 to 5, 2.5 to 7.5, 2.5 to 10, 2.5 to 15, 2.5 to 20, 5 to 10, 5 to 15, 5 to 20, 5 to 25, or 5 to 30 μg / kg / day. In some embodiments, G-CSF is administered in an amount of about 0.05, 0.75, 0.1, 0.2, 0.3, 0.4, 0.48, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.2, 1.5, 1.75, or 2 mg per administration. In some embodiments, G-CSF is administered in a range of about 0.05-0.5 mg, 0.05-1.0 mg, 0.1-1.0 mg, or 0.05-2.0 mg per administration.

[0093] Administration of plinabulin and G-CSF can help prevent or treat severe neutropenia induced by chemotherapy treatment. In some embodiments, G-CSF (e.g., pegfilgrastim or filgrastim) is administered once per chemotherapy cycle. In some embodiments, G-CSF (e.g., pegfilgrastim or filgrastim) is not administered 14 to 24 hours after administration of the cytotoxic chemotherapy agent. In some embodiments, G-CSF (e.g., pegfilgrastim or filgrastim) is not administered 24 hours before administration of the cytotoxic chemotherapy agent. In some embodiments, two doses of G-CSF (e.g., pegfilgrastim or filgrastim) are administered one week apart. In some embodiments, G-CSF (e.g., pegfilgrastim or filgrastim) is administered once, twice, three times, four times, five times, six times, or seven times per week for one or two weeks. In some embodiments, G-CSF (e.g., pegfilgrastim or filgrastim) is administered once every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks. In some embodiments, the first dose of G-CSF (e.g., pegfilgrastim or filgrastim) is administered soon after suspected or confirmed exposure to myelosuppressive chemotherapy or a dose of myelosuppressive radiation. In some embodiments, G-CSF (e.g., pegfilgrastim or filgrastim) is administered subcutaneously.

[0094] In some embodiments, during a chemotherapy treatment cycle, the chemotherapy drug is administered only once at the beginning of the treatment cycle, and then plinabulin and G-CSF are co-administered once, twice, three times, four times, five times, or six times during the treatment cycle. In some embodiments, during a chemotherapy treatment cycle, the chemotherapy drug is administered only once at the beginning of the treatment cycle, and then plinabulin and G-CSF are co-administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, during a chemotherapy treatment cycle, the chemotherapy drug is administered only once at the beginning of the treatment cycle, and then plinabulin and G-CSF are co-administered once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or every day for one, two, three, four, or five week treatment cycles.

[0095] In some embodiments, G-CSF and plinabulin can be administered simultaneously or separately once every three weeks. In some embodiments, G-CSF and plinabulin can be administered simultaneously or separately once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, G-CSF and plinabulin can be administered simultaneously or separately once a week. In some embodiments, G-CSF and plinabulin can be administered simultaneously or separately once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or daily for a one-, two-, three-, four-, or five-week treatment cycle. Administration can occur on the same or different days each week in a treatment cycle. In some embodiments, plinabulin is administered before G-CSF administration. In some embodiments, plinabulin is administered simultaneously with G-CSF administration. In some embodiments, plinabulin is administered after G-CSF administration.

[0096] In some embodiments, G-CSF is administered before the administration of plinabulin. In some embodiments, G-CSF is administered simultaneously with the administration of plinabulin. In some embodiments, G-CSF is administered after the administration of plinabulin. In some embodiments, G-CSF is administered about 10 to about 72 hours, about 20 to about 72 hours, about 20 to about 70 hours, about 20 to about 60 hours, about 20 to about 50 hours, about 20 to about 48 hours, about 20 to about 40 hours, about 20 to about 36 hours, about 20 to about 30 hours, or about 20 to about 24 hours after the administration of plinabulin. In still further embodiments, G-CSF is administered within 48 hours, within 24 hours, or within 12 hours after the administration of plinabulin.

[0097] In some embodiments, G-CSF (or, if short-acting G-CSF is used, the first dose of G-CSF) is administered about 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, or 72 hours after chemotherapy administration. In some embodiments, G-CSF (or, if short-acting G-CSF is used, the first dose of G-CSF) is administered less than about 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, 72 hours, 84 hours, 96 hours, 5 days, 6 days, or 7 days after chemotherapy administration. In some embodiments, G-CSF (or, if short-acting G-CSF is used, the first dose of G-CSF) is administered about 1 hour to 24 hours, 12 hours to 36 hours, 10 hours to 40 hours, 24 hours to 36 hours, 1 day to 2 days, 1 day to 5 days, or 1 day to 1 week after chemotherapy administration. In some embodiments, G-CSF (if short-acting G-CSF is used, the first administration of G-CSF) is administered at least about 24 hours after chemotherapy administration. In some embodiments, G-CSF (if short-acting G-CSF is used, the first administration of G-CSF) is administered at least about 48 hours after chemotherapy administration. In some embodiments, G-CSF (if short-acting G-CSF is used, the first administration of G-CSF) is administered about 24 hours after chemotherapy administration. In some embodiments, G-CSF (if short-acting G-CSF is used, the first administration of G-CSF) is administered about 48 hours after chemotherapy administration.

[0098] Some embodiments include administering 1, 2, 3, 4, 5, 6, or more cycles of a chemotherapy regimen, wherein each cycle of the chemotherapy regimen independently comprises administering one or more chemotherapy agents on day 1, day 2, day 3, day 4, day 5, or a combination thereof; administering plinabulin on day 1, day 2, day 3, day 4, day 5, day 6, day 7, or a combination thereof; and administering one or more G-CSF formulations on day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 13, day 14, or a combination thereof. In some embodiments, one or more chemotherapy agents may be administered independently in each cycle of chemotherapy according to the foregoing descriptions or any of the descriptions elsewhere herein. In some embodiments, plinabulin may be administered independently in each cycle of chemotherapy according to the foregoing descriptions or any of the descriptions elsewhere herein. In some embodiments, one or more G-CSF formulations may be administered independently in each cycle of chemotherapy as described above or elsewhere herein. In some embodiments, each cycle of the chemotherapy regimen lasts for up to 30 days, 21 days, 14 days, or 7 days. In some embodiments, each cycle of the chemotherapy regimen lasts for 30 days, 21 days, 14 days, or 7 days.

[0099] Administration of the pharmaceutical compositions described herein can be via any of the accepted modes of administration for agents serving similar utilities, including, but not limited to, oral, sublingual, buccal, subcutaneous, intravenous, intranasal, topical, transdermal, intradermal, intraperitoneal, intramuscular, pulmonary, intravaginal, rectal, or ocular. Oral and parenteral administration are common in the treatment of indications covered by preferred embodiments.

[0100] Pharmaceutical Composition Some embodiments relate to pharmaceutical compositions comprising plinabulin.Some embodiments relate to pharmaceutical compositions comprising about 1 mg to about 100 mg of plinabulin.

[0101] In some embodiments, the compositions described herein can be administered or used in combination with docetaxel treatment.

[0102] Other embodiments include simultaneous administration of plinabulin, G-CSF, and docetaxel in separate compositions or the same composition. Accordingly, some embodiments include a first pharmaceutical composition comprising (a) a safe and therapeutically effective amount of docetaxel or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof; a second pharmaceutical composition comprising (a) a safe and therapeutically effective amount of plinabulin and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof; and a third pharmaceutical composition comprising (a) a safe and therapeutically effective amount of G-CSF and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof. Some embodiments include pharmaceutical compositions comprising (a) a safe and therapeutically effective amount of docetaxel or a pharmaceutically acceptable salt thereof; (b) a safe and therapeutically effective amount of plinabulin; (c) a safe and therapeutically effective amount of G-CSF; and (d) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0103] In some embodiments, the pharmaceutical compositions described herein can further comprise one or more pharmaceutically acceptable diluents. In some embodiments, the pharmaceutically acceptable diluent can comprise Kolliphor® (polyethylene glycol (15)-hydroxystearate). In some embodiments, the pharmaceutically acceptable diluent can comprise propylene glycol. In some embodiments, the pharmaceutically acceptable diluent can comprise Kolliphor (Kolliphor HS15) and propylene glycol. In some embodiments, the pharmaceutically acceptable diluent can comprise Kolliphor and propylene glycol, wherein Kolliphor 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 can further comprise one or more other pharmaceutically acceptable excipients.

[0104] Remington's The Science and Practice of Pharmacy,21st Ed.,Lippincott Williams & Standard pharmaceutical formulation techniques can be used to prepare the pharmaceutical compositions described herein, such as those disclosed in Wilkins (2005), which is incorporated herein 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 a combination thereof.

[0105] 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 pharmaceutically active substances is well known in the art. Except insofar as any conventional media is incompatible with the active ingredient, its use in therapeutic compositions is expected. In addition, various adjuvants commonly used in the art may be included. Discussions regarding the inclusion of various ingredients in pharmaceutical compositions are found, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press (incorporated herein by reference in its entirety).

[0106] Some examples of substances which 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, ethyl cellulose, and methyl cellulose; 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 butter; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as TWEENS; wetting agents such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffers.

[0107] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is 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, a single or unit dosage formulation does not imply administration once per day or once per course of treatment. Such dosage forms may be administered once per day, twice per day, three or more times per day, may be administered by infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or may be administered by continuous infusion, and may be given more than once during a course of treatment, although single administration is not specifically excluded. One skilled in the art will recognize that the formulation does not specifically consider the entire course of treatment, and such determinations are made by those skilled in the art of treatment rather than by such formulation.

[0108] The compositions useful as described above may be in any of a variety of suitable forms for various routes of administration, such as oral, sublingual, buccal, intranasal, rectal, topical (including transdermal and intradermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes. Those skilled in the art will recognize that oral and nasal compositions include compositions administered by inhalation and prepared using available methods. Depending on the particular route of administration desired, various pharmaceutically acceptable carriers known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating materials. Pharmaceutically active substances that do not substantially interfere with the activity of the compound or composition may be included, if desired. The amount of carrier used with the compound or composition is sufficient to provide a practical amount of the substance for administration per unit dose of the compound. Techniques and compositions for producing dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0109] A variety of oral dosage forms can be used, including solid forms such as tablets, capsules (e.g., liquid gel capsules and solid gel capsules), granules, and mixed powders. Tablets can be compressed tablets, molded tablets, enteric-coated tablets, sugar-coated tablets, film-coated tablets, or multi-layer tablets containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow agents, and melting agents. Liquid oral dosage forms include solutions and / or suspensions prepared prior to administration from aqueous solutions, emulsions, suspensions, and effervescent granules containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings.

[0110] Pharmaceutically acceptable carriers suitable for the formulation of unit dosage forms for oral administration are well known in the art. Tablets are well known in the art. Tablets usually contain conventional pharmaceutically acceptable adjuvants 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. Glidants, such as silicon dioxide, can be used to improve the flow characteristics of powder mixtures. Coloring agents, such as FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, sucrose, and fruit flavors, are useful adjuvants for chewable tablets. Capsules usually contain one or more solid diluents as disclosed above. The selection of carrier ingredients depends on secondary considerations, such as taste, cost, and shelf life, which are less important, and can be easily prepared by those skilled in the art.

[0111] Oral compositions also include solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for formulating 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 sugar, 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; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may contain one or more ingredients, such as the sweeteners, flavors, and colorants disclosed above.

[0112] Such compositions may be coated by conventional methods, typically with a pH- or time-dependent coating, to release the subject composition in the gastrointestinal tract near the desired topical application or to extend the desired effect over various periods of time. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes, and shellac.

[0113] The compositions described herein may optionally contain other active agents.

[0114] Other compositions useful for achieving systemic delivery of target compound include sublingual, oral and nasal dosage forms.This composition typically comprises soluble filler such as sucrose, sorbitol and mannitol; and one or more binders such as acacia, microcrystalline cellulose, carboxymethylcellulose and hydroxypropylmethylcellulose.Can also comprise glidants, lubricants, sweeteners, coloring agents, antioxidants and flavoring agents as disclosed above.

[0115] The liquid composition formulated for topical ophthalmic use is formulated so that it can be administered topically to the eye.Formulation considerations (e.g., drug stability) may not always require optimal comfort, but may maximize comfort as much as possible.If comfort cannot be maximized, the liquid may be formulated so that the liquid can be tolerated by patients for topical ophthalmic use.In addition, the ophthalmologically acceptable liquid may be packaged for single use or may contain a preservative to prevent impurities over multiple uses.

[0116] For ophthalmic use, solutions or drugs are often formulated using saline as the primary vehicle. Ophthalmic solutions may preferably be maintained at a comfortable pH using an appropriate buffer system. Formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0117] Preservatives that may 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 may be used in the ophthalmic preparations disclosed herein.These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0118] Tonicity adjusting agents may be added as needed or convenient, including but not limited to salts, particularly sodium chloride, potassium chloride, mannitol and gelatin, or any other suitable ophthalmically acceptable tonicity adjusting agent.

[0119] Various buffers and means for adjusting pH may be used as long as the resulting formulation is ophthalmologically acceptable. In many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers, and borate buffers. The pH of these formulations may be adjusted using acids or bases as needed.

[0120] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0121] 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 used instead or in combination with it.

[0122] For topical use, creams, ointments, gels, solutions or suspensions, etc. containing the compositions disclosed herein are used. Topical formulations may generally consist of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0123] For intravenous administration, the compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose 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, preferably 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone-sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Additional acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antibacterial agents may be used to provide a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0124] Compositions for intravenous administration may be provided to the caregiver in one or more solid forms that are prepared with a suitable diluent, such as sterile water, saline, or dextrose in water, immediately prior to administration. In other embodiments, the compositions are provided in a solution that is ready for parenteral administration. In still other embodiments, the compositions are 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.

[0125] The actual dose of plinabulin described herein will depend on the chemotherapeutic agent used and the condition being treated; selection of an appropriate dose is well within the knowledge of one of ordinary skill in the art. In some embodiments, a single dose of plinabulin is about 5 mg / m2 of body surface area. 2 ~about 150mg / m 2 , approximately 5 mg / m of body surface area 2 ~about 100mg / m 2 , approximately 10 mg / m of body surface area 2 ~about 100mg / m 2 , approximately 10 mg / m of body surface area 2 ~about 80mg / m 2 , approximately 10 mg / m of body surface area 2 ~about 50mg / m 2 , approximately 10 mg / m of body surface area 2 ~about 40mg / m 2 , approximately 10 mg / m of body surface area 2 ~about 30mg / m 2 , approximately 13.5 mg / m of body surface area 2 ~about 100mg / m 2 , approximately 13.5 mg / m of body surface area 2 ~about 80mg / m 2 , approximately 13.5 mg / m of body surface area 2 ~about 50mg / m 2 , approximately 13.5 mg / m of body surface area 2 ~about 40mg / m 2 , approximately 13.5 mg / m of body surface area 2 ~about 30mg / m 2, approximately 15 mg / m of body surface area 2 ~about 80mg / m 2 , approximately 15 mg / m of body surface area 2 ~about 50mg / m 2 , or approximately 15 mg / m of body surface area. 2 ~about 30mg / m 2 In some embodiments, a single dose of plinabulin may be about 13.5 mg / m of body surface area. 2 ~about 30mg / m 2 In some embodiments, a single dose of plinabulin may be about 5 mg / m of body surface area. 2 , about 10mg / m 2 , about 12.5mg / m 2 , about 13.5mg / m 2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 22.5mg / m 2 , about 25mg / m 2 , about 27.5mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , or about 100 mg / m 2 In some embodiments, a single dose of plinabulin may be greater than about 5 mg / m2 of body surface area. 2 , about 10mg / m 2 , about 12.5mg / m 2 , about 13.5mg / m 2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 22.5mg / m 2 , about 25mg / m 2 , about 27.5mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2, about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , or about 100 mg / m 2 In some embodiments, a single dose of plinabulin is about 5 mg / m of body surface area. 2 , about 10mg / m 2 , about 12.5mg / m 2 , about 13.5mg / m 2 , about 15mg / m 2 , about 17.5mg / m 2 , about 20mg / m 2 , about 22.5mg / m 2 , about 25mg / m 2 , about 27.5mg / m 2 , about 30mg / m 2 , about 40mg / m 2 , about 50mg / m 2 , about 60mg / m 2 , about 70mg / m 2 , about 80mg / m 2 , about 90mg / m 2 , or about 100 mg / m 2 It may be.

[0126] Some embodiments relate to a composition comprising about 1 mg to 100 mg of plinabulin. In some embodiments, the composition comprises about 5 mg to about 300 mg, about 5 mg to about 200 mg, about 7.5 mg to about 200 mg, about 10 mg to about 100 mg, about 15 mg to about 100 mg, about 20 mg to about 100 mg, about 30 mg to about 100 mg, about 40 mg to about 100 mg, about 10 mg to about 80 mg, about 15 mg to about 80 mg, about 20 mg to about 80 mg, about 30 mg to about 80 mg, about 40 mg to about 80 mg, about 10 mg to about 60 mg, about 15 mg to about 60 mg, about 20 mg to about 60 mg, about 30 mg to about 60 mg, or about 40 mg to about 60 mg of plinabulin. In some embodiments, a single dose of plinabulin or other therapeutic agent may be about 20 mg to about 60 mg, about 27 mg to about 60 mg, about 20 mg to about 45 mg, or about 27 mg to about 45 mg. In some embodiments, a single dose of plinabulin or other therapeutic agent may be about 5 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, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or more than about 200 mg. In some embodiments, a single dose of plinabulin or other therapeutic agent may be less than about 5 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, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg.

[0127] Some embodiments relate to pharmaceutical compositions comprising plinabulin and one or more G-CSF preparations.

[0128] Some embodiments relate to a sterile container containing a pharmaceutical composition of plinabulin described herein. Some embodiments relate to a kit containing a chemotherapeutic agent, about 1 mg to about 80 mg of plinabulin, and about 0.1 mg to about 20 mg of G-CSF, wherein the chemotherapeutic agent, G-CSF, and plinabulin are provided in separate sterile containers.

[0129] In some embodiments, the amount of plinabulin in the kit is less than 50 mg. In some embodiments, the amount of plinabulin in the sterile container is about 10 mg. In some embodiments, the amount of plinabulin in the sterile container is about 20 mg. In some embodiments, the amount of plinabulin in the sterile container is about 30 mg. In some embodiments, the amount of plinabulin in the sterile container is about 40 mg. In some embodiments, the amount of G-CSF in the sterile container is less than 10 mg. In some embodiments, the amount of G-CSF in the sterile container is about 6 mg. In some embodiments, the amount of G-CSF in the sterile container is about 3 mg. In some embodiments, the amount of G-CSF in the sterile container is about 1.5 mg.

[0130] Some embodiments include a kit containing plinabulin, G-CSF, and docetaxel. In one embodiment, plinabulin, G-CSF, and docetaxel are provided in separate sterile containers. In the case of solids to be prepared immediately before administration, the drugs may be added to the container at the same time, or may be dry powders filled into the container in a separate step. In some embodiments, the solid is a sterile crystalline product. In other embodiments, the solid is a lyophilized product. [Example]

[0131] Example 1 A randomized, double-blind study was conducted to evaluate the use of plinabulin versus pegfilgrastim in patients with solid tumors receiving docetaxel myelosuppressive chemotherapy to treat severe neutropenia. Patients were randomly assigned to the following groups (with respective sample sizes): Group 1: Docetaxel (75 mg / m 2) + pegfilgrastim (6 mg) (n = 14); Group 2: docetaxel (75 mg / m 2 ) + plinabulin (20 mg / m 2 ) (n = 14); Group 3: docetaxel (75 mg / m 2 ) + plinabulin (10 mg / m 2 ) (n = 14); and Group 4: docetaxel (75 mg / m 2 ) + plinabulin (5 mg / m 2 ) (n=13). The test results are shown in Figure 1.

[0132] As shown in Figure 1, the neutrophil count in the pegfilgrastim group began to decline after 10 days, while the neutrophil count in the plinabulin group began to rise again after 10 days. The results showed that plinabulin was effective in treating chemotherapy-induced neutropenia. This study demonstrated that plinabulin and pegfilgrastim have different profiles of neutropenia relief, with the nadir being different for plinabulin compared with pegfilgrastim, suggesting that the two drugs can be combined to continuously maintain neutrophil count levels. Plinabulin prevented ANC overshoot during relief. The results also suggested that the amount of G-CSF or plinabulin required for neutropenia treatment may be reduced due to the additive effect of the combination.

[0133] Example 2 A multicenter randomized trial of G-CSF and plinabulin was conducted. The phase 2 portion was randomized and open-label. The decision to complete the phase 2 portion of the trial as open-label was made to reduce the complexity of study conduct and to allow for evaluation of QoL outcomes with same-day plinabulin administration (i.e., the day of chemotherapy administration) versus next-day administration of G-CSF. Patients with first-line breast cancer were enrolled in the trial.

[0134] Patients received up to four cycles of a docetaxel / doxorubicin / cyclophosphamide-based chemotherapy regimen every 3 weeks (21 days). On day 1 of cycle 1, all patients received docetaxel (75 mg / m 2), doxorubicin (50 mg / m 2 ), and cyclophosphamide (500 mg / m 2 )-Taxotere, Adriamycin, and Cyclophosphamide (TAC).

[0135] During cycles 2-4, the doxorubicin component may be omitted at the investigator's discretion, i.e., TC may be administered instead of TAC.

[0136] Eligibility for all patients was determined during a 28-day screening period.

[0137] Plinabulin has demonstrated efficacy against docetaxel-induced neutropenia in humans, and we have demonstrated beneficial effects of plinabulin in nonclinical studies with two other components of the TAC regimen, so plinabulin helped to ameliorate TAC-induced neutropenia.

[0138] Phase 2 (open label): In phase 2, patients were randomly assigned to one of the groups, with group assignment and planned intervention as shown in Table 2. [Table 2]

[0139] Patients were randomized to receive TAC (or TC for cycles 2-4) plus pegfilgrastim or a combination of plinabulin and pegfilgrastim in each of arms 1, 2, 3, and 4.

[0140] In phase 2 (open-label), cycles 1 to 4 consisted of TAC (or TC for cycles 2 to 4) administered intravenously on day 1 of every 21 days. Patients in groups 2 and 3 received a single dose of plinabulin over 30 minutes (±5 minutes) 30 minutes after the end of TAC (or TC for cycles 2 to 4) on day 1. On day 2 of each cycle (≥24 hours after completion of chemotherapy), patients in group 1 received a single dose (subcutaneous injection) of pegfilgrastim (6.0 mg) in open-label treatment.

[0141] Docetaxel: Docetaxel was administered at 75 mg / m 2 The dose prescribed by this clinical trial protocol (75 mg / m 2 Dexamethasone (8 mg twice daily for a total of 16 mg daily or according to institutional standards) was given the day before, the day of infusion (day 1), and the day after infusion (day 2).

[0142] Doxorubicin: Doxorubicin was administered at 50 mg / m 2 Doxorubicin has the potential for cardiac toxicity. The risk of cardiac toxicity from doxorubicin increases with the cumulative lifetime dose of doxorubicin. The doxorubicin dose and schedule in this study placed patients at 240 mg / m² of body surface area, below the threshold for symptomatic cardiac dysfunction. 2 Patients received a cumulative doxorubicin dose of 100 mg / kg / day. Patients were monitored for doxorubicin cardiac toxicity according to institutional standards.

[0143] During cycles 2-4, the doxorubicin component may be omitted at the investigator's discretion, i.e., TC may be administered instead of TAC.

[0144] Cyclophosphamide: Cyclophosphamide, 500 mg / m 2 was administered at a dose of

[0145] TAC regimen: All patients received 3-week cycles of TAC chemotherapy. Each cycle included doxorubicin (50 mg / m ) given as a 15-minute intravenous infusion. 2 ) was administered first, followed immediately by cyclophosphamide (500 mg / m ) given as a 30-minute intravenous infusion. 2 ) followed by docetaxel (75 mg / m ) as a 1-hour intravenous infusion (infusion times mentioned are approximate). 2Patients receiving TAC chemotherapy as adjuvant treatment for early-stage breast cancer received four cycles of TAC chemotherapy, or up to six cycles of TAC chemotherapy at the investigator's discretion (i.e., after completing four protocol-based cycles, these patients continued to receive TAC chemotherapy but with open-label pegfilgrastim to prevent neutropenia).

[0146] TAC carries a high risk of causing FN (>20%). NCCN guidelines recommend routine primary prophylaxis with myeloid growth factor support in patients treated with high-risk regimens such as TAC. During cycles 2–4, the doxorubicin component may be omitted at the investigator's discretion; i.e., TC may be administered instead of TAC.

[0147] The combination of plinabulin and G-CSF (e.g., pegfilgrastim) was surprisingly effective in reducing neutropenia. Figure 2 shows the results for the pegfilgrastim group as well as the plinabulin (20 mg / m 2 ) and pegfilgrastim (6 mg) groups. 2 The combination of rivaroxaban and pegfilgrastim (6 mg) maintained ANC nadirs within the normal range, while the pegfilgrastim group demonstrated ANC nadirs within the grade 3 / 4 neutropenic range.

[0148] The study results also showed that the combination of plinabulin and pegfilgrastim significantly reduced the incidence of severe neutropenia. Figure 3 shows that in cycle 1 after TAC treatment for breast cancer, the pegfilgrastim (6 mg) group showed an 81% incidence of grade 3 / 4 neutropenia, while the plinabulin (20 mg / m 2 ) and pegfilgrastim (6 mg) group showed a 50% incidence of grade 3 / 4 neutropenia, and plinabulin (20 mg / m 2 The thalidomide (thalidomide) plus pegfilgrastim (3 mg) group had a 57% incidence of grade 3 / 4 neutropenia.

[0149] In addition, the combination of plinabulin and pegfilgrastim significantly reduced the incidence of bone pain and its duration. Figure 4 shows that the pegfilgrastim (6 mg) group showed a 95% incidence of bone pain in cycle 1 after TAC treatment for breast cancer, while the plinabulin (20 mg / m 2 The group receiving plinabulin (20 mg / m 2 ) and pegfilgrastim (3 mg) group showed a 33% incidence of bone pain, and plinabulin (20 mg / m 2 The group receiving plinabulin (20 mg / m ) and pegfilgrastim (1.5 mg) showed a 36% incidence of bone pain. Figure 5 shows that in cycle 1 after TAC treatment for breast cancer, the pegfilgrastim (6 mg) group showed over 90% of patients with bone pain for at least 1 day, over 80% of patients with bone pain for at least 2 days, and almost 40% of patients with bone pain for at least 3 days. In comparison, the plinabulin (20 mg / m ) group showed a 36% incidence of bone pain. 2 The group receiving plinabulin (20 mg / m) plus pegfilgrastim (6 mg) showed less than 10% of patients with bone pain for at least 1 day, and no patients reported bone pain for at least 3 days. 2 ) and pegfilgrastim (3 mg) group showed less than 40% of patients with bone pain for at least 1 day, and plinabulin (20 mg / m 2 The 1.5 mg and pegfilgrastim groups showed less than 40% of patients with bone pain.

[0150] The study results showed that plinabulin was effective in reducing the immunosuppressive effects of pegfilgrastim, as measured using the neutrophil to lymphocyte ratio (NLR) and LMR (lymphocyte to monocyte ratio). Figure 6 shows the percentage of patients with NLR values ​​greater than 5 in the various treatment groups. Elevated NLR values ​​are often associated with immunosuppression and poor prognosis in cancer treatment. Figure 6 shows that in cycle 1 after TAC treatment for breast cancer, the pegfilgrastim (6 mg) group had 76% of patients with NLR greater than 5, while the plinabulin (20 mg / m 2 ) and pegfilgrastim (6 mg) group showed 50% of patients with NRLs >5, and plinabulin (20 mg / m 2 ) and pegfilgrastim (3 mg) group showed 35% of patients with more than 5 NRLs, and plinabulin (20 mg / m 2 The group receiving brodalumab plus pegfilgrastim (1.5 mg) showed 7% of patients with more than 5 NRLs.

[0151] Figure 7A shows the effect of plinabulin (20 mg / m 2 ) alone, plinabulin (20 mg / m 2 Figure 7B shows the percentage of patients with an NLR greater than 5 in the control group with plinabulin (20 mg / m ) + Neulasta 6 mg, and Neulasta (6 mg). 2 ) alone, plinabulin (20 mg / m 2 ) + Neulasta 6 mg, and Neulasta (6 mg) show the percentage of patients with an LMR less than 3.2. [Table 3] [Table 4]

[0152] Table 4 shows the superiority profile of the combination of plinabulin and pegfilgrastim over pegfilgrastim treatment.

[0153] Example 3 A phase 3 multi-center randomized trial will be conducted. The phase 3 portion will be double-blind. A total of 180 prospective breast cancer patients can be enrolled in the phase 3 portion of the trial. Patients will be stratified by region (China and Japan vs. rest of the world).

[0154] Patients will receive up to four cycles of a docetaxel / doxorubicin / cyclophosphamide-based chemotherapy regimen every three weeks (21 days). On day 1 of cycle 1, all patients will Docetaxel (75 mg / m 2 ), doxorubicin (50 mg / m 2 ), and cyclophosphamide (500 mg / m 2 )-Taxotere, Adriamycin, and Cyclophosphamide (TAC).

[0155] In Phase 3 (double-blind treatment), cycles 1-4 consist of intravenous TAC (or TC for cycles 2-4) administered intravenously on day 1 of every 21 days. Patients receive a single double-blind intravenous dose of plinabulin or placebo over a 30-minute (±5-minute) period 30 minutes after the end of the TAC (or TC for cycles 2-4) infusion. On day 2 of each cycle (≥24 hours after completion of chemotherapy), patients receive a single double-blind subcutaneous injection of pegfilgrastim (6.0 mg) or placebo. Plinabulin and matching placebo are administered in equal volumes. Pegfilgrastim is administered at a dose of 6 mg as a single-dose syringe. Matching placebo is administered in equal volumes.

[0156] Example 4 The combination of G-CSF (e.g., pegfilgrastim or filgrastim) and plinabulin is tested for its effectiveness in reducing neutropenia induced by chemotherapy or radiation therapy. Cancer patients undergoing myelosuppressive chemotherapy or radiation therapy are assigned to the following groups: Group (1) G-CSF (e.g., pegfilgrastim or filgrastim) in the range of approximately 1 mg / m to 25 mg (e.g., 0.1 mg / m to 6 mg, 1 mg / m to 5.5 mg, 2 mg / m to 5.5 mg, 2 mg / m to 5.5 mg, 3 mg / m to 6 mg, 3 mg / m to 5.5 mg, 4 mg / m to 5.5 mg, or less than 6 mg). 2 ~50mg / m 2 (e.g., 1-20, 1-30, 5-10, 5-30, 5, 10, 20, 30 mg / m 2 Group (2) administration of G-CSF (e.g., pegfilgrastim or filgrastim) alone; Group (3) administration of plinabulin alone; and Group (4) administration of placebo.

[0157] Plinabulin or matching placebo: Plinabulin at the selected dose (e.g., 1–20, 1–30, 5–10, 5–30, 5, 10, 20, 30 mg / m 2 In one control group, a matching placebo will be administered in the same volume. Pegfilgrastim or matching placebo: Pegfilgrastim will be administered subcutaneously as a single-dose syringe at the selected dose (e.g., 0.1 mg to 6 mg, 1 mg to 5.5 mg, 2 mg to 5.5 mg, 2 mg to 4 mg, 3 mg to 6 mg, 3 mg to 5.5 mg, 4 mg to 5.5 mg, or less than 6 mg). In another control group, a matching placebo will be administered in the same volume.

[0158] Population pharmacokinetic methods can be used to characterize the pharmacokinetics of plinabulin and pegfilgrastim following chemotherapy or radiation therapy. Pharmacokinetic assessments include blood pressure and DSN during various cycles of the study.

[0159] The combination of G-CSF (e.g., pegfilgrastim or filgrastim) and plinabulin is effective in reducing the incidence of neutropenia, particularly grade 3 / 4 neutropenia, and it is expected that this combination will maintain patients' neutrophil counts, allowing them to continue chemotherapy treatment.

[0160] Other embodiments of the present invention are set forth below. [1] A method for treating chemotherapy-induced neutropenia, comprising the simultaneous administration of plinabulin and one or more G-CSF preparations. [2] A method for stimulating neutrophil survival, comprising co-administering plinabulin and one or more G-CSF preparations. [3] The method according to [1] or [2], wherein the G-CSF preparation is pegfilgrastim. How to do it. [4] The method of [1] or [2], wherein the G-CSF preparation is selected from Neupogen®, Tevagrastim®, Biograstim®, Ratiograstim®, Zarxio®, Filgrastim Hexal®, Neulasta®, Granocyte®, Neutrogin®, Neu-up®, Rolontis®, Aiduo (mecapegfilgrastim, Hengrui), and Fulphila®. [5] The method according to any one of [1] to [4], wherein the total dose of the G-CSF formulation used in a 21-day cycle is in the range of about 0.1 mg to about 20 mg. [6] The method according to [5], wherein the total dose of the G-CSF formulation used in a 21-day cycle is less than about 6 mg. [7] The method according to [5], wherein the total dose of the G-CSF formulation used in a 21-day cycle is approximately 1.5 mg. [8] The method according to [5], wherein the total dose of the G-CSF formulation in a 21-day cycle is approximately 3 mg. [9] The method according to [5], wherein the total dose of the G-CSF formulation in a 21-day cycle is approximately 6 mg.

[10] The method according to any one of [1] to [9], wherein the G-CSF formulation is administered once in a 21-day cycle.

[11] The method according to any one of [1] to [9], wherein the G-CSF formulation is administered two or more times in a 21-day cycle.

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

[11] , wherein the G-CSF formulation is administered using an on-body injector.

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

[12] , wherein the G-CSF formulation is administered subcutaneously.

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

[13] , comprising administering the G-CSF preparation at least 24 hours after administration of the chemotherapeutic agent.

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

[13] , comprising administering the G-CSF preparation within 24 hours after administration of the chemotherapy agent.

[16] The patient has a blood concentration of about 1.5 × 10 9 The method according to any one of [1] to

[13] , comprising administering the G-CSF preparation when the patient has an absolute neutrophil count of less than 1 / L.

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

[13] , which comprises administering the G-CSF preparation two or more times, and administering a first dose of the G-CSF preparation approximately 24 to 48 hours after administration of the chemotherapy agent.

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

[17] , which comprises administering plinabulin within 24 hours after administration of the chemotherapeutic agent.

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

[18] , comprising administering plinabulin within 2 hours after administration of the chemotherapeutic agent.

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

[19] , comprising administering plinabulin within 1 hour after administration of the chemotherapeutic agent.

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

[20] , comprising administering plinabulin once in a 21-day treatment cycle.

[22] Approximately 1 mg / m on a 21-day cycle 2 ~about 50mg / m 2The method according to any one of [1] to

[21] , comprising administering plinabulin at a total dose in the range of

[23] 40 mg / m in a 21-day cycle 2 The method according to any one of [1] to

[22] , comprising administering plinabulin at the following total dose:

[24] Approximately 10 mg / m on a 21-day cycle 2 The method according to any one of [1] to

[23] , comprising administering plinabulin at a total dose of

[25] Approximately 20 mg / m on a 21-day cycle 2 Administer plinabulin at a total dose of The method according to any one of [1] to

[23] , comprising:

[26] Approximately 30 mg / m on a 21-day cycle 2 The method according to any one of [1] to

[23] , comprising administering plinabulin at a total dose of

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

[23] , comprising administering plinabulin in a total amount ranging from about 10 mg to about 60 mg in a 21-day cycle.

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

[23] , comprising administering plinabulin in a total amount of about 40 mg in a 21-day cycle.

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

[27] , wherein the chemotherapy comprises administration of docetaxel and does not comprise any other chemotherapeutic agent.

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

[27] , wherein the chemotherapy comprises administering docetaxel, doxorubicin and cyclophosphamide (TAC); docetaxel and cyclophosphamide (TC); doxorubicin and cyclophosphamide (AC); docetaxel and doxorubicin (TA); docetaxel; doxorubicin; or cyclophosphamide.

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

[27] , wherein the chemotherapy does not include docetaxel.

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

[31] , wherein the patient is suffering from advanced or metastatic breast cancer, early stage breast cancer, non-small cell lung cancer, or resistant metastatic prostate cancer.

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

[31] , wherein the patient is suffering from head and neck cancer, lung cancer, stomach cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, kidney cancer, bladder cancer, ovarian cancer, cervical cancer, melanoma, glioblastoma, myeloid leukemia, myeloma, lymphoma, or leukemia.

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

[33] , wherein the plinabulin is administered within one hour after the administration of the chemotherapeutic agent.

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

[34] , wherein the plinabulin is administered approximately 30 minutes after the administration of the chemotherapeutic agent.

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

[35] , wherein the neutropenia is grade 3 or 4 neutropenia.

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

[36] , wherein the neutropenia is grade 4 neutropenia.

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

[37] , comprising reducing the incidence of grade 3 or 4 neutropenia by at least 5%.

[39] A method according to any one of [1] to

[38] , comprising shortening the duration of grade 3 or 4 neutropenia by at least approximately two times.

[40] A kit comprising a chemotherapy drug, about 1 mg to about 80 mg of plinabulin, and about 0.1 mg to about 20 mg of G-CSF, wherein the chemotherapy drug, G-CSF, and plinabulin are provided in separate sterile containers.

[41] The kit according to

[40] , wherein the amount of plinabulin is less than 50 mg.

[42] The kit according to

[40] , wherein the amount of plinabulin is about 10 mg.

[43] The kit according to

[40] , wherein the amount of plinabulin is about 20 mg.

[44] The kit according to

[40] , wherein the amount of plinabulin is about 30 mg.

[45] The kit according to

[40] , wherein the amount of plinabulin is about 40 mg.

[46] The kit container according to any one of

[40] to

[45] , wherein the amount of G-CSF is less than 10 mg.

[47] The kit according to any one of

[40] to

[46] , wherein the amount of G-CSF is about 6 mg.

[48] ​​The kit according to any one of

[40] to

[46] , wherein the amount of G-CSF is about 3 mg.

[49] The kit according to any one of

[40] to

[46] , wherein the amount of G-CSF is about 1.5 mg.

[50] A method for reducing bone pain induced by a G-CSF preparation, comprising administering an effective amount of plinabulin.

[51] A method for reducing the immunosuppressive effects induced by a G-CSF preparation, comprising administering an effective amount of plinabulin.

[52] A method for treating chemotherapy-induced neutropenia or stimulating neutrophil survival comprising one or more cycles of a chemotherapy regimen, wherein each cycle of the chemotherapy regimen comprises: administration of one or more chemotherapy drugs on day 1; administering plinabulin on day 1; and administering one or more G-CSF preparations on day 2; independently includes, administering plinabulin within 12 hours, within 4 hours, within 2 hours, or within 1 hour after administration of the one or more chemotherapeutic agents; method.

[53] The method according to

[52] , wherein the one or more G-CSF preparations are administered within 24 hours after the administration of the plinabulin.

[54] The method according to

[52] , comprising 2 to 4 cycles of the chemotherapy regimen.

[55] The method according to

[52] , wherein each cycle of the chemotherapy regimen continues independently for up to 30 days.

[56] The method according to

[55] , wherein each cycle of the chemotherapy regimen lasts for 21 days.

[57] The method of

[52] , wherein, in each cycle of the chemotherapy regimen, independently, the one or more chemotherapeutic agents are selected from the group consisting of docetaxel, doxorubicin, and cyclophosphamide.

[58] In each cycle of the chemotherapy regimen, independently, about 10 to 50 minutes, or about 20 to 40 minutes after administration of the one or more chemotherapeutic agents, about 40 mg / m 2 The method according to

[56] , wherein the plinabulin is administered once or repeatedly.

[59] In each cycle of the chemotherapy regimen, independently, about 5 mg / m 2 , about 10mg / m 2 , or approximately 20 mg / m 2 The method according to

[56] , wherein the plinabulin is administered in a single dose.

[60] The method of

[52] , wherein, in each cycle of the chemotherapy regimen, independently, the one or more G-CSF preparations are selected from the group consisting of Neupogen®, Tevagrastim®, Biograstim®, Ratiograstim®, Zarxio®, Filgrastim Hexal®, Neulasta®, Granocyte®, Neutrogin®, Neu-up®, Rolontis®, Aiduo (mecapegfilgrastim, Hengrui), and Fulphila®.

[61] The method according to

[52] , wherein the one or more G-CSF preparations is pegfilgrastim.

[62] The method of

[52] , wherein, in each cycle of the chemotherapy regimen, independently, the one or more G-CSF preparations are administered in a single dose or multiple doses at about 6 mg or less at least about 24 hours after administration of the one or more chemotherapy agents.

[63] The method according to

[52] , wherein, in each cycle of the chemotherapy regimen, independently, the one or more G-CSF preparations are administered in a single dose or repeatedly at about 6 mg or less about 20 to about 50 hours after the administration of plinabulin.

[64] The method according to

[52] , wherein, in each cycle of the chemotherapy regimen, independently, the one or more G-CSF preparations are administered as a single dose at about 1.5 mg, about 3.0 mg, or about 6 mg about 20 to about 30 hours after administration of the plinabulin.

[65] In combination with one or more G-CSF preparations for the treatment of chemotherapy-induced neutropenia Plinabulin for use in combination with

[66] Plinabulin for use in combination with one or more G-CSF preparations for stimulation of neutrophil survival.

[67] Plinabulin for use in the reduction of bone pain induced by G-CSF preparations.

[68] Plinabulin for use in reducing the immunosuppressive effects induced by G-CSF preparations.

[69] Plinabulin for use in combination with one or more G-CSF preparations for the treatment of chemotherapy-induced neutropenia or stimulation of neutrophil survival in one or more cycles of a chemotherapy regimen, wherein each cycle of the chemotherapy regimen comprises: administration of one or more chemotherapy drugs on day 1; administering plinabulin on day 1; and administering one or more G-CSF preparations on day 2; independently includes, administering plinabulin within 12 hours, within 4 hours, within 2 hours, or within 1 hour after administration of the one or more chemotherapeutic agents; Plinabulin.

Claims

1. 1. A composition comprising plinabulin for treating chemotherapy-induced neutropenia, for use in combination with one or more G-CSF preparations, wherein the subject is undergoing one or more cycles of a chemotherapy regimen, each cycle of the chemotherapy regimen comprising: administering a first dose of one or more chemotherapeutic agents on day 1; administering a first dose of plinabulin on day 1; administering a second dose of one or more chemotherapeutic agents at least 24 hours after administering a first dose of one or more chemotherapeutic agents; and administering a second dose of plinabulin at least 24 hours after administering a first dose of one or more chemotherapeutic agents. and the subject is administered one or more G-CSF preparations at least 24 hours after administration of the last chemotherapy agent in the chemotherapy regimen and within 24 hours of administration of a second dose of plinabulin; The composition, wherein each dose of plinabulin is administered within 12 hours, within 4 hours, within 2 hours, or within 1 hour after administration of said one or more chemotherapeutic agents.

2. The composition of claim 1, wherein the chemotherapy regimen comprises 2 to 4 cycles.

3. 10. The method of claim 1, wherein each cycle of the chemotherapy regimen independently lasts for up to 30 days.

4. 4. The method of claim 3, wherein each cycle of the chemotherapy regimen independently lasts 21 days.

5. 10. The composition of claim 1, wherein, independently in each cycle of the chemotherapy regimen, the one or more chemotherapeutic agents are selected from the group consisting of docetaxel, doxorubicin, and cyclophosphamide.

6. and, in each cycle of the chemotherapy regimen, independently, administering about 40 mg / m 2 or about 10 to 50 minutes, or about 20 to 40 minutes, after administration of the one or more chemotherapeutic agents. ２ The composition of claim 4, wherein plinabulin is administered in a single dose or multiple doses.

7. and, in each cycle of the chemotherapy regimen, independently, administering about 5 mg / m 25-35 minutes, or about 28-32 minutes, or about 30 minutes after administration of the one or more chemotherapeutic agents. ２ , about 10mg / m ２ , or about 20 mg / m ２ The composition according to claim 4, wherein plinabulin is administered in a single dose.

8. 2. The composition of claim 1, wherein the one or more G-CSF preparations is pegfilgrastim.

9. 2. The composition of claim 1, wherein each cycle of the chemotherapy regimen independently comprises a single or repeated administration of the one or more G-CSF formulations at about 6 mg or less at least about 24 hours after administration of the one or more chemotherapeutic agents.

10. The composition of claim 1, wherein in each cycle of the chemotherapy regimen, independently, the one or more G-CSF formulations are administered in a single dose or multiple doses at about 6 mg or less, about 20 to about 50 hours after administration of plinabulin.

11. The composition of claim 1, wherein, in each cycle of the chemotherapy regimen, independently, the one or more G-CSF formulations are administered as a single dose at about 1.5 mg, about 3.0 mg, or about 6 mg, about 20 to about 30 hours after administration of plinabulin.

12. The target is about 1.5×10 ９ The composition according to any one of claims 1 to 11, wherein the subject is administered the G-CSF preparation when the subject has an absolute neutrophil count lower than 1 / L.

13. 1. Use of plinabulin or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating chemotherapy-induced neutropenia or for stimulating neutrophil survival, wherein the subject is undergoing one or more cycles of a chemotherapy regimen, each cycle of the chemotherapy regimen comprising: administering a first dose of one or more chemotherapeutic agents on day 1; administering a first dose of plinabulin on day 1; administering a second dose of one or more chemotherapeutic agents at least 24 hours after administering a first dose of one or more chemotherapeutic agents; and administering a second dose of plinabulin at least 24 hours after administering a first dose of one or more chemotherapeutic agents. and the subject is administered one or more G-CSF preparations at least 24 hours after administration of the last chemotherapy agent in the chemotherapy regimen and within 24 hours of administration of a second dose of plinabulin; The use wherein each dose of plinabulin is administered within 12 hours, within 4 hours, within 2 hours, or within 1 hour after administration of said one or more chemotherapeutic agents.

14. The use according to claim 13, wherein plinabulin is administered within 1 hour after administration of the chemotherapy agent.

15. 15. The use according to claim 13 or 14, wherein plinabulin is administered as a single dose in a 21-day treatment cycle.

16. Approximately 1 mg / m on a 21-day cycle ２ ~Approx. 50mg / m ２ The use according to any one of claims 13 to 15, wherein plinabulin is administered at a total dose in the range of

17. 40 mg / m on a 21-day cycle ２ The use according to any one of claims 13 to 16, wherein plinabulin is administered at a total dose of:

18. The use according to claim 13, wherein plinabulin is administered in a total amount ranging from about 10 mg to about 60 mg in a 21-day cycle.

19. The use according to any one of claims 13 to 18, wherein the chemotherapy comprises the administration of docetaxel and does not comprise any other chemotherapeutic agent.

20. 19. The use of any one of claims 13 to 18, wherein the chemotherapy comprises administering docetaxel, doxorubicin and cyclophosphamide (TAC); docetaxel and cyclophosphamide (TC); doxorubicin and cyclophosphamide (AC); docetaxel and doxorubicin (TA); docetaxel; doxorubicin; or cyclophosphamide.

21. The use according to any one of claims 13 to 18, wherein the chemotherapy does not include docetaxel.

22. The use according to any one of claims 13 to 21, wherein the subject is suffering from advanced or metastatic breast cancer, early stage breast cancer, non-small cell lung cancer, or resistant metastatic prostate cancer.

23. The use according to any one of claims 13 to 22, wherein the neutropenia is grade 4 neutropenia.

24. 24. The use of any one of claims 13 to 23, comprising reducing the incidence of grade 3 or 4 neutropenia by at least 5%.

25. 25. The use of any one of claims 13 to 24, comprising reducing the duration of grade 3 or 4 neutropenia by at least about two-fold.

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