Therapeutic compositions and methods for treating treatment resistant tumors with plinabulin

Abstract

Disclosed herein are methods of treating, preventing or ameliorating a disease or condition associated with cancer or a tumor. Some embodiments relate to methods of treating, preventing, or ameliorating relapsed or refractory classical Hodgkin's lymphoma in a subject. In some embodiments, the method includes administering plinabulin to a subject in need thereof, wherein the Hodgkin's lymphoma has progressed following autologous or allogeneic stem cell transplantation and has demonstrated resistance to one or more immune checkpoint inhibitors. In certain embodiments, the method further includes co-administering an immune checkpoint inhibitor, such as a PD-1 or PD-L1 inhibitor, and optionally radiation therapy or a chemotherapeutic agent. In some embodiments, the disclosed methods result in re-sensitization to immune checkpoint inhibitors and provide durable clinical responses in subjects with limited remaining treatment options.

Description

DALWC.213WO PATENT THERAPEUTIC COMPOSITIONS AND METHODS FOR TREATING TREATMENT RESISTANT TUMORS WITH PLINABULINCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 775938, filed March 21, 2025, the content of which is incorporated by reference in its entirety.Field of the Disclosure

[0002] The present disclosure relates to the field of chemistry and medicine. More particularly, the present disclosure relates to compositions containing Plinabulin, and its use in treatment.BACKGROUND

[0003] Human cancers harbor numerous genetic and epigenetic alterations, generating neoantigens potentially recognizable by the immune system (Sjoblom et al, 2006). The adaptive immune system, comprised of T and B lymphocytes, has powerful anti-cancer potential, with a broad capacity and exquisite specificity to respond to diverse tumor antigens.

[0004] Recent cancer immunotherapy research has focused substantial effort on approaches that enhance anti-tumor immunity by mediating an adaptive immune response to relevant antigens, providing specific immune-stimulatory agents such as immune checkpoint inhibitors. While cancer remains as an incurable disease for the great majority of patients, there exists a particular need for developing 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 at a later time become unresponsive (resistant) to these checkpoint inhibitors, or may not respond to these checkpoint inhibitors from the start of their administration (‘non-responders’). Addressing resistance and non-responsiveness to immune checkpoint inhibitors is therefore an important focus of ongoing research in oncology.

[0005] In the specific context of Hodgkin’s lymphoma, stem cell transplant therapy has been a key treatment for patients with relapsed or refractory disease after standard of care chemotherapies such as Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) and Rituximab, Ifosfamide, Carboplatin, and Etoposide (RICE). However, even after undergoingautologous or allogeneic stem cell transplantation, a subset of patients continues to experience disease progression. These patients are often treated with immune checkpoint inhibitors, such as PD-1 and PD-L1 inhibitors, which can provide meaningful responses, around 8 months for median PFS. Despite this, many patients eventually relapse or fail to respond entirely to immunotherapy with limited treatment options at this stage.SUMMARY OF THE DISCLOSURE

[0006] Some aspects described herein relate to a method of treating cancer in a subject. Some embodiments relate to a method of treating treatment-resistant cancers. Some embodiments relate to a method of treating stem-cell transplant resistant cancers.

[0007] Some embodiments relate to a method of treating stem-cell transplant resistant Hodgkin’s lymphoma. Some embodiments relate to a method of treating stem-cell transplant resistant Hodgkin’s lymphoma, comprising administering an immune checkpoint inhibitor and plinabulin to a subject with disease progression following stem cell transplantation. In some embodiments, the immune checkpoint inhibitor is a PD-1 or PD-L1 inhibitor, such as nivolumab, pembrolizumab, atezolizumab or durvalumab. In some embodiments, plinabulin is administered at a dose sufficient to induce dendritic cell maturation and enhance the subject’s adaptive immune response.

[0008] Some embodiments relate to a method of re-sensitizing relapsed or refractory Hodgkin’s lymphoma patients, including those who have failed prior immune checkpoint inhibitor therapies, by co-administering plinabulin with immune checkpoint inhibitors. In some embodiments, plinabulin is administered in combination with radiation therapy to facilitate dendritic cell activation and promote anti-tumor immunity. Some embodiments relate to the treatment of patients who have undergone multiple prior lines of therapy, including autologous stem cell transplantation, and who have demonstrated resistance to standard immunotherapy regimens. In certain embodiments, disclosed combination therapies result in clinically meaningful responses, including partial responses and prolonged stable disease.

[0009] Some embodiments relate to a method of enhancing immune checkpoint inhibitor efficacy in Hodgkin’s lymphoma by administering plinabulin to patients with T-cell exhaustion or antigen-presenting cell pathway mutations. In some embodiments, the subjecthas Hodgkin’s lymphoma that is resistant to stem cell transplant therapy. Tn some embodiments, the Hodgkin’s lymphoma progressed after undergoing autologous or allogeneic stem cell transplantation. In some embodiments, the Hodgkin’s lymphoma patient does not respond to stem cell transplant therapy and continues to progress. In some embodiments, the subject has a tumor that is resistant to immune checkpoint inhibitors. In some embodiments, the subject has a stem-cell transplant resistant Hodgkin’s lymphoma. In some embodiments, the tumor progressed after treatment with one or more of immune checkpoint inhibitor therapy following stem-cell transplant therapy and other medications by the physician’s choice.

[0010] Some aspects described herein relate to methods of achieving durable tumor control in Hodgkin’s lymphoma, with responses lasting several months beyond treatment cessation. In some embodiments, plinabulin is administered in a treatment regimen alongside immune checkpoint inhibitors and radiation therapy to maximize therapeutic benefit in relapsed or refractory patient populations. In some embodiments, the method further comprises administering an immune checkpoint inhibitor in combination with plinabulin. In some embodiments, plinabulin induces dendritic cell maturation, as evidenced by upregulation of CCR7, CD80, and CD83 markers in peripheral blood, leading to improved T-cell activation. The publication by Lin et al., Plinabulin following radiation enhances dendritic cell maturation and checkpoint inhibitor retreatment of relap sed / refractory cancers, Med. 2025 Oct 10;6(10): 100752, is hereby incorporated by reference in its entirety into the present patent application.

[0011] In some embodiments, the immune checkpoint inhibitor is administered prior to or concurrently with plinabulin. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor, PD-L1 inhibitor, or a combination thereof. In some embodiments, the immune checkpoint inhibitor is pembrolizumab or nivolumab. In some embodiments, plinabulin is administered to enhance dendritic cell maturation and restore responsiveness to immune checkpoint inhibition. In some embodiments, the method further includes the administration of radiation therapy to augment dendritic cell activation and improve treatment outcomes. In some embodiments, the cancer being treated is Hodgkin’s lymphoma that is relapsed or refractory following stem cell transplantation and prior immunotherapy. In certain embodiments, the treatment regimen results in partial tumor response or prolonged stabledisease in subjects who previously failed multiple lines of therapy, including chemotherapy, stem cell transplant and checkpoint inhibitors.

[0012] Some aspects described herein relate to methods of selecting a patient for the treatment and administering the treatment. Some embodiments relate to methods of treating relapsed or refractory Hodgkin’s lymphoma in a subject selected based on clinical criteria indicating prior treatment failure. In some embodiments, the subject has previously undergone autologous or allogeneic stem cell transplantation and has demonstrated disease progression following such transplant therapy. In some embodiments, the subject has also failed prior immune checkpoint inhibitor therapy, including but not limited to PD-1 or PD-L1 inhibitors such as nivolumab, pembrolizumab, atezolizumab and durvalumab. In certain embodiments, the subject has relapsed or refractory disease after multiple prior lines of systemic therapy, which may include chemotherapy agents such as ABVD, ifosfamide, carboplatin and etoposide (ICE), RICE, or targeted agents like brentuximab vedotin and CD30 CAR-T therapy.

[0013] In some embodiments, the subject is selected based on clinical parameters that indicate a high unmet medical need, such as resistance to both stem cell transplantation and immune checkpoint inhibitors, and may exhibit T cell exhaustion or antigen-presenting cell pathway mutations. In certain embodiments, subjects are selected for treatment with a combination regimen comprising plinabulin and an immune checkpoint inhibitor, with or without radiation therapy, to enhance dendritic cell maturation and adaptive immune response. In some embodiments, selection criteria may include patients who previously demonstrated stable disease or partial response with plinabulin-based combination therapy, as evidenced by biomarker upregulation (CCR7, CD80, CD83) and early dendritic cell maturation in peripheral blood samples. In certain embodiments, this method of patient selection aims to identify those most likely to benefit from plinabulin-mediated re-sensitization to immune checkpoint blockade in the treatment of Hodgkin’s lymphoma.

[0014] In some embodiments, the method further comprises administering an additional chemotherapy agent. In some embodiments, the additional chemotherapy agent is a taxane. In some embodiments, the taxane is docetaxel. In some embodiments, the method further comprises co-administering to the subject an immune checkpoint inhibitor. In some embodiments, the co-administered one or more immune checkpoint inhibitor is a PD-1 inhibitor, PD-L1 inhibitor, or a combination thereof.

[0015] In some embodiments, one or more immune checkpoint inhibitors used according to any one of the disclosed methods is one or more of isnivolumab, pembrolizumab, cemiplimab, and pidilizumab, sasanlimab, , dostarlimab, retifanlimab, toripalimab, tislelizumab, atezolizumab, avelumab, durvalumab, cosibelimab, spartalizumab, camrelizumab, sintilimab, pidilizumab, ipilimumab, BMS 936559, INCMGA00012, KN035, AUNP12, CA-170, and BMS-986189. In some embodiments, the co-administered one or more immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, durvalumab, spartalizumab, or any combinations thereof. In some embodiments, the comprises administering a PD-1 antibody. In some embodiments, the nivolumab is administered at a range from about 100 mg to 600 mg. In some embodiments, the nivolumab is administered at a range from about 240 mg to 480 mg. In some embodiments, the co-administered one or more immune checkpoint inhibitor and plinabulin is administered during four dosing cycles. In some embodiments, the subject receives the co-administered one or more immune checkpoint inhibitor and plinabulin every 21 -days or every 28-days. In some embodiments, the method further comprises administering radiation to the subject. In some embodiments, the radiation is administered before administering plinabulin to the subject.

[0016] Some aspects relate to a method of halting or reversing progressive Hodgkin’s lymphoma in a subject. In some embodiments, the method comprises administering plinabulin or a pharmaceutically acceptable salt thereof to a subject who was resistant to prior treatment with one or more immune checkpoint inhibitors. In some embodiments, the immune checkpoint inhibitors include PD-1 inhibitors, such as nivolumab or pembrolizumab, or PD-L1 inhibitors. In some embodiments, the method further comprises administering an additional therapeutic agent, such as chemotherapy or radiation therapy, to enhance the anti-tumor immune response.

[0017] In some embodiments, the method comprises administering a PD-1 or PD-L1 inhibitor in combination with plinabulin to the subject. In some embodiments, the progressive disease is a relapsed or refractory Hodgkin’s lymphoma tumor. In some embodiments, administration of the therapeutic regimen results in a reduction of tumor mass from about 50% to about 100%. In some embodiments, tumor mass reduction ranges from about 50% to about 70%. In some embodiments, radiation therapy is administered before theadministration of plinabulin, while in other embodiments, radiation is administered after plinabulin. In certain embodiments, plinabulin is administered as a single dose following radiation therapy. In other embodiments, plinabulin is administered in two or more doses after radiation therapy.BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 shows a series of three PET scans demonstrating the progression of disease response in a patient

[0019] FIG. 2 shows a series of two PET scans demonstrating the progression of disease response in a patientDETAILED DESCRIPTION

[0020] The present disclosure provides method and therapeutic compositions for reversing non-response or enhancing response to cancer treatment. Hodgkin’ s lymphoma (HL) is a malignancy of the lymphatic system that often responds to initial chemotherapy and autologous stem cell transplantation (autoSCT). However, a significant subset of patients relapses after transplant or fail to respond. For these relapsed / refractory (R / R) HL patients, PD-1 immune checkpoint inhibitors, such as nivolumab or pembrolizumab, represent standard therapies. Nonetheless, a portion of patients exhibit primary resistance (non-responders) or develop acquired resistance after initial response. Following failure of stem cell transplantation and immune checkpoint inhibition, treatment options are limited, and durable clinical responses are rare.

[0021] For patients with relapsed or refractory Hodgkin’s lymphoma (R / R cHL), particularly those who have progressed following autologous stem cell transplantation (autoSCT) and immune checkpoint inhibitor therapy, treatment options have been highly limited. After failure of standard frontline chemotherapy regimens such as Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) names as above) and salvage therapies like ICE (Ifosfamide, Carboplatin, and Etoposide) or RICE (Rituximab, Ifosfamide, Carboplatin, and Etoposide), autologous stem cell transplantation (autoSCT) is typically pursued. While many patients achieve remission with autoSCT, a significant proportion will experience relapse. For these patients, PD-1 and PD-L1 immune checkpoint inhibitors, such as nivolumab,pembrolizumab, atezolizumab and durvalumab, have become a standard approach due to their activity in Hodgkin’s lymphoma, which often expresses high levels of PD-L1. However, not all patients respond to checkpoint blockade, and some who initially respond eventually develop resistance or relapse.

[0022] Following failure of both transplant and checkpoint inhibitors, the treatment landscape becomes more challenging. Options are often limited to targeted therapies like brentuximab vedotin (anti-CD30 antibody-drug conjugate), CD30-directed CAR-T therapies, or investigational agents in clinical trials. Patients may also receive additional lines of chemotherapy (such as gemcitabine-based regimens or bendamustine), mTOR inhibitors (e.g., everolimus), histone deacetylase inhibitors (e.g., vorinostat), or kinase inhibitors like HMPL-523. For heavily pretreated patients, particularly those who have received more than 10 prior lines of therapy, prognosis is poor, and treatment options are limited.

[0023] Patients who have progressed after treatment with PD-1 or PD-L1 immune checkpoint inhibitors face very limited treatment options. The current standard of care for these patients without targetable genetic alterations is chemotherapy (such as docetaxel chemotherapy), either alone or in combination with other agents. However, despite widespread use, docetaxel chemotherapy, for example, provides modest clinical benefits. Multiple phase 3 clinical trials, including those evaluating combinations of antibody-drug conjugates (ADCs), PD-1 or PD-L1 inhibitors with tyrosine kinase inhibitors (TKIs), have failed to demonstrate an overall survival benefit superior to that of docetaxel. Notably, there has been no new drug approval in over a decade for patient’s with, for example NSCLC, who have progressed after treatment .

[0024] For patients who have progressed following immune checkpoint inhibitors, clinical outcomes are generally poor. For example, for NSCLC, the TROPION Lung-01 phase 3 study showed an overall response rate (ORR) of only 12.8% and a median progression-free survival (mPFS) of 3.7 months when docetaxel was used. Even in patients who had initially derived clinical benefit from prior anti-PD-l / PD-Ll therapy (defined as progression-free survival of three months or more), the combination of Keytruda (pembrolizumab) and docetaxel resulted in a median progression-free survival of just 5.5 months and an ORR of 23.5%. These statistics underscore the significant unmet medical need for more effective treatment strategies in this and other heavily pretreated patient population. Resistancemechanisms, such as T cell exhaustion and mutations in antigen-presenting cell pathways, further complicate treatment and highlight the need for novel approaches.

[0025] The present disclosure provides methods for treating stem cell transplant resistant Hodgkin’s lymphoma. In some embodiments, the methods comprise administering plinabulin and an immune checkpoint inhibitor to a subject with Hodgkin’s lymphoma that has relapsed or progressed following autologous or allogeneic stem cell transplant therapy. In certain embodiments, the immune checkpoint inhibitor is a PD-1 or PD-L1 inhibitor, such as nivolumab or pembrolizumab. In some embodiments, the method further comprises administering radiation therapy to the subject.

[0026] In some embodiments, the subject is selected based on resistance to one or more immune checkpoint inhibitors, having shown disease progression following treatment with agents such as nivolumab or pembrolizumab. In certain embodiments, the subject has undergone three, four, five, six, seven, eight, nine, or more than ten prior lines of therapy and demonstrates a high unmet medical need. In some embodiments, treatment with plinabulin results in re-sensitization to checkpoint inhibitors, providing durable responses, including partial response (PR), immune-related partial response (irPR), or stable disease (SD).

[0027] Some aspects relate to methods of treating patients with cancer who have progressed following treatment with prior immune checkpoint inhibitors targeting PD-1 or PD-L1. In some embodiments, the method addresses patients who have received two or more lines of systemic therapy (2L / 3L) and exhibit acquired resistance to immune checkpoint blockade. In certain embodiments, the resistance is associated with mechanisms such as T cell exhaustion or mutations in the antigen-presenting cell pathways, which compromise immune recognition and limit the effectiveness of PD-1 / PD-L1 inhibitors.

[0028] In some embodiments, the treatment involves administering plinabulin in combination with a PD-1 orPD-Ll inhibitor and optionally with chemotherapy agents. In some embodiments, this regimen is designed to overcome immune resistance by enhancing dendritic cell maturation and promoting T cell activation, thus improving immune response against tumor cells. The use of plinabulin may extend progression-free survival (PFS) and increase overall response rates (ORR) compared to standard-of-care treatments, that have historically shown limited efficacy. In certain embodiments, the combined regimen aims to provide clinically meaningful responses in a patient population with few remaining therapeutic options.

[0029] Before the present disclosure is further described, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. Methods recited herein may be carried out in any order of the recited events which is logically possible, as well as the recited order of events.

[0030] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit 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.

[0031] All publications mentioned herein are incorporated herein 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 is to be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0032] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.Definitions

[0033] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which thisdisclosure belongs. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0034] 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 materials.

[0035] The term “antagonist” as used herein refers to a compound that can combine with a receptor (e.g., an immune checkpoint receptor) to block a cellular activity. An antagonist may be a ligand that directly binds to the receptor. Alternatively, an antagonist may combine with a receptor indirectly by, for example, (a) forming a complex with another molecule that directly binds to the receptor, or (b) otherwise results in the modification of another compound so that the other compound directly binds to the receptor.

[0036] The term “ameliorate” as used herein refers to any reduction in the extent, severity, frequency, and / or likelihood of a symptom or clinical sign characteristic of a particular condition.

[0037] The term “antibody” or “antibody moiety” is intended to include any polypeptide chain-containing molecular structure with a specific shape that fits to and recognizes an epitope, where one or more non-covalent binding interactions stabilize the complex between the molecular structure and the epitope. Antibodies utilized in the present disclosure may be polyclonal antibodies or monoclonal antibodies. Antibodies also include free antibodies and antigen binding fragments derived therefrom, and conjugates, e.g. pegylated antibodies, drug, radioisotope, or toxin conjugates, and the like. Monoclonal antibodies directed against a specific epitope, or combination of epitopes, will allow for the targeting and / or depletion of cellular populations expressing the marker. Various techniques can be utilized using monoclonal antibodies to screen for cellular populations expressing the marker(s), and include magnetic separation using antibody-coated magnetic beads, “panning” with antibody 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 the screening of particular populations of cells; in immunohistochemistry of biopsy samples; in detecting the presence of markers shed by cancer cells into the blood and other biologic fluids, and the like. Humanized versions of such antibodies are also within the scope of this disclosure.Humanized antibodies are especially useful for in vivo applications in humans due to their low antigenicity.

[0038] The terms “cancer”, “neoplasm”, and “carcinoma”, are used interchangeably herein to refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. Detection of cancerous cells is of particular interest.

[0039] The term “immune checkpoint inhibitor” as used herein refers to a molecule (e.g., small molecule, peptide, polypeptide, protein, antibody, antibody fragment and the like) that acts as an inhibitor (antagonist) of an immune checkpoint pathway. Inhibition of a pathway can include blockade of the pathway through binding to a receptor or signaling molecule that is part of the immune checkpoint pathway.

[0040] The term “polypeptide” is used herein as a generic term to refer to native protein, fragments, or analogs of a polypeptide sequence. Hence, native protein fragments, and analogs are species of the polypeptide genus.

[0041] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants such as are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e g., 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 can be a monosaccharide or monosaccharide derivative.

[0042] The term “subject” as used herein, means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0043] The term “mammal” is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rodents, rats, mice, guinea pigs, or the like.

[0044] The terms “effective amount” or a “therapeutically effective amount” as used herein refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and can include curing a disease or condition.

[0045] The terms “treat,” “treatment,” or “treating,” as used herein refers to administering a compound or pharmaceutical composition to a subject for prophylactic and / or therapeutic purposes. The term “prophylactic treatment” refers to treating a subject who does not yet exhibit symptoms of a disease or condition, but who is susceptible to, or otherwise at risk of, a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term “therapeutic treatment” refers to administering treatment to a subject already suffering from a disease or condition.

[0046] As used herein, the term “chemotherapeutic agent” refers to an agent that reduces, prevents, mitigates, limits, and / or delays the growth of metastases or neoplasms, or kills neoplastic cells directly by necrosis or apoptosis of neoplasms or any other mechanism, or that can be otherwise used, in a pharmaceutically-effective amount, to reduce, prevent, mitigate, limit, and / or delay the growth of metastases or neoplasms in a subject with neoplastic disease. Chemotherapeutic agents include but are not limited to, for example, fluoropyrimidines; pyrimidine nucleosides; purine nucleosides; anti-folates, platinum-based agents; anthracyclines / anthracenediones; epipodophyllotoxins; camptothecins; hormones; hormonal complexes; antihormonals; enzymes, proteins, peptides and polyclonal and / or monoclonal antibodies; vinca alkaloids; taxanes; epothilones; antimicrotubule agents; alkylating agents; antimetabolites; topoisomerase inhibitors; antivirals; and various other cytotoxic and cytostatic agents.Compounds

[0047] In some embodiments, the compounds and therapeutic compositions for treating cancer or tumor described herein include plinabulin. In some embodiments, thecompound is plinabulin monohydrate. Tn some embodiments, the compound is a salt form of plinabulin. In some embodiments, the compound is a deuterated form of plinabulin.Immune Checkpoint Inhibitors

[0048] In some embodiments, one or more immune checkpoint inhibitor may be co-administered with plinabulin. A review describing immune checkpoint pathways and the blockade of such pathways with 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 check point inhibitor compounds display anti-tumor activity by blocking one or more of the endogenous immune checkpoint pathways that downregulate an anti-tumor immune response. The inhibition or blockade of an immune checkpoint pathway typically involves inhibiting a checkpoint receptor and ligand interaction with an immune checkpoint inhibitor compound to reduce or eliminate the down regulation signal and resulting diminishment of the anti-tumor response.

[0049] In some embodiments of the present disclosure, the immune checkpoint inhibitor compound inhibits the signaling interaction between an immune checkpoint receptor and the corresponding ligand of the immune checkpoint receptor. The immune checkpoint inhibitor compound can act by blocking activation of the immune checkpoint pathway by inhibition (antagonism) of an immune checkpoint receptor (some examples of receptors include CTLA-4, PD-1, LAG-3, TIM-3, BTLA, and KIR) or by inhibition of a ligand of an immune checkpoint receptor (some examples of ligands include PD-L1 and PD-L2). In such embodiments, the effect of the immune checkpoint inhibitor compound is to reduce or eliminate down regulation of certain aspects of the immune system anti-tumor response in the tumor microenvironment.

[0050] Methods for the preparation and use of immune checkpoint antibodies are described in the following illustrative publications. The preparation and therapeutic uses of anti-CTLA-4 antibodies are described in U.S. Pat. No. 7,229,628 (Allison), U.S. Pat. No.7,311,910 (Linsley), and U.S. Pat. No. 8,017,144 (Korman), which are incorporated herein by reference in their entirety. The preparation and therapeutic uses of anti -PD-1 antibodies are described in U.S. Pat. No. 8,008,449 (Korman) and U.S. Patent Application No. 2011 / 0271358 (Freeman), which are incorporated herein by reference in their entirety. The preparation andtherapeutic uses of anti-PD-Ll antibodies are described in U.S. Pat. No. 7,943,743 (Korman), which is incorporated herein by reference in its entirety. The preparation and therapeutic uses of anti-TIM-3 antibodies are described in U.S. Pat. No. 8,101,176 (Kuchroo) and U.S. Pat. No.8,552,156 (Tagayanagi), which are incorporated herein by reference in their entirety. The preparation and therapeutic uses of anti -LAG-3 antibodies are described in U.S. Patent Application No. 2011 / 0150892 (Thudium) and International Publication Number W02014 / 008218 (Lonberg), which are incorporated herein by reference in their entirety. The preparation and therapeutic uses of anti-KIR antibodies are described in U.S. Pat. No.8,119,775 (Moretta), which is incorporated herein by reference in its entirety. The preparation of antibodies that block BTLA regulated inhibitory pathways (anti-BTLA antibodies) are described in U.S. Pat. No. 8,563,694 (Mataraza), which is incorporated herein by reference in its entirety.

[0051] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, durvalumab, spartalizumab, or any combinations thereof. In some embodiments, the one or more immune checkpoint inhibitor may include an anti-PD-1 HuMAbs can be selected from 17D8, 2D3, 4H1, 5C4 (also referred to herein as nivolumab), 4A1 1, 7D3 and 5F4, all of which are described in U.S. Pat. No. 8,008,449, which is incorporated herein by reference in its entirety. In some embodiments, the anti-PD-1 HuMAbs can be selected from 3G10, 12A4 (also referred to herein as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 1 1E6, 12B7, and 13G4, all of which are described in U.S. Pat. No. 7,943,743, which is incorporated herein by reference in its entirety.

[0052] In some embodiments, the immune checkpoint inhibitor is one or more of a PD-1 and PD-L1 inhibitor in late-stage clinical development. Non-limiting examples include spartalizumab (PDR001), which is in Phase III trials for solid tumors and lymphomas, and camrelizumab (SHR1210), Sintilimab (IB 1308) is in Phase III trials, Vopratelimab (JTX-4014) is in Phase I trials, INCMGA00012 (MGA012), KNO35, a PD-L1 antibody with a subcutaneous formulation. AUNP12, a peptide PD-1 / PD-L1 inhibitor, is in clinical trials. CA-170, a PD-L1 and VISTA antagonist, is in Phase I trials for mesothelioma patients. Finally, BMS-986189,

[0053] The precise amount of immune checkpoint inhibitor compound incorporated in a particular method or therapeutic combination of the disclosure may vary according to factors known in art such as for example, the physical and clinical status of the subject, the method of administration, the content of the formulation, the physical and chemical nature of the immune checkpoint inhibitor compound, the intended dosing regimen or sequence. Those of ordinary skill in the art, however, can readily determine the appropriate amount with due consideration of such factors.Chemotherapeutic Agents

[0054] In some embodiments, plinabulin is co-administered with an additional chemotherapeutic agent. In some embodiments, an additional chemotherapeutic agent can be selected from the group consisting of Abiraterone, Acetate, Abitrexate (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), Akynzeo (Netupitant and Palonosetron Hydrochloride), Aldara (Imiquimod), Aldesleukin, Alecensa (Alectinib), Alectinib, Alemtuzumab, Alimta (Pemetrexed Disodium), Aloxi (Palonosetron Hydrochloride), Ambochlorin (Chlorambucil), Amboclorin (Chlorambucil), Aminolevulinic Acid, \ Anastrozole, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic Trioxide, Arzerra (Ofatumumab), Asparaginase Erwinia chrysanthemi, Avastin (Bevacizumab), Axitinib, Azacitidine, BEACOPP, Becenum (Carmustine), Beleodaq (Belinostat), Belinostat, Bendamustine Hydrochloride, BEP, Bevacizumab, Bexarotene, Bexxar (Tositumomab and Iodine I 131 Tositumomab), Bicalutamide, BiCNU (Carmustine), Bleomycin, Blinatumomab, Blincyto (Blinatumomab), Bortezomib, Bosulif (Bosutinib), Bosutinib, Brentuximab Vedotin, Busulfan, Cabazitaxel, Cabozantinib-S-Malate, CAF, Campath (Alemtuzumab), Camptosar (Irinotecan Hydrochloride), Capecitabine, CAPOX, Carac (Fluorouracil— Topical), Carboplatin, CARBOPLATIN-TAXOL, Carfilzomib, Carmubris (Carmustine), Carmustine, Carmustine Implant, Casodex (Bicalutamide), CeeNU (Lomustine), Ceritinib, Cerubidine (Daunorubicin Hydrochloride), Cervarix (Recombinant HPV Bivalent Vaccine), Cetuximab, Chlorambucil, CHLORAMBUCIL-PREDNISONE, CHOP, Cisplatin, Clafen(Cyclophosphamide), Clofarabine, Clofarex (Clofarabine), Clolar (Clofarabine), CMF, Cobimetinib, Cometriq (Cabozantinib-S-Malate), COPDAC, COPP, COPP -ABV, Cosmegen (Dactinomycin), Cotellic (Cobimetinib), Crizotinib, CVP, Cyclophosphamide, Cyfos (Ifosfamide), Cyramza (Ramucirumab), Cytarabine, Cytarabine Liposome, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide), Dabrafenib, Dacarbazine, Dacogen (Decitabine), 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), Elitek (Rasburicase), Ellence (Epirubicin Hydrochloride), Elotuzumab, Eloxatin (Oxaliplatin), Eltrombopag Olamine, Emend (Aprepitant), Empliciti (Elotuzumab), Enzalutamide, Epirubicin Hydrochloride, EPOCH, Erbitux (Cetuximab), Eribulin Mesylate, Erivedge (Vismodegib), Erlotinib Hydrochloride, Erwinaze (Asparaginase Erwinia chrysanthemi), Etopophos (Etoposide Phosphate), Etoposide, Etoposide Phosphate, Evacet (Doxorubicin Hydrochloride Liposome), Everolimus, Evista (Raloxifene Hydrochloride), Exemestane, 5-FU (Fluorouracil Injection), 5-FU (Fluorouracil-Topical), Fareston (Toremifene), Farydak (Panobinostat), Faslodex (Fulvestrant), FEC, Femara (Letrozole), Filgrastim, Fludara (Fludarabine Phosphate), Fludarabine Phosphate, Fluoroplex (Fluorouracil— Topical), Fluorouracil Injection, Fluorouracil — Topical, Flutamide, Folex (Methotrexate), Folex PF S (Methotrexate), FOLFIRI, FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, Folotyn (Pralatrexate), FU-LV, Fulvestrant, Gardasil (Recombinant HPV Quadrivalent Vaccine), Gardasil 9 (Recombinant HPV Nonavalent 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 (Carmustine Implant), Glucarpidase, Goserelin Acetate, Halaven (Eribulin Mesylate), Herceptin (Trastuzumab), HPV Bivalent Vaccine, Recombinant, HPV Nonavalent Vaccine, Recombinant, HPV Quadrivalent Vaccine, Recombinant, Hycamtin (Topotecan Hydrochloride), Hyper-CVAD, Ibrance (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE, Iclusig (Ponatinib Hydrochloride),Idamycin (Idarubicin Hydrochloride), Idelalisib, Ifex (Ifosfamide), Ifosfamide, IL-2 (Aldesleukin), Imatinib Mesylate, Imbruvica (Ibrutinib), Imiquimod, Imlygic (Talimogene Laherparepvec), Inlyta (Axitinib), Interferon Alfa-2b, Recombinant, Interleukin-2 (Aldesleukin), Intron A (Recombinant Interferon Alfa-2b), Iodine I 131 Tositumomab and Tositumomab, Iressa (Gefitinib), Irinotecan Hydrochloride, Irinotecan Hydrochloride Liposome, Istodax (Romidepsin), Ixabepilone, Ixazomib Citrate, Ixempra (Ixabepilone), Jakafi (Ruxolitinib Phosphate), Jevtana (Cabazitaxel), Kadcyla (Ado-Trastuzumab Emtansine), Keoxifene (Raloxifene Hydrochloride), Kepivance (Palifermin), Kyprolis (Carfilzomib), Lanreotide Acetate, Lapatinib Ditosylate, Lenalidomide, Lenvatinib Mesylate, Lenvima (Lenvatinib Mesylate), Letrozole, Leucovorin Calcium, Leukeran (Chlorambucil), Leuprolide Acetate, Levulan (Aminolevulinic Acid), Linfolizin (Chlorambucil), LipoDox (Doxorubicin Hydrochloride Liposome), Lomustine, Lonsurf (Trifluridine and Tipiracil Hydrochloride), Lupron (Leuprolide Acetate) ,Lupron Depot (Leuprolide Acetate), Lupron Depot-Ped (Leuprolide Acetate), Lupron Depot-3 Month (Leuprolide Acetate), Lupron Depot-4 Month (Leuprolide Acetate), Lynparza (Olaparib), Marqibo (Vincristine Sulfate Liposome), Matulane (Procarbazine Hydrochloride), Mechlorethamine Hydrochloride, Megace (Megestrol Acetate), Megestrol Acetate, Mekinist (Trametinib), Mercaptopurine, Mesna, Mesnex (Mesna), Methazolastone (Temozolomide), Methotrexate, Methotrexate LPF (Methotrexate), Mexate (Methotrexate), Mexate-AQ (Methotrexate), Mitomycin C, Mitoxantrone Hydrochloride, Mitozytrex (Mitomycin C), MOPP,Mozobil (Plerixafor), Mustargen (Mechlorethamine Hydrochloride), Mutamycin (Mitomycin C), Myleran (Busulfan), Mylosar (Azacitidine), Mylotarg (Gemtuzumab Ozogamicin), Nanoparticle Paclitaxel (Paclitaxel Albumin-stabilized Nanoparticle Formulation), Navelbine (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 (Pegaspargase), Ondansetron Hydrochloride, Onivyde (Irinotecan Hydrochloride Liposome), Ontak (Denileukin Diftitox), OPP A, Osimertinib, Oxaliplatin, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation, PAD, Palbociclib, Palifermin, Palonosetron Hydrochloride, Palonosetron Hydrochloride and Netupitant,Pamidronate Disodium, Panitumumab, Panobinostat, Paraplat (Carbopl atin), Paraplatin (Carboplatin), Pazopanib Hydrochloride, PCV, Pegaspargase, Peginterferon Alfa-2b, PEG-Intron (Peginterferon Alfa-2b), Pemetrexed Disodium Peijeta (Pertuzumab), Pertuzumab, Platinol (Cisplatin), Platinol-AQ (Cisplatin), Plerixafor, Pomalidomide, Pomalyst (Pomalidomide), Ponatinib Hydrochloride, Portrazza (Necitumumab), Pralatrexate, Prednisone, Procarbazine Hydrochloride, Proleukin (Aldesleukin), Prolia (Denosumab), Promacta (Eltrombopag Olamine), Provenge (Sipuleucel-T), Purinethol (Mercaptopurine), Purixan (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 Alfa-2b, Regorafenib, R-EPOCH, Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituximab, Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubidomycin (Daunorubicin Hydrochloride), Ruxolitinib Phosphate, Sclerosol Intrapleural Aerosol (Talc),Siltuximab, 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), Sylatron (Peginterferon Alfa- 2b), Sylvant (Siltuximab), Synovir (Thalidomide), Synribo (Omacetaxine Mepesuccinate), Tabloid (Thioguanine), TAC, Tafmlar (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 I 131, Tositumomab, Totect (Dexrazoxane Hydrochloride), TPF, Trabectedin, Trametinib, Trastuzumab, Treanda (Bendamustine Hydrochloride), Trifluridine and Tipiracil Hydrochloride, Trisenox (Arsenic Trioxide), Tykerb (Lapatinib Ditosylate), Unituxin (Dinutuximab), Uridine Triacetate, VAC, Vandetanib, VAMP, Varubi (Rolapitant Hydrochloride), Vectibix (Panitumumab), VelP, Velban (Vinblastine Sulfate), Velcade (Bortezomib), Velsar (Vinblastine Sulfate), Vemurafenib, VePesid (Etoposide), Viadur (Leuprolide Acetate), Vidaza (Azacitidine), Vinblastine Sulfate, Vincasar PFS (VincristineSulfate), Vincristine Sulfate, Vincristine Sulfate Liposome, Vinorelbine Tartrate, VIP, Vismodegib, Vistogard (Uridine Triacetate), Voraxaze (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), Zarxio (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 (Idelali sib), Zykadia (Ceritinib), and Zytiga (Abiraterone Acetate).

[0055] In some embodiments, the additional chemotherapeutic agent is docetaxel.Radiation Therapy

[0056] In some embodiments, the plinabulin is co-administered with radiation. In some embodiments, the radiation may be selected from external beam radiation therapy or internal radiation therapy. In some embodiments, the external beam radiation therapy may 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 may be selected from intraoperative radiation therapy (IORT), systemic radiation therapy, radioimmunotherapy, radiosensitizers, radioprotectors, or a combination thereof.Use and Method of Treatment

[0057] In aspects, the present disclosure provides methods for treating relapsed or refractory classical Hodgkin’s lymphoma (R / R cHL) in subjects who have demonstrated resistance to stem cell transplantation and / or prior immune checkpoint inhibitor therapy. In some embodiments, the method comprises administering plinabulin, or a pharmaceutically acceptable salt thereof, to a subject who has exhibited disease progression following autologous or allogeneic stem cell transplantation, immune checkpoint inhibition, or both. In certain embodiments, the immune checkpoint inhibitors include PD-1 inhibitors, such as nivolumab or pembrolizumab. In other embodiments, the method includes the administration of additional therapies such as radiation and / or chemotherapeutic agents.

[0058] In some embodiments, the method comprises administering a therapeutically effective amount of plinabulin to a subject having exhibited resistance to an immune checkpoint inhibitor selected from the group consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, or combinations thereof. In certain embodiments, the immune checkpoint inhibitors include, but are not limited to, nivolumab, pembrolizumab, cemiplimab, ipilimumab, and durvalumab. In some embodiments, plinabulin is administered after the failure of treatment with two or more immune checkpoint inhibitors, including combinations such as nivolumab and ipilimumab.

[0059] In some embodiments, the method comprises co-administering plinabulin with an immune checkpoint inhibitor and radiation therapy. In certain embodiments, radiation is administered locally to a tumor site (e.g., 20 Gy in five fractions) to enhance antigen presentation and dendritic cell activation. In other embodiments, plinabulin is administered before or after each radiation fraction, for example, within 1 hour, 1 day, or 3 days of radiation. In some embodiments, plinabulin is administered on the same day as immune checkpoint inhibition and / or radiation therapy.

[0060] In some embodiments, the method includes co-administering plinabulin with additional chemotherapeutic agents, such as a taxane. In some embodiments, the taxane is docetaxel. In other embodiments, plinabulin is administered after prior chemotherapy or concurrent with chemotherapy and / or radiation therapy. In certain embodiments, plinabulin is administered at a dose ranging from about 13.5 mg / m2to about 30 mg / m2on Day 1 of a 21-day cycle. In some embodiments, plinabulin is administered as part of a multi-cycle regimen that may include one or more immune checkpoint inhibitors and radiation therapy.

[0061] In some embodiments, treatment with plinabulin, either alone or in combination with immune checkpoint inhibitors and / or radiation, results in partial response (PR), immune-related partial response (irPR), or stable disease (SD) in subjects who have otherwise exhausted standard treatment options. In certain embodiments, the duration of response is at least 19 months, 23 months, or longer.

[0062] Aspects of the disclosure relate to treatment protocols for patients with Hodgkin's lymphoma who have relapsed following prior therapies. In some embodiments, a combination treatment may be used where plinabulin is administered intravenously in conjunction with immune checkpoint inhibitors (ICIs), including PD-1 or PD-L1 monoclonalantibodies. These ICTs can be administered according to their established dosing instructions, with allowance for subcutaneous delivery where appropriate for PD-1 or PD-L1 monoclonal antibodies. The treatment regimens disclosed herein are designed to assess and improve safety, tolerability, and overall response rates (ORR) in this patient population.

[0063] In some embodiments, the combination treatment protocol consists of radiation therapy (RT), plinabulin, and an ICI. For ICIs administered on a 4-week cycle (Q4W), such as Nivolumab, Durvalumab, or Avelumab, one treatment cycle consists of four weeks. In some embodiments, one treatment cycle consists of three weeks. In some embodiments, the treatment cycle may be any duration of weeks sufficient to complete one cycle of therapy.

[0064] In some embodiments, radiation therapy (RT) is delivered at the beginning of Cycle 1, on either Days 1 through 3 (8 Gy x 3 fractions), Days 1 through 4 (12.5 Gy x 4 fractions), or Days 1 through 5 (4 Gy x 5 fractions). In some embodiments, radiation therapy is delivered at the beginning of any of Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15. Iln some embodiments, radiation therapy is delivered during any of Cycle 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15. In some embodiments, the radiation therapy is any one of once, twice, three times, four times, five times, or any more times as recommended by a doctor.

[0065] In some embodiments, Plinabulin is administered intravenously at a dose of 30 mg / m2on Cycle 1 Day 1 (C1D1) and Day 4 (C1D4), with subsequent doses on Cycle 2 Day 1 and Day 4, if optional RT is administered on Cycle 2 Day 1. In some embodiments, from Cycle 3 onward, plinabulin is administered on Day 1 of each cycle. In some embodiments, Nivolumab is administered intravenously at 240 mg over 30-60 minutes on Day 1 and Day 15 of each 4-week cycle. In some embodiments, Durvalumab is administered at 10 mg / kg intravenously over one hour on Day 1 and Day 15 of each 4-week cycle, or Avelumab is administered at 800 mg intravenously over one hour on Day 1 and Day 15 of each 4-week cycle.

[0066] In some embodiments, one or more ICIs are administered on a 3-week cycle (Q3W), such as the nonlimiting examples of Pembrolizumab or Atezolizumab, where each treatment cycle is typically three weeks in duration. In some embodiments, RT is delivered at the beginning of Cycle 1 on Days 1 through 3 (8 Gy x 3 fractions), Days 1 through 4 (12.5 Gy x 4 fractions), or Days 1 through 5 (4 Gy x 5 fractions). In some embodiments, Plinabulin isadministered intravenously at 30 mg / m2on Cycle 1 , Day 1 (Cycle #, Day # C1D1) and C1D4, and again on C2D1 and C2D4 if optional RT is delivered on C2D1. In some embodiments, from Cycle 3 onward, plinabulin is given on Day 1 of each cycle. Pembrolizumab is administered intravenously at 200 mg over 30 minutes on Day 1 of each 3-week cycle. In some embodiments, Atezolizumab is administered intravenously at 1200 mg over one hour for the first dose; if well -tolerated, subsequent doses may be administered over 30 minutes on Day 1 of each 3-week cycle.

[0067] The disclosed treatment regimens are designed to improve anti-tumor efficacy through the synergistic effects of plinabulin, radiation therapy, and checkpoint inhibition.Patient Selection

[0068] In aspects, the present disclosure provides methods for selecting patients with relapsed or refractory classical Hodgkin’s lymphoma who are candidates for treatment with plinabulin in combination with immune checkpoint inhibitors and / or radiation therapy. In some embodiments, the method includes identifying a subject who has relapsed following autologous or allogeneic stem cell transplantation. In other embodiments, the subject has previously failed treatment with immune checkpoint inhibitors, including but not limited to PD-1 inhibitors (e.g., nivolumab, pembrolizumab), and PD-L1 inhibitors.

[0069] In certain embodiments, the subject has received multiple prior lines of systemic therapy, including but not limited to chemotherapy regimens such as ABVD, ICE, RICE, targeted therapies including brentuximab vedotin and CD30 CAR-T cells, and other investigational agents (e.g., HMPL-523, AZD 4573). In some embodiments, the subject has undergone at least 10, 12, or more prior lines of therapy.

[0070] In some embodiments, the subject is identified based on clinical features indicative of T cell exhaustion or antigen-presenting cell pathway mutations. In certain embodiments, the patient’s tumor exhibits biomarkers predictive of immune resistance, such as low dendritic cell maturation markers or evidence of acquired resistance to prior immunotherapies.

[0071] In some embodiments, subjects may be selected based on radiographic or PET imaging showing progression of disease despite prior immune checkpoint inhibitortherapy. In other embodiments, subjects may have demonstrated stable disease or partial response during treatment with plinabulin-containing regimens in previous cycles.

[0072] In certain embodiments, patients are selected for treatment if they exhibit relapsed or refractory Hodgkin’s lymphoma with active disease in non-irradiated tumor sites, where combination therapy with plinabulin and radiation has shown evidence of systemic immune reactivation.

[0073] In some embodiments, patients with no remaining standard therapeutic options, or who have declined further chemotherapy or stem cell transplant procedures, are identified as candidates for treatment with plinabulin and combination regimens disclosed herein.Administration

[0074] Administration of the pharmaceutical compositions described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, sublingually, buccally, subcutaneously, intravenously, intranasally, intratumorally, topically, transdermally, intradermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.

[0075] The compositions described herein may be provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of a compound or composition that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, although a single administration is not specifically excluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0076] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, sublingual, buccal, nasal, rectal, topical (including transdermal and intradermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions include compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound or composition. The amount of carrier employed in conjunction with the compound or composition is sufficient to provide a practical quantity of 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 incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0077] Various oral dosage forms can be used, including such solid forms as tablets, capsules (e.g. solid gel capsules and liquid gel capsules), granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0078] The pharmaceutically-acceptable carriers suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatinand sucrose; disintegrants such as starch, alginic acid and croscarm elose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FD&C dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0079] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of 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 a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

[0080] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject composition is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0081] Compositions described herein may optionally include additional drug actives.

[0082] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0083] A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort may be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid may be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid may either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.

[0084] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions may preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0085] Preservatives that may be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric, acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

[0086] Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

[0087] Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

[0088] Ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.

[0089] Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.

[0090] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the composition disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0091] For intravenous administration, the compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. In some embodiments, excipients utilized for intravenous delivery may include Kolliphor HS 15 (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 may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA P harm 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, 65287-332, both of which are incorporated herein by reference in their entirety. Antimicrobial agents may also be included to achieve a bacteriostatic or fungistatic solution, including but not limited to phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0092] The compositions for intravenous administration may 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 shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. In still other embodiments, the compositions are provided in a solution that is further diluted prior toadministration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

[0093] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. In some embodiments, plinabulin may be administered at a dose in the range of about 1 mg / m2to about 50 mg / m2. In some embodiments, plinabulin is administered at a dose in the range of about 1-50 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose in the range of about 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-13.75, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22.5, 1-25, 1-27.5, 1-30, 1.5-2, 1.5-3, 1.5-4, 1.5-5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10, 1.5-11, 1.5-12, 1.5-13, 1.5-13.75, 1.5-14, 1.5-15, 1.5-16, 1.5-17, 1.5-18, 1.5-19, 1.5-20, 1.5-22.5, 1.5-25, 1.5-27.5, 1.5-30, 2.5-2, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-11, 2.5-12, 2.5-13, 2.5-13.75, 2.5-14, 2.5-15, 2.5-16, 2.5-17, 2.5-18, 2.5-19, 2.5-20, 2.5-22.5, 2.5-25, 2.5-27.5, 2.5-30, 2.5-7.5, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-13.75, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-22.5, 3-25, 3-27.5, 3-30, 3.5- 6.5, 3.5-13.75, 3.5-15, 2.5- 17.5, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-13.75, 4-14, 4-15, 4-16, 4-17, 4-18, 4- 19, 4-20, 4-22.5, 4-25, 4-27.5, 4-30, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-13.75, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-22.5, 5-25, 5-27.5, 5-30, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-13.75, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-22.5, 6-25, 6-27.5, 6-30, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-13.75, 7-14, 7-15, 7-16, 7-17, 7-18, 7-19, 7-20, 7-22.5, 7-25, 7-27.5, 7-30, 7.5-12.5, 7.5-13.5, 7.5-15, 8-9, 8-10, 8-11, 8-12, 8-13, 8-13.75, 8-14, 8-15, 8-16, 8-17, 8-18, 8-19, 8-20, 8-22.5, 8-25, 8-27.5, 8-30, 9-10, 9-11, 9-12, 9-13, 9-13.75, 9-14, 9-15, 9-16, 9-17, 9-18, 9-19, 9-20, 9-22.5, 9-25, 9-27.5, 9-30, 10-11, 10-12, 10-13, 10-13.75, 10-14, 10-15, 10-16, 10-17, 10-18, 10-19, 10-20, 10-22.5, 10-25, 10-27.5, 10-30, 11.5-15.5, 12.5-14.5, 7.5- 22.5, 8.5-32.5, 9.5-15.5, 15.5-24.5, 5-35, 17.5-22.5, 22.5-32.5, 25-35, 25.5-34.5, 27.5-32.5, 2- 20, 2.5-22.5, or 9.5-21.5 mg / m2, of the body surface area. In some embodiments, plinabulin is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29,29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose 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 mg / m2of the body surface area. In some embodiments, plinabulin is administered at a dose greater than about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 mg / m2of the body surface area.

[0094] In some embodiments, plinabulin dose is about 5 mg - 300 mg, 5 mg -200 mg, 7.5 mg - 200 mg, 10 mg - 100 mg, 15 mg - 100 mg, 20 mg - 100 mg, 30 mg - 100 mg, 40 mg - 100 mg, 10 mg - 80 mg, 15 mg - 80 mg, 20 mg - 80 mg, 30 mg - 80 mg, 40 mg - 80 mg, 10 mg - 60 mg, 15 mg - 60 mg, 20 mg - 60 mg, 30 mg - 60 mg, or about 40 mg - 60 mg. In some embodiments, plinabulin administered is about 20 mg - 60 mg, 27 mg - 60 mg, 20 mg -45 mg, or 27 mg - 45 mg. In some embodiments, plinabulin administered is about 5 mg-7.5 mg, 5 mg-9 mg, 5 mg- 10 mg, 5 mg-12mg, 5mg-14mg, 5mg-15 mg, 5 mg- 16 mg, 5 mg- 18 mg, 5 mg-20 mg, 5 mg-22 mg, 5 mg-24 mg, 5 mg-26 mg, 5 mg-28mg, 5mg-30mg, 5mg-32mg, 5mg-34mg, 5mg-36mg, 5mg-38mg, 5mg-40mg, 5mg-42mg, 5mg-44mg, 5mg-46mg, 5mg-48mg, 5mg-50mg, 5mg-52mg, 5mg-54mg, 5mg-56mg, 5mg-58mg, 5mg-60mg, 7 mg-7.7 mg, 7 mg-9 mg, 7 mg-10 mg, 7 mg-12mg, 7mg-14mg, 7mg-15 mg, 7 mg-16 mg, 7 mg-18 mg, 7 mg-20 mg, 7 mg-22 mg, 7 mg-24 mg, 7 mg-26 mg, 7 mg-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, 9 mg-10 mg, 9 mg-12mg, 9mg-14mg, 9mg-15 mg, 9 mg-16 mg, 9 mg-18 mg, 9 mg-20 mg, 9 mg-22 mg, 9 mg-24 mg, 9 mg-26 mg, 9 mg-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, 10 mg-12mg, 10mg-14mg, 10mg-15 mg, 10 mg-16 mg, 10 mg-18 mg, 10 mg-20 mg, 10 mg-22 mg, 10 mg-24 mg, 10 mg-26 mg, 10 mg-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-15 mg, 12 mg-16 mg, 12 mg-18 mg, 12 mg-20 mg, 12 mg-22 mg, 12 mg-24 mg, 12 mg-26 mg, 12 mg-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, 15 mg-16 mg, 15 mg-18 mg, 15 mg-20 mg, 15 mg-22 mg, 15 mg-24 mg, 15 mg-26 mg, 15 mg-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, 17 mg-18 mg, 17 mg-20 mg, 17 mg-22 mg, 17 mg-24 mg, 17 mg-26 mg, 17 mg-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, 20 mg-22 mg, 20 mg-24 mg, 20 mg-26 mg, 20 mg-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, 22 mg-24 mg, 22 mg-26 mg, 22 mg-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, 25 mg-26 mg, 25 mg-28mg, 25mg-30mg, 25mg-32mg, 25mg-34mg, 25mg-36mg, 25mg-38mg, 25mg-40mg, 25mg-42mg, 25mg-44mg, 25mg-46mg, 25mg-48mg, 25mg-50mg, 25mg-52mg, 25mg-54mg, 25mg-56mg, 25mg-58mg, 25mg-60mg, 27 mg-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-54mg, 52mg-56mg, 52mg-58mg, or 52mg-60mg. In some embodiments, plinabulin dose is greater 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 150mg, or about 200 mg. In some embodiments, plinabulin dose is about 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 150mg, or about 200 mg.

[0095] In some embodiments, a dose of one or more immune checkpoint inhibitors may be from about 100 pg to about 1000 mg, from about 500 pg or less to about 800 mg, from about 1.0 mg to about 600 mg, from about 100 mg to about 600 mg, or from about 200 mg to 500 mg. In some embodiments, a dose of one or more immune checkpoint inhibitors may be from about 240 mg to about 480 mg per dose. In some embodiments, the dose of the one or more immune checkpoint inhibitors is about 240 mg. In some embodiments, the dose of the one or more immune checkpoint inhibitors is about 480 mg.

[0096] In some embodiments, one or more immune checkpoint inhibitors may be administered at a dose in the range of about 100 mg / kg to about 5000 mg / kg. In some embodiments, one or more immune checkpoint inhibitors is administered at a dose in the range of about 100-1000 mg / kg. In some embodiments, one or more immune checkpoint inhibitors is administered at a dose in the 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, 100-2500, 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, one or more immune checkpoint inhibitors is administered at a dose of about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg, or a range between any two of these values.

[0097] In some embodiments, one or more immune checkpoint inhibitor dose is about 0.5 mg - 3000 mg, 0.5 mg - 2500 mg, 0.5 mg - 2000 mg, 0.5 mg - 1500 mg, 0.5 mg -1000 mg, 0.5 mg - 500 mg, 0.5 mg -200 mg, 0.75 mg - 200 mg, 1.0 mg - 100 mg, 1.5 mg - 100 mg, 2.0 mg - 100 mg, 3.0 mg - 100 mg, 4.0 mg - 100 mg, 1.0 mg - 80 mg, 1.5 mg - 80 mg, 2.0 mg - 80 mg, 3.0 mg - 80 mg, 4.0 mg - 80 mg, 1.0 mg - 60 mg, 1.5 mg - 60 mg, 2.0 mg - 60 mg, 3.0 mg - 60 mg, or about 4.0 mg - 60 mg. In some embodiments, one or more immune checkpoint inhibitors administered is about 20 mg - 60 mg, 27 mg - 60 mg, 20 mg - 45 mg, or 27 mg - 45 mg. In some embodiments, one or more immune checkpoint inhibitors administered is about 5 mg-7.5 mg, 5 mg-9 mg, 5 mg-10 mg, 5 mg-12mg, 5mg-14mg, 5mg-15 mg, 5 mg-16 mg, 5 mg- 18 mg, 5 mg-20 mg, 5 mg-22 mg, 5 mg-24 mg, 5 mg-26 mg, 5 mg-28mg, 5mg-30mg, 5mg-32mg, 5mg-34mg, 5mg-36mg, 5mg-38mg, 5mg-40mg, 5mg-42mg, 5mg-44mg, 5mg-46mg, 5mg-48mg, 5mg-50mg, 5mg-52mg, 5mg-54mg, 5mg-56mg, 5mg-58mg, 5mg-60mg, 7 mg-7.7 mg, 7 mg-9 mg, 7 mg-10 mg, 7 mg-12mg, 7mg-14mg, 7mg-15 mg, 7 mg-16 mg, 7 mg- 18 mg, 7 mg-20 mg, 7 mg-22 mg, 7 mg-24 mg, 7 mg-26 mg, 7 mg-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, 9 mg-10 mg, 9 mg-12mg, 9mg-14mg, 9mg-15 mg, 9 mg-16 mg, 9 mg- 18 mg, 9 mg-20 mg, 9 mg-22 mg, 9 mg-24 mg, 9 mg-26 mg, 9 mg-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-15 mg, 10 mg-16 mg, 10 mg- 18 mg, 10 mg-20 mg, 10 mg-22 mg, 10 mg-24 mg, 10 mg-26 mg, 10 mg-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-15 mg, 12 mg-16mg, 12 mg- 18 mg, 12 mg-20 mg, 12 mg-22 mg, 12 mg-24 mg, 12 mg-26 mg, 12 mg-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, 15 mg-16 mg, 15 mg-18 mg, 15 mg-20 mg, 15 mg-22 mg, 15 mg-24 mg, 15 mg-26 mg, 15 mg-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, 17 mg-18 mg, 17 mg-20 mg, 17 mg-22 mg, 17 mg-24 mg, 17 mg-26 mg, 17 mg-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, 20 mg-22 mg, 20 mg-24 mg, 20 mg-26 mg, 20 mg-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, 22 mg-24 mg, 22 mg-26 mg, 22 mg-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, 25 mg-26 mg, 25 mg-28mg, 25mg-30mg, 25mg-32mg, 25mg-34mg, 25mg-36mg, 25mg-38mg, 25mg-40mg, 25mg-42mg, 25mg-44mg, 25mg-46mg, 25mg-48mg, 25mg-50mg, 25mg-52mg, 25mg-54mg, 25mg-56mg, 25mg-58mg, 25mg-60mg, 27 mg-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-54mg, 52mg-56mg, 52mg-58mg, 52mg-60mg, 100mg-200mg, 200mg-300mg, 300mg-400mg, 400mg-500mg, 500mg-1000mg, 1000mg-2000mg, or 1000mg-3000mg. In some embodiments, one or more immune checkpoint inhibitor dose is greater than 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 150mg, or about 200 mg. In some embodiments, one or more immune checkpoint inhibitor dose is about 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 150mg, or about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 1000 mg, about 2000 mg, or about 3000 mg.

[0098] In some embodiments, the initial dose of one or more immune checkpoint inhibitor is 1 mg on day 1 followed a dose of a second immune checkpoint inhibitor is 3 mg.

[0099] In some embodiments, plinabulin is administered prior to the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered concurrently with one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered after one or more immune checkpoint inhibitor.

[0100] In some embodiments, plinabulin is administered about 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 24h, 30h, 36h, 40h, or 48h, or a range between any two of these values, after the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered about 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 24h, 30h, 36h, 40h, or48h, or a range between any two of these values, before the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered in less than about 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 30h, 36h, 40h, or 48h after the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered in more thanabout 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1 5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h30h, 36h, 40h, or 48h after the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered in less than about 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23 h, 24h, 30h, 36h, 40h, or48h after the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered in more than about 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h30h, 36h, 40h, or 48h before the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered in about lmin-5min, Imin-lOmin, lmin-15min, lmin-20min, 1 min-25min, 1 min-30min, 0.25h-0.5h, 0.25-0.75h, 0.25-lh,0. Shih, 0.5h-2h, 0.5h-2.5h, lh-2h, lh-3h, lh-5h, lh-24h, lmin-24h, or 1 min-2h, 1 day- 2days, Iday - 3 days, 1 day -4 days, 1 day-5 days, or 1 day-6 days after the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered in about lmin-5min, Imin-lOmin, lmin-15min, lmin-20min, 1 min-25min, 1 min-30min, 0.25h-0.5h, 0.25-0.75h, 0.25-lh,0.5h-lh, 0.5h-2h, 0.5h-2.5h, lh-2h, lh-3h, lh-5h, lh-24h, lmin-24h, or 1 min-2h, 1 day- 2days, Iday - 3 days, 1 day -4 days, 1 day-5 days, or 1 day-6 before the administration of one or more immune checkpoint inhibitor.

[0101] In some embodiments, when plinabulin is administered prior to one or more immune checkpoint inhibitor administration, plinabulin is administered about lmin-5min, Imin-lOmin, lmin-15min, lmin-20min, 1 min-25min, 1 min-30min, 0.25h-0.5h, 0.25-0.75h, 0.25-lh,0.5h-lh, 0.5h-2h, 0.5h-2.5h, lh-2h, lh-3h, lh-5h, lh-24h, Imin-lh, lmin-2h, Imin-5h, lmin-24h, 1 day- 2days, Iday - 3days, 1 day-4 days, 1 day-5 days, or 1 day-6 days before the administration of the one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered about 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 30h, 36h, 40h, 48h, 4 days, 5 days, 6 days, or 7 days, or a range between any two of these values, before the administration of the one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered in less than about 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h,24h, 30h, 36h, 40h, 48h, 4 days, 5 days, 6 days, or 7 days before the administration of one or more immune checkpoint inhibitor. In some embodiments, plinabulin is administered in more than about 1 min, 5min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, llh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 30h, 36h, 40h, 48h, 3 days, 4 days, 5 days, 6 days, or 7 days before the administration of the one or more immune checkpoint inhibitor.

[0102] In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin once every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin two times every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin once every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin twice every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1, day 8, and day 15 of a 21 -day treatment cycle. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1 of a 21 -day treatment cycle. In some embodiments, co-administration of one or more immune checkpoint inhibitor and plinabulin includes administering one or more immune checkpoint inhibitor prior to administering plinabulin. In some embodiments, co-administration of one or more immune checkpoint inhibitor and plinabulin includes administering one or more immune checkpoint inhibitor after administering plinabulin. In some embodiments, co-administration of one or more immune checkpoint inhibitor and plinabulin includes administering the one or more immune checkpoint inhibitor concurrently with plinabulin. In some embodiments, one or more immune checkpoint inhibitor described in this paragraph can independently be a first, second, third, fourth, fifth, sixth, seventh, or eighth immune checkpoint inhibitor. In some embodiments, the treatmentschedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin every day of the week for a week. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin every day of the week for 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1 in weekly treatment. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1 and day 2 in weekly treatment. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1, day 2, and day 3 in weekly treatment. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1, day 2, day 3 in weekly treatment. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1, day 2, day 3, and day 4 in weekly treatment. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1, day 2, day 3, day 4, and day 5 in weekly treatment. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1, day 2, day 3, day 4, day 5, and day 6 in weekly treatment. In some embodiments, the treatment schedule includes co-administration of one or more immune checkpoint inhibitor composition and plinabulin on day 1, day 3, and day 5 in weekly treatment. In some embodiments, the treatment cycle for plinabulin and the one or more immune checkpoint inhibitors may be the same. In other embodiments, the treatment cycle for plinabulin and the one or more immune checkpoint inhibitors may be different. For example, in some embodiments, the treatment cycle for plinabulin is 21 days, whereas the treatment cycle for the one or more immune checkpoint inhibitors is 14 days. In some embodiments, one or more immune checkpoint inhibitor is used on each administration day can be the same or different. In some embodiments, one or more immune checkpoint inhibitor used on the first administration day is different from one or more immune checkpoint inhibitor used on the rest of the administration days. In some embodiments, one or more immune checkpoint inhibitor used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the second administration day. In some embodiments, one or moreimmune checkpoint inhibitor used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the third administration day. In some embodiments, one or more immune checkpoint inhibitor composition used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the fourth administration day. In some embodiments, one or more immune checkpoint inhibitor used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the fifth administration day. In some embodiments, one or more immune checkpoint inhibitor used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the sixth administration day. In some embodiments, one or more immune checkpoint inhibitor used on the first administration day is the same as or different from one or more immune checkpoint inhibitor used on the seventh administration day.

[0103] In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor (e.g., the first, the second, the third, the fourth, the fifth, the sixth, the seventh, or the eighth) once every 3 weeks. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor once every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor two times every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor once every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor twice every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor three times (e.g., day 1, 2, 3, or day 1, 3, 5) every week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor day 1, day 8, and day 15 of a 21 -day treatment cycle. The one or more immune checkpoint inhibitor described in this paragraph can independently be the first, second, third, fourth, fifth, sixth, seventh, or eighth one or more immune checkpointinhibitor. Tn some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor every day of the week for a week. In some embodiments, the treatment schedule includes administration of the one or more immune checkpoint inhibitor every day of the week for 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor composition on day 1 in weekly treatment. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor on day 1 and day 2 in weekly treatment. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor on day 1, day 2, and day 3 in weekly treatment. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor on day 1, day 3, day 5 in weekly treatment. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor on day 1, day 2, day 3, and day 4 in weekly treatment. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor on day 1, day 2, day 3, day 4, and day 5 in weekly treatment. In some embodiments, the treatment schedule includes administration of one or more immune checkpoint inhibitor on day 1, day 2, day 3, day 4, day 5, and day 6 in weekly treatment.

[0104] In some embodiments, the treatment schedule includes administration of plinabulin once every 3 weeks. In some embodiments, the treatment schedule includes administration of plinabulin once every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of plinabulin two times every 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of plinabulin once every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of plinabulin twice every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of plinabulin three times (e.g., day 1, 2, 3, or day 1, 3, 5) every 1 week in a treatment cycle of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In some embodiments, the treatment schedule includes administration of plinabulin on day 1 of a 21 -day treatment cycle. In some embodiments, the treatment scheduleincludes administration of plinabulin on day 1 and day 8 of a 21 -day treatment cycle. In some embodiments, the treatment schedule includes administration of plinabulin day 1, day 8, and day 15 of a 21 -day treatment cycle. In some embodiments, the treatment schedule includes administration of plinabulin every day of the week for a week. In some embodiments, the treatment schedule includes administration of plinabulin every day of the week for 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the treatment schedule includes administration of plinabulin on day 1 in weekly treatment. In some embodiments, the treatment schedule includes administration of plinabulin on day 1 and day 2 in weekly treatment. In some embodiments, the treatment schedule includes administration of plinabulin on day 1, day 2, and day 3 in weekly treatment. In some embodiments, the treatment schedule includes administration of plinabulin on day 1, day 3, day 5 in weekly treatment. In some embodiments, the treatment schedule includes administration of plinabulin on day 1, day 2, day 3, and day 4 in weekly treatment. In some embodiments, the treatment schedule includes administration of plinabulin on day 1, day 2, day 3, day 4, and day 5 in weekly treatment. The treatment schedule includes administration of plinabulin on day 1, day 2, day 3, day 4, day 5, and day 6 in weekly treatment.

[0105] The treatment cycle can be repeated as long as the regimen is clinically tolerated. In some embodiments, the treatment cycle for one or more immune checkpoint inhibitor and plinabulin is repeated for n times, wherein n is an integer in the range of 2 to 30. In some embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, a new treatment cycle can occur immediately after the completion of the previous treatment cycle. In some embodiments, a new treatment cycle can occur a period of time after the completion of the previous treatment cycle. In some embodiments, a new treatment cycle can occur after 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, or 7 weeks after the completion of the previous treatment cycle.

[0106] Administration of the compositions disclosed herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, buccally, subcutaneously, intravenously, intranasally, intratumorally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, intragastrically, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of some embodiments.

[0107] In some embodiments, the compositions described herein can be used in combination with other therapeutic agents. In some embodiments, the compositions described herein can be administered or used in combination with treatments such as chemotherapy, radiation, and biologic therapies.EXAMPLES

[0108] To further illustrate this disclosure, the following examples are included. The examples should not, of course, be construed as specifically limiting the disclosure. Variations of these examples within the scope of the claims are within the purview of one skilled in the art and are considered to fall within the scope of the disclosure as described and claimed herein. The reader will recognize that the skilled artisan, armed with the present disclosure, and skill in the art is able to prepare and use the disclosure without exhaustive examples.

[0109] The following examples report results from a treatment regimen involving the administration of a combination therapy including plinabulin, an immune-modulating agent, in conjunction with a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, such as nivolumab, and localized radiation therapy. This protocol is specifically designed for patients diagnosed with relapsed or refractory classical Hodgkin lymphoma (cHL) who have demonstrated disease progression following prior treatment with PD-1 or programmed death-ligand 1 (PD-L1) targeted therapies. The objective of this regimen was to enhance antitumor immune responses by promoting dendritic cell maturation and subsequent T-cell activation, thereby overcoming immune resistance mechanisms commonly observed in heavily pre-treated patients.

[0110] The method of administration begins with baseline evaluations, including imaging studies and biopsies of the target lesions, prior to the initiation of therapy. In the first cycle of treatment, radiation therapy is administered to a designated tumor site beginning on Day 1. Radiation is delivered over a period of three to five consecutive days, with a total dose typically ranging from 20 Gray (Gy) administered in five fractions to alternative regimens such as 24 Gy in three fractions or 50 Gy in four fractions, depending on clinical judgment and patient tolerance. Within three to six hours following the first dose of radiation on Day 1, the patient receives an intravenous infusion of plinabulin, delivered over 30 to 60 minutes. Asecond dose of plinabulin is administered on Day 4 of the same cycle. Concurrently, the PD-1 inhibitor nivolumab is administered intravenously on Day 1 of each cycle, either as 240 mg every two weeks or 480 mg every four weeks, based on the specific dosing schedule determined by the treating physician.

[0111] Subsequent treatment cycles follow a similar structure, with plinabulin administered intravenously on Day 1 of each 21 -day cycle. An optional second dose of plinabulin may be administered on Day 4 if additional radiation therapy is employed in Cycle 2 or beyond. Radiation therapy in Cycle 2 is provided at the discretion of the treating physician and may target new or residual tumor sites. Throughout the treatment period, patients undergo regular monitoring, including blood draws on Day 1 of each cycle and periodic biopsies to assess tumor response and immune activation. The treatment is continued for up to fourteen cycles or until the patient exhibits disease progression, experiences unacceptable toxicity, or elects to discontinue therapy.

[0112] The patients subsequently received treatment per trial design with the combination regimen described herein. Specifically, the patients are treated on a 4-week cycle, where radiation therapy was administered on Cycle 1 Day 1 through Day 3 (CID 1-3) at a dose of 8 Gy per fraction over three fractions. As an option patients may receive radiation on CID 1-4 (12.5 Gy x 4 fractions) or C1D1-5 (4 Gy x 5 fractions), depending on clinical discretion and protocol allowances.

[0113] Following radiation therapy, plinabulin is administered intravenously at 30 mg / m2over 60 minutes on Cycle 1 Day 1 (C1D1) and Cycle 1 Day 4 (C1D4). In subsequent cycles, plinabulin is administered on Cycle 2 Day 1 and Day 4 (C2D1, C2D4) if optional radiation therapy was delivered on C2D1. From Cycle 3 onward, plinabulin is administered on Day 1 of each cycle. Nivolumab is co-administered intravenously at a dose of 240 mg over 30 to 60 minutes on Day 1 and Day 15 of each 4-week cycle.

[0114] This nonlimiting examples of a regimen has been demonstrated to provide prolonged disease control, evidenced by durable partial responses and stable disease in patients who have exhausted multiple prior lines of therapy.Example 1

[0115] Figure 1 shows a series of three PET scans demonstrating the progression of disease response in a 60-year-old female patient with relapsed / refractory classical Hodgkin’s lymphoma following treatment with a combination of plinabulin, radiation therapy, and nivolumab. The patient had received an extensive treatment history, consisting of 12 prior lines of therapy, including ABVD x6, RICE, autologous stem cell transplant (autoSCT) with BEAM conditioning, GVD, SGN-35 (brentuximab vedotin), CAL-101, everolimus, vorinostat, nivolumab, pembrolizumab, HMPL-523, BV, and AZD4573. Despite these therapies, the disease remained refractory or relapsed.

[0116] The patient subsequently received treatment per trial design with the combination regimen described herein. Specifically, the patient was treated on a 4-week cycle, where radiation therapy was administered on Cycle 1 Day 1 through Day 3 (CID 1-3) at a dose of 8 Gy per fraction over three fractions. As an option patients may receive radiation on CID 1-4 (12.5 Gy x 4 fractions) or C1D1-5 (4 Gy x 5 fractions), depending on clinical discretion and protocol allowances.

[0117] Following radiation therapy, plinabulin was administered intravenously at 30 mg / m2over 60 minutes on Cycle 1 Day 1 (C1D1) and Cycle 1 Day 4 (C1D4). In subsequent cycles, plinabulin was administered on Cycle 2 Day 1 and Day 4 (C2D1, C2D4) if optional radiation therapy was delivered on C2D1. From Cycle 3 onward, plinabulin was administered on Day 1 of each cycle. Nivolumab was co-administered intravenously at a dose of 240 mg over 30 to 60 minutes on Day 1 and Day 15 of each 4-week cycle.

[0118] The treatment began at Cycle l,Day 1 (ClDl)and proceeded through Cycle 11. In Cycle 1, RT was administered on Day 1, delivering between 3 to 5 fractions depending on the radiation plan — common dosing regimens shown in the study include 24 Gy in 3 fractions, 50 Gy in 4 fractions, or 20 Gy in 5 fractions. Plinabulin was administered intravenously 3 to 6 hours after the first RT dose. The anti-PD-l / PD-Ll agent, in this case nivolumab, was also administered during this cycle according to the study schedule, typically on Day 1.

[0119] Plinabulin was then administered again on Day 4 of Cycle 1. Starting with Cycle 2 and continuing through subsequent cycles (up to Cycle 11), both plinabulin and nivolumab were given on Day 1 of each 21 -day cycle. RT was optional in Cycle 2 based on clinical judgment and patient response. Additional monitoring procedures were incorporatedinto the cycles, including blood draws on Day 1 of odd cycles and biopsies of index lesions, particularly in Cycle 3, Day 1 (C3D1), to assess treatment response in non-radiated tumors. The treatment maintained disease control with stable disease observed four months off-treatment and an ongoing response with duration of response of 23 months.

[0120] Nivolumab, an immune checkpoint inhibitor targeting PD-1, is commonly administered at a dosage of 3 mg / kg intravenously over 60 minutes every two or three weeks. In clinical studies, plinabulin has been administered at a dosage of 30 mg / m2on Day 1 of each 21 -day cycle, in combination with other agents.

[0121] The left panel of Figure 1 shows the pre-treatment PET scan prior to initiating the combination therapy of plinabulin and nivolumab with adjunctive neck radiation therapy (20 Gy in 5 fractions at the beginning of treatment). This scan displays extensive areas of high metabolic activity, as indicated by multiple dark regions throughout the chest, abdomen, and pelvis, consistent with widespread active disease. Active tumor burden was particularly indicated in the mediastinum, abdomen, and pelvic regions.

[0122] The middle panel shows the PET scan during treatment, labeled “PR / irPR with plinabulin / RT / nivo.” There is a marked reduction in the intensity and distribution of hypermetabolic lesions compared to baseline, consistent with a partial response (PR) or immune-related partial response (irPR). The reduction in disease burden suggests that the combination regimen effectively targeted the lymphoma.

[0123] The right panel presents a PET scan taken four months after the patient was taken off study, following the last dose of treatment provided by the sponsor. The PET scan demonstrates continued disease control, with no new hypermetabolic lesions and maintenance of stable disease (SD). The duration of response at this point was 23 months and ongoing, highlighting a clinically meaningful and sustained benefit from the combined plinabulin, immune checkpoint inhibitor, and radiation treatment regimen, even in a patient population that had previously failed multiple immunotherapy approaches.

[0124] This treatment approach demonstrates the application of the trial protocol in a heavily pre-treated patient population, with the goal of assessing safety, tolerability, and potential clinical benefit through this novel combination of plinabulin, radiation therapy, and immune checkpoint blockade with nivolumab.

[0125] The observed response in this heavily pre-treated patient with relapsed / refractory classical Hodgkin’s lymphoma represents a surprising and unexpected result for several reasons. First, the patient had previously undergone 12 different lines of therapy, including multiple standard chemotherapies (ABVD, RICE, GVD), autologous stem cell transplantation with BEAM conditioning, and several targeted agents (brentuximab vedotin, CAL-101, everolimus, vorinostat, HMPL-523, and AZD4573). The patient had also received prior PD-1 inhibitors with no durable or meaningful response. Based on this extensive treatment history, the disease was characterized as highly refractory, and conventional clinical expectations would predict minimal likelihood of response to further immunotherapy or chemotherapy. Typically, patients with disease that has progressed through immune checkpoint inhibitors (ICIs) are considered resistant to subsequent ICI therapy, as the mechanism of resistance, without being bound to a theory of operation, is thought to be intrinsic to the tumor microenvironment or due to immune escape.

[0126] The ability of plinabulin, when administered in the specific dosing schedule and combination with ICIs as described, to restore or enhance sensitivity to checkpoint inhibitors in patients who are otherwise refractory, is a novel discovery. The increase in duration of response (DOR) from an expected median of approximately 8 months to over 19 months in patients treated with the combination of plinabulin, radiation therapy, and an immune checkpoint inhibitor represents a dramatic and unexpected improvement in patient outcomes. In this heavily pre-treated, relapsed / refractory Hodgkin’s lymphoma population — particularly among those who had already failed multiple prior lines of therapy including PD-1 inhibitors — such an extension of DOR far exceeds existing benchmarks, even for novel therapies. Typically, patients with disease resistant to both chemotherapy and immunotherapy have limited remaining treatment options, and their prognosis is poor. Achieving more than a doubling in median DOR highlights a significant and surprising therapeutic benefit that could not have been predicted based on the known activity of the individual agents alone, reinforcing the novelty and clinical impact of this combination regimen.Example 2

[0127] Figure 2 presents PET scans from another female patient with relapsed / refractory classical Hodgkin’s lymphoma (R / R cHL), initially diagnosed over twodecades earlier. The patient had a history of extensive prior treatments, having undergone 16 different therapeutic regimens. Her treatment history included ABVD x8, ICE x3, autologous stem cell transplant with busulfan / melphalan (Bu / Mel), brentuximab vedotin, sirolimus, vorinostat, nivolumab, Revlimid, bendamustine, ibrutinib, ADCT-301, CD30 CAR-T therapy, HMPL-523, and gemcitabine. Despite aggressive and repeated treatments, the disease remained refractory.

[0128] The left panel in Figure 2 shows the pre-treatment PET scan before the initiation of combination therapy with plinabulin and nivolumab, alongside radiation therapy (20 Gy in five fractions to the left axilla). This scan reveals multiple areas of intense metabolic activity, consistent with widespread active disease, particularly in the axillary and mediastinal regions, indicating high tumor burden.

[0129] This patient, a 59-year-old female with relapsed / refractory classical Hodgkin lymphoma (cHL), the treatment regimen involved a combination of plinabulin and nivolumab administered over 14 cycles. Treatment began in at Cycle 1, Day 1 (or C1D1) and continued Cycle 14. As part of the regimen, the patient also received radiation therapy (RT) targeting the left axilla. This RT was delivered at the beginning of treatment at a dose of 20 Gray (Gy), administered in 5 fractions.

[0130] In Cycle 1, RT was administered on Day 1 with plinabulin given 3 to 6 hours later, mirroring the structure from the broader study protocol. Nivolumab, an anti-PD-1 immune checkpoint inhibitor, was administered on Day 1 of each cycle along with plinabulin. From Cycle 2 through Cycle 14, the patient continued on plinabulin and nivolumab, both given on Day 1 of each cycle. Biopsies and blood draws were incorporated into the regimen for immune monitoring and assessment of disease response, though specific cycle days for these are not detailed in the figure.

[0131] The right panel demonstrates the PET scan taken during the combination treatment period, labeled “PR / irPR with plinabulin / RT / nivo.” There is a clear reduction in the number and intensity of hyperm etabolic lesions compared to the pre-treatment scan, reflecting a partial response (PR) or immune-related partial response (irPR). The reduction is particularly notable in previously involved regions, suggesting effective tumor control in non-irradiated sites as well.

[0132] This patient’s best response was achieved during the combination therapy period. Treatment was discontinued by patient choice, and the disease remained controlled until progression was observed over 6 months later. The duration of response to the combination therapy was 19 months. This prolonged clinical benefit in a heavily pre-treated and refractory patient highlights the potential of plinabulin combined with immune checkpoint inhibitors and radiation to provide meaningful and durable responses in Hodgkin’s lymphoma.

Claims

WHAT TS CLAIMED IS:

1. A method of treating stem cell transplant resistant Hodgkin’s lymphoma in a subject, comprising:(a) administering an immune checkpoint inhibitor to the subject; and(b) administering plinabulin to the subject.

2. A method of treating Hodgkin’s lymphoma in a subject that failed immune checkpoint therapy, comprising:(a) administering an immune checkpoint inhibitor to the subject; and(b) administering plinabulin to the subject.

3. The method of claim 1 or 2, wherein the immune checkpoint inhibitor is selected from a PD-1 inhibitor, a PD-L1 inhibitor, or a combination thereof.

4. The method of claim 3, wherein the PD-1 inhibitor is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, and pidilizumab, sasanlimab, , dostarlimab, retifanlimab, toripalimab, tislelizumab, atezolizumab, avelumab, durvalumab, cosibelimab, spartalizumab, camrelizumab, sintilimab, pidilizumab, toripalimab, BMS 936559, INCMGA00012, KNO35, AUNP12, CA-170, and BMS-986189.

5. The method of claim 1 or 2, further comprising administering radiation therapy to the subject.

6. The method of claim 1 or 2, wherein the subject has previously received autologous stem cell transplantation and subsequently relapsed.

7. The method of claim 1 or 2, wherein the subject has demonstrated resistance to prior treatment with an immune checkpoint inhibitor.

8. The method of claim 1 or 2, wherein the plinabulin is administered at a dose from about 13.5 mg / m2to about 50 mg / m2on Day 1 of a treatment cycle.

9. The method of claim 1 or 2, wherein the immune checkpoint inhibitor is administered prior to the administration of plinabulin.

10. The method of claim 1 or 2, wherein the plinabulin is administered after or during radiation therapy.

11. The method of claim 1 or 2, further comprising administering a chemotherapeutic agent to the subject.

12. The method of claim 11, wherein the chemotherapeutic agent is docetaxel.

13. The method of claim 1 or 2, wherein the administration of plinabulin results in a response selected from partial response (PR), immune-related partial response (irPR), or stable disease (SD).

14. A method of identifying a subject for treatment with plinabulin, the method comprising,identifying a subj ect having Hodgkin’ s lymphoma that has relapsed after at least two lines of therapies; andadministering plinabulin and one or more immune checkpoint inhibitors.

15. The method of claim 14, wherein at least one of the at least two lines of therapies comprises stem cell transplantation.

16. The method of claim 14, wherein at least one of the at least two lines of therapies comprises immune checkpoint inhibitor therapy.

17. The method of claim 16, wherein the immune checkpoint inhibitor therapy comprises administering PD-1.

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