Compositions and methods for treating tumors

Abstract

Disclosed herein are methods of treating, preventing, or ameliorating a disease or condition associated with a cancer or tumor. In some embodiments, the methods include administering a compound of Formula (I) to a subject in need thereof, wherein the cancer or tumor is or becomes resistant to one or more immune checkpoint inhibitors.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This patent application claims the benefit of priority to U.S. Provisional Application No. 63 / 214010, filed June 23, 2021, and U.S. Provisional Application No. 63 / 173015, filed April 9, 2021. Both of the foregoing applications are hereby fully incorporated by reference in their entirety for all purposes.

[0002] The present disclosure relates to the fields of chemistry and medicine. More particularly, the present disclosure relates to compositions containing plinabulin and their use in therapy. [Background technology]

[0003] Human cancers contain many genetic and epigenetic changes that generate neoantigens that can be recognized by the immune system (Sjoblom et al., 2006). The adaptive immune system, consisting of T and B lymphocytes, has a broad ability and excellent specificity to react to various tumor antigens, and has a strong anti-cancer ability.

[0004] In recent cancer immunotherapy research, considerable efforts have been focused on approaches to enhance antitumor immunity by mediating adaptive immune responses against relevant antigens and providing specific immune stimulants such as immune checkpoint inhibitors. Although cancer remains an incurable disease for the majority of patients, there is a particular need to develop effective therapeutic agents and treatment regimens that can be used in cancer therapy. Patients receiving immune checkpoint inhibitors may initially respond to these checkpoint inhibitors, but later become unresponsive (resistant) to these checkpoint inhibitors or may not respond to these checkpoint inhibitors from the start of treatment ("non-responders"). Summary of the Invention

[0005] Some aspects described herein relate to a method of treating cancer in a subject. In some embodiments, the subject is administered a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, wherein R1, R4, and R6 are each independently selected from a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C1-C 24 Alkyl, unsaturated C1-C 24 Alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, -CO-O-R7, cyano, alkylthio, alkyl halides including polyhalogenated alkyls, carbonyl halides, and carbonyl -CH2CO- R7 is selected from the group consisting of a hydrogen atom, a halogen atom, and a saturated C1-C 24 Alkyl, unsaturated C1-C 24 R' and R" are each independently selected from hydrogen, deuterium, halogen, and saturated C-C alkyl groups. 24 Alkyl, unsaturated C1-C 24 is selected from the group consisting of alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, -CO-O-R7, cyano, alkylthio, alkyl halides including polyhalogenated alkyls, carbonyl halides, and carbonyl -CH2CO-R7, where R7 is a hydrogen atom, a halogen atom, or a saturated C1-C 24 Alkyl, unsaturated C1-C 24R, R′ and R″ are each independently selected from a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C1-C1H alkyl group; R, R′ and R″ are each independently selected from a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C1-C1H alkyl group; R, R′ and R″ are each independently selected from a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C1-C1H alkyl group; 12 Alkyl, unsaturated C1-C 12 m is an integer equal to zero, 1, or 2; X1 and X2 are independently selected from the group consisting of oxygen, nitrogen, and sulfur atoms, and Y is selected from the group consisting of NR5, oxygen, sulfur, oxidized sulfur, methylene, and substituted methylene groups; Z (for each individual n, when not zero), and Z1, Z2, Z3, and Z4 are independently selected from carbon, sulfur, nitrogen, or oxygen atoms; the dashed bond can be either a single bond or a double bond, and the cancer is resistant to prior treatment with one or more immune checkpoint inhibitors.

[0006] In some embodiments, the subject has a tumor that is resistant to an immune checkpoint inhibitor. In some embodiments, a tumor that has progressed after use of an immune checkpoint inhibitor. In some embodiments, a tumor that has not responded to a checkpoint inhibitor. In some embodiments, the method further comprises administering an additional chemotherapeutic agent. In some embodiments, the additional chemotherapeutic agent is administered prior to administering a compound of Formula (I) to the subject. In some embodiments, the additional chemotherapeutic agent is a taxane. In some embodiments, the taxane is docetaxel. In some embodiments, the one or more immune checkpoint inhibitors to which the subject has been resistant are a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, or a combination thereof. In some embodiments, the one or more immune checkpoint inhibitors to which the subject has been resistant are a PD-1 inhibitor. In some embodiments, the one or more immune checkpoint inhibitors to which the subject has been resistant are a PD-L1 inhibitor. In some embodiments, the one or more immune checkpoint inhibitors to which the subject has been resistant are a CTLA-4 inhibitor. In some embodiments, the one or more immune checkpoint inhibitors to which the subject is resistant are pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS-936559, durvalumab, spartalizumab, or any combination thereof. In some embodiments, the one or more immune checkpoint inhibitors to which the subject is resistant are nivolumab and ipilimumab. In some embodiments, the cancer is selected from the group consisting of breast cancer, bladder cancer, glioma, glioblastoma, head and neck cancer, non-small cell lung cancer, small cell lung cancer, recurrent small cell lung cancer (SCLC), colorectal cancer, gastrointestinal stromal tumor, gastroesophageal cancer, renal cell carcinoma, prostate cancer, liver cancer, colon cancer, pancreatic cancer, ovarian cancer, lymphoma, or cutaneous T-cell lymphoma, or melanoma. In some embodiments, the cancer is recurrent small cell lung cancer (SCLC).

[0007] In some embodiments, the method further comprises co-administering an immune checkpoint inhibitor to the subject. In some embodiments, the co-administered one or more immune checkpoint inhibitors are a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, or a combination thereof. In some embodiments, the co-administered one or more immune checkpoint inhibitors are pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS-936559, durvalumab, spartalizumab, or any combination thereof. In some embodiments, the method comprises administering a PD-1 antibody and a CTLA-4 antibody. In some embodiments, the PD-1 antibody is nivolumab and the CTLA-4 antibody is ipilimumab. In some embodiments, nivolumab is administered first, followed by ipilimumab. In some embodiments, nivolumab is administered on the same day as ipilimumab. In some embodiments, nivolumab and ipilimumab are administered on the same day every two weeks. In some embodiments, nivolumab and ipilimumab according to claim 21 are administered on the same day every three weeks. In some embodiments, nivolumab and ipilimumab are administered four times on the same day every three weeks. In some embodiments, nivolumab is administered in the range of about 100 mg to 600 mg. In some embodiments, nivolumab is administered in the range of about 240 mg to 480 mg. In some embodiments, the co-administered one or more immune checkpoint inhibitors and the compound of formula (I) are administered for four administration cycles. In some embodiments, the subject receives the co-administered one or more immune checkpoint inhibitors and the compound of formula (I) every 21 days. In some embodiments, the method further comprises administering radiation to the subject. In some embodiments, the radiation is administered prior to administering the compound of formula (I) to the subject.

[0008] In some embodiments, the method further comprises administering to the subject an inhibitor of PD-1 or PD-L1 and an additional chemotherapeutic agent. In some embodiments, the method further comprises administering to the subject an inhibitor of PD-1 or PD-L1 and radiation. In some embodiments, the method further comprises administering to the subject an inhibitor of PD-1 or PD-L1 and a CTLA-4 inhibitor. In some embodiments, the method further comprises administering to the subject a CTLA-4 inhibitor and radiation. In some embodiments, the compound of formula (I) is administered at a dose of about 5 mg / m 2 ~150mg / m 2 In some embodiments, the compound of formula (I) is administered at a dose of about 20 mg / m 2 ~about 30mg / m 2In some embodiments, the compound of formula (I) is administered orally, sublingually, buccally, subcutaneously, intravenously, intranasally, intratumorally, topically, transdermally, intradermally, intraperitoneally, intramuscularly, intrapulmonary, vaginally, rectally, or intraocularly. In some embodiments, the compound of formula (I) is administered on day 1 of a 14-day dosing cycle. In some embodiments, the compound of formula (I) is administered on day 1 of a 21-day dosing cycle. In some embodiments, the compound of formula (I) is plinabulin, (3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione; (3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-d-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione; (3Z,6Z)-3-(phenylmethylene-d)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione; methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(phenylmethylene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-d-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d )piperazine-2,5-dione;(3Z,6Z)-3-(4-fluoro-(phenyl-2,3,5,6-d4))-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione;(3Z,6Z)-3-(4-fluoro-(phenyl-2,3,5,6-d4))-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z, 6Z)-3-(3-fluorobenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(3-benzoylbenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(3-(4-fluorobenzoyl)benzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione (3Z,6Z)-3-(3-(4-methoxybenzoyl)benzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(3-methoxybenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(3-methoxybenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-( 3-(trifluoromethylenediene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; and pharma- ceutically acceptable salts thereof. In some embodiments, the compound of Formula (I) is plinabulin or a pharma- ceutically acceptable salt thereof. In some embodiments, the tumor mass is reduced by about 50% to about 100%. In some embodiments, the tumor mass is reduced by about 50% to about 70%.

[0009] Some aspects relate to methods of halting or reversing progressive cancer in a subject. In some embodiments, the method comprises administering a compound of Formula (I), wherein the subject has been refractory to prior treatment with one or more immune checkpoint inhibitors. In some embodiments, the compound of Formula I is plinabulin or a pharma- ceutically acceptable salt thereof. In some embodiments, the method comprises administering an additional chemotherapeutic agent to the subject. In some embodiments, the method comprises administering an inhibitor of PD-1 or PD-L1 to the subject. In some embodiments, the method comprises administering a CTLA-4 inhibitor to the subject. In some embodiments, the method comprises administering radiation to the subject. In some embodiments, the method comprises administering an inhibitor of PD-1 or PD-L1 to the subject. In some embodiments, the method comprises administering a CTLA-4 inhibitor to the subject. In some embodiments, the method comprises administering an inhibitor of PD-1 or PD-L1 and a CTLA-4 inhibitor to the subject. In some embodiments, the progressive disease is a tumor. In some embodiments, the tumor mass is reduced by about 50% to about 100%. In some embodiments, the tumor mass is reduced by about 50% to about 70%. In some embodiments, radiation is administered after administration of a compound of formula (I). In some embodiments, radiation is administered before administration of a compound of formula (I). In some embodiments, a compound of formula (I) is administered as a single dose after administration of radiation. In some embodiments, a compound of formula (I) is administered in two doses after administration of radiation. [Brief description of the drawings]

[0010] [Figure 1] Figure 1 shows a waterfall plot of best overall response in target lesions compared with baseline. [Figure 2A] FIG. 2A shows a plot of the log-transformed mean erythrocyte sedimentation rate (ESR) for each cycle. [Figure 2B] FIG. 2B shows a plot of the log-transformed values ​​of mean high-sensitivity C-reactive protein (CRP) for each cycle. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The present disclosure provides methods and therapeutic compositions for reversing non-response or enhancing response to immune checkpoint inhibitor therapy for treating, ameliorating, or preventing cancer or tumors in a subject. In some embodiments, the methods and compositions provided herein are useful for treating, delaying progression, preventing recurrence, or alleviating symptoms of cancer or other neoplastic conditions using a compound of formula (I). In some embodiments, the compound of formula (I) is plinabulin. 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 efficiently promotes antigen processing and presentation by dendritic cells to effector cells such as T cells, and promotes migration of dendritic cells to lymph nodes, where tumor-specific antigens are presented by dendritic cells to stimulate immune effector cells. Exposure of dendritic cells to plinabulin induces their maturation and significantly enhances their ability to stimulate T cells.

[0012] Some embodiments disclosed herein include administering a compound of formula (I) (e.g., plinabulin) to a cancer subject who initially responded to but has become refractory to a prior immuno-oncology therapy, such as therapy with one or more immune checkpoint inhibitors. As described herein, it has surprisingly been discovered that plinabulin is effective against such refractory cancers.

[0013] Some embodiments disclosed herein include administration of a compound of Formula (I) (e.g., plinabulin) to cancer subjects who have not initially responded to a prior immuno-oncology therapy, such as therapy with one or more immune checkpoint inhibitors (non-responders). As described herein, it has surprisingly been discovered that adding plinabulin to a checkpoint inhibitor is effective in non-responders.

[0014] Before further describing the present disclosure, it should be understood that the present disclosure is not limited to the specific embodiments described, as they may of course vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. The method described herein can be carried out in any order of the described events that is logically possible, as well as the order of the described events.

[0015] Where a range of values ​​is stated, unless the context clearly dictates otherwise, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any other stated or intervening value within that range is encompassed within the disclosed scope. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosed scope, subject to any specifically excluded limits in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0016] All publications mentioned herein are incorporated by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present disclosure is not entitled to antedate such publication by prior disclosure. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0017] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise. It is further noted that the claims may be drafted to exclude any element. Accordingly, this statement is intended to serve as an antecedent basis for use of exclusive terminology such as "solely," "only," and the like, or for use of a "negative" limitation in connection with the recitation of claim elements.

[0018] 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 a term herein, the definition in this section prevails unless otherwise stated.

[0019] The term "agent" is used herein to denote a chemical compound, a mixture of chemical compounds, a biological macromolecule, or an extract made from biological material.

[0020] The term "antagonist" as used herein refers to a compound that can bind to a receptor (e.g., an immune checkpoint receptor) and block cellular activity. An antagonist can be a ligand that directly binds to the receptor. Alternatively, an antagonist can indirectly bind to the receptor, for example, (a) by forming a complex with another molecule that directly binds to the receptor, or (b) as a result of otherwise modifying another compound such that the other compound directly binds to the receptor.

[0021] As used herein, the term "ameliorate" refers to any decrease in the degree, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular condition.

[0022] The term "antibody" or "antibody portion" is intended to encompass a polypeptide chain-containing molecular structure with a specific shape that fits and recognizes an epitope, with one or more non-covalent interactions stabilizing the complex between the molecular structure and the epitope. The antibodies used in this disclosure may be polyclonal or monoclonal. Antibodies also include free antibodies and antigen-binding fragments derived therefrom, as well as conjugates, such as pegylated antibodies, drug, radioisotope, or toxin conjugates. Monoclonal antibodies against a specific epitope, or combination of epitopes, allow for targeting and / or ablation of cell populations expressing the marker. A variety of techniques are available for using monoclonal antibodies to screen cell populations expressing marker(s), including magnetic separation using antibody-coated magnetic beads, "panning" using antibodies attached to a solid matrix (i.e., plate), and flow cytometry (see, e.g., U.S. Pat. No. 5,985,660; and Morrison et al. Cell, 96:737-49 (1999)). These techniques allow for screening of specific cell populations, immunohistochemistry of biopsy samples, detection of the presence of markers released by cancer cells into blood and other biological fluids, and the like. Humanized versions of such antibodies are also within the scope of the present disclosure. Humanized antibodies are particularly useful for in vivo applications in humans, as they are less antigenic.

[0023] The terms "cancer," "neoplasm," and "carcinoma" are used interchangeably herein to refer to cells that exhibit an abnormal growth phenotype characterized by relatively autonomous growth resulting in a significant loss of control of cell proliferation. In general, cells that are of interest for detection or treatment in this application include precancerous cells (e.g., benign cells), malignant cells, premetastatic cells, metastatic cells, and nonmetastatic cells. The detection of cancerous cells is of particular interest.

[0024] As used herein, the term "immune checkpoint inhibitor" refers to a molecule (e.g., a small molecule, peptide, polypeptide, protein, antibody, antibody fragment, etc.) that acts as an inhibitor (antagonist) of an immune checkpoint pathway. Inhibition of the pathway can include blocking the pathway through binding to a receptor or signaling molecule that is part of the immune checkpoint pathway.

[0025] The term "polypeptide" is used herein generically to mean a native protein, a fragment, or an analog of a polypeptide sequence. Thus, native protein fragments and analogs are species of the polypeptide genus.

[0026] 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 with pharmaceutically active substances is well known in the art. Except where any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. In addition, various adjuvants as are commonly used in the art may be included. A discussion of the inclusion of various ingredients in pharmaceutical compositions is found, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety. The pharmaceutically acceptable excipient may be a monosaccharide or monosaccharide derivative.

[0027] The term "subject" as used herein means a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate or bird, such as a chicken, as well as other vertebrates or invertebrates.

[0028] The term "mammal" is used in its normal biological sense, and thus specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, and the like.

[0029] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent effective to alleviate to some extent one or more symptoms of a disease or condition or reduce the likelihood of occurrence, and can include curing the disease or condition.

[0030] 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 the disease or condition, but who is susceptible to or otherwise at risk of a particular disease or condition, thereby reducing the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering treatment to a subject who is already suffering from a disease or condition.

[0031] As used herein, the term "chemotherapeutic agent" refers to an agent that reduces, prevents, reduces, limits, and / or slows the growth of metastases or neoplasms, or directly inhibits neoplastic cells by necrosis or apoptosis or other mechanisms of neoplasia. By "chemotherapeutic agent" is meant an agent that can be used in a pharmacologic effective amount to kill cells or otherwise reduce, prevent, alleviate, limit, and / or slow the growth of metastases or neoplasms in a subject with a neoplastic disease. Chemotherapeutic agents include, but are not limited to, fluoropyrimidines, pyrimidine nucleosides, purine nucleosides, antifolates, platinum-based agents, anthracyclines / anthracenediones, epipodophyllotoxins, camptothecins, hormones, hormone conjugates, antihormones, enzymes, proteins, peptides, and polyclonal and / or monoclonal antibodies, vinca alkaloids, taxanes, epothilones, antimicrotubule agents, alkylating agents, antimetabolites, topoisomerase inhibitors, antiviral agents, and various other cytotoxic and cytostatic agents.

[0032] compound In some embodiments, the compounds and therapeutic compositions for treating cancer or tumors described herein comprise a compound represented by formula (I): [ka]

[0033] In some embodiments of Formula (I), R, R, and R are each independently selected from a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C-C 24 Alkyl, unsaturated C1-C 24 is selected from the group consisting of alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, -CO-O-R7, cyano, alkylthio, alkyl halides including polyhalogenated alkyls, carbonyl halides, and carbonyl -CH2CO-R7, where R7 is a hydrogen atom, a halogen atom, or a saturated C1-C 24 Alkyl, unsaturated C1-C 24It is selected from alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups.

[0034] In some embodiments of Formula (I), R′ and R″ are each independently selected from a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C-C 24 Alkyl, unsaturated C1-C 24 is selected from the group consisting of alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, -CO-O-R7, cyano, alkylthio, alkyl halides including polyhalogenated alkyls, carbonyl halides, and carbonyl -CH2CO-R7, where R7 is a hydrogen atom, a halogen atom, or a saturated C1-C 24 Alkyl, unsaturated C1-C 24 It is selected from alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups.

[0035] In some embodiments of formula (I), R, R′, and R″ are covalently bonded to each other. or are not covalently bonded to each other.

[0036] In some embodiments of Formula (I), R2, R3, and R5 are each independently selected from a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C1-C 12 Alkyl, unsaturated C1-C 12 It is selected from the group consisting of alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl, and substituted sulfonyl groups.

[0037] In some embodiments of Formula (I), m is an integer equal to zero, one, or two.

[0038] In some embodiments of Formula (I), X1 and X2 are independently selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms.

[0039] In some embodiments of Formula (I), Y is selected from the group consisting of NR5, an oxygen atom, a sulfur atom, an oxidized sulfur atom, a methylene group, and a substituted methylene group.

[0040] In some embodiments of formula (I), Z (for each individual n, when not zero), and Z1, Z2, Z3, and Z4 are each selected from a carbon atom, a sulfur atom, a nitrogen atom, or an oxygen atom; the dashed bond may be either a single bond or a double bond.

[0041] Compounds of formula (I) can be readily prepared according to the methods and procedures detailed in U.S. Pat. Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entireties.

[0042] In some embodiments, the compound described herein is a dehydrophenylahistine having the formula (II): [ka]

[0043] In some embodiments of formula (II), R and R are each independently a hydrogen atom; a halogen atom; a mono-substituted, poly-substituted or unsubstituted, linear or branched variant of the following residues: C-C 12 Alkyl, C1-C 12alkenyl, acyl, and alkoxy; and mono-, poly- or unsubstituted variants of the following residues: cycloalkyl, cycloalkoxy, aryl, heteroaryl, amino, nitro, and sulfonyl; or R2 is attached to Ar.

[0044] In some embodiments of formula (II), R and R are each independently selected from the group consisting of hydrogen; halogen; hydroxyl; mono-, poly- or unsubstituted, linear or branched variants of the following residues: C-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 Alkynyl, alkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxy, carbonyloxy, ester, arylalkoxy, alkoxy, and alkylthio; mono-, poly- or unsubstituted variants of the following residues: acyloxy, aryloxycarbonyloxy, is selected from the group consisting of cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, carbonyl, amino, aminocarbonyl, amido, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, thio, alkylthio, arylthio, thiosulfonyl, thiophene, carboxy, and cyano.

[0045] In some embodiments of Formula (II), X1 and X2 are independently selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom substituted with an R5 group.

[0046] In some embodiments of formula (II), R5 is selected from the group consisting of hydrogen atoms, halogen atoms, and saturated C1-C 12 Alkyl, unsaturated C1-C 12 It is selected from the group consisting of alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl, and substituted sulfonyl groups.

[0047] In some embodiments of Formula (II), Y is selected from the group consisting of NR5, an oxygen atom, a sulfur atom, an oxidized sulfur atom, a methylene group, and a substituted methylene group.

[0048] In some embodiments of Formula (II), n is 0, 1, 2, 3, or 4.

[0049] In some embodiments of Formula (II), Ar is a cyclic or polycyclic aryl or heteroaryl ring system containing 1-3 rings. In some embodiments, each ring of the system is individually a 5-, 6-, 7-, or 8-membered ring. In some embodiments, each ring of the system is individually a 0, 1, 2, 3, or 4 heteroatom selected from the group consisting of oxygen, sulfur, and nitrogen. In some embodiments, each ring of the system is optionally selected from the group consisting of hydrogen; halogen; hydroxyl; mono-, poly-, or unsubstituted, linear or branched variants of the following residues: C1-C 24 Alkyl, C2-C 24 Alkenyl, C2-C 24 alkynyl, alkoxy, acyl, arylalkyl, heteroarylalkyl, alkyloxy, carbonyloxy, ester, arylalkoxy, alkoxy, and alkylthio; mono-substituted, poly-substituted or unsubstituted variants of the following residues: acyloxy, aryloxycarbonyloxy, cycloalkyl, cycloalkenyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylcarbonyl, heterocycloalkyl, carbonyl, amino, aminocarbonyl, amido, aminocarbonyloxy, nitro, azido, phenyl, hydroxyl, thio, alkylthio, arylthio, thiophene, oxysulfonyl, sulfonyl, carboxy, and cyano; and optionally substituted fused rings selected from the group consisting of dioxole, dithiol, oxathiol, dioxine, dithiin, and oxathiin.

[0050] Compounds of formula (II) can be readily prepared according to the methods and procedures detailed in U.S. Pat. Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entireties.

[0051] In some embodiments, the compound of formula (I) is plinabulin, (3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione; (3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-d-6-((5-( tert-Butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione;(3Z,6Z)-3-(phenylmethylene-d)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-6-((5 -(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(phenylmethylene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(phenyl-2,3,4,5,6-d5)-methylene-d-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(4-fluoro 4-Fluoro-(phenyl-2,3,5,6-d4))-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione;(3Z,6Z)-3-(4-Fluoro-(phenyl-2,3,5,6-d4))-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(3-fluorobenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl) methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(3-benzoylbenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(3-(4-fluorobenzoyl)benzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione;(3Z,6Z)-3-(3-(4-methoxybenzoyl)benzylidene)-6-((5-(t (3Z,6Z)-3-(3-methoxybenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(3-(trifluoromethylenediene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; and pharma- ceutically acceptable salts thereof.

[0052] In some embodiments, the compound of formula (I) is plinabulin. In some embodiments, the compound of formula (I) is plinabulin monohydrate. In some embodiments, the compound of formula (I) is a salt form of plinabulin.

[0053] Immune checkpoint inhibitors In some embodiments, one or more immune checkpoint inhibitors can be co-administered with the compound of formula (I). A review of immune checkpoint pathways and their blocking by immune checkpoint inhibitor compounds is provided by Pardoll in Nature Reviews Cancer (April, 2012), pages 252-264, which is incorporated herein by reference in its entirety. Immune checkpoint inhibitor compounds exhibit anti-tumor activity by blocking one or more endogenous immune checkpoint pathways that downregulate anti-tumor immune responses. Typically, the inhibition or blocking of immune checkpoint pathways involves the inhibition of checkpoint receptor-ligand interactions by immune checkpoint inhibitor compounds, thereby reducing or eliminating downregulatory signals and the resulting reduced anti-tumor response.

[0054] In some embodiments of the present disclosure, immune checkpoint inhibitor compounds inhibit signaling interactions between immune checkpoint receptors and their corresponding ligands. Immune checkpoint inhibitor compounds can act by blocking activation of immune checkpoint pathways through inhibition (antagonism) of immune checkpoint receptors (some examples of receptors include CTLA-4, PD-1, LAG-3, TIM-3, BTLA, and KIR) or by inhibition of ligands of immune checkpoint receptors (some examples of ligands include PD-L1 and PD-L2). In such embodiments, the effect of immune checkpoint inhibitor compounds is to downregulate certain aspects of the immune system's anti-tumor response in the tumor microenvironment. The aim of this study is to reduce or eliminate the effects of

[0055] The Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28 / CTLA-4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8; which are incorporated herein by reference in their entireties). Other members of the CD28 family include CD28, CTLA-4, ICOS, and BTLA. PD-1 has been suggested to exist as a monomer, lacking the unpaired cysteine ​​residue characteristic of other CD28 family members. PD-1 is expressed on activated B cells, T cells, and monocytes.

[0056] The PD-1 gene encodes a 55 kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8:765-72, which is incorporated herein by reference in its entirety). It is structurally similar to CTLA-4, but PD-1 lacks the MYPPY motif that is important for binding to B7-1 and B7-2. Two ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), have been defined and shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carter et al. (2002) Eur. J. Immunol. 32:634-43, which are incorporated herein by reference in their entireties). Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but not to other CD28 family members. PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9, which is incorporated herein by reference in its entirety.

[0057] PD-1 is known as an immunosuppressive protein that negatively regulates TCR signaling (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745; which are incorporated herein by reference in their entireties). The interaction between PD-1 and PD-L1 can act as an immune checkpoint and can lead, for example, to a reduction in tumor-infiltrating lymphocytes, a reduction in T cell receptor-mediated proliferation, and / or immune evasion by cancerous cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100; which are incorporated by reference in their entireties herein). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2, and the effect is additive when the interaction of PD-1 with PD-L2 is also inhibited (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66; which are incorporated by reference in their entireties herein).

[0058] The immune checkpoint receptor cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is expressed on T cells and is involved in signaling pathways that reduce the level of T cell activation. It is believed that CTLA-4 may suppress T cell activation through competitive binding and sequestration of CD80 and CD86. Furthermore, CTLA-4 inhibits T Reg It has been shown to be involved in enhancing the immunosuppressive activity of cells.

[0059] The immune checkpoint receptor programmed death 1 (PD-1) is expressed by activated T cells upon prolonged exposure to antigen. Binding of PD-1 to its known binding ligands PD-L1 and PD-L2 occurs primarily within the tumor microenvironment and results in downregulation of anti-tumor specific T cell responses. Both PD-L1 and PD-L2 are known to be expressed on tumor cells. Expression of PD-L1 and PD-L2 in tumors correlates with poor survival outcomes.

[0060] The immune checkpoint receptor T cell membrane protein 3 (TIM-3) is expressed on Th1 and Tc1 cells, but not on other T cells. The interaction of TIM-3 with its ligand galectin-9 generates a Th1 cell death signal. TIM-3 has been reported to play a role in maintaining T cell exhaustion, and blockade of TIM-3 has been shown to restore the activity of exhausted T cells.

[0061] The immune checkpoint receptor, B and T lymphocyte attenuator (BTLA) receptor, is expressed on both resting and activated B and T cells. Activation of BTLA upon binding to its ligand HVEM (herpes virus entry mediator) results in downregulation of both T cell activation and proliferation. HVEM is expressed on certain tumors (e.g., melanoma) and tumor-associated endothelial cells.

[0062] Immune checkpoint receptors known as killer cell immunoglobulin-like receptors (KIRs) are a family of polymorphic receptors expressed on NK cells and some T cells that function as regulators of immune tolerance associated with natural killer (NK) cells. Blocking certain KIR receptors with inhibitor compounds can promote tumor destruction through increased NK cell activity.

[0063] In some embodiments of the present disclosure, the immune checkpoint inhibitor compound is a small organic molecule (molecular weight less than 1000 daltons), a peptide, a polypeptide, a protein, an antibody, an antibody fragment, or an antibody derivative. In some embodiments, the immune checkpoint inhibitor compound is an antibody. In some embodiments, the antibody is a monoclonal antibody, particularly a human or humanized monoclonal antibody.

[0064] Monoclonal antibodies, antibody fragments, and antibody derivatives for blocking immune checkpoint pathways can be prepared by any of several methods known to those of skill in the art, including, but not limited to, somatic cell hybridization techniques and hybridoma methods. For the generation of hybridomas, see Antibodies, A Laboratory Manual, Harlow and Lane, 1988, Cold Spring Harbor Publications, New York, which is incorporated herein by reference in its entirety. Human monoclonal antibodies can be identified and isolated by screening phage display libraries of human immunoglobulin genes by the methods described in U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,698, 6,582,915, and 6,593,081, which are incorporated herein by reference in their entireties. Monoclonal antibodies can be prepared using the general methods described in U.S. Patent No. 6,331,415 (Cabilly), which is incorporated herein by reference in its entirety.

[0065] As an example, human monoclonal antibodies can be prepared using XenoMouse™ (Abgenix, Fremont, Calif.), or hybridomas of B cells derived from the XenoMouse. XenoMouse is a US A mouse host having functional human immunoglobulin genes as described in Patent No. 6,162,963 (Kucherlapati), which is incorporated herein by reference in its entirety.

[0066] Methods for the preparation and use of immune checkpoint antibodies are described in the following exemplary publications: The production and therapeutic use of anti-CTLA-4 antibodies are described in U.S. Patent No. 7,229,628 (Allison), U.S. Patent No. 7,311,910 (Linsley), and U.S. Patent No. 8,017,144 (Korman), which are incorporated herein by reference in their entireties. The production and therapeutic use of anti-PD-1 antibodies are described in U.S. Patent No. 8,008,449 (Korman) and U.S. Patent Application Publication No. 2011 / 0271358 (Freeman), which are incorporated herein by reference in their entireties. The production and therapeutic use of anti-PD-L1 antibodies are described in U.S. Patent No. 7,943,743 (Korman), which are incorporated herein by reference in their entireties. The production and therapeutic use of anti-TIM-3 antibodies are described in U.S. Patent No. 8,101,176 (Kuchroo) and U.S. Patent No. 8,552,156 (Tagayanagi), which are incorporated herein by reference in their entirety. The production and therapeutic use of anti-LAG-3 antibodies are described in U.S. Patent Application Publication No. 2011 / 0150892 (Thudium) and International Publication Number 2014 / 008218 (Lonberg), which are incorporated herein by reference in their entirety. The production and therapeutic use of anti-KIR antibodies are described in U.S. Patent No. 8,119,775 (Moretta), which is incorporated herein by reference in its entirety. The production of antibodies that block the inhibitory pathway regulated by BTLA (anti-BTLA antibodies) is described in U.S. Patent No. 8,563,694 (Mataraza), which is incorporated herein by reference in its entirety.

[0067] In some embodiments, the one or more immune checkpoint inhibitors are inhibitors of PD-1, PD-L1, or CTLA-4. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a binding ligand of PD-L1. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0068] In some embodiments, the one or more immune checkpoint inhibitors described herein include a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, and the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor. In some embodiments, the first and second immune checkpoint inhibitors are independently inhibitors of PD-1, PD-L1, or CTLA-4. In some embodiments, the first immune checkpoint inhibitor is a PD-1 inhibitor and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0069] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS-936559, durvalumab, spartalizumab, or any combination thereof. In some embodiments, the one or more immune checkpoint inhibitors may include an anti-PD-1 HuMAb, which may be selected from 17D8, 2D3, 4H1, 5C4 (also referred to herein as nivolumab), 4A11, 7D3, and 5F4, all of which are described in U.S. Patent No. 8,008,449, which is incorporated herein by reference in its entirety. In some embodiments, the anti-PD-1 HuMAbs are 3G10, 12A4 (also referred to herein as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13 G4, all of which are described in U.S. Pat. No. 7,943,743, which is incorporated herein by reference in its entirety.

[0070] In some embodiments, one or more immune checkpoint inhibitors can be incorporated into a pharma- ceutically acceptable formulation. In some embodiments, one or more immune checkpoint inhibitors are incorporated into a pharma- ceutically acceptable aqueous formulation. Examples of acceptable aqueous formulations include saline solutions, such as lactated Ringer's solution, that are isotonic and buffered to a pH of 4.5-8.

[0071] In some embodiments, the immune checkpoint inhibitor compound is incorporated into a pharma- ceutically acceptable liposomal formulation, which may be a passive liposomal formulation or a targeted liposomal formulation. Examples of methods for preparing suitable liposomal formulations of antibodies are described in U.S. Patent No. 5,399,331 (Loughrey), U.S. Patent No. 8,304,565 (Wu), and U.S. Patent No. 7,780,882 (Chang), which are incorporated herein by reference in their entireties.

[0072] In some embodiments, the one or more immune checkpoint inhibitors may be antibodies. In some embodiments, the antibodies are dry, lyophilized solids that are reconstituted in an aqueous reconstitution solvent prior to use. In some embodiments, the antibodies are incorporated into a pharma- ceutically acceptable formulation, and the pharma-ceutically acceptable formulation is injected directly into the tumor. In some embodiments, the immune checkpoint inhibitor antibodies are incorporated into a pharma-ceutically acceptable formulation, and the pharma-ceutically acceptable formulation is injected into the peritumoral region surrounding the tumor. The peritumoral region may contain anti-tumor immune cells. In some embodiments, the antibodies are incorporated into a pharma-ceutically acceptable formulation, and the pharma-ceutically acceptable formulation is administered by intravenous injection or infusion. In some embodiments, the immune checkpoint inhibitor antibodies are incorporated into a pharma-ceutically acceptable formulation, and the pharma-ceutically acceptable formulation is administered by subcutaneous or intradermal injection. In some embodiments, the antibodies are incorporated into a pharma-ceutically acceptable formulation, and the pharma-ceutically acceptable formulation is administered by intraperitoneal injection or peritoneal lavage.

[0073] The exact amount of immune checkpoint inhibitor compound incorporated into a particular method or therapeutic combination of the present disclosure may vary depending on factors known in the art, such as, for example, the physical and clinical condition of the subject, the method of administration, the contents of the formulation, the physical and chemical properties of the immune checkpoint inhibitor compound, the intended administration regimen or sequence, etc. However, one of ordinary skill in the art can readily determine the appropriate amount with due consideration of such factors.

[0074] Chemotherapeutic agents In some embodiments, the compound of formula (I) is co-administered with an additional chemotherapeutic agent. In some embodiments, the additional chemotherapeutic agent is selected from the group consisting of: abiraterone, acetate, avitrexate (methotrexate), abraxane (paclitaxel albumin stabilized nanoparticle formulation), ABVD, ABVE, ABVE-PC, AC, AC-T, ADE, ado-trastuzumab emtansine, adriamycin (doxorubicin hydrochloride), afatinib dimaleate, afinitor (everolimus), aquinzeo (netupitant and palonosetron hydrochloride), aldara (imiquimod), aldesleukin, alecensa (alectinib). , alectinib, alemtuzumab, Alimta (pemetrexed disodium), Aloxi (palonosetron hydrochloride), ambochlorin (chlorambucil), ambochlorin (chlorambucil), aminolevulinic acid, anastrozole, aprepitant, Aredia (pamidronate disodium), Arimidex (anastrozole), Aromasin (exemestane), Alanone (nelarabine), arsenic trioxide, Alzera (ofatumumab), Erwinia chrysanthemi-derived asparaginase, Avastin (bevacizumab), axitinib, azacine Tysin, BEACOPP, Besenam (carmustine), Beleodac (belinostat), belinstat, bendamustine hydrochloride, BEP, bevacizumab, bexarotene, Bexar (tositumomab and iodine I131 tositumomab), bicalutamide, BiCNU (carmustine), bleomycin, blinatumomab, Blincyto (blinatumomab), bortezomib, Bosulif (bosutinib), bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib-S-malate, CAF, Campas (alemtuzumab), Ca Mamptosar (irinotecan hydrochloride), capecitabine, CAPOX, Carac (fluorouracil - topical medication), carboplatin, carboplatin-taxol, carfilzomib, Carmbris (carmustine), carmustine, carmustine implant, Casodex (bicalutamide), CeeNU (lomustine), ceritinib, Cervizin (daunorubicin hydrochloride), Cervarix (recombinant HPV bivalent vaccine), cetuximab, chlorambucil, chlorambucil-prednisone, CHOP, cisplatin, Clafen (cyclophosphamide) ), clofarabine, Clofarex (clofarabine), Chloral (clofarabine), CMF, cobimetinib, Cometrik (cabozantinib-S-malate), COPDAC, COPP, COPP-ABV, Cosmegen (dactinomycin), Cotellic (cobimetinib), crizotinib, CVP, cyclophosphamide, Cyphos (ifosfamide), Cyramza (ramucirumab), cytarabine, cytarabine liposomal, Cytosa-U (cytarabine), Cytoxan (cyclophosphamide), dabrafenib, dacarbazine, Dacogen (de Citabine), Dactinomycin, Daratumumab, Darzalex (Daratumumab), Dasatinib, Daunorubicin hydrochloride, Decitabine, Degarelix, Denileukin diftitox, Denosumab, Depocyt (Cytarabine liposome), Dexamethasone, Dexrazoxane hydrochloride, Dinutuximab, Docetaxel, Doxil (Doxorubicin hydrochloride liposome), Doxorubicin hydrochloride, Doxorubicin hydrochloride liposome, Dox-SL (Doxorubicin hydrochloride liposome), Efudex (Fluorouracil - topical), Erythek (Rasburicase),Elence (epirubicin hydrochloride), elotuzumab, Eloxatin (oxaliplatin), eltrombopag olamine, Emend (aprepitant), Empliciti (elotuzumab), enzalutamide, epirubicin hydrochloride, Epoch, Erbitux (cetuximab), eribulin mesylate, Erivedge (vismodegib), erlotinib hydrochloride, Erwinase (Erwinia chrysanthemis) chrysanthemi-derived asparaginase), Etopophos (etoposide phosphate), etoposide, etoposide phosphate, Everset (doxorubicin hydrochloride liposome), everolimus, Evista (raloxifene hydrochloride), exemestane, 5-FU (fluorouracil injection), 5-FU (fluorouracil topical), Fairston (toremifene), Faridak (panobinostat), Faslodex (fulvestrant), FEC, Femara (letrozole), filgrastim, Fludara (fludarabine phosphate), fludarabine phosphate, Fluoroplex (fluorouracil topical), fluorouracil injection, fluorouracil topical, flutamide, Folex (methotrexate), FOLFIRINOX, FOLFOX, FOLOTHIN (pralatrexate), FU-LV, fulvestrant, Gardasil (genetically modified HPV 4-valent vaccine), Gardasil 9 (genetically modified HPV 9-valent vaccine), Gazyva (obinutuzumab), gefitinib, gemcitabine hydrochloride, gemcitabine-cisplatin, gemcitabine-oxaliplatin, gemtuzumab ozogamicin, Gemzar (gemcitabine hydrochloride), Gilotrif (afatinib dimaleate), Gleevec (imatinib mesylate), Gliadel (carmustine implant), Gliadel wafer (Gliadel, wafer) (carmustine implant), glucarpidase, goserelin acetate, Halaven (eribulin mesylate), Herceptin (trastuzumab), HPV bivalent vaccine, genetically modified, HPV 9-valent vaccine, genetically modified, HPV 4-valent vaccine, genetically modified, Hicamtine (topotecan hydrochloride), Hyper-CVAD, In Brance (palbociclib), ibritumomab tiuxetan, ibrutinib, ICE, Iclusig (ponatinib hydrochloride), Idamycin (idarubicin hydrochloride), idelalisib, Ifex (ifosfamide), ifosfamide, IL-2 (aldesleukin), imatinib mesylate, Imbruvica (ibrutinib), imiquimod, Imligic (talimogene laherparepvec), Inlyta (axitinib), interferon alpha-2b, recombinant, interleukin-2 (aldesleukin), Intron A (recombinant interferon alpha-2b ), iodine I131 tositumomab and tositumomab, Iressa (gefitinib), irinotecan hydrochloride, irinotecan hydrochloride liposomal, Istodax (romidepsin), ixabepilone, ixazomib citrate, Ixempra (ixabepilone), Jakafi (ruxolitinib phosphate), Jevtana (cabazitaxel), Kadcyla (ado-trastuzumab emtansine), Keoxifen (raloxifene hydrochloride), Kepivans (palifermin), Kyprolis (carfilzomib), lanreotide acetate Salt, Lapatinib Ditosylate, Lenalidomide, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Letrozole, Leucovorin Calcium, Leukeran (Chlorambucil), Leuprolide Acetate, Levulan (Aminolevulinic Acid), Lympholidine (Chlorambucil), Lipodox (Doxorubicin Hydrochloride Liposomal), Lomustine, Lonsurf (Trifluridine and Tipiracil Hydrochloride), Lupron (Leuprolide Acetate), Leupron Depot (Leuprolide Acetate), Leupron Depot - Pediatric (Leupro leuprolide acetate), Leupro Depot-3 months (leuprolide acetate), Leupro Depot-4 months (leuprolide acetate), Lynparza (olaparib), Marqibo (vincristine sulfate liposomal), Matulane (procarbazine hydrochloride), Mechlorethamine hydrochloride, Megase (megestrol acetate), Megestrol acetate, Mekinist (trametinib), Mercaptopurine, Mesna, Mesnex (mesna), Metazolastone (temozolomide), Methotrexate,Methotrexate LPF (methotrexate), Mexate (methotrexate), Mexate-AQ (methotrexate), Mitomycin C, Mitoxantrone hydrochloride, Mitoditrex (mitomycin C), MOPP, Mozobil (plelixafor), Mustagen (mechlorethamine hydrochloride), Mutamycin (mitomycin C), Myleran (busulfan), Mylosar (azacitidine), Mylotarg (gemtuzumab ozogamicin), Nanoparticle Paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation), Nabe Lubin (vinorelbine tartrate), necitumumab, nelarabine, Neosar (cyclophosphamide), netupitant and palonosetron hydrochloride, Neupogen (filgrastim), Nexavar (sorafenib tosylate), nilotinib, Ninlaro (ixazomib citrate), Nolvadex (tamoxifen citrate), Nplate (romiplostim), obinutuzumab, Odomzo (sonidegib), OEPA, ofatumumab, OFF, olaparib, omacetaxine mepesuccinate, Oncaspar (peguasparaga -ase), ondansetron hydrochloride, Onivyde (irinotecan hydrochloride liposomal), Ontak (denileukin diftitox), OPPA, osimertinib, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, PAD, palbociclib, palifermin, palonosetron hydrochloride, palonosetron hydrochloride and netupitant, pamidronate disodium, panitumumab, panobinostat, Paraplat (carboplatin), Paraplatin (carboplatin), pazopanib hydrochloride, PCV, pegaspar Gauze, peginterferon alfa-2b, PEG-Intron (peginterferon alfa-2b), pemetrexed disodium, Perjeta (pertuzumab), pertuzumab, Platinol (cisplatin), Platinol-AQ (cisplatin), plerixafor, pomalidomide, Pomalyst (pomalidomide), ponatinib hydrochloride, Portraza (necitumumab), pralatrexate, prednisone, procarbazine hydrochloride, Proleukin (aldesleukin), Prolia (denosumab), Promacta (eltrombopag olamine),Provenge (Sipuleucel-T), Purinetol (Mercaptopuri, ), Prixan (mercaptopurine), radium 223 dichloride, raloxifene hydrochloride, ramucirumab, rasburicase, R-CHOP, R-CVP, recombinant human papillomavirus (HPV) bivalent vaccine, recombinant human papillomavirus (HPV) nonavalent vaccine, recombinant human papillomavirus (HPV) quadrivalent vaccine, recombinant interferon α-2b, regorafenib, R-EPOCH, Revlimid (lenalidomide), Rheumatrex (methotrexate), rituximab, rolapitant hydrochloride, romidepsin, romiplostim, rubidomycin (daunorubicin hydrochloride), Ruxolitinib phosphate, Sclerosol intrapleural aerosol (talc), siltoximab, Sipuleucel-T, Somatuline depot (lanreotide acetate), sonidegib, sorafenib tosylate, Sprycel (dasatinib), Stanford V, sterile talc powder (talc), Steritalc (talc), Stivarga (regorafenib), sunitinib malate, Sutent (sunitinib malate), Silatron (peginterferon alpha-2b), Silvant (siltoximab), Sinovir (thalidomide), Synribo (omacetaxine mepesuccinate), Tabloid (thioguanine), TAC, Tafinlar (dabrafenib), Tagrisso (osimertinib), Talc, Talimogene laherparepvec, Tamoxifen citrate, Tarabine PFS (cytarabine), Tarceva (erlotinib hydrochloride), Targretin (bexarotene), Tasigna (nilotinib), Taxol (paclitaxel), Taxotere (docetaxel), Temodar (temozolomide), Temozolomide, Temsirolimus, Thalidomide, Thioguanine, Thiotepa, Tolak (fluorouracil - topical), Toposar (etoposide) , topotecan hydrochloride, toremifene, Torisel (temsirolimus), tositumomab and iodine I131, tositumomab, Totect (dexrazoxane hydrochloride), TPF, trabectedin, trametinib, trastuzumab, Treanda (bendamustine hydrochloride), trifluridine and tipiracil hydrochloride, Trisenox (arsenic trioxide), Tykerb (lapatinib ditosilate), Unituxin (dinutuximab), uridine triacetate, VAC, vandetanib, VAMP, Valvi (rolapitant hydrochloride), Vectibix (panitumumab) (Vinblastine sulfate), VeIP, Velban (Vinblastine sulfate), Velcade (Bortezomib), Velsar (Vinblastine sulfate), Vemurafenib, Bepcid (Etoposide), Viadur (Leuprolide acetate), Vidaza (Azacitidine), Vinblastine sulfate, Vincasar PFS (Vincristine sulfate), Vincristine sulfate, Vincristine sulfate liposomal, Vinorelbine tartrate, VIP, Vismodegib, Vistogard (Uridine triacetate), Boraxazepam (glucarpidase), vorinostat, Votrient (pazopanib hydrochloride), Wellcovorin (leucovorin calcium), Xalkori (crizotinib), Xeloda (capecitabine), XELIRI, XELOX, Xgeva (denosumab), Xofigo (radium-223 dichloride), Xtandi (enzalutamide), Yervoy (ipilimumab), Yondelis (trabectedin), Zaltrap (Ziv-aflibercept), Zalcio (filgrastim), Zelboraf (vemurafenib), Zevalin (ibritumomab)Tiuxetan), Zinecard (dexrazoxane hydrochloride), Ziv-aflibercept, Zofran (ondansetron hydrochloride), Zoladex (goserelin acetate), zoledronic acid, Zolinza (vorinostat), Zometa (zoledronic acid), Zydelig (idelalisib), Zykadia (ceritinib), and Zytiga (abiraterone acetate).

[0075] In some embodiments, the additional chemotherapeutic agent is docetaxel.

[0076] Radiation therapy In some embodiments, the compound of formula (I) is co-administered with radiation. In some embodiments, the radiation can be selected from external beam radiation therapy or internal beam radiation therapy. In some embodiments, the external beam radiation therapy can be selected from three-dimensional conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), proton beam therapy, image-guided radiation therapy (IGRT), stereotactic radiation therapy (SRT), or a combination thereof. In some embodiments, the radiation can be selected from intraoperative radiation therapy (IORT), total body radiation therapy, radioimmunotherapy, radiosensitizers, radioprotectors, or a combination thereof.

[0077] Methods of Use and Treatment In an aspect, the disclosure provides methods and therapeutic compositions for treating, preventing, or ameliorating cancer or tumors in a subject by administering a compound of Formula (I) (e.g., plinabulin), or a pharma- ceutically acceptable salt thereof, where the subject was refractory to prior treatment with an immune checkpoint inhibitor. Some embodiments include identifying the subject as being refractory to prior immune checkpoint inhibitor therapy, and then administering a compound of Formula (I) (e.g., plinabulin).

[0078] In some embodiments, the method includes treating a subject resistant to a PD-1 inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method includes treating a subject resistant to a PD-L1 inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method includes treating a subject resistant to a PD-L2 inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method includes treating a subject resistant to a CTLA-4 inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method includes administering a compound of Formula (I) when the subject is resistant to two different immune checkpoint inhibitors. The two different immune inhibitors can be selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor. In some embodiments, the methods include treating a subject that has developed resistance to a PD-1 inhibitor and a CTLA-4 inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the methods include treating a subject that has developed resistance to a PD-L1 inhibitor and a CTLA-4 inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the methods include treating a subject that has developed resistance to a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor by administering a therapeutically effective amount of a compound of Formula (I).

[0079] In some embodiments, the method includes treating a subject resistant to a LAG-3 inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method includes treating a subject resistant to a TIM-3 inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method includes treating a subject resistant to a BLTA inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method includes treating a subject resistant to a KIR inhibitor by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the anti-KIR receptor antibody is lirilumab. In some embodiments, the method includes treating a subject resistant to a blocking antibody by administering a therapeutically effective amount of a compound of Formula (I). In some embodiments, the method includes treating a subject having a tumor by administering a therapeutically effective amount of a compound of Formula (I) after the subject has failed treatment with an anti-CTLA-4 receptor antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the method comprises administering to the subject a compound of formula (I) after failure of treatment with an anti-PD-1 receptor antibody. In some embodiments, the method comprises administering a therapeutically effective amount of the anti-PD-1 antibody to a subject having a tumor.

[0080] In some embodiments, the compound of formula (I) is co-administered with a chemotherapeutic agent. In some such embodiments, the compound of formula (I) is administered after administration of the chemotherapeutic agent, for example, at least 30 minutes, 1 hour, 2 hours, 4 hours, 1 day, 2 days, or 3 days after administration of the chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is docetaxel. In some embodiments, the compound of formula (I) is co-administered with one or more immune checkpoint inhibitors, with or without additional chemotherapeutic agents. In some embodiments, the compound of formula (I) is co-administered with radiation, with or without additional chemotherapeutic agents, with or without one or more immune checkpoint inhibitors. In some such embodiments, the compound of formula (I) is administered after radiation therapy, for example, at least 30 minutes, 1 hour, 2 hours, 4 hours, 1 day, 2 days, or 3 days after administration of radiation therapy. In some embodiments, the compound of formula (I) can be administered with radiation on the same day that radiation is administered. In some embodiments, the one or more immune checkpoint inhibitors can be administered prior to administration of the compound of Formula (I) and radiation. In some embodiments, the one or more immune checkpoint inhibitors can be administered prior to administration of the compound of Formula (I), the additional chemotherapeutic agent, and radiation. In other embodiments, the one or more immune checkpoint inhibitors are administered after administration of the compound of Formula (I) and the additional chemotherapeutic agent and / or radiation.

[0081] As used herein, the terms "co-administer", "co-administering" or "co-administration" refer to two or more agents or therapies that have a simultaneous biological effect on a subject, regardless of when and how they are actually administered. In one embodiment, the agents or therapies are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents or therapies are administered sequentially. In some embodiments, administration can be separated by a period of time, for example, 30 minutes, 1 hour, 2 hours, 1 day, 2 days, 3 days, or 1 week. In one embodiment, the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one administered orally and the other administered intravenously.

[0082] In some embodiments where an immune checkpoint inhibitor is co-administered, a method for treating a subject having cancer or a tumor can include administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof after the subject has been administered one or more immune checkpoint inhibitors. In some embodiments, a method for inhibiting the proliferation of cancer or tumor cells in a subject can include administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof after the subject has been administered one or more immune checkpoint inhibitors. In some embodiments, a method for increasing a cellular immune response of a cell population can include administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof after the subject has been administered one or more immune checkpoint inhibitors.

[0083] In some embodiments, a compound of formula (I) is co-administered with a CTLA-4 receptor inhibitor compound. In some embodiments, a compound of formula (I) is co-administered with a PD-1 or PD-L1 receptor inhibitor compound.

[0084] In some embodiments, the method includes treating a subject by co-administering a therapeutically effective amount of a compound of formula (I) and a LAG-3 receptor inhibitor compound. In some embodiments, the method includes treating a subject by co-administering a therapeutically effective amount of a compound of formula (I) and a TIM-3 receptor inhibitor compound. In some embodiments, the method includes treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I) and a BTLA receptor inhibitor compound. In some embodiments, the method includes treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I) and a KIR receptor inhibitor compound. In some embodiments, the method includes treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I) and a PD-L1 inhibitor compound. In some embodiments, the method includes treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I) and a PD-L2 inhibitor compound.

[0085] In some embodiments of the present disclosure, the method comprises treating a subject by co-administering a therapeutically effective amount of a compound of Formula (I) and an immune checkpoint pathway blocking antibody. In some embodiments, the method comprises treating a subject by co-administering a therapeutically effective amount of a compound of Formula (I) and an anti-CTLA-4 receptor antibody. In some embodiments, the method comprises treating a subject by co-administering a therapeutically effective amount of a compound of Formula (I) and an anti-PD-1 receptor antibody.

[0086] In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I) and an anti-LAG-3 receptor antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I) and an anti-TIM-3 receptor antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I) and an anti-BTLA receptor antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I) and an anti-KIR receptor antibody. In some embodiments, the anti-KIR receptor antibody is lirilumab. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I) and an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is cemiplimab, pembrolizumab, pidilizumab, or nivolumab. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I) and an anti-PD-L1 antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I) and an anti-PD-L2 antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I) and an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0087] In some embodiments, the method includes treating a subject that has developed resistance to one or more immune checkpoint inhibitors by co-administering a therapeutically effective amount of a compound of Formula (I) and an additional chemotherapeutic agent. In some embodiments, the additional chemotherapeutic agent is a taxane. In some embodiments, the taxane is docetaxel.

[0088] In some embodiments, the methods include treating a subject that has developed resistance to one or more immune checkpoint inhibitors by co-administering a therapeutically effective amount of a compound of Formula (I) and radiation therapy.

[0089] In some embodiments, a method of treating a subject with cancer where prior immune checkpoint inhibitor therapy has failed comprises administering a therapeutic combination comprising a compound of Formula (I). In some embodiments, the compound of Formula (I) is plinabulin. In some embodiments, the therapeutic combination comprises an additional chemotherapeutic agent. In some embodiments, the additional chemotherapeutic agent is docetaxel. In some embodiments, the therapeutic combination comprises radiation. In some embodiments, the therapeutic combination comprises plinabulin, a chemotherapeutic agent, and radiation. In some embodiments, the therapeutic combination comprises plinabulin, an inhibitor of PD-1 or PD-L1, and an additional chemotherapeutic agent. In some embodiments, the therapeutic In some embodiments, the therapeutic combination comprises plinabulin, a PD-1 or PD-L1 inhibitor, and radiation therapy. In some embodiments, the therapeutic combination comprises plinabulin, a PD-1 or PD-1 inhibitor, and a CTLA-4 inhibitor. In some embodiments, the therapeutic combination comprises plinabulin, a PD-1 or PD-1 inhibitor, a CTLA-4 inhibitor, and an additional chemotherapeutic agent. In some embodiments, the therapeutic combination comprises plinabulin, a PD-1 or PD-1 inhibitor, a CTLA-4 inhibitor, and radiation therapy.

[0090] In some embodiments, a method for halting or reversing progressive cancer in a subject, comprising administering a compound of formula (I). In some embodiments, the invention comprises co-administering a compound of formula (I) with one or more additional chemotherapeutic agents, one or more immune checkpoint inhibitors, and / or radiation, as described above.

[0091] In some embodiments, the present disclosure provides a method for treating breast cancer, bladder cancer, glioblastoma, metastatic brain tumor, head and neck cancer, non-small cell lung cancer, small cell lung cancer, colorectal cancer, gastrointestinal cancer, gastroesophageal cancer, renal cell carcinoma, prostate cancer, liver cancer, colon cancer, pancreatic cancer tumor, ovarian cancer tumor, lymphoma, cutaneous T-cell lymphoma, sarcoma, multiple myeloma, metastatic melanoma, hepatocellular carcinoma, malignant pleural mesothelioma, urothelial carcinoma, esophageal cancer, Merkel cell carcinoma, endometrial cancer, basal cell carcinoma, or melanoma.

[0092] In some embodiments, the present disclosure provides a method for treating a solid tumor. In some embodiments, the present disclosure provides a method for treating a breast cancer tumor, a bladder cancer tumor, a glioblastoma tumor, a metastatic brain tumor, a head and neck cancer tumor, a non-small cell lung cancer tumor, a small cell lung cancer tumor, a colorectal cancer tumor, a gastrointestinal stromal tumor, a gastroesophageal cancer tumor, a renal cell carcinoma tumor, a prostate cancer tumor, a liver cancer tumor, a colon cancer tumor, a pancreatic cancer tumor, an ovarian cancer tumor, a lymphoma tumor, a cutaneous T-cell lymphoma tumor, a sarcoma tumor, a multiple myeloma tumor, a metastatic melanoma tumor, a hepatocellular carcinoma tumor, a malignant pleural mesothelioma tumor, a urothelial cancer tumor, an esophageal cancer tumor, a Merkel cell carcinoma tumor, an endometrial cancer tumor, a basal cell carcinoma tumor, or a melanoma tumor. In some embodiments, the present disclosure provides a method for treating an immunosuppressive tumor. An immunosuppressive tumor can be, for example, a T Reg These tumors contain immune suppression-related cells such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages, or immune suppressive factors such as inducible nitric oxide synthase (iNOS) and PD-L1.

[0093] In some embodiments, the cancer comprises cancer cells that express a binding ligand of PD-1. In some embodiments, the binding ligand of PD-1 is PD-L1. In some embodiments, the binding ligand of PD-1 is PD-L2.

[0094] In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express a binding ligand of PD-1. In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express PD-L1. In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express PD-L2.

[0095] In some embodiments, identifying cancer cells that express a binding ligand of PD-1 comprises using an assay to detect the presence of the binding ligand. Examples of applicable assays include, but are not limited to, the PD-L1 IHC 22C3 pharmDx kit and PD-L1 IHC 28-8 pharmDx available from Dako.

[0096] In some embodiments, the cancer comprises cancer cells that express a binding ligand for CTLA-4. In some embodiments, the binding ligand for CTLA-4 is B7.1 or B7.2. be.

[0097] In some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express a binding ligand of CTLA-4, hi some embodiments, the methods of treating cancer described herein further comprise identifying cancer cells that express B7.1 or B7.2.

[0098] In some embodiments, the cancer is 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, glioma including glioblastoma, myeloma, lymphoma, sarcoma, multiple myeloma, or leukemia. In some embodiments, the cancer is renal cell carcinoma, malignant melanoma, non-small cell lung cancer (NSCLC), ovarian cancer, Hodgkin's lymphoma, or squamous cell carcinoma. In some embodiments, the cancer is selected 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 cancer is a solid tumor or a hematological cancer.

[0099] In some embodiments, the cancer does not have detectable levels of cells that express PD-1, PD-L1, or PD-L2.

[0100] In some embodiments, the cancer is selected from breast cancer, colon cancer, glioma, metastatic brain cancer, rectal cancer, lung cancer, prostate cancer, melanoma, leukemia, ovarian cancer, gastric cancer, renal cell carcinoma, liver cancer, pancreatic cancer, lymphoma, sarcoma, multiple myeloma, and myeloma. In some embodiments, the cancer is a solid tumor or a hematological cancer.

[0101] In some embodiments, the subject may be an animal, e.g., a mammal, a human, hi some embodiments, the subject is a human.

[0102] In some embodiments, the compound of formula (I) is incorporated into a pharma- ceutically acceptable solution. In some embodiments, the compound of formula (I) is incorporated into an injectable. In some embodiments, the compound of formula (I) is incorporated into an injectable that substantially maintains the compound of formula (I) at or near the injection site.

[0103] The exact amount of the compound of formula (I) incorporated in a particular method or therapeutic combination of the present disclosure may vary according to factors known in the art, such as, for example, the subject's physical and clinical condition, the method of administration, the content of the formulation, the intended administration regimen or sequence, etc. Therefore, it is not practical to specifically describe the amount of the compound of formula (I) that is therapeutically effective for all possible applications. However, those skilled in the art can easily determine the appropriate amount by fully considering such factors.

[0104] Some embodiments relate to methods of treating cancer in a subject that has become resistant to checkpoint inhibitor therapy. In some embodiments, the method includes identifying a subject with a cancer that is resistant to one or more immune checkpoint inhibitor therapies, and co-administering to the subject plinabulin and one or more immune checkpoint inhibitors, where the one or more immune checkpoint inhibitors are inhibitors of PD-1, PD-L1, or CTLA-4. In some embodiments, the PD-1 inhibitor is nivolumab and is administered at 1 mg / kg. In some embodiments, the CTLA-4 inhibitor is ipilimumab and is administered at 3 mg / kg. In some embodiments, plinabulin is administered at about 13.5 mg / m 2 ~about 30mg / m 2 is administered on day 1 of a 21 day cycle. In some embodiments, the cancer is recurrent extensive-stage small cell lung cancer. In some embodiments, the cancer is a SCLC. In some embodiments, the cancer has previously been identified as unresponsive to platinum-based chemotherapy. In some embodiments, the PD-1 inhibitor and the CTLA-4 inhibitor can be administered on day 1 of a 21-day cycle. In some embodiments, the subject is administered 1, 2, 3, or 4 treatment cycles. In some embodiments, the subject can be administered 5 or more treatment cycles of the PD-1 inhibitor and plinabulin every 2 weeks.

[0105] Administration Administration of the pharmaceutical compositions described herein can be via any of the accepted methods of administration for agents providing similar utilities, including, but not limited to, oral, sublingual, buccal, subcutaneous, intravenous, intranasal, intratumoral, topical, transdermal, intradermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, or intraocular. Oral and parenteral administration are conventional in the treatment of the indications that are the subject of the preferred embodiments.

[0106] The compositions described herein can be 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 in a single dose in accordance with appropriate medical practice to an animal, preferably a mammalian subject. However, the preparation of a single dosage form or unit dosage form does not imply that the dosage form is administered once per day or once per course of treatment. Such dosage forms are contemplated to be administered once, twice, three times or more per day, and may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours) or as a continuous infusion, and may be administered more than once during the course of treatment (although a single dose is not specifically excluded). One of ordinary skill in the art will recognize that the formulations are not specifically contemplated for an entire course of treatment, and such a determination is left to the skilled artisan of treatment rather than formulation.

[0107] 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, nasal, rectal, topical (including transdermal and intradermal), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. Those skilled in the art will appreciate that oral and nasal include compositions administered by inhalation and made using available methodologies. Depending on the particular route of administration desired, a variety of pharmaceutically acceptable carriers well known in the art can be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surfactants, and encapsulating materials. Optional pharmaceutically active materials that do not substantially interfere with the inhibitory activity of the compound or composition can be included. The amount of carrier used in conjunction with the compound or composition is sufficient to provide a practical amount of the material for administration per unit dose of the compound. Techniques and compositions for making 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: Forms 8th Edition (2004).

[0108] A variety of oral dosage forms can be used, including solid forms such as tablets, capsules (e.g., solid and liquid gel capsules), granules, and bulk powders. Tablets can be compressed tablets, tablet triturates, enteric coated, sugar coated, or powdered tablets containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow-inducing agents, and melting agents. The liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants and flavorings.

[0109] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for peroral administration are well known in the art. Typically, tablets contain conventional pharma- ceutically compatible adjuvants such as calcium carbonate, sodium carbonate, mannitol, lactose, cellulose, etc. as inert diluents; binders such as starch, gelatin, sucrose, etc.; disintegrants such as starch, alginic acid, croscarmellose, etc.; lubricants such as magnesium stearate, stearic acid, talc, etc. Flow agents such as silicon dioxide can be used to improve the flow properties 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, fruit flavors, etc. are useful adjuvants for chewable tablets. Typically, capsules contain one or more solid diluents as disclosed above. The selection of carrier components depends on secondary considerations such as taste, cost, and storage stability, which are not critical and can be easily made by those skilled in the art.

[0110] Oral compositions also include solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate; typical wetting agents include lecithin and polysorbate 80; typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions can also contain one or more components, such as sweeteners, flavorings, and colorings disclosed above.

[0111] Such compositions can also be coated in a conventional manner, typically with a pH or time-dependent coating, so that the subject composition is released in the digestive tract near the desired local application or at various times to extend the desired effect.Typically, such dosage forms include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes and shellac.

[0112] The compositions described herein can optionally include additional pharmacoactive agents.

[0113] Other compositions useful for achieving systemic delivery of the target compound include sublingual, buccal and nasal dosage forms.Typically, such compositions include one or more of soluble filler materials such as sucrose, sorbitol, mannitol, and the like; and binders such as acacia, microcrystalline cellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, and the like.They can also include the flow agents, lubricants, sweeteners, colorants, antioxidants, and flavors disclosed above.

[0114] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered topically to the eye. Comfort should be maximized as much as possible, but formulation considerations (e.g., drug stability) may dictate less than optimal comfort. If comfort cannot be maximized, the liquid should be formulated so that it is tolerable to patients for topical ophthalmic use. Additionally, the ophthalmically acceptable liquids can be packaged for a single use or can contain a preservative to prevent contamination over multiple uses.

[0115] In ophthalmic applications, solutions and medicaments are often prepared using saline as the primary vehicle. Ophthalmic solutions are preferably maintained at a comfortable pH using an appropriate buffer system. The formulations may also contain conventional pharma- ceutically acceptable preservatives, stabilizers, and surfactants.

[0116] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. Useful surfactants are, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic formulations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose and purified water.

[0117] Tonicity adjustors can be added as necessary or convenient, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerin, or other suitable ophthalmically acceptable tonicity adjusters.

[0118] Various buffers and means for adjusting pH can be used as long as the resulting formulation is ophthalmologically acceptable. In many compositions, the pH will be 4 to 9. Thus, buffers include acetate buffer, citrate buffer, phosphate buffer, borate buffer. Acids or bases can be used as needed to adjust the pH of these formulations.

[0119] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, butylated hydroxytoluene.

[0120] Another excipient component that may be included in the ophthalmic formulation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may be used instead or in combination.

[0121] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compositions disclosed herein are used. Topical formulations generally consist of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0122] For intravenous administration, the compositions described herein can be dissolved or dispersed in a pharma- ceutically acceptable diluent, such as saline or glucose solution. Suitable excipients, including but not limited to NaOH, sodium carbonate, sodium acetate, HCl, and citric acid, can be included to achieve the desired pH. In various embodiments, the pH of the final composition ranges from 2 to 8, preferably 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. In some embodiments, excipients utilized for intravenous delivery can include Kolliphor HS15 (polyoxyl 15 hydroxystearate or Solutol HS-15), propylene glycol, and 5% dextrose in water (D5W). Other non-limiting examples of suitable excipients found in the final intravenous composition include sodium or potassium phosphate. Excipients that may be used include, for example, glycerol, citric acid, tartaric acid, gelatin, and glucose, as well as carbohydrates such as 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 entireties. Antimicrobial agents, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol, can be included to provide a bacteriostatic or fungistatic solution.

[0123] Compositions for intravenous administration can be provided to caregivers in the form of one more solids that are reconstituted 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 to be administered parenterally. In yet other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments involving administration of a combination of a compound described herein and another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0124] The actual dosage of the active compounds described herein will depend on the particular compound and the condition being treated, and selection of an appropriate dosage is well within the knowledge of one of ordinary skill in the art. In some embodiments, the compound of formula (I) is administered at a dose of about 1 mg / m 2 ~about 50mg / m 2 In some embodiments, the compound of formula (I) can be administered at a dose of about 1 to 50 mg / m of body surface area. 2In some embodiments, the compound of formula (I) is administered in a dose 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 to 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, 8~1 2, 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, 25.5~34.5, 27.5~32.5, 2~20, 2.5~22.5, or 9.5~21.5 mg / m 2 In some embodiments, the compound of formula (I) is administered in a dose range of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 10 7, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 2 6, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / m 2In some embodiments, the compound of formula (I) 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, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 10 7, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 2 6, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40mg / m 2 In some embodiments, the compound of formula (I) is administered at a dose of 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, 50mg / m 2 It is administered in doses exceeding 100 mg / kg / day.

[0125] In some embodiments, the compound of formula (I) is administered in an amount of 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, or about 40 mg to 60 mg. In some embodiments, the compound of formula (I) 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 compound of formula (I) administered is about 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg, 5 mg to 26 mg, 5 mg to 28 mg, 5 mg to 30 mg, 5 mg to 32 mg, 5 mg to 34 mg, 5 mg to 36 mg, 5 mg to 38 mg, 5 mg to 39 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 49 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 59 mg, 5 mg to 60 mg, 5 mg to 61 mg, 5 mg to 62 mg, 5 mg to 63 mg, 5 mg to 64 mg, 5 mg to 65 mg, 5 mg to 66 mg, 5 mg to 67 mg, 5 mg to 68 mg, 5 mg to 69 mg, 5 mg to 70 mg, 5 mg to 71 mg, 5 mg to 72 mg, 5 mg to 75 mg, 5 mg to 76 mg, 5 mg to 77 mg, 5 mg to 78 mg, 5 mg to 79 mg, 5 mg to 80 mg, 5 mg to 82 mg, 5 mg to 84 mg, 5 mg to 85 mg, 5 mg to 86 mg, 5 mg to 87 mg, 5 8mg、5mg~40mg、5mg~42mg、5mg~44mg、5mg~46mg、5mg~48mg、5mg~50mg、5mg~52mg、5mg~54mg、5mg~56mg、5mg~58mg、5mg~60mg、7mg~7.7mg、7mg~9mg、7mg~10mg、7mg~12mg、7mg~14mg、7mg~15mg、7mg~16mg、7mg~18mg、7mg~20mg、7mg~22mg、7mg~24mg、7mg~26mg、7mg~28mg、7mg~30mg、7mg~32mg、7mg~34mg、7mg~36mg、7mg~38mg、7mg~40mg、7mg~42mg、7mg~44mg、7mg~46mg、7mg~48mg、7mg~50mg、7mg~52mg、7mg~54mg、7mg~56mg、7mg~58mg、7mg~60mg、9mg~10mg、9mg~12mg、9mg~14mg、9mg~15mg、9mg~16mg、9mg~18mg、9mg~20mg、9mg~22mg、9mg~24mg、9mg~26mg、9mg~28mg、9mg~30mg、9mg~32mg、9mg~34mg、9mg~36mg、9mg~38mg、9mg~40mg、9mg~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、25m、 g~34mg、25mg~36mg、25mg~38mg、25mg~40mg、25mg~42mg、25mg~44mg、25mg~46mg、25mg~48mg、25mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg、30mg~36mg、30mg~38mg、30mg~40mg、30mg~42mg、30mg~44mg、30mg~46mg、30mg~48mg、30mg~50mg、30mg~52mg、30mg~54mg、30mg~56mg、30mg~58mg、30mg~60mg、33mg~34mg、33mg~36mg、33mg~38mg、33mg~40mg、33mg~42mg、33mg~44mg、33mg~46mg、33mg~48mg、33mg~50mg、33mg~52mg、33mg~54mg、33mg~56mg、33mg~58mg、33mg~60mg、36mg~38mg、36mg~40mg、36mg~42mg、36mg~44mg、36mg~46mg、36mg~48mg、36mg~50mg、36mg~52mg、36mg~54mg、36mg~56mg、36mg~58mg、36mg~60mg、40mg~42mg、40mg~44mg、40mg~46mg、40mg~48mg、40mg~50mg、40mg~52mg、40mg~54mg、40mg~56mg、40mg~58mg、40mg~60mg、43mg~46mg、43mg~48mg、43mg~50mg、43mg~52mg、43mg~54mg、43mg~56mg、43mg~58mg、42mg~60mg、45mg~48mg、45mg~50mg、45mg~52mg、45mg~54mg、45mg~56mg、45mg~58mg、45mg~60mg、48mg~50mg、48mg~52mg、48mg~54mg、48 mg to 56 mg, 48 mg to 58 mg, 48 mg to 60 mg, 50 mg to 52 mg, 50 mg to 54 mg, 50 mg to 56 mg, 50 mg to 58 mg, 50 mg to 60 mg, 52 mg to 54 mg, 52 mg to 56 mg, 52 mg to 58 mg, or 52 mg to 60 mg. In some embodiments, the dosage of the compound of formula (I) 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 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 dosage of the compound of formula (I) is 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.

[0126] In some embodiments, the dosage of one or more immune checkpoint inhibitors can be about 100 μg to about 1000 mg, about less than 500 μg to about 800 mg, about 1.0 mg to about 600 mg, about 100 mg to about 600 mg, or about 200 mg to 500 mg. In some embodiments, the dosage of one or more immune checkpoint inhibitors can be about 240 mg to about 480 mg per administration. In some embodiments, the dosage of one or more immune checkpoint inhibitors is about 240 mg. In some embodiments, the dosage of one or more immune checkpoint inhibitors is about 480 mg.

[0127] In some embodiments, the one or more immune checkpoint inhibitors can be administered at a dosage ranging from about 100 mg / kg to about 5000 mg / kg. In some embodiments, the one or more immune checkpoint inhibitors can be administered at a dosage ranging from about 100 to about 1000 mg / kg. In some embodiments, the one or more immune checkpoint inhibitors are administered in a dosage range of about 100-200, 100-300, 100-400, 100-500, 100-600, 100-700, 100-800, 100-900, 100-1000, 100-1100, 100-1200, 100-1300, 100-1375, 100-1400, 100-1500, 100-1600, 100-1700, 100-1800, 100-1900, 100-2000, 100-2250, 100-2400, 100-2600, 100-2800, 100-2900, 100-3000, 100-3100, 100-3250, 100-3300, 100-3400, 100-3500, 100-3600, 100-3750, 100-3800, 100-3900, 100-4000, 100-4100, 100-4250, 100-4300, 100-4400, 100-4500, 100-4600, 100-4700, 100-4800, 100-4900, 100-5000, 100-5100, 100-5200, 100-5300, 100-540 2500, 100~2750, 100~3000, 150~200, 150~300, 150~400, 150~500, 150~600, 150~700, 150~800, 150~900, 150~1000, 150~1100, 150~1200, 150~1300, 150~1375, 150~1400, 150~1500, 150~1600, 150~1700, 150~1800, 150~1900, 150~2000, 150~2250, 150~2500, 150~2750 , 150~3000, 250~2000, 250~3000, 250~4000, 250~5000, 250~600, 250~700, 250~800, 250~900, 250~1000, 250~1100, 250~1200, 250~1300, 250~1375, 250~1400, 250~1500, 250~1600, 250~1700, 250~1800, 250~1900, 250~2000, 250~2250, 250~2500, 250~2750, 250~3000 , 250-750, 300-400, 300-500, 300-600, 300-700, 300-800, 300-900, 300-1000, 300-1100, 300-1200, 300-1300, 300-1375, 300-1400, 300-1500, 300-1600, 300-1700, 300-1800, 300-1900, 300-2000, 300-2250, 300-2500, 300-2750, or 300-3000 mg / kg.In some embodiments, the one or more immune checkpoint inhibitors are administered at a concentration of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 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, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg doses.

[0128] In some embodiments, the dosage of the one or more immune checkpoint inhibitors is about 0.5 mg to 3000 mg, 0.5 mg to 2500 mg, 0.5 mg to 2000 mg, 0.5 mg to 1500 mg, 0.5 mg to 1000 mg, 0.5 mg to 500 mg, 0.5 mg to 200 mg, 0.75 mg to 200 mg, 1.0 mg to 100 mg, 1.5 mg to 100 mg, 2.0 mg to 100 mg, 3.0 mg to 100 mg, 4.0 mg to 100 mg, 1.0 mg to 80 mg, 1.5 mg to 80 mg, 2.0 mg to 80 mg, 3.0 mg to 80 mg, 4.0 mg to 80 mg, 1.0 mg to 60 mg, 1.5 mg to 60 mg, 2.0 mg to 60 mg, 3.0 mg to 60 mg, or about 4.0 mg to 60 mg. In some embodiments, the one or more immune checkpoint inhibitors 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 one or more immune checkpoint inhibitors administered are between about 5 mg and 7.5 mg, 5 mg and 9 mg, 5 mg and 10 mg, 5 mg and 12 mg, 5 mg and 14 mg, 5 mg and 15 mg, 5 mg and 16 mg, 5 mg and 18 mg, 5 mg and 20 mg, 5 mg and 22 mg, 5 mg and 24 mg, 5 mg and 26 mg, 5 mg and 28 mg, 5 mg and 30 mg, 5 mg and 32 mg, 5 mg and 34 mg, 5 mg and 36 mg, 5 mg and 38 mg, 5 mg and 40 mg, 5 mg and 42 mg, 5 mg and 44 mg, 5 mg and 46 mg, 5 mg and 48 mg, 5 mg and 50 mg, 5 mg and 52 mg, 5 mg and 54 mg, 5 mg and 5 mg, ~56mg、5mg~58mg、5mg~60mg、7mg~7.7mg、7mg~9mg、7mg~10mg、7mg~12mg、7mg~14mg、7mg~15mg、7mg~16mg、7mg~18mg、7mg~20mg、7mg~22mg、7mg~24mg、7mg~26mg、7mg~28mg、7mg~30mg、7mg~32mg、7mg~34mg、7mg~36mg、7mg~38mg、7mg~40mg、7mg~42mg、7mg~44mg、7mg~46mg、7mg~48mg、7mg~50mg、7mg~52mg、7mg~54mg、7mg~56mg、7mg~58mg、7mg~60mg、9mg~10mg、9mg~12mg、9mg~14mg、9mg~15mg、9mg~16mg、9mg~18mg、9mg~20mg、9mg~22mg、9mg~24mg、9mg~26mg、9mg~28mg、9mg~30mg、9mg~32mg、9mg~34mg、9mg~36mg、9mg~38mg、9mg~40mg、9mg~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、25、 mg~50mg、25mg~52mg、25mg~54mg、25mg~56mg、25mg~58mg、25mg~60mg、27mg~28mg、27mg~30mg、27mg~32mg、27mg~34mg、27mg~36mg、27mg~38mg、27mg~40mg、27mg~42mg、27mg~44mg、27mg~46mg、27mg~48mg、27mg~50mg、27mg~52mg、27mg~54mg、27mg~56mg、27mg~58mg、27mg~60mg、30mg~32mg、30mg~34mg、30mg~36mg、30mg~38mg、30mg~40mg、30mg~42mg、30mg~44mg、30mg~46mg、30mg~48mg、30mg~50mg、30mg~52mg、30mg~54mg、30mg~56mg、30mg~58mg、30mg~60mg、33mg~34mg、33mg~36mg、33mg~38mg、33mg~40mg、33mg~42mg、33mg~44mg、33mg~46mg、33mg~48mg、33mg~50mg、33mg~52mg、33mg~54mg、33mg~56mg、33mg~58mg、33mg~60mg、36mg~38mg、36mg~40mg、36mg~42mg、36mg~44mg、36mg~46mg、36mg~48mg、36mg~50mg、36mg~52mg、36mg~54mg、36mg~56mg、36mg~58mg、36mg~60mg、40mg~42mg、40mg~44mg、40mg~46mg、40mg~48mg、40mg~50mg、40mg~52mg、40mg~54mg、40mg~56mg、40mg~58mg、40mg~60mg、43mg~46mg、43mg~48mg、43mg~50mg、43mg~52mg、43mg~54mg、43mg~56mg、43mg~58mg、42mg~60mg、45mg~48mg、45mg~50mg、45mg~52mg、45mg~54mg、45mg~56mg、45mg~58mg、45mg~60mg、48mg~50mg、48mg~52mg、48mg~54mg、48mg~56mg、48mg~58mg、48mg~60mg、50mg~52mg、50mg~54mg、50mg~56mg、50mg~58mg、50mg~60mg、52mg to 54mg, 52mg to 56mg, 52mg to 58mg, 52mg to 60mg, 100mg to 200mg, 200mg to 300mg, 300mg to 400mg, 400mg to 500mg, 500mg to 1000mg, 1000mg to 2000mg, or 1000mg to 3000mg. In some embodiments, the dosage of the one or more immune checkpoint inhibitors is about 1 mg, 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, the dosage of the one or more immune checkpoint inhibitors is 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, about 300 mg, about 400 mg, about 500 mg, about 1000 mg, about 2000 mg, or about 3000 mg.

[0129] In some embodiments, the initial dose of one or more immune checkpoint inhibitors is 1 mg on day 1, followed by a dose of 3 mg of a second immune checkpoint inhibitor.

[0130] In some embodiments, the compound of formula (I) is administered prior to administration of one or more immune checkpoint inhibitors. In some embodiments, the compound of formula (I) is administered simultaneously with one or more immune checkpoint inhibitors. In some embodiments, the compound of formula (I) is administered after one or more immune checkpoint inhibitors.

[0131] In some embodiments, the compound of formula (I) inhibits one or more immune checkpoints. The administration is 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, 24 hours, 30 hours, 36 hours, 40 hours, or 48 hours after administration of the inhibitor. In some embodiments, the compound of Formula (I) 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, 24 hours, 30 hours, 36 hours, 40 hours, or 48 hours prior to administration of the one or more immune checkpoint inhibitors. In some embodiments, the compound of Formula (I) 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, 24 hours, 30 hours, 36 hours, 40 hours, or 48 hours after administration of the one or more immune checkpoint inhibitors. In some embodiments, the compound of Formula (I) 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, 24 hours, 30 hours, 36 hours, 40 hours, or more than 48 hours after administration of the one or more immune checkpoint inhibitors.In some embodiments, the compound of Formula (I) 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, 24 hours, 30 hours, 36 hours, 40 hours, or 48 hours after administration of the one or more immune checkpoint inhibitors. In some embodiments, the compound of Formula (I) 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, 24 hours, 30 hours, 36 hours, 40 hours, or more than 48 hours prior to administration of the one or more immune checkpoint inhibitors. In some embodiments, the compound of Formula (I) 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 hours to 0.5 hours, 0.25 to 0.75 hours, 0.25 to 1 hour, 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, 1 hour to 5 hours, 1 hour to 24 hours, 1 minute to 24 hours, or 1 minute to 2 hours, 1 day to 2 days, 1 day to 3 days, 1 day to 4 days, 1 day to 5 days, or 1 day to 6 days after administration of the one or more immune checkpoint inhibitors. In some embodiments, the compound of formula (I) 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 hours to 0.5 hours, 0.25 to 0.75 hours, 0.25 to 1 hour, 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, 1 hour to 5 hours, 1 hour to 24 hours, 1 minute to 24 hours, or 1 minute to 2 hours, 1 day to 2 days, 1 day to 3 days, 1 day to 4 days, 1 day to 5 days, or 1 day to 6 days prior to administration of the one or more immune checkpoint inhibitors.

[0132] In some embodiments, when a compound of Formula (I) is administered prior to administration of one or more immune checkpoint inhibitors, the compound of Formula (I) 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, 0.25 hours to 0.5 hours, 0.25 to 0.75 hours, 0. 25 to 1 hour, 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, 1 hour to 5 hours, 1 hour to 24 hours, 1 minute to 1 hour, 1 minute to 2 hours, 1 minute to 5 hours, 1 minute to 24 hours, 1 day to 2 days, 1 day to 3 days, 1 day to 4 days, 1 day to 5 days, or 1 day to 6 days prior to administration of one or more immune checkpoint inhibitors. In some embodiments, the compound of formula (I) 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, 30 hours, 36 hours, 40 hours, 48 ​​hours, 4 days, 5 days, 6 days, or 7 days prior to administration of one or more immune checkpoint inhibitors. In some embodiments, the compound of Formula (I) 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, 24 hours, 30 hours, 36 hours, 40 hours, 48 ​​hours, 4 days, 5 days, 6 days, or 7 days prior to administration of the one or more immune checkpoint inhibitors. In some embodiments, the compound of Formula (I) 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, 24 hours, 30 hours, 36 hours, 40 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, or more than 7 days prior to administration of the one or more immune checkpoint inhibitors.

[0133] In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I). In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) twice every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) once a week in a treatment cycle of 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) twice a week 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 co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) on days 1, 8, and 15 of a 21-day treatment cycle. In some embodiments, the co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) comprises administering one or more immune checkpoint inhibitors prior to administering plinabulin. In some embodiments, the co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) comprises administering one or more immune checkpoint inhibitors after administering plinabulin. In some embodiments, the co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) comprises administering one or more immune checkpoint inhibitors simultaneously with a compound of Formula (I). In some embodiments, the one or more immune checkpoint inhibitors described in this paragraph can independently be a first, second, third, fourth, fifth, sixth, seventh, or eighth immune checkpoint inhibitor. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) daily for one week.In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) daily for 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of Formula (I) on day 1 of weekly treatment. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and compounds of Formula (I) on days 1 and 2 of weekly treatment. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and compounds of Formula (I) on days 1, 2, and 3 of weekly treatment. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and compounds of Formula (I) on days 1, 2, and 3 of weekly treatment. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and compounds of Formula (I) on days 1, 2, 3, and 4 of weekly treatment. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and compounds of Formula (I) on days 1, 2, 3, 4, and 5 of weekly treatment. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitors and a compound of formula (I) on days 1, 2, 3, 4, 5, and 6 of weekly treatment. In some embodiments, the treatment schedule comprises co-administration of one or more immune checkpoint inhibitor compositions and a compound of formula (I) on days 1, 3, and 5 of weekly treatment. In some embodiments, the treatment cycle of the compound of formula (I) and the one or more immune checkpoint inhibitors can be the same. In other embodiments, the treatment cycle of the compound of formula (I) and the one or more immune checkpoint inhibitors can be different. For example, in some embodiments, the treatment cycle of the compound of formula (I) is 21 days, while the treatment cycle of the one or more immune checkpoint inhibitors is 14 days. In some embodiments, the one or more immune checkpoint inhibitors used on each administration day can be the same or different. In some embodiments, the one or more immune checkpoint inhibitors used on the first administration day are different from the one or more immune checkpoint inhibitors used on the remaining administration days.In some embodiments, the one or more immune checkpoint inhibitors used on the first administration day are the same as or different from the one or more immune checkpoint inhibitors used on the second administration day. In some embodiments, the one or more immune checkpoint inhibitors used on the first administration day are the same as or different from the one or more immune checkpoint inhibitors used on the third administration day. In some embodiments, the one or more immune checkpoint inhibitor compositions used on the first administration day are the same as or different from the one or more immune checkpoint inhibitors used on the fourth administration day. In some embodiments, the one or more immune checkpoint inhibitors used on the first administration day are the same as or different from the one or more immune checkpoint inhibitors used on the fifth administration day. In some embodiments, the one or more immune checkpoint inhibitors used on the first administration day are the same as or different from the one or more immune checkpoint inhibitors used on the sixth administration day. In some embodiments, the one or more immune checkpoint inhibitors used on the first administration day are the same as or different from the one or more immune checkpoint inhibitors used on the seventh administration day.

[0134] In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors (e.g., first, second, third, fourth, fifth, sixth, seventh, or eighth) once every three weeks. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors once every one, two, three, four, five, six, seven, or eight weeks. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors twice every one, two, three, four, five, six, seven, or eight weeks. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors once per week in a one, two, three, four, five, six, seven, or eight week treatment cycle. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors twice per week in a one, two, three, four, five, six, seven, or eight week treatment cycle. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors three times per week (e.g., on days 1, 2, 3, or on days 1, 3, 5) 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 administration of one or more immune checkpoint inhibitors on days 1, 8, and 15 of a 21-day treatment cycle. The one or more immune checkpoint inhibitors described in this paragraph may independently be the first, second, third, fourth, fifth, sixth, seventh, or eighth one or more immune checkpoint inhibitors. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors daily for one week. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors daily for two, three, or four weeks. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitor compositions on day 1 of weekly treatment. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors on days 1 and 2 of the weekly treatment. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors on days 1, 2, and 3 of the weekly treatment. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors on days 1, 3, and 5 of the weekly treatment. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors on days 1, 2, 3, and 4 of the weekly treatment. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors on days 1, 2, 3, 4, and 5 of the weekly treatment. In some embodiments, the treatment schedule comprises administration of one or more immune checkpoint inhibitors on days 1, 2, 3, 4, 5, and 6 of the weekly treatment.

[0135] In some embodiments, the treatment schedule comprises administration of a compound of formula (I) once every 3 weeks. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) twice every 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) once per week in a 1, 2, 3, 4, 5, 6, 7, or 8 week treatment cycle. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) twice per week in a 1, 2, 3, 4, 5, 6, 7, or 8 week treatment cycle. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) three times per week (e.g., on days 1, 2, and 3, or on days 1, 3, and 5) 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 administration of a compound of formula (I) on day 1 of a 21-day treatment cycle. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) on days 1 and 8 of a 21-day treatment cycle. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) on days 1, 8, and 15 of a 21-day treatment cycle. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) every day for one week. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) every day for two, three, or four weeks. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) on day 1 of weekly treatment. In some embodiments, the treatment schedule comprises administration of plinabulin on days 1 and 2 of weekly treatment. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) on days 1, 2, and 3 of weekly treatment. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) on days 1, 3, and 5 of weekly treatment. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) on days 1, 3, and 5 of weekly treatment. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) on days 1, 2, 3, and 4 of weekly treatment. In some embodiments, the treatment schedule comprises administration of a compound of formula (I) on days 1, 2, 3, 4, and 5 of weekly treatment. The treatment schedule comprises administration of a compound of formula (I) on days 1, 2, 3, 4, 5, and 6 of weekly treatment.

[0136] The treatment cycle can be repeated as long as the regimen is clinically tolerated. In some embodiments, the treatment cycle of one or more immune checkpoint inhibitors and the compound of formula (I) is repeated n times, where n is an integer ranging from 2 to 30. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the new treatment cycle can be performed immediately after the completion of the previous treatment cycle. In some embodiments, the new treatment cycle can be performed a certain period of time after the completion of the previous treatment cycle. In some embodiments, the new treatment cycle can be performed 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks after the completion of the previous treatment cycle.

[0137] Administration of the compositions disclosed herein can be via any accepted method of administration for agents providing similar utilities, including, but not limited to, oral, subcutaneous, buccal, subcutaneous, intravenous, intranasal, intratumoral, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, vaginal, rectal, intragastric, or intraocular. Oral and parenteral administration are conventional in the treatment of indications that are the subject of some embodiments.

[0138] In some embodiments, the compositions described herein can be used in combination with other therapeutic agents, hi some embodiments, the compositions described herein can be administered or used in combination with other treatments, such as chemotherapy, radiation, biologic therapy, etc. EXAMPLES

[0139] The following examples are included to further illustrate the present disclosure. These examples should not be interpreted as specifically limiting the present disclosure, of course. Variations of these examples within the scope of the claims are within the scope of those skilled in the art and are considered to be within the scope of the present disclosure as described and claimed herein. The reader will recognize that those skilled in the art with this disclosure and the skills of the art can prepare and use the present disclosure without the exhaustive examples.

[0140] Example 1 We conducted a phase 3 randomized, single-blind, active-controlled trial in patients with advanced or metastatic NSCLC who had progressed after 1-2 prior treatments with docetaxel-free systemic therapy regimens and / or PD-1 / PD-L1 checkpoint inhibitor therapy for advanced or metastatic disease and had at least one measurable pulmonary lesion.The trial included two treatment arms: an experimental arm (docetaxel + plinabulin [DP]) and a control arm (docetaxel + placebo [D]).

[0141] 75 mg / m2 for all patients (DP and D groups) on day 1 of a 21-day cycle. 2 Patients were treated with 10 mg of docetaxel administered by intravenous infusion (IV) over 1 hour (± 10 minutes). On days 1 and 8, patients randomized to DP received plinabulin (diluted in D5W). On days 1 and 8, patients randomized to D received D5W. Plinabulin and D5W were infused IV over 60 minutes (± 10 minutes) starting 2 hours (± 10 minutes) after the start of the docetaxel infusion on day 1 and again on day 8. Dexamethasone (16 mg, 8 mg twice daily, or IV or oral as per institution standard) was administered the day before, the day of (day 1), and the day after (day 2) the docetaxel infusion. Dexamethasone premedication was administered when docetaxel was administered. was only necessary in certain cases.

[0142] One patient in the group of patients in the DP arm who had failed treatment with a platinum doublet and 13 cycles of anti-PD-1 therapy achieved stable disease with 29 cycles (21 days per cycle). Thus, surprisingly, docetaxel + plinabulin therapy was shown to be effective even in patients who were resistant to immune checkpoint inhibitor therapy.

[0143] Example 2 In this dose-escalation phase I study, patients with extensive-stage recurrent small cell lung cancer (SCLC) that had progressed on prior platinum-based chemotherapy were enrolled using a 3+3 design. The primary objective was to determine dose-limiting toxicities (DLTs) and the recommended phase II dose (RP2D). Patients were evaluable for DLTs if they had received at least two cycles of therapy, and the DLT period was defined as the first 6 weeks. Secondary endpoints were ORR, PFS, and frequency of irAEs. Correlation analyses included inflammatory biomarkers: hsCRP, ESR, SAA, and haptoglobin. The treatment schema is shown in Table 1. [Table 1]

[0144] Patients received nivolumab (1 mg / kg), ipilimumab (3 mg / kg), and plinabulin (as per dose escalation schema) IV on day 1 of each 21-day cycle. After completing 4 cycles, patients continued therapy with nivolumab (240 mg) and plinabulin every 2 weeks until progression or unacceptable toxicity. Patients were evaluable for DLT if they had received at least 2 cycles of therapy, and the DLT period was defined as the first 6 weeks from C1D1.

[0145] Seventeen patients were enrolled (one patient withdrew consent prior to treatment, and 16 were evaluable for safety). Median age was 59 years (range 43-78 years), nine were male, and ten had received previous checkpoint inhibitor (CPI) therapy. Eight (50%) patients were treated with plinabulin at dose level 1 (20 mg / m 2) and 8 patients were treated with 30 mg / m 2 plinabulin (level 2) was administered at 10 mg / kg / day, and dose level 2 was designated the RP2D. There were 2 DLTs, 1 level 1 (grade 3 impaired consciousness lasting <24 hours) and 1 level 2 (grade 3 infusion reaction). Eight (50%) patients had at least one treatment-related AE of grade 3 or higher, but there were no treatment-related deaths. The most common treatment-related AEs (all grades) were nausea (10 patients; 63%), infusion reactions (8 patients; 50%), vomiting (7 patients; 44%), diarrhea (7 patients; 44%), and fatigue (6 patients, 32%). Seven (44%) patients had at least one treatment-related AE of grade 3 or higher, but there were no treatment-related deaths. Two (13%) patients had irAEs of grade 3 or higher requiring steroids (diarrhea in 1 patient, transaminemia in 1 patient), but both were level 1 and not level 2. At the time of data cutoff, three patients (3 / 6; 50%) had a partial response among those not previously receiving a checkpoint inhibitor (CPI), and one patient (1 / 2; 10%) had a partial response after failure of previous CPI treatment. Of the seven evaluable patients who showed disease progression, three patients had a partial response (3 / 7; 43%). These three patients continued treatment for 3 months, 5 months (still on treatment), and 18 months. In the three CPI-resistant patients, tumor shrinkage rates were 52%, 75%, and 78%. Treatment-related events are further described in Table 2. [Table 2]

[0146] Figure 1 shows a waterfall plot of best overall response in target lesions compared with baseline.

[0147] Thirteen patients were evaluable for efficacy (1 withdrew consent, 1 died from unrelated causes, 1 was replaced due to DLT); 6 patients had a PR (ORR 46%). In PD-1 / PD-L1 naive patients, there were 3 PRs (3 / 6; 50%). In PD-1 / PD-L1 resistant patients, there were 3 PRs (3 / 7; 43%). The 3 patients continued treatment for 3 months, 5 months (still on treatment), and 18 months.

[0148] High-sensitivity C-reactive protein [hsCRP], erythrocyte sedimentation rate [ESR], and serum amyloid A [SAA] levels were measured in whole blood on day 1 of each cycle. Figures 2A and 2B show plots of the mean log-transformed values ​​for each cycle. hsCRP, ESR, and SAA levels were transiently elevated around cycle 4 and then returned to baseline values.

[0149] Plinabulin in combination with nivolumab and ipilimumab was safe and well tolerated. Surprisingly, plinabulin in combination with CPI therapy was shown to be effective even in patients resistant to CPI therapy.

[0150] Example 3 This is an open-label, single-center study to evaluate the safety and tolerability of plinabulin administered in combination with a radiation / immunotherapy regimen and to assess the objective response rate of the study regimen in subjects with one of seven metastatic or locally advanced cancer types who have progressed on standard-of-care anti-PD-1 / PD-L1 mAb treatment. The seven target cancer types are: bladder cancer, melanoma, Merkel cell carcinoma, MSI-H cancer (any histology), non-small cell lung cancer, renal cell carcinoma, and small cell lung cancer.

[0151] The study cohorts were classified by tumor type. There were seven study cohorts for the seven tumor types mentioned above. The anti-PD-1 / PD-L1 mAb treatment cycle was set as the treatment cycle for the subjects in this study.

[0152] All Phase 1b subjects will receive the triple combination of RT + plinabulin + anti-PD-1 / PD-L1 mAb in cycle 1, followed by anti-PD-1 / PD-L1 mAb and plinabulin in cycles 2 and onward until disease progression or unacceptable toxicity, discontinuation of study treatment, or discontinuation of the study (see table below). Short-course local consolidation RT will be administered starting on day 1 of cycle 1. Both regimens will be administered for 2 cycles. In some eyes, optional sequential RT may be administered at the discretion of the treating physician to target other untreated disease. Plinabulin will be administered on days 1 and 4 of cycle 1 of any anti-PD-1 / PD-L1 regimen, and also on day 4 of cycle 2 if optional RT was administered in cycle 2. Plinabulin will be administered on day 1 of cycles 3 and beyond. Anti-PD-1 / PD-L1 mAbs will be administered on day 1 of all treatment cycles (and on day 15 (Q4W) for regimens containing avelumab, durvalumab, or nivolumab as the anti-PD-1 / PD-L1 mAb). Subjects must continue to receive the same anti-PD-1 / PD-L1 mAb that failed the previous treatment. [Table 3]

[0153] This study included a total dose of anti-PD-1 / PD-L1 mAb at 30 mg / m in combination with RT. 2 Start with plinabulin at 20 mg / m2, if necessary, depending on observed toxicity. 2 Dosage levels as low as 10 mg / kg / day will be considered. Doses of anti-PD-1 or PD-L1 antibodies per FDA drug inserts will not be changed in Phase 1b.

[0154] Once the minimal toxic dose (MTD) has been determined, an additional 10 patients will be enrolled to gain further insight into safety and efficacy in each of the seven tumor cohorts and to determine the recommended phase 2 dose (RP2D). The RP2D will be selected based on both safety and the overall clinical evidence (e.g., PK / PD data) and is not necessarily the MTD. Patients dosed at the MTD / RP2D in the dose setting will be rolled over into cohort expansion. Dosing of the anti-PD-1 / PD-L1 mAb will follow FDA recommendations for each indication and will not change in the expansion.

[0155] Phase 2:

[0156] Subjects with selected tumor types will be recruited to receive the MTD / RP2D of plinabulin in combination with RT and anti-PD-1 / PD-L1 mAb. The dose of anti-PD-1 / PD-L1 mAb will be as recommended by FDA and will not be changed in this study. Patients will be randomly assigned in a 1:1 ratio to one of two treatment arms. Randomization will be stratified by number of metastases (oligo (<=3 vs. >3) and ECOG 0-1 vs. 2).

[0157] Group A: Radiotherapy + Plinabulin + Anti-PD-1 / PD-L1 mAb (experimental)

[0158] Group B: Radiotherapy + anti-PD-1 / PD-L1 mAb (control)

[0159] Subjects in group A will receive the triple combination in the first cycle, and from the second cycle onwards, the dual combination of plinabulin and anti-PD-1 / PD-L1 mAb (see table below).

[0160] Subjects in arm B will receive a combination regimen of RT and anti-PD-1 / PD-L1 mAb in cycle 1, followed by anti-PD-1 / PD-L1 mAb alone from cycle 2 onwards (see table below).

[0161] Treatment will continue until disease progression, unacceptable toxicity, withdrawal from study treatment, or discontinuation from the study. Because the experimental combination arm is not expected to perform worse than the control arm, futility monitoring is not planned.

[0162] In cycle 1, short-course local consolidation RT will be administered starting on day 1. Optional continuous RT for other untreated disease will be permitted at the discretion of the treating physician (cycle 2 Q4W; cycle 2 Q3W). Based on treatment assignment, subjects will receive plinabulin on day 1 of each treatment cycle and / or anti-PD-1 / PD-L1 mAb on day 1 of each treatment cycle (and also on day 15 [Q4W] for regimens containing avelumab, durvalumab, or nivolumab as the anti-PD-1 / PD-L1 mAb).

[0163] For Phase 1b and Phase 2 subjects, toxicity will be managed by treatment interruption, dose reduction, and / or treatment cessation according to predefined dose modification instructions. [Table 4] Plinabulin marked with N / A applies only to Phase 2 Arm B and not to Arm A. Plinabulin will be administered to Arm A subjects on the dates listed in the Phase 1b / Phase 2: Investigational Products / Regimen table above.

[0164] Delivery of radiation therapy (RT) Radiation therapy is performed using external beam radiation using either 2D / conventional techniques, 3D conformal radiation therapy, intensity modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS) or proton beam therapy (PBT) at the discretion of the treating radiation oncologist.

[0165] Radiation therapy (RT) is administered in one of three regimens: 8 Gy × 3 fractions, 12.5 Gy × 4 fractions, and / or 4 Gy × 5 fractions on days 1-3 (3 fractions), 1-4 (4 fractions), or 1-5 (5 fractions) of cycle 1. The choice of RT regimen for tumor and lesion is at the discretion of the treating radiation oncologist. RT will target up to five tumor lesions, and any radiation regimen may be used simultaneously or sequentially. Optional sequential RT is at the discretion of the treating radiation oncologist and may be appropriate to target other untreated lesions with the same regimen as above (cycle 2 Q4W; cycle 2 Q3W). Treatment may also be administered to any lymph node or organ lesions, including brain and bone. At least one measurable lesion will remain untreated for disease evaluation throughout the study. However, response assessment is not dependent on tumor and bone lesions receiving RT. Brain metastases are treated and are not used in irRECIST response assessment.

[0166] If a patient develops radiation-attributable toxicity after receiving at least one radiation dose, the remaining radiation treatments may be discontinued and the AE recorded. The number of fractions ranges from 3 to 5, so patients may receive at least 1 fraction and up to 5 fractions. The first prescribed dose per fraction is not changed, but the total dose delivered may simply be reduced. Patients are seen by their radiation oncologist at the end of each cycle of radiation treatment.

[0167] PD-1 or PD-L1 Dosing: Subjects will receive the same anti-PD-1 / PD-L1 mAb treatment that failed the previous treatment. Anti-PD-1 / PD-L1 mAb will be administered according to FDA recommendations as specified for Phase 1b and Phase 2 above. Each treatment cycle of anti-PD-1 / PD-L1 mAb will be the subject's treatment cycle in this study. Here is a list of anti-PD-1 / PD-L1 mAbs approved to date for the following indications:

[0168] Merkel cell carcinoma: avelumab, pembrolizumab, renal cell carcinoma: pembrolizumab, nivolumab, bladder cancer: durvalumab, MSI-H cancer (regardless of histological type): pembrolizumab, nivolumab, non-small cell lung cancer: pembrolizumab, nivolumab, atezolizumab, durvalumab, small cell lung cancer: pembrolizumab, nivolumab, atezolizumab, melanoma: nivolumab or pembrolizumab alone.

[0169] Any approved anti-PD-1 / PD-L1 mAb may be used in this study. Dosage and route of administration of anti-PD-1 / PD-L1 mAbs: Avelumab 800 mg Q4W IV over 1 hour on days 1 and 15 Atezolizumab 1200 mg Q3W first dose IV over 1 hour, subsequent doses may be infused over 30 minutes if well tolerated Durvalumab 10 mg / kg Q4W IV over 1 hour on days 1 and 15 Nivolumab 240 mg Q4W IV over 30-60 minutes on days 1 and 15 Pembrolizumab 200 mg Q3W IV over 30 minutes. Anti-PD-1 / PD-L1 mAbs will be administered after the RT rest period (at least 3 hours, but no later than 12 hours) and before the infusion of plinabulin, if applicable. Therapeutic dosing and toxicity management for each approved anti-PD-1 or PD-L1 mAb are in accordance with the FDA product label.

[0170] Administration of plinabulin Plinabulin will be administered intravenously on days 1 and 4 of the first cycle. If optional RT is given in cycle 2, plinabulin is also given on days 1 and 4 of cycle 2. Optional RT is always given on day 1 of cycle 2. Plinabulin is always given on day 1 of cycles 3 and beyond.

[0171] Two plinabulin dose levels may be examined in the Phase 1b study: 30 mg / m 2 This plinabulin dose level will be initially tested in a Phase 1b study. If not tolerated, 20 mg / m 2The dosage will be considered.

[0172] 30 mg / m 2 For plinabulin at the dose level, a 60-minute IV infusion with a ±10-minute window is recommended. 2 For plinabulin at the dose level, a 30-minute IV infusion with a ±5-minute window is recommended. 2 For patients with >2.4 mg / kg / day, the maximum BSA of plinabulin is 2.4 mg / kg / day. 2 The dosage is calculated using:

[0173] Plinabulin is administered 1 to 2 hours (if applicable) after completion of anti-PD-1 or PD-L1 mAb infusion or at least 3 hours (but no more than 12 hours) after radiation therapy.

[0174] Safety and efficacy evaluation Safety and tolerability will be evaluated throughout the study according to NCI-CTCAE version 5.0. Vital signs, physical examination, and safety test results (blood, chemistry, and urine tests) should be obtained prior to study drug administration to ensure that the study drug is being administered safely.

[0175] Tumor assessments will be performed by the investigator based on both immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) and modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Investigator treatment decisions will be based on irRECIST.

[0176] Tumor assessments will be performed during screening and every 9 weeks (± 1 week) for 27 weeks (Q3W dosing period) or every 8 weeks (± 1 week) for 24 weeks (Q4W dosing period), and then every 12 weeks during treatment cycles of the treatment phase, regardless of treatment cycle and follow-up period. Computed tomography (CT) / magnetic resonance imaging (MRI) scans of the chest, abdomen, pelvis, and other sites of known disease will be performed at screening (within 28 days prior to Cycle 1 / Day 1), at all tumor assessment time points, and when clinically indicated. RT-treated lesions will not be used for response assessment. At least one measurable tumor lesion will be left RT-untreated for disease response assessment throughout treatment.

[0177] Subjects who discontinue treatment without disease progression will also undergo tumor evaluation according to the schedule of procedures / assessments until disease progression is documented or alternative anti-cancer therapy is initiated.

[0178] If tumor assessment at that time indicates progressive disease (PD), treatment will continue and tumors will be evaluated again at least 4 weeks later to confirm immune-mediated disease progression (irPD).

[0179] Study population: Subjects with advanced cancer who have failed or relapsed after prior standard PD-1 or PD-L1 regimens + / - chemotherapy or anti-CTLA4 for one of the following seven cancer types: non-small cell lung cancer, small cell lung cancer, renal cell carcinoma, bladder cancer, Merkel cell carcinoma, MSI-H cancer (regardless of prior history), and melanoma.

[0180] Duration of Treatment: Treatment will continue until disease progression, occurrence of unacceptable toxicity (i.e., DLT), withdrawal from study treatment, or discontinuation from this study.

[0181] Study Duration: Screening Period: Up to 28 days. Treatment Period: Study treatment will continue until disease progression (estimated 2-6 months), onset of unacceptable toxicity (i.e. DLT), withdrawal from study treatment, or discontinuation of the study. Follow-up Period: Study follow-up will consist of an end-of-treatment visit and a follow-up visit. The end-of-treatment visit will occur within 30 days of the last dose of study treatment, followed by a follow-up visit period. Follow-up visits every 12 weeks (± 1 week) will continue for as long as the subject is alive, until the subject withdraws consent or the sponsor discontinues the study. During the follow-up period, subjects who discontinue for reasons other than disease progression (and withdrawal from study treatment) will continue to visit approximately every 12 weeks for study evaluations and disease assessment by CT, MRI, or positron emission tomography (PET) / CT scans until disease progression is determined and the patient receives further antineoplastic medication, or subjects who discontinue treatment due to disease progression will be followed for vital status.

Claims

1. 1. A pharmaceutical composition for treating cancer in a subject, comprising: Compounds of formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein: R １ , R ４ , and R ６ are each independently a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C １ -C ２４ Alkyl, unsaturated C １ -C ２４ Alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, -CO-O-R ７ , cyano, alkylthio, alkyl halides including polyalkyl halides, carbonyl halides, and carbonyl-CH ２ C.O.R. ７ R is selected from the group consisting of ７ is a hydrogen atom, a halogen atom, or a saturated C １ -C ２４ Alkyl, unsaturated C １ -C ２４ selected from alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups; R １ ' and R １ " are each independently a hydrogen atom, a deuterium atom, a halogen atom, or a saturated C １ -C ２４ Alkyl, unsaturated C １ -C ２４ Alkenyl, cycloalkyl, cyclo Alkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups, hydroxy, carboxy, -CO-O-R ７ , cyano, alkylthio, alkyl halides including polyalkyl halides, carbonyl halides, and carbonyl-CH ２ C.O.R. ７ R is selected from the group consisting of ７ is a hydrogen atom, a halogen atom, or a saturated C １ -C ２４ Alkyl, unsaturated C １ -C ２４ selected from alkenyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, azido, substituted nitro, phenyl, and substituted phenyl groups; R, R １ ' and R １ " are covalently bonded to each other or are not covalently bonded to each other; R ２ , R ３ , and R ５ are each independently a hydrogen atom, a deuterium atom, a halogen atom, and a saturated C １ -C １２ Alkyl, unsaturated C １ -C １２ selected from the group consisting of alkenyl, acyl, cycloalkyl, alkoxy, cycloalkoxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, amino, substituted amino, nitro, and substituted nitro groups, sulfonyl, and substituted sulfonyl groups; m is an integer equal to zero, 1, or 2; X １ and X ２ are individually selected from the group consisting of oxygen atoms, nitrogen atoms, and sulfur atoms; and Y is NR ５ , an oxygen atom, a sulfur atom, an oxidized sulfur atom, a methylene group, and a substituted methylene group; Z (for each distinct n, if non-zero), and Z １ , Z ２ , Z ３ and Z ４ are each selected from a carbon atom, a sulfur atom, a nitrogen atom, or an oxygen atom; The dashed bond can be either a single bond or a double bond; The pharmaceutical composition, wherein the cancer is resistant to prior treatment with one or more immune checkpoint inhibitors.

2. The pharmaceutical composition of claim 1, wherein the cancer is a tumor that has been resistant to one or more immune checkpoint inhibitors.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for administration together with an additional chemotherapeutic agent.

4. The pharmaceutical composition of claim 3, wherein the additional chemotherapeutic agent is docetaxel.

5. 2. The pharmaceutical composition of claim 1, wherein the one or more immune checkpoint inhibitors to which the cancer is resistant are a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, or a combination thereof.

6. 2. The pharmaceutical composition of claim 1, wherein the one or more immune checkpoint inhibitors to which the subject was resistant are pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS-936559, durvalumab, spartalizumab, or any combination thereof.

7. 2. The pharmaceutical composition of claim 1, wherein the cancer is selected from breast cancer, bladder cancer, glioma, glioblastoma, head and neck cancer, non-small cell lung cancer, small cell lung cancer, recurrent small cell lung cancer (SCLC), colorectal cancer, gastrointestinal stromal tumor, gastroesophageal cancer, renal cell carcinoma, prostate cancer, liver cancer, colon cancer, pancreatic cancer, ovarian cancer, lymphoma or cutaneous T-cell lymphoma, metastatic melanoma, hepatocellular carcinoma, malignant pleural mesothelioma, urothelial carcinoma, esophageal cancer, Merkel cell carcinoma, endometrial cancer, basal cell carcinoma, or melanoma.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for co-administering one or more immune checkpoint inhibitors to the subject.

9. 9. The pharmaceutical composition of claim 8, wherein the co-administered one or more immune checkpoint inhibitors are pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS-936559, durvalumab, spartalizumab, or any combination thereof.

10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is for administration together with a PD-1 antibody and a CTLA-4 antibody, the PD-1 antibody being nivolumab and the CTLA-4 antibody being ipilimumab.

11. 11. The pharmaceutical composition of claim 10, wherein the nivolumab and the ipilimumab are administered on the same day every two or three weeks.

12. The compound of formula (I) is plinabulin, (3Z,6Z)-3-(phenyl-2,3,4,5,6-d ５ )-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione; (3Z,6Z)-3-(phenyl-2,3,4,5,6-d ５ )-methylene-d-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione; (3Z,6Z)-3-(phenylmethylene-d)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(phenyl-2,3,4,5,6-d ５ )-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(phenylmethylene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(phenyl-2,3,4,5,6-d ５ )-methylene-d-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(4-fluoro-(phenyl-2,3,5,6-d ４ ))-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione; (3Z,6Z)-3-(4-fluoro-(phenyl-2,3,5,6-d ４ ))-methylene-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(3-fluorobenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(3-benzoylbenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(3-(4-fluorobenzoyl)benzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine 2. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of (3Z,6Z)-3-(3-(4-methoxybenzoyl)benzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(3-methoxybenzylidene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; (3Z,6Z)-3-(3-(trifluoromethylenediene)-6-((5-(tert-butyl)-1H-imidazol-4-yl)methylene-d)piperazine-2,5-dione; and pharma- ceutically acceptable salts thereof.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the compound of formula (I) is plinabulin or a pharma- ceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 2, wherein the tumor mass is reduced by about 50% to about 100%.

15. The pharmaceutical composition of claim 14, wherein the tumor mass is reduced by about 50% to about 70%.

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