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WO2025151374A1 - Oncology combination therapy and methods of use - Google Patents

Oncology combination therapy and methods of use

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Publication number
WO2025151374A1
WO2025151374A1 PCT/US2025/010480 US2025010480W WO2025151374A1 WO 2025151374 A1 WO2025151374 A1 WO 2025151374A1 US 2025010480 W US2025010480 W US 2025010480W WO 2025151374 A1 WO2025151374 A1 WO 2025151374A1
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WO
WIPO (PCT)
Prior art keywords
administered
cancer
plinabulin
day
antibody
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/010480
Other languages
French (fr)
Inventor
Lan Huang
Yingjuan June Lu
Key LLOYD
James Tonra
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BeyondSpring Pharmaceuticals Inc
Original Assignee
BeyondSpring Pharmaceuticals Inc
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Filing date
Publication date
Application filed by BeyondSpring Pharmaceuticals Inc filed Critical BeyondSpring Pharmaceuticals Inc
Publication of WO2025151374A1 publication Critical patent/WO2025151374A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
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    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the dose of the antibody-drug conjugate is from about 0.1 mg/kg to about 15 mg/kg. In some embodiments, the antibody-drug conjugate is from about 0.5 mg/kg to about 5 mg/kg. In some embodiments, the dose of the antibody-drug conjugate is 1.0 mg/kg. In some embodiments, the antibody-drug conjugate is administered intravenously.
  • the antibody-drug conjugate is administered on day 1 of the treatment cycle. In some embodiments, the antibody-drug conjugate is administered on day 8 of the treatment cycle.
  • the method disclosed herein further includes, administration of: radiation therapy, an immune checkpoint inhibitor, a chemotherapeutic agent, or a combination thereof, to the subject.
  • the methods disclosed herein comprises administration of an immune checkpoint inhibitor.
  • the one or more immune checkpoint inhibitor is administered intravenously.
  • the immune checkpoint inhibitor is administered to the subject in an amount of from 50 mg to 2000 mg.
  • the one or more immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pidilizumab, ipilimumab, BMS 936559, RMP1-14, durvalumab, or a combination thereof.
  • the method disclosed herein further includes administration of radiation therapy to the subject.
  • radiation therapy is administered in one to ten fractions.
  • radiation therapy is administered three to five fractions.
  • radiation therapy is administered in three fractions, four fractions or five fractions.
  • the total dose of radiation administered is from about 1 Gy to about 20 Gy.
  • the total dose of radiation administered is from about 2 Gy to about 15 Gy.
  • the total dose of radiation administered is from about 4 Gy to about 15 Gy.
  • the total dose of radiation administered is about 4 Gy, or about 8 Gy, or about 12.5 Gy.
  • radiation therapy is administered on days 1, 2, and 3 of the treatment cycle, or on days 1, 2, 3, and 4 of the treatment cycle, or on days 1, 2, 3, 4, and 5 of the treatment cycle.
  • the plinabulin is administered from about 3 hours to about 12 hours after completion of administration of the radiation therapy.
  • FIG. 1 depicts the single compound ICso tests against the NCI -Hl 975 nonsmall cell lung cancer cell line.
  • FIG. 2 depicts the single compound ICso tests against the KPL-4 metastatic breast cancer cell line.
  • FIG. 5 shows the Bliss synergy plot for combination testing of plinabulin with sacituzumab govetican on NCI-H1975 non-small cell lung cancer cells.
  • the present disclosure provides methods and therapeutic compositions for treating, ameliorating, or preventing a cancer or a tumor in a subject using plinabulin.
  • methods and compositions provided herein are useful in treating, delaying the progression of, preventing relapse of, or alleviating a symptom of a cancer or other neoplastic condition using plinabulin.
  • Plinabulin, (3Z,6Z)-3-Benzylidene-6- ⁇ [5-(2-methyl-2-propanyl)- l/7-imidazol-4-yl]methylene ⁇ -2,5-piperazinedione is a synthetic analog of the natural compound phenylahistin.
  • Plinabulin can be readily prepared according to methods and procedures detailed in U.S.
  • Trop-2 is a 40-kDa glycoprotein that was the first described transducer of intracellular calcium signaling Lipinski et al. Proc Natl Acad Set USA 1981, 78(8):5147-50; Ripani et al. Int J Cancer. 1998;76(5):671-676. It contains a 274-amino-acid extracellular epidermal growth factor-like repeat portion with three domains, a cysteine- rich domain, a thyroglobulin type-1 domain, and a cysteine-poor domain. Goldenberg et al. Oncotarget. 2018, 9(48):28989-29006.
  • the ADC is an anti-Human epidermal growth factor receptor-2 (HER2) ADC. In some embodiments, the ADC is an anti-Human epidermal growth factor receptor-3 (HER3) ADC. In some embodiments, the ADC is an anti-B7-H3 ADC. In some embodiments, the ADC is an anti- CDH6 ADC. In some embodiments, the ADC may be an anti-EGFR, anti- Nectin-4, anti-cMet, anti-Integrin-beta-6, anti-Tissue factor, anti-SEZ6 (seizure-related homolog protein 6), or anti-DLL3 (delta-like ligand 3) ADC. In some embodiments, the plinabulin and ADC may be administered in combination with one or more immune checkpoint inhibitor, additional chemotherapeutic agents, and/or radiation therapy.
  • 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.
  • antagonist refers to a compound that can combine with a receptor (e.g., an immune checkpoint receptor) to block a cellular activity.
  • a receptor e.g., an immune checkpoint receptor
  • An antagonist may be a ligand that directly binds to the receptor.
  • 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.
  • 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.
  • antibody may refer to an immunoglobulin (Ig) defined as a protein belonging to the class IgG, IgM, IgE, IgA, or IgD (or any subclass thereof), or a functional binding fragment or binding domain of an immunoglobulin.
  • Ig immunoglobulin
  • An antibody or antibody fragment as disclosed herein may be conjugated or otherwise derivatized.
  • the antibody is an anti-Trop-2 antibody.
  • the antibody is an anti-Trop-2 monoclonal antibody.
  • cancer neoplasm
  • cancerma a cell which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation.
  • 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.
  • ADC or “antibody drug conjugate” as used herein refers to a compound that comprises an antibody (or fragment thereof) that is used to target and/or bind to the cell, a drug (or payload), and a linker which covalently binds the drug to the antibody.
  • anti-Trop-2 ADC or “anti-Trop 2-antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-Trop-2 antibody.
  • anti-HER2 ADC or “anti-HER2-antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-HER2 antibody.
  • anti-HER3 ADC or “anti-HER3 -antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-HER3 antibody.
  • 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.
  • anti-Trop-2 ADCs for use as described herein may be prepared from a number of anti-Trop-2 antibodies.
  • anti-Trop-2 antibodies are commercially available from a number of sources and include, but are not limited to LS-C126418, LS- C178765, LS-C126416, LS-C126417 (LifeSpan BioSciences, Inc., Seattle, Wash.); 10428- MM01, 10428-MM02, 10428-R001, 10428-R030 (Sino Biological Inc., Beijing, China); MR54 (eBioscience, San Diego, Calif); sc-376181, sc-376746, Santa Cruz Biotechnology (Santa Cruz, Calif.); MM0588-49D6, (Novus Biologicals, Littleton, Colo.); ab79976, and ab89928 (ABCAM®, Cambridge, Mass.).
  • anti-Trop-2 antibodies 162-25.3 and 162-46.2 discloses anti-Trop-2 antibodies 162-25.3 and 162-46.2, which is incorporated herein by reference in its entirety.
  • the anti-Trop-2 antibodies may be sacituzumab or datopotamab. All of the antibodies disclosed above can be used in an ADC for use as described herein.
  • the anti-Trop-2 ADC comprises a drug (payload) that may be cytotoxic to cells.
  • the drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents.
  • the drug may be ozogamicin, vedotin, emtansine, camptothecins, exatecan, topotecan, irinotecan, belotecan, deruxtecan, govitecan, mafodotin, pasudotox tesirine, calicheamicin yl, or doxorubicin.
  • the drug may be govitecan. In other specific embodiments, the drug may be deruxtecan.
  • the anti-Trop-2 ADC may be sacituzumab govitecan (IMMU-132, hRS7-SN-38, Trodelvy®), datopotamab deruxtecan, (Dato-Dxd, DS-1062a), SKB264, LCB84, STI-3258, BAT8008, FDA018-ADC, BIO-106, JS108, PF-06664178, or a combination thereof.
  • the anti-Trop-2 ADC may be sacituzumab govitecan.
  • the anti-Trop-2 ADC may be datopotamab deruxtecan.
  • HER2 is a protein (Human epidermal growth factor receptor-2) that normally resides in the membranes of cells. Overexpression of HER2 is believed to play a crucial role in the malignant transformation of normal cells and in the continued growth of normal cells. HER2 is a validated cancer target, and both monoclonal antibodies and small molecule inhibitors of HER2 have been approved for the treatment of various cancers.
  • Therapeutic conjugates comprising an anti-HER2 can be used to treat carcinomas such as breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, or prostate cancer.
  • Anti HER2 ADCs may include, but are not limited to, trastuzumab emtansine, trastuzumab deruxtecan, and RC-48.
  • the anti-HER2 ADC comprises a drug (payload) that may be cytotoxic to cells.
  • the drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents.
  • anti-HER2 ADCs for use as described herein may be prepared from a number of anti-HER2 antibodies.
  • anti-HER2 antibodies may include, but are not limited to, trastuzumab, margetuximab, pertuzumab, GB235, huMAb4D5-l, huMAb4D5- 2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8.
  • HER3 Human epidermal growth factor receptor-3 is a membrane-bound protein. HER3, as a heterodimerization partner with HER2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis. Holbro et al., Proc. Natl. Acad. Set. U.S.A. 100 (15): 8933-8; Wang et al. Oncogene. 29 (29): 4225-36. HER3 is widely expressed in solid tumors and associated with tumor growth and drug resistance.
  • anti-HER3 ADCs could potentially be used to treat cancers.
  • anti HER3 ADCs maybe used to treat carcinomas such as breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, or prostate cancer.
  • Anti HER3 ADCs may include, but are not limited to, Patritumab deruxtecan and SHR-A2009.
  • the anti-HER3 ADC comprises a drug (payload) that may be cytotoxic to cells.
  • the drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents.
  • anti-HER3 antibodies may include, but are not limited to, Patritumab, Seribantumab, Lumretuzumab, GSK2849330, CDX-3379, Barecetamab, AV-203, Elgemtumab, HMBD-001, U3P1287/01, and SIBP-03.
  • ADCS Adsorption Control Codon
  • the anti-B7-H3 ADC may be ifinatamab deruxtecan.
  • the anti-CDH6 ADC may be DS-6000.
  • the ADC may be an anti-EGFR, anti-Nectin-4, anti-cMet, anti-Integrin-beta-6, anti-Tissue factor, anti-SEZ6 (seizure-related homolog protein 6), or anti-DLL3 (delta-like ligand 3) ADC.
  • one or more immune checkpoint inhibitor may be co-administered with plinabulin and the ADCs described herein.
  • 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 antitumor 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.
  • 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).
  • 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.
  • the Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA-4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8; which are incorporated herein by reference in their entirety).
  • Other members of the CD28 family include CD28, CTLA-4, ICOS and BTLA.
  • PD-1 is suggested to exist as a monomer, lacking the unpaired cysteine residue characteristic of other CD28 family members. PD-1 is expressed on activated B cells, T cells, and monocytes.
  • the PD-1 gene encodes a 55 kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8:765-72, which is incorporated herein by reference in its entirety). Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif that is important for B7-1 and B7-2 binding. Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD- L2 (B7-DC), that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carter et al. (2002) Eur. J. Immunol.
  • Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but do not bind to other CD28 family members.
  • PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9, which is incorporated herein by reference in its entirety).
  • PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals (Ishida, Y. et al. (1992) EMBO J. 11 :3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5): 739-745; which are incorporated herein by reference in their entirety).
  • the interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, e.g., a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells (Dong et al. (2003) J. Mol. Med.
  • Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99: 12293-7; Brown et al. (2003) J. Immunol. 170: 1257-66; which are incorporated herein by reference in their entirety).
  • CTLA-4 cytotoxic T-lymphocyte associated antigen 4
  • the immune checkpoint receptor cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) is expressed on T-cells and is involved in signaling pathways that reduce the level of T-cell activation. It is believed that CTLA-4 can downregulate T-cell activation through competitive binding and sequestration of CD80 and CD86. In addition, CTLA-4 has been shown to be involved in enhancing the immunosuppressive activity of TR eg cells.
  • the immune checkpoint receptor B- and T-lymphocyte attenuator (BTLA) receptor is expressed on both resting and activated B-cells and T-cells.
  • BTLA T-lymphocyte attenuator
  • HVEM herpes virus entry mediator
  • T-cell activation and proliferation results in downregulation of both T-cell activation and proliferation.
  • HVEM is expressed by certain tumors (e.g., melanoma) and tumor-associated endothelial cells.
  • the immune checkpoint inhibitor compound is a small organic molecule (molecular weight less than 1000 daltons), a peptide, a polypeptide, a protein, an antibody, an antibody fragment, or an antibody derivative.
  • the immune checkpoint inhibitor compound is an antibody.
  • the antibody is a monoclonal antibody, specifically a human or a humanized monoclonal antibody.
  • 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.
  • the immune checkpoint inhibitor is Pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, RMP1-14, durvalumab, or any combinations thereof.
  • the immune checkpoint inhibitor may be RMP1-14.
  • 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.
  • the anti-PD-1 HuMAbs can be selected from 3 G10, 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.
  • the immune checkpoint inhibitor compound is incorporated in a pharmaceutically acceptable liposome formulation, wherein the formulation is a passive or targeted liposome formulation.
  • a pharmaceutically acceptable liposome formulation wherein the formulation is a passive or targeted liposome formulation.
  • suitable liposome formulations of antibodies are described U.S. Pat. No. 5,399,331 (Loughrey), U.S. Pat. No. 8,304,565 (Wu) and U.S. Pat. No. 7,780,882 (Chang), which are incorporated herein by reference in their entirety.
  • the one or more immune checkpoint inhibitor may be an antibody.
  • the antibody is a dry, lyophilized solid that is reconstituted with an aqueous reconstitution solvent prior to use.
  • the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is injected directly into a tumor.
  • the immune checkpoint inhibitor antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is injected into the peritumoral region surrounding a tumor. The peritumoral region may contain antitumor immune cells.
  • the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by intravenous injection or infusion.
  • the immune checkpoint inhibitor antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by subcutaneous injection or intradermal injection. In some embodiments, the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by intraperitoneal injection or lavage.
  • the ADC is administered on day 1 of the treatment cycle and plinabulin is administered on day 1 of the treatment cycle. In other embodiments, the ADC is administered on day 1 of the treatment cycle and plinabulin is administered on day 1 and day 4 of the treatment cycle. In some embodiments, the ADC is administered on day 1 of the treatment cycle, plinabulin is administered on day 1 and day 4 of the treatment cycle. In some embodiments, the ADC is administered on day 1 and day 8 of the treatment cycle, plinabulin is administered on day 1 of the treatment cycle.
  • plinabulin is administered in about lmin-5min, Imin-lOmin, Imin- 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 - 3days, 1 day-4 days, 1 day-5 days, or 1 day-6 days after the administration of one or more immune checkpoint inhibitor.
  • 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.
  • the treatment cycle includes administration of one or more immune checkpoint inhibitor on day 1, day 3, day 5 in weekly treatment. In some embodiments, the treatment cycle 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 cycle 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 cycle 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.
  • the radiation therapy may be administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and/or 28 of the treatment cycle.
  • the radiation therapy may be administered on day 1, 2, and 3 of the treatment cycle.
  • radiation therapy may be administered on day 1, 2, 3, and 4 of the treatment cycle.
  • radiation therapy may be administered on day 1, 2, 3, 4, and 5 of the treatment cycle.
  • radiation therapy may be administered on day 2, 3, and 4 of the treatment cycle.
  • the total dose of radiation administered to the subject during the treatment cycle can be about 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, or 20 Gy, or more, or within a range defined by any two of the aforementioned values.
  • the total dose of radiation administered to the subject can be from about 1 Gy to about 20 Gy, from about 2 Gy to about 15 Gy, from about 4 Gy to about 15 Gy. In some embodiments, the total dose of radiation administered to the subject is about 4 Gy. In other embodiments, the total dose of radiation administered to the subject is about 8 Gy.
  • the total dose of radiation administered to the subject is about 12.5 Gy.
  • radiation may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fractions, or more.
  • radiation may be administered in three to five fractions.
  • radiation may be administered in three fractions.
  • radiation may be administered in four fractions.
  • radiation may be administered in five fractions.
  • the plinabulin when radiation therapy and plinabulin are administered on the same day, is administered from about 3 hours to about 12 hours after completion of administration of the radiation therapy.
  • the plinabulin is administered from about 4 hours to about 10 hours, about 4 hours to about 8 hours, or about 5 hours to about 8 hours after completion of administration of the radiation therapy.
  • the present disclosure provides a method for treating a breast cancer, a bladder cancer, a glioma, a glioblastoma, a head and neck cancer, a nonsmall cell lung cancer, a small cell lung cancer, recurrent small cell lung cancer (SCLC), a colorectal cancer, a gastrointestinal stromal tumor, a gastroesophageal carcinoma, a renal cell cancer, a prostate cancer, a liver cancer, a colon cancer, a pancreatic cancer, an ovarian cancer, a lymphoma, or a cutaneous T-cell lymphoma, or a melanoma.
  • the cancer is a colorectal cancer, a breast cancer, gastrointestinal stromal tumor, or a gastroesophageal carcinoma.
  • the cancer is triple negative breast cancer (TNBC).
  • the present disclosure provides a method for treating Fibrolamellar hepatocellular carcinoma, MSI-H cancers of any histology including but not limited to: colorectal, endometrial, adrenocortical, anal, appendiceal cancer, biliary, bladder, brain, breast, cervical, gastric or gastroesophageal junction, head and neck squamous cell, liver, mesothelioma, nasopharyngeal, neuroendocrine, ovarian, pancreatic, prostate, renal cell, retroperitoneal, salivary, sarcoma, small cell lung, small intestinal, testicular, thyroid, vaginal and vulvar.
  • MSI-H cancers of any histology including but not limited to: colorectal, endometrial, adrenocortical, anal, appendiceal cancer, biliary, bladder, brain, breast, cervical, gastric or gastroesophageal junction, head and neck squamous
  • the subject can be an animal, e.g., a mammal, a human. In some embodiments, the subject is a human.
  • plinabulin or a pharmaceutically acceptable salt thereof is incorporated in a pharmaceutically acceptable solution. In some embodiments, plinabulin or a pharmaceutically acceptable salt thereof is incorporated in an injectable formulation. In some embodiments, plinabulin or a pharmaceutically acceptable salt thereof is incorporated in an injectable formulation that substantially maintains plinabulin or a pharmaceutically acceptable salt thereof at or near the injection site.
  • the precise amount of plinabulin or a pharmaceutically acceptable salt thereof 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 intended dosing regimen or sequence. Accordingly, it is not practical to specifically set forth an amount that constitutes an amount of plinabulin or a pharmaceutically acceptable salt thereof therapeutically effective for all possible applications. Those of ordinary skill in the art, however, can readily determine an appropriate amount with due consideration of such factors.
  • the ADC is incorporated in a pharmaceutically acceptable solution. In some embodiments, the ADC is incorporated in an injectable formulation. In some embodiments, ADC is incorporated in an injectable formulation that substantially maintains ADC at or near the injection site.
  • ADC ADC incorporated in a particular method or therapeutic combination of the disclosure
  • 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 intended dosing regimen or sequence. Accordingly, it is not practical to specifically set forth an amount that constitutes an amount of ADC therapeutically effective for all possible applications. Those of ordinary skill in the art, however, can readily determine an appropriate amount with due consideration of such factors.
  • 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.
  • 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, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; 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.
  • 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.
  • 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.
  • 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,
  • 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
  • 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.
  • compositions described herein can be used in combination with other therapeutic agents.
  • compositions described herein can be administered or used in combination with treatments such as additional chemotherapeutic agents, radiation therapy, and/or biologic therapies.
  • sacituzumab govitecan To groups 2 and 4, sacituzumab govitecan is administered biweekly via intravenous injection at a dosage of 1 mg/kg.
  • mice are weighed on day 1 prior to administration of treatment. The mice are subsequently weighed three times weekly through the end of the 4- week study. Tumor wet weight of the mice are obtained at the end of the four- week study.
  • Example 2 Combination of plinabulin with sacituzumab govitecan and immune checkpoint inhibito
  • Plinabulin Administration To groups 2, 5, 7, and 8, Plinabulin is administered biweekly starting on day 1 of the study via intraperitoneal injection at a dosage of 7.5 mg/kg. In study groups 5 and 8, the plinabulin is administered one hour after administration of sacituzumab govitecan is complete.
  • sacituzumab govitecan To groups 3, 5, 6, and 8, sacituzumab govitecan is administered biweekly via intravenous injection at a dosage of 1 mg/kg.
  • RMP1 -14 Administration To groups 4, 6, 7, and 8, MPR-14 is administered biweekly via intraperitoneal injection at a dosage of 1 mg/kg.
  • mice are weighed on day 1 prior to administration of treatment. The mice are subsequently weighed three times weekly through the end of the 4- week study. Tumor wet weight of the mice are obtained at the end of the four- week study.
  • This study assessed the combination effect of test compounds on a metastatic breast cancer cell line that overexpress HER2. The combination was assessed in reference to a cisplatin control. All solutions containing plinabulin were protected from direct exposure to white light for the duration of the study.
  • Table 6 Combination testing of sacituzumab govitecan and plinabulin against NCI-H1975 cells [0163] The results for the testing of the combination of Trastuzumab deruxtecan and plinabulin against the KPL-4 cell line are shown in Table 7. The bolded cells in Table 7 shows an increased effect of the two compounds together as compared to each individual compound as a single agent.
  • the combination testing data of trastuzumab deruxtecan and plinabulin against KPL-4 cells was also analyzed using the Bliss model (Bliss C. I. Ann. Appl. Biol. 1939, 26, 585-615, which is incorporated herein by reference in its entirety) and using the Loewe model (Loewe, S. ArzneimiettelForschung 1953, 3286-290, which is incorporated herein by reference in its entirety).
  • the Bliss model is a reference model for evaluating the combination effect of two drugs.
  • the basic assumption of this model is the expected effect of two drugs acting independently; i.e. when each target a different signaling pathway.
  • the Loewe model is based on the assumption that both drugs have similar modes of action on the same targets or pathways.
  • CI Di/Ei+ D2/E2
  • £>i and £>2 are the actual drug doses used in the combinations during dosing experiments and Ei and 2 are theoretical individual drug levels that would be expected to be needed to achieve the experimentally measured response. While Di and £>2 are known from experimental design, £ and £2 can be calculated using the D m and in values previously computed.
  • a CI value less than 1 indicates synergism, greater than 1 indicates antagonism, and equal to 1 indicating additivity.
  • Inhibition of KPL-4 cells was determined using a fixed molar ratio of trastuzumab deruxtecan to plinabulin of 4:1. These values are provided in Table 16. The Combination Index was determined for this concentration ratio of trastuzumab deruxtecan to plinabulin. Values of the fraction of cells affected and the CI are provided in Table 17. The median CI was found to be 0.25, indicating synergism.

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Abstract

The present disclosure relates to combination therapies comprising plinabulin and antibody-drug conjugates for the treatment of cancer. Specifically, the present disclosure is directed to combination therapies comprising plinabulin and anti-Trop-2 antibody-drug conjugates for the treatment of solid tumors.

Description

DALWC.210WO PATENT
ONCOLOGY COMBINATION THERAPY AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims the benefit of priority to U.S. Provisional Application No. 63/618,835, filed January 8, 2024 and U.S. Provisional Application No. 63/661,509, filed June 18, 2024. The foregoing applications are fully incorporated herein by reference in their entireties for all purposes.
BACKGROUND
Field
[0002] The present disclosure relates to the field of chemistry and medicine. More specifically, it relates to combination therapies comprising plinabulin and antibody-drug conjugates for the treatment of cancer.
Description of the Related Art
[0003] Cancer is among the most common fatal diseases, causing millions of deaths worldwide annually. Multiple therapeutic interventions for cancer include chemotherapy, immunotherapy, radiation therapy, and surgery. Chemotherapy is generally regarded as the most common treatment, and small molecule anticancer drugs are the most widely used chemotherapy drugs. However, most chemotherapy drugs show a low therapeutic index, do not discern between healthy and diseased cells, and may cause severe side effects attributed to non-specific drug exposure.
[0004] Antibody-drug conjugates (ADC) are among the fastest growing cancer therapeutics and combine the potent cytotoxicity of chemotherapy with the antigen -specific targeted approach of antibodies into one single molecule. ADCs are a target therapy which are intended to target and destroy cancer cells while sparing healthy cells. An ADC is composed of three components: an antibody which targets a tumor antigen or protein that is found in or on the cancer cell; a cytotoxic payload or warhead, which elicits the desired therapeutic response; and a linker which attaches the warhead to the antibody. Trop-2 has garnered interest as a therapeutic target for solid cancers (Cubas et al., Biochim Biophys Acta 2009; 1796:309- 14). Trop-2 is overexpressed Trop-2 in breast (Huang et al., Clin Cancer Res 2005; 11:4357- 64), colorectal (Ohmachi et al., Clin Cancer Res 2006; 12:3057-63; Fang et al., Int J Colorectal Dis 2009; 24:875-84), and oral squamous cell (Fong et al., Modern Pathol 2008; 21: 186-91) carcinomas. Thus, anti-Trop-2 antibody-drug conjugates provide a promising avenue for designing cancer therapeutics. Additional targets of interest include HER2 and HER3. HER2 is a validated cancer target, and both monoclonal antibodies and small molecule inhibitors of HER2 have been approved for the treatment of various cancers. HER3 is widely expressed in solid tumors and associated with tumor growth and drug resistance. Thus, anti-HER2 and anti- HER3 antibody-drug conjugates provide a promising avenue for designing cancer therapeutics [0005] Using ADCs as part of a therapeutic approach allows for a more targeted treatment of cancer, which may deliver a desired therapeutic to the cancer cell while sparing healthy tissue. Accordingly, a need exists for therapeutic approaches utilizing ADCs as part of a combination therapy for targeted cancer treatments that can improve patient outcomes and reduce the side effects associated with chemotherapy.
SUMMARY
[0006] Provided herein is a method of treating cancer in a subject, the method comprising administering plinabulin or a pharmaceutically acceptable salt thereof to the subject in combination with an antibody-drug conjugate (ADC).
[0007] In some embodiments, the cancer overexpresses Trop-2. In some embodiments, the cancer overexpresses HER2. In some embodiments, the cancer overexpresses HER3. In some embodiments, the cancer is a breast cancer, a bladder cancer, a glioma, a glioblastoma, a head and neck cancer, a non-small cell lung cancer, a small cell lung cancer, recurrent small cell lung cancer (SCLC), a colorectal cancer, a gastrointestinal stromal tumor, a gastroesophageal carcinoma, a renal cell cancer, a prostate cancer, a liver cancer, a colon cancer, a pancreatic cancer, an ovarian cancer, a lymphoma, a cutaneous T-cell lymphoma, or a melanoma. In some embodiments, the cancer is colorectal cancer, a breast cancer, gastrointestinal stromal tumor, or a gastroesophageal carcinoma. In some embodiments, the cancer is breast cancer. In some such embodiments, the cancer is triple negative breast cancer (TNBC).
[0008] In some embodiments, the dose of plinabulin is from about 10 mg/m2 to about 50 mg/m2. In some such embodiments, the dose of plinabulin is about 20 mg/m2. In other such embodiments, the dose of plinabulin is about 30 mg/m2. In some embodiments, the dose of plinabulin is about 40 mg. In some embodiments, the plinabulin is administered intravenously.
[0009] In some embodiments, the ADC comprises an anti-Trop-2 antibody selected from the group consisting of: LS-C126418, LS-C178765, LS-C126416, LS-C126417, 10428- MM01, 10428-MM02, 10428-R001, 10428-R030, MR54, sc-376181, sc-376746, MM0588- 49D6, ab79976, ab89928, BRI 10, hRS7, sacituzumab and datopotamab.
[0010] In some embodiments, the ADC comprises an anti-HER2 antibody selected from the group consisting of: trastuzumab, margetuximab pertuzumab, GB235, huMAb4D5- 1, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8.
[0011] In some embodiments, the ADC comprises an anti-HER3 antibody selected from the group consisting of: Patritumab, Seribantumab, Lumretuzumab, GSK2849330, CDX- 3379, Barecetamab, AV-203, Elgemtumab, HMBD-001, U3P1287/01, and SIBP-03.
[0012] In some embodiments, the ADC comprises a topoisomerase inhibitor. In some embodiments the topoisomerase inhibitor is a topoisomerase I inhibitor.
[0013] In some embodiments, the ADC comprises a drug selected from ozogamicin, vedotin, emtansine, camptothecins, exatecan, topotecan, irinotecan, belotecan, deruxtecan, govitecan, mafodotin, pasudotox tesirine, calicheamicin yl, or doxorubicin.
[0014] In some embodiments, the ADC comprises a drug selected from deruxtecan and govitecan.
[0015] In some embodiments, the antibody-drug conjugate is sacituzumab govitecan, datopotamab deruxtecan, trastuzumab emtansine, trastuzumab deruxtecan, Patritumab deruxtecan. ifinatamab deruxtecan, Raludotatug deruxtecan, DS-6000, SHR- A2009, RC-48 SKB264, LCB84, STI-3258, BAT8008, FDA018-ADC, BIO-106, JS108, PF- 06664178, or a combination thereof. In some specific embodiments, the antibody-drug conjugate is sacituzumab govitecan. In other embodiments, the antibody-drug conjugate is trastuzumab deruxtecan,
[0016] In some embodiments, the dose of the antibody-drug conjugate is from about 0.1 mg/kg to about 15 mg/kg. In some embodiments, the antibody-drug conjugate is from about 0.5 mg/kg to about 5 mg/kg. In some embodiments, the dose of the antibody-drug conjugate is 1.0 mg/kg. In some embodiments, the antibody-drug conjugate is administered intravenously.
[0017] In some embodiments, the method disclosed herein comprises a treatment cycle. In some embodiments, the treatment cycle is from 1 day to 30 days. In some such embodiments, the treatment cycle is 21 days. In other such embodiments, the treatment cycle is 28 days.
[0018] In some embodiments, the plinabulin is administered on day 1 of the treatment cycle. In some embodiments, the plinabulin is administered on day 4 of the treatment cycle.
[0019] In some embodiments, the antibody-drug conjugate is administered on day 1 of the treatment cycle. In some embodiments, the antibody-drug conjugate is administered on day 8 of the treatment cycle.
[0020] In some embodiments, the method disclosed herein further includes, administration of: radiation therapy, an immune checkpoint inhibitor, a chemotherapeutic agent, or a combination thereof, to the subject.
[0021] In some embodiments, the methods disclosed herein comprises administration of an immune checkpoint inhibitor. In some such embodiments, the one or more immune checkpoint inhibitor is administered intravenously. In some embodiments, the immune checkpoint inhibitor is administered to the subject in an amount of from 50 mg to 2000 mg. In some embodiments, the one or more immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pidilizumab, ipilimumab, BMS 936559, RMP1-14, durvalumab, or a combination thereof.
[0022] In some embodiments, the method disclosed herein further includes administration of radiation therapy to the subject. In some embodiments, radiation therapy is administered in one to ten fractions. In some embodiments, radiation therapy is administered three to five fractions. In some such embodiments, radiation therapy is administered in three fractions, four fractions or five fractions. In some embodiments, the total dose of radiation administered is from about 1 Gy to about 20 Gy. In some embodiments, the total dose of radiation administered is from about 2 Gy to about 15 Gy. In some embodiments, the total dose of radiation administered is from about 4 Gy to about 15 Gy. In some embodiments, the total dose of radiation administered is about 4 Gy, or about 8 Gy, or about 12.5 Gy. In some embodiments, radiation therapy is administered on days 1, 2, and 3 of the treatment cycle, or on days 1, 2, 3, and 4 of the treatment cycle, or on days 1, 2, 3, 4, and 5 of the treatment cycle. In some embodiments, when radiation therapy and plinabulin are administered on the same day, the plinabulin is administered from about 3 hours to about 12 hours after completion of administration of the radiation therapy.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 depicts the single compound ICso tests against the NCI -Hl 975 nonsmall cell lung cancer cell line.
[0024] FIG. 2 depicts the single compound ICso tests against the KPL-4 metastatic breast cancer cell line.
[0025] FIG. 3 shows the Bliss synergy plot for combination testing of plinabulin with trastuzumab deruxtecan on HER2-positve KPL-4 breast cancer cells.
[0026] FIG. 4 shows the Loewe synergy plot for combination testing of plinabulin with trastuzumab deruxtecan on HER2-positve KPL-4 breast cancer cells.
[0027] FIG. 5 shows the Bliss synergy plot for combination testing of plinabulin with sacituzumab govetican on NCI-H1975 non-small cell lung cancer cells.
[0028] FIG.6 shows the Loewe synergy plot for combination testing of plinabulin with sacituzumab govetican on NCI-H1975 non-small cell lung cancer cells.
DETAILED DESCRIPTION
[0029] The present disclosure provides methods and therapeutic compositions for treating, ameliorating, or preventing a cancer or a tumor in a subject using plinabulin. In some embodiments, methods and compositions provided herein are useful in treating, delaying the progression of, preventing relapse of, or alleviating a symptom of a cancer or other neoplastic condition using plinabulin. Plinabulin, (3Z,6Z)-3-Benzylidene-6-{[5-(2-methyl-2-propanyl)- l/7-imidazol-4-yl]methylene}-2,5-piperazinedione, is a synthetic analog of the natural compound phenylahistin. Plinabulin can be readily prepared according to methods and procedures detailed in U.S. Pat. Nos. 7,064,201 and 7,919,497, which are incorporated herein by reference in their entireties. [0030] Some embodiments disclosed herein include administration of plinabulin, or a pharmaceutically acceptable salt thereof, to a cancer subject, in combination with an antibody-drug conjugate (ADC). In some embodiments, the ADC is an anti-Trophoblast cell surface antigen 2 (Trop-2) ADC. Trop-2 is a transmembrane glycoprotein involved in calcium signal transduction and is expressed in multiple tumor types including, but not limited to squamous cell carcinomas of various origins, urothelial, breast, prostate, pancreatic, and ovarian cancers. Dum et al. Pathobiology 2022, 89(4): 245-258. Trop-2 is a 40-kDa glycoprotein that was the first described transducer of intracellular calcium signaling Lipinski et al. Proc Natl Acad Set USA 1981, 78(8):5147-50; Ripani et al. Int J Cancer. 1998;76(5):671-676. It contains a 274-amino-acid extracellular epidermal growth factor-like repeat portion with three domains, a cysteine- rich domain, a thyroglobulin type-1 domain, and a cysteine-poor domain. Goldenberg et al. Oncotarget. 2018, 9(48):28989-29006. In some embodiments, the ADC is an anti-Human epidermal growth factor receptor-2 (HER2) ADC. In some embodiments, the ADC is an anti-Human epidermal growth factor receptor-3 (HER3) ADC. In some embodiments, the ADC is an anti-B7-H3 ADC. In some embodiments, the ADC is an anti- CDH6 ADC. In some embodiments, the ADC may be an anti-EGFR, anti- Nectin-4, anti-cMet, anti-Integrin-beta-6, anti-Tissue factor, anti-SEZ6 (seizure-related homolog protein 6), or anti-DLL3 (delta-like ligand 3) ADC. In some embodiments, the plinabulin and ADC may be administered in combination with one or more immune checkpoint inhibitor, additional chemotherapeutic agents, and/or radiation therapy.
[0031] Before the present disclosure is further described, it is to be understood that this invention 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 invention will be limited only by the appended claims.
[0032] 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 invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, 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 invention.
[0033] 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.
[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.
[0035] 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.
[0036] 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.
[0037] 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 invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
Definitions
[0038] 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 this disclosure 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. [0039] 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.
[0040] 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.
[0041] 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.
[0042] 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. In some embodiments, antibody may refer to an immunoglobulin (Ig) defined as a protein belonging to the class IgG, IgM, IgE, IgA, or IgD (or any subclass thereof), or a functional binding fragment or binding domain of an immunoglobulin. An antibody or antibody fragment as disclosed herein may be conjugated or otherwise derivatized. In some embodiments, the antibody is an anti-Trop-2 antibody. In some embodiments, the antibody is an anti-Trop-2 monoclonal antibody.
[0043] 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.
[0044] The term “ADC” or “antibody drug conjugate” as used herein refers to a compound that comprises an antibody (or fragment thereof) that is used to target and/or bind to the cell, a drug (or payload), and a linker which covalently binds the drug to the antibody. The term “anti-Trop-2 ADC” or “anti-Trop 2-antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-Trop-2 antibody. The term “anti-HER2 ADC” or “anti-HER2-antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-HER2 antibody. The term “anti-HER3 ADC” or “anti-HER3 -antibody drug conjugate” as used herein refers to an ADC wherein the antibody is an anti-HER3 antibody.
[0045] 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.
[0046] 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.
[0047] 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.
[0048] 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.
[0049] 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.
[0050] 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.
[0051] 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.
[0052] 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.
Anti-Trop-2 Antibodies and Anti-Trop-2 ADCs
[0053] Various embodiments described herein are directed to the use of ADCs wherein the antibodies or fragments thereof in the ADC bind to Trop-2. Trop-2 is a type-I transmembrane protein and has been cloned from both human (Fornaro et al., Int J Cancer 1995; 62:610-8) and mouse cells (Sewedy et al., Int J Cancer 1998; 75:324-30). The amino acid sequence of human Trop-2 is known (see, e.g., NCBI Accession No. P09758.3). In addition to its role as a tumor-associated calcium signal transducer (Ripani et al., Int J Cancer 1998; 76:671-6), the expression of human Trop-2 was shown to be necessary for tumorigenesis and invasiveness of colon cancer cells, which could be effectively reduced with a polyclonal antibody against the extracellular domain of Trop-2 (Wang et al., Mol Cancer Ther 2008; 7:280-5).
[0054] Therapeutic conjugates comprising an anti-TROP-2 antibody such as the hRS7 monoclonal antibody can be used to treat carcinomas such as carcinomas of the esophagus, pancreas, lung, stomach, colon and rectum, urinary bladder, breast, ovary, uterus, kidney and prostate, as disclosed, e.g., in U.S. Patent No. 7,238,785; 7,517,964 and 8,084,583, which are incorporated herein by reference in their entirety. An hRS7 antibody is a humanized antibody that comprises light chain complementarity-determining region (CDR) sequences CDR1 (KASQDVSIAVA); CDR2 (SASYRYT); and CDR3 (QQHYITPLT) and heavy chain CDR sequences CDR1 (NYGMN); CDR2 (WINTYTGEPTYTDDFKG) and CDR3 (GGFGSSYWYFDV)
[0055] Other anti-Trop-2 ADCs for use as described herein may be prepared from a number of anti-Trop-2 antibodies. For instance, anti-Trop-2 antibodies are commercially available from a number of sources and include, but are not limited to LS-C126418, LS- C178765, LS-C126416, LS-C126417 (LifeSpan BioSciences, Inc., Seattle, Wash.); 10428- MM01, 10428-MM02, 10428-R001, 10428-R030 (Sino Biological Inc., Beijing, China); MR54 (eBioscience, San Diego, Calif); sc-376181, sc-376746, Santa Cruz Biotechnology (Santa Cruz, Calif.); MM0588-49D6, (Novus Biologicals, Littleton, Colo.); ab79976, and ab89928 (ABCAM®, Cambridge, Mass.).
[0056] Other anti-Trop-2 antibodies have been disclosed in the art and can be used in the ADCs disclosed herein. For example, U.S. Publ. No. 2013/0089872 (incorporated herein by reference in its entirety) discloses anti-Trop-2 antibodies K5-70 (Accession No. FERM BP- 11251), K5-107 (Accession No. FERM BP- 11252), K5- 116-2-1 (Accession No. FERM BP- 11253), T6-16 (Accession No. FERM BP-11346), and T5-86 (Accession No. FERM BP- 11254), deposited with the International Patent Organism Depositary, Tsukuba, Japan. U.S. Pat. No. 5,840,854 (incorporated herein by reference in its entirety) discloses the anti-Trop-2 monoclonal antibody BRI 10 (ATCC No. HB11698). U.S. Pat. No. 7,420,040 (incorporated herein by reference in its entirety) discloses an anti-Trop-2 antibody produced by hybridoma cell line AR47A6.4.2, deposited with the ID AC (International Depository Authority of Canada, Winnipeg, Canada) as accession number 141205-05. U.S. Pat. No. 7,420,041 (incorporated herein by reference in its entirety) discloses an anti-Trop-2 antibody produced by hybridoma cell line AR52A301.5, deposited with the IDAC as accession number 141205-03. U.S. Publ. No. 2013/0122020 (incorporated herein by reference in its entirety) discloses anti-Trop-2 antibodies 3E9, 6G11 , 7E6, 15E2, 18B1. Hybridomas encoding a representative antibody were deposited with the American Type Culture Collection (ATCC), Accession Nos. PTA-12871 and PTA-12872. ADC PF 06263507, comprising an anti-5T4 (anti-Trop-2) antibody attached to the tubulin inhibitor monomethylauristatin F (MMAF) is available from Pfizer, Inc. (Groton, Conn.) (see, e.g., Sapra et al., 2013, Mol Cancer Ther 12:38-47, which is incorporated herein by reference in its entirety). U.S. Pat. No. 8,715,662 (incorporated herein by reference in its entirety) discloses anti-Trop-2 antibodies produced by hybridomas deposited at the AID-ICLC (Genoa, Italy) with deposit numbers PD 08019, PD 08020 and PD 08021. U.S. Patent Application Publ. No. 20120237518 (incorporated herein by reference in its entirety) discloses anti-Trop-2 antibodies 77220, KM4097 and KM4590. U.S. Pat. No. 8,309,094 (incorporated herein by reference in its entirety) discloses antibodies Al and A3, identified therein by sequence listing. Non-patent publication Lipinski et al. (1981, Proc Natl. Acad Sci USA, 78:5147-50) discloses anti-Trop-2 antibodies 162-25.3 and 162-46.2, which is incorporated herein by reference in its entirety. In some embodiments, the anti-Trop-2 antibodies may be sacituzumab or datopotamab. All of the antibodies disclosed above can be used in an ADC for use as described herein.
[0057] In some embodiments, the anti-Trop-2 ADC comprises a drug (payload) that may be cytotoxic to cells. The drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents. In some embodiments, the drug may be ozogamicin, vedotin, emtansine, camptothecins, exatecan, topotecan, irinotecan, belotecan, deruxtecan, govitecan, mafodotin, pasudotox tesirine, calicheamicin yl, or doxorubicin.. In some specific embodiments, the drug may be govitecan. In other specific embodiments, the drug may be deruxtecan.
[0058] In some embodiments, the anti-Trop-2 ADC may be sacituzumab govitecan (IMMU-132, hRS7-SN-38, Trodelvy®), datopotamab deruxtecan, (Dato-Dxd, DS-1062a), SKB264, LCB84, STI-3258, BAT8008, FDA018-ADC, BIO-106, JS108, PF-06664178, or a combination thereof. In some specific embodiments, the anti-Trop-2 ADC may be sacituzumab govitecan. In other embodiments, the anti-Trop-2 ADC may be datopotamab deruxtecan. Anti-HER2 Antibodies and Anti-HER2 ADCs
[0059] Various embodiments described herein are directed to the use of ADCs wherein the antibodies or fragments thereof in the ADC bind to HER2. HER2 is a protein (Human epidermal growth factor receptor-2) that normally resides in the membranes of cells. Overexpression of HER2 is believed to play a crucial role in the malignant transformation of normal cells and in the continued growth of normal cells. HER2 is a validated cancer target, and both monoclonal antibodies and small molecule inhibitors of HER2 have been approved for the treatment of various cancers.
[0060] Therapeutic conjugates comprising an anti-HER2 can be used to treat carcinomas such as breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, or prostate cancer. Anti HER2 ADCs may include, but are not limited to, trastuzumab emtansine, trastuzumab deruxtecan, and RC-48.
[0061] In some embodiments, the anti-HER2 ADC comprises a drug (payload) that may be cytotoxic to cells. The drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents. In some embodiments, the drug may be ozogamicin, vedotin, emtansine, camptothecins, exatecan, topotecan, irinotecan, belotecan, deruxtecan, govitecan, mafodotin, pasudotox tesirine, calicheamicin yl, or doxorubicin..
[0062] Other anti-HER2 ADCs for use as described herein may be prepared from a number of anti-HER2 antibodies. For instance, anti-HER2 antibodies may include, but are not limited to, trastuzumab, margetuximab, pertuzumab, GB235, huMAb4D5-l, huMAb4D5- 2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8.
Anti-HER3 Antibodies and Anti-HER3 ADCs
[0063] Various embodiments described herein are directed to the use of ADCs wherein the antibodies or fragments thereof in the ADC bind to HER3. HER3 (Human epidermal growth factor receptor-3) is a membrane-bound protein. HER3, as a heterodimerization partner with HER2, is implicated in growth, proliferation, chemotherapeutic resistance, and the promotion of invasion and metastasis. Holbro et al., Proc. Natl. Acad. Set. U.S.A. 100 (15): 8933-8; Wang et al. Oncogene. 29 (29): 4225-36. HER3 is widely expressed in solid tumors and associated with tumor growth and drug resistance.
[0064] Therapeutic conjugates comprising an anti-HER3 could potentially be used to treat cancers. For example, anti HER3 ADCs maybe used to treat carcinomas such as breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, or prostate cancer. Anti HER3 ADCs may include, but are not limited to, Patritumab deruxtecan and SHR-A2009.
[0065] In some embodiments, the anti-HER3 ADC comprises a drug (payload) that may be cytotoxic to cells. The drug may belong to a variety of classes of drugs, including but not limited to auristatins, maytansinoids, pyrrolobenzodiazepines, tubulysins, erubulin, taxol derivatives, duocarmycins, camptothecins, topoisomerase inhibitors, calicheamicins, thalianstatins, or DNA damaging agents. In some embodiments, the drug may be ozogamicin, vedotin, emtansine, camptothecins, exatecan, topotecan, irinotecan, belotecan, deruxtecan, govitecan, mafodotin, pasudotox tesirine, calicheamicin yl, or doxorubicin.. [0066] Other anti-HER3 ADCs for use as described herein may be prepared from a number of anti-HER3 antibodies. For instance, anti-HER3 antibodies may include, but are not limited to, Patritumab, Seribantumab, Lumretuzumab, GSK2849330, CDX-3379, Barecetamab, AV-203, Elgemtumab, HMBD-001, U3P1287/01, and SIBP-03. Other ADCS
[0067] Various embodiments described herein are directed to the use of ADCs wherein the antibodies or fragments thereof in the ADC bind to other targets including, but not limited to B7-H3 and CDH6. In some embodiments, the anti-B7-H3 ADC may be ifinatamab deruxtecan. In some embodiments, the anti-CDH6 ADC may be DS-6000. In some embodiments, the ADC may be an anti-EGFR, anti-Nectin-4, anti-cMet, anti-Integrin-beta-6, anti-Tissue factor, anti-SEZ6 (seizure-related homolog protein 6), or anti-DLL3 (delta-like ligand 3) ADC.
Immune Checkpoint Inhibitors
[0068] In some embodiments, one or more immune checkpoint inhibitor may be co-administered with plinabulin and the ADCs described herein. 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 antitumor 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.
[0069] 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.
[0070] The Programmed Death 1 (PD-1) protein is an inhibitory member of the extended CD28/CTLA-4 family of T cell regulators (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8; which are incorporated herein by reference in their entirety). Other members of the CD28 family include CD28, CTLA-4, ICOS and BTLA. PD-1 is suggested to exist as a monomer, lacking the unpaired cysteine residue characteristic of other CD28 family members. PD-1 is expressed on activated B cells, T cells, and monocytes.
[0071] The PD-1 gene encodes a 55 kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8:765-72, which is incorporated herein by reference in its entirety). Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif that is important for B7-1 and B7-2 binding. Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD- L2 (B7-DC), that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carter et al. (2002) Eur. J. Immunol. 32:634- 43; which are incorporated herein by reference in their entirety). Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1, but do not bind to other CD28 family members. PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9, which is incorporated herein by reference in its entirety).
[0072] PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signals (Ishida, Y. et al. (1992) EMBO J. 11 :3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5): 739-745; which are incorporated herein by reference in their entirety). The interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can lead to, e.g., a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and/or immune evasion by cancerous cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100; which are incorporated herein by reference in their entirety). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99: 12293-7; Brown et al. (2003) J. Immunol. 170: 1257-66; which are incorporated herein by reference in their entirety).
[0073] The immune checkpoint receptor cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) is expressed on T-cells and is involved in signaling pathways that reduce the level of T-cell activation. It is believed that CTLA-4 can downregulate T-cell activation through competitive binding and sequestration of CD80 and CD86. In addition, CTLA-4 has been shown to be involved in enhancing the immunosuppressive activity of TReg cells.
[0074] The immune checkpoint receptor programmed death 1 (PD-1) is expressed by activated T-cells upon extended exposure to antigen. Engagement of PD-1 with its known binding ligands, PD-L1 and PD-L2, occurs primarily within the tumor microenvironment and results in downregulation of anti-tumor specific T-cell responses. Both PD-L1 and PD-L2 are known to be expressed on tumor cells. The expression of PD-L1 and PD-L2 on tumors has been correlated with decreased survival outcomes.
[0075] The immune checkpoint receptor T cell membrane protein 3 (TIM-3) is expressed on Thl and Tel cells, but not other T-cells. Interaction of TIM-3 with its ligand, galectin-9, produces a Thl cell death signal. TTM-3 has been reported to play a role in maintaining T-cell exhaustion and blockade of TIM-3 has been shown to restore activity to exhausted T-cells.
[0076] The immune checkpoint receptor B- and T-lymphocyte attenuator (BTLA) receptor is expressed on both resting and activated B-cells and T-cells. Activation of BTLA when combined with its ligand HVEM (herpes virus entry mediator) results in downregulation of both T-cell activation and proliferation. HVEM is expressed by certain tumors (e.g., melanoma) and tumor-associated endothelial cells.
[0077] The immune checkpoint receptors known as killer cell immunoglobulin- like receptors (KIR) are a polymorphic family of receptors expressed on NK cells and some T- cells and function as regulators of immune tolerance associated with natural killer (NK) cells. Blocking certain KIR receptors with inhibitor compounds can facilitate the destruction of tumors through the increased activity of NK cells.
[0078] In some embodiments of the present disclosure, the immune checkpoint inhibitor compound is a small organic molecule (molecular weight less than 1000 daltons), a peptide, a polypeptide, a protein, an antibody, an antibody fragment, or an antibody derivative. In some embodiments, the immune checkpoint inhibitor compound is an antibody. In some embodiments, the antibody is a monoclonal antibody, specifically a human or a humanized monoclonal antibody.
[0079] Monoclonal antibodies, antibody fragments, and antibody derivatives for blocking immune checkpoint pathways can be prepared by any of several methods known to those of ordinary skill in the art, including but not limited to, somatic cell hybridization techniques and hybridoma, methods. Hybridoma generation is described in Antibodies, A Laboratory Manual, Harlow and Lane, 1988, Cold Spring Harbor Publications, New York, which is incorporated herein by reference in its entirety. Human monoclonal antibodies can be identified and isolated by screening phage display libraries of human immunoglobulin genes by methods described for example in U.S. Pat. Nos. 5,223,409, 5,403,484, 5,571,698, 6,582,915, and 6,593,081, which are incorporated herein by reference in their entirety. Monoclonal antibodies can be prepared using the general methods described in U.S. Pat. No. 6,331,415 (Cabilly), which is incorporated herein by reference in its entirety.
[0080] As an example, human monoclonal antibodies can be prepared using a XenoMouse™ (Abgenix, Freemont, Calif) or hybridomas of B cells from a XenoMouse. A XenoMouse is a murine host having functional human immunoglobulin genes as described in U.S. Pat. No. 6,162,963 (Kucherlapati), which is incorporated herein by reference in its entirety.
[0081] 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 and therapeutic 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.
[0082] In some embodiments, the one or more immune checkpoint inhibitor is an inhibitor of PD-1, PD-L1, or CTLA-4. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a binding ligand of PD-L1. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.
[0083] In some embodiments, the one or more immune checkpoint inhibitor as described herein includes a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, wherein the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor. In some embodiments, the first and the second immune checkpoint inhibitor are independently an inhibitor of PD-1, PD-L1 or CTLA-4. In some embodiments, the first immune checkpoint inhibitor is a PD- 1 inhibitor, and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.
[0084] In some embodiments, the immune checkpoint inhibitor is Pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, RMP1-14, durvalumab, or any combinations thereof. In some specific embodiments, the immune checkpoint inhibitor may be RMP1-14. 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 3 G10, 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. [0085] In some embodiments, the one or more immune checkpoint inhibitor may be incorporated in a pharmaceutically acceptable formulation. In some embodiments, the one or more immune checkpoint inhibitor is incorporated in a pharmaceutically acceptable aqueous formulation. Examples of acceptable aqueous formulations include isotonic buffered and pH 4.5-8 adjusted saline solutions such as Lactated Ringer's Solution and the like.
[0086] In some embodiments, the immune checkpoint inhibitor compound is incorporated in a pharmaceutically acceptable liposome formulation, wherein the formulation is a passive or targeted liposome formulation. Examples of methods for the preparation of suitable liposome formulations of antibodies are described U.S. Pat. No. 5,399,331 (Loughrey), U.S. Pat. No. 8,304,565 (Wu) and U.S. Pat. No. 7,780,882 (Chang), which are incorporated herein by reference in their entirety.
[0087] In some embodiments, the one or more immune checkpoint inhibitor may be an antibody. In some embodiments, the antibody is a dry, lyophilized solid that is reconstituted with an aqueous reconstitution solvent prior to use. In some embodiments, the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is injected directly into a tumor. In some embodiments, the immune checkpoint inhibitor antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is injected into the peritumoral region surrounding a tumor. The peritumoral region may contain antitumor immune cells. In some embodiments, the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by intravenous injection or infusion. In some embodiments, the immune checkpoint inhibitor antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by subcutaneous injection or intradermal injection. In some embodiments, the antibody is incorporated in a pharmaceutically acceptable formulation and the pharmaceutically acceptable formulation is administered by intraperitoneal injection or lavage.
[0088] 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
[0089] In some embodiments, the plinabulin, ADC, and optionally one or more immune checkpoint inhibitor may be administered in combination 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, CARBOPLAHN-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, Fluor oplex (Fluorouracil— Topical), Fluorouracil Injection, Fluorouracil — Topical, Flutamide, Folex (Methotrexate), Folex PFS (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 LPP (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 Lormulation), Navelbine (Vinorelbine Tartrate), Necitumumab, Nelarabine, Neosar (Cyclophosphamide), Netupitant and Palonosetron Hydrochloride, Neupogen (Lilgrastim), Nexavar (Sorafenib Tosylate) , Nilotinib, Ninlaro (Ixazomib Citrate), Nolvadex (Tamoxifen Citrate), Nplate (Romiplostim), Obinutuzumab, Odomzo (Soni degib), OEPA, Ofatumumab, OPP, Olaparib, Omacetaxine Mepesuccinate, Oncaspar (Pegaspargase), Ondansetron Hydrochloride, Onivyde (Irinotecan Hydrochloride Liposome), Ontak (Denileukin Diftitox), OPPA , Osimertinib, Oxaliplatin, Paclitaxel, Paclitaxel Albumin-stabilized Nanoparticle Formulation, PAD, Palbociclib, Palifermin, Palonosetron Hydrochloride, Palonosetron Hydrochloride and Netupitant, Pamidronate Disodium, Panitumumab, Panobinostat, Paraplat (Carboplatin), Paraplatin (Carboplatin), Pazopanib Hydrochloride, PCV , Pegaspargase, Peginterferon Alfa-2b, PEG- Intron (Peginterferon Alfa- 2b), Pemetrexed Disodium Perjeta (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, Tafinlar (Dabrafenib), Tagrisso (Osimertinib), Talc, Talimogene Laherparepvec, Tamoxifen Citrate, Tarabine PFS (Cytarabine), Tarceva (Erlotinib Hydrochloride), Targretin (Bexarotene), Tasigna (Nilotinib), Taxol (Paclitaxel), Taxotere (Docetaxel), Temodar (Temozolomide), Temozolomide, Temsirolimus, Thalidomide, Thioguanine, Thiotepa, Tolak (Fluorouracil— Topical), Toposar (Etoposide), Topotecan Hydrochloride, Toremifene, Torisel (Temsirolimus), Tositumomab and Iodine 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 (Vincristine Sulfate), 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 (Idelalisib), Zykadia (Ceritinib), and Zytiga (Abiraterone Acetate).
[0090] In some embodiments, the additional chemotherapeutic agent is docetaxel.
[0091] The precise amount of additional chemotherapeutic agent incorporated in a particular method 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 additional chemotherapeutic agent, 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. Radiation Therapy
[0092] In some embodiments, the combination of plinabulin, ADC, optionally one or more immune checkpoint inhibitor, and optionally one or more additional chemotherapeutic agent 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
[0093] In some aspects, provided herein is a method of treating cancer in a subject, the method comprising administering plinabulin or a pharmaceutically acceptable salt thereof to the subject in combination with an antibody-drug conjugate (ADC)
[0094] In some embodiments, the treatment methods disclosed herein may comprise treatment cycles. The treatment cycles disclosed herein begin on day 1 and end on the last day of the cycle. For example, three week treatment cycles begin on day 1 and end on day 21, while four week treatment cycles begin on day 1 and end on day 28. In some embodiments, the treatment cycle may be 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days, or longer. In some embodiments, the treatment cycle may be 14 days (three weeks or “Q2W”). In some embodiments, the treatment cycle may be 21 days (three weeks or “Q3W”). In some embodiments, the treatment cycle may be 28 days (four weeks or “Q4W”). In some embodiments, the treatment cycle may be repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more times.
[0095] As used herein, the terms “co-administer,” “co-administering,” or “coadministration,” refers to two or more agents or therapies that have a biological effect on a subject at the same time, regardless of when or how they are actually administered. In one embodiment, the agents or therapies are administered simultaneously. In one such embodiment, administration in combination is accomplished by combining the agents in a single dosage form. In another embodiment, the agents or therapies are administered sequentially. In some embodiments, the administration may be separated by a period of time, for example, 30 minutes, 1 hour, 2 hours, 1 day, 2 days, 3 days, or 1 week. In one embodiment the agents are administered through the same route, such as orally. In another embodiment, the agents are administered through different routes, such as one being administered orally and another being administered i.v.
[0096] In some embodiments, a method for treating cancer in a subject may include co-administering a therapeutically effective amount of plinabulin, or a pharmaceutically acceptable salt thereof, with one or more ADC. In some embodiments, the ADC is an anti- Trop-2 ADC. In some such embodiments, the anti-Trop-2 ADC may be sacituzumab govitecan. In other such embodiments, the anti-Trop-2 ADC may be datopotamab deruxtecan. In other embodiments, the ADC is an anti-HER2 ADC. In some such embodiments, the anti- HER2 ADC may be trastuzumab deruxtecan. In other such embodiments, the anti-HER2 ADC may be trastuzumab emtansine. In yet other such embodiments, the anti-HER2 ADC may be RC-48. In yet other embodiments, the ADC is an anti-HER3 ADC. In some such embodiments, the HER3 ADC may be patritumab deruxtecan. In other such embodiments, the anti-HER3 ADC may be SHR-A2009.
[0097] In some embodiments, when the ADC and the plinabulin are administered on the same day, the plinabulin is administered from about 0.5 hours to about 3 hours after completion of administration of the ADC. For example, when the ADC and the plinabulin are administered on the same day, the plinabulin is administered 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours, or a range between any two of these times, after administration of the ADC.
[0098] In some embodiments, when the ADC and the plinabulin are administered on the same day, the ADC is administered from about 0.5 hours to about 3 hours after completion of administration of the plinabulin. For example, when the ADC and the plinabulin are administered on the same day, the ADC is administered 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours, or a range between any two of these times, after administration of the plinabulin.
[0099] In some embodiments, the ADC is administered on day 1 of the treatment cycle and plinabulin is administered on day 1 of the treatment cycle. In other embodiments, the ADC is administered on day 1 of the treatment cycle and plinabulin is administered on day 1 and day 4 of the treatment cycle. In some embodiments, the ADC is administered on day 1 of the treatment cycle, plinabulin is administered on day 1 and day 4 of the treatment cycle. In some embodiments, the ADC is administered on day 1 and day 8 of the treatment cycle, plinabulin is administered on day 1 of the treatment cycle.
[0100] In some embodiments, the ADC is administered on day 1 of the treatment cycle and plinabulin is administered on day 1 of the treatment cycle. In other embodiments, the ADC is administered on day 1 of the treatment cycle and plinabulin is administered on day 1 and day 4 of the treatment cycle. In some embodiments, the ADC is administered on day 1 of the treatment cycle, plinabulin is administered on day 1 and day 4 of the treatment cycle. In some embodiments, the ADC is administered on day 1 and day 8 of the treatment cycle, plinabulin is administered on day 1 of the treatment cycle.
[0101] In some embodiments, the ADC is administered twice a week throughout the duration of the treatment cycle and plinabulin is administered twice a week throughout the duration of the treatment cycle. In some such embodiments, the treatment cycle may be 3 weeks (21 day). In other such embodiments, the treatment cycle may be 4 weeks (28 day).
[0102] In some embodiments, the ADC is administered 1, 2, 3, 4, or 5 times per treatment cycle. In some embodiments, the ADC is administered 1 time per cycle. In other embodiments, the ADC is administered 2 times per cycle. In some embodiments, wherein the treatment cycle is three weeks (Q3W), the ADC is administered 1 time per cycle. In some such embodiments, the ADC is administered on day 1 of the cycle. In some embodiments, wherein the treatment cycle is three weeks (Q3W), the ADC is administered 2 times per cycle. In some such embodiments, the ADC is administered on day 1 and day 8 of the cycle. In some embodiments, wherein the treatment cycle is three weeks (Q4W), the ADC is administered 1 time per cycle. In some such embodiments, the ADC is administered on day 1 of the cycle. In some embodiments, wherein the treatment cycle is three weeks (Q4W), the ADC is administered 2 times per cycle. In some such embodiments, the ADC is administered on day 1 and day 8 of the cycle.
[0103] In some embodiments, the method of treating cancer described herein may include co-administration of one or more immune checkpoint inhibitor, an additional chemotherapeutic agent, and/or radiation therapy. In some embodiments, the method of treating cancer described herein may include co-administration of one or more immune checkpoint inhibitor. In some such embodiments, the immune checkpoint inhibitor may be administered 1, 2, 3, or 4 times a week during the treatment cycle. In some embodiments, the one or more immune checkpoint inhibitor is administered 1, 2, 3, 4, or 5 times per treatment cycle. In some embodiments, the one or more immune checkpoint inhibitor is administered 1 time per cycle. In other embodiments, the one or more immune checkpoint inhibitor is administered 2 times per cycle. In yet other embodiments, the one or more immune checkpoint inhibitor is administered 3 times per cycle. In some embodiments, the treatment cycle may be three weeks. In other embodiments, the treatment cycle may be four weeks.
[0104] In some embodiments wherein the method of treating cancer includes administration of one or more checkpoint inhibitor, plinabulin is administered about 1 min, 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, l lh, 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 mm, 25 mm, 30 mm, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 24h, 3 Oh, 36h, 40h, or 48h, 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 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 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 30h, 36h, 40h, or48h, 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 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 30h, 36h, 40h, or48h, 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 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 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 about lmin-5min, Imin-lOmin, Imin- 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 - 3days, 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 Imin- 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.
[0105] In some embodiments, the treatment cycle 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 cycle 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 cycle 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 cycle 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 cycle includes coadministration 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 cycle includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1 of a 21 -day treatment cycle. In some embodiments, the treatment cycle includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1 and day 4 of a 28-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 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 treatment cycle 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 cycle includes co-administration of one or more immune checkpoint inhibitor plinabulin every day of the week for 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the treatment cycle includes co-administration of one or more immune checkpoint inhibitor and plinabulin on day 1 in weekly treatment. In some embodiments, the treatment cycle 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 cycle 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 cycle 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 cycle 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 cycle 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 cycle 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 cycle 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 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 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.
[0106] In some embodiments, the treatment cycle 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 cycle 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 cycle 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 cycle 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 cycle 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 cycle 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 cycle 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 checkpoint inhibitor. In some embodiments, the treatment cycle includes administration of one or more immune checkpoint inhibitor every day of the week for a week. In some embodiments, the treatment cycle 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 cycle includes administration of one or more immune checkpoint inhibitor composition on day 1 in weekly treatment. In some embodiments, the treatment cycle includes administration of one or more immune checkpoint inhibitor on day 1 and day 2 in weekly treatment. In some embodiments, the treatment cycle 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 cycle includes administration of one or more immune checkpoint inhibitor on day 1, day 3, day 5 in weekly treatment. In some embodiments, the treatment cycle 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 cycle 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 cycle 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.
[0107] In some embodiments wherein the method of treating cancer disclosed herein includes co-administration of radiation therapy, the radiation therapy may be administered on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, and/or 28 of the treatment cycle. For example, in some embodiments, the radiation therapy may be administered on day 1, 2, and 3 of the treatment cycle. In other embodiments, radiation therapy may be administered on day 1, 2, 3, and 4 of the treatment cycle. In yet other embodiments, radiation therapy may be administered on day 1, 2, 3, 4, and 5 of the treatment cycle. In still yet other embodiments, radiation therapy may be administered on day 2, 3, and 4 of the treatment cycle.
[0108] The total dose of radiation administered to the subject during the treatment cycle can be about 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, or 20 Gy, or more, or within a range defined by any two of the aforementioned values. For example, the total dose of radiation administered to the subject can be from about 1 Gy to about 20 Gy, from about 2 Gy to about 15 Gy, from about 4 Gy to about 15 Gy. In some embodiments, the total dose of radiation administered to the subject is about 4 Gy. In other embodiments, the total dose of radiation administered to the subject is about 8 Gy. the total dose of radiation administered to the subject is about 12.5 Gy. In some embodiments, radiation may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 fractions, or more. In some embodiments, radiation may be administered in three to five fractions. In some embodiments, radiation may be administered in three fractions. In some embodiments, radiation may be administered in four fractions. In some embodiments, radiation may be administered in five fractions.
[0109] In some embodiments, when radiation therapy and plinabulin are administered on the same day, the plinabulin is administered from about 3 hours to about 12 hours after completion of administration of the radiation therapy. For example, in some such embodiments, plinabulin is administered from about 4 hours to about 10 hours, about 4 hours to about 8 hours, or about 5 hours to about 8 hours after completion of administration of the radiation therapy. [0110] In some embodiments, the present disclosure provides a method for treating a breast cancer, a bladder cancer, a glioma, a glioblastoma, a head and neck cancer, a nonsmall cell lung cancer, a small cell lung cancer, recurrent small cell lung cancer (SCLC), a colorectal cancer, a gastrointestinal stromal tumor, a gastroesophageal carcinoma, a renal cell cancer, a prostate cancer, a liver cancer, a colon cancer, a pancreatic cancer, an ovarian cancer, a lymphoma, or a cutaneous T-cell lymphoma, or a melanoma. In some embodiments the cancer is a colorectal cancer, a breast cancer, gastrointestinal stromal tumor, or a gastroesophageal carcinoma. In some embodiments, the cancer is triple negative breast cancer (TNBC).
[0111] In some embodiments, the present disclosure provides a method for treating Fibrolamellar hepatocellular carcinoma, MSI-H cancers of any histology including but not limited to: colorectal, endometrial, adrenocortical, anal, appendiceal cancer, biliary, bladder, brain, breast, cervical, gastric or gastroesophageal junction, head and neck squamous cell, liver, mesothelioma, nasopharyngeal, neuroendocrine, ovarian, pancreatic, prostate, renal cell, retroperitoneal, salivary, sarcoma, small cell lung, small intestinal, testicular, thyroid, vaginal and vulvar.
[0112] In some embodiments, the subject can be an animal, e.g., a mammal, a human. In some embodiments, the subject is a human.
[0113] In some embodiments, plinabulin or a pharmaceutically acceptable salt thereof is incorporated in a pharmaceutically acceptable solution. In some embodiments, plinabulin or a pharmaceutically acceptable salt thereof is incorporated in an injectable formulation. In some embodiments, plinabulin or a pharmaceutically acceptable salt thereof is incorporated in an injectable formulation that substantially maintains plinabulin or a pharmaceutically acceptable salt thereof at or near the injection site.
[0114] The precise amount of plinabulin or a pharmaceutically acceptable salt thereof 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 intended dosing regimen or sequence. Accordingly, it is not practical to specifically set forth an amount that constitutes an amount of plinabulin or a pharmaceutically acceptable salt thereof therapeutically effective for all possible applications. Those of ordinary skill in the art, however, can readily determine an appropriate amount with due consideration of such factors.
[0115] In some embodiments, the ADC is incorporated in a pharmaceutically acceptable solution. In some embodiments, the ADC is incorporated in an injectable formulation. In some embodiments, ADC is incorporated in an injectable formulation that substantially maintains ADC at or near the injection site.
[0116] The precise amount of ADC 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 intended dosing regimen or sequence. Accordingly, it is not practical to specifically set forth an amount that constitutes an amount of ADC therapeutically effective for all possible applications. Those of ordinary skill in the art, however, can readily determine an appropriate amount with due consideration of such factors.
Administration
[0117] 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.
[0118] 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.
[0119] 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 el al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).
[0120] 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.
[0121] 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, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; 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.
[0122] 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.
[0123] 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.
[0124] Compositions described herein may optionally include additional drug actives.
[0125] 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.
[0126] 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, hydroxy ethyl cellulose and purified water.
[0127] 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.
[0128] 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 J Pharm Sci and Tech 1998, 52 238-311 and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 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. [0129] 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 to administration. 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.
[0130] 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/m2 to about 50 mg/m2 In some embodiments, plinabulin is administered at a dose in the range of about 1-50 mg/m2 of 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/m2 of 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/m2 of 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/m2 of the body surface area.
[0131] In some embodiments, the 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, the dose of plinabulin administered is about 20 mg - 60 mg, 27 mg - 60 mg, 20 mg - 45 mg, or 27 mg - 45 mg. In some embodiments, the dose of 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, the 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, the 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.
[0132] In some embodiments, ADC may be administered at a dose in the range of about 1 mg/m2 to about 50 mg/m2. In some embodiments, the ADC is administered at a dose in the range of about 1-50 mg/m2 of the body surface area. In some embodiments, the ADC 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, the ADC 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/m2 of the body surface area. In some embodiments, the ADC 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/m2 of the body surface area. In some embodiments, the ADC 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/m2 of the body surface area.
[0133] In some embodiments, the ADC 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, the dose of the ADC administered is about 20 mg - 60 mg, 27 mg - 60 mg, 20 mg - 45 mg, or 27 mg - 45 mg. In some embodiments, the dose of the ADC 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, the ADC 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, the ADC 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.
[0134] In some embodiments, the ADC may be administered at a dose in the range of about 100 gg/kg to about 5000 gg/kg. In some embodiments, the ADC is administered at a dose in the range of about 100-1000 gg/kg. In some embodiments, the ADC 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, pg/kg. In some embodiments, the ADC is administered at a dose of about 100,150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000,2050, 2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, 3000, 3100, 3200, 3300, 3400, 3500, 3600, 3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700, 4800, 4900, or 5000 pg/kg.
[0135] In some embodiments, the plinabulin may be administered at a dose of about 1 mg-100 mg, 2 mg-100 mg, 1 mg-75 mg, 2 mg-75 mg, 5 mg-70 mg, 5 mg- 50mg, 10 mg-70 mg, 10 mg-60 mg, 15 mg - 50 mg, 20 mg-60 mg, 25 mg-50 mg, 30 mg-50 mg, 35-50 mg, or 35 mg to 45 mg; and the ADC may be administered at a dose of about 1-100, 2-100, 5-100, 5- 75, 5-50, 5-40, 5-30, 5-20, 5-15, 10-100, 10-50, 10-30, 10-20, or 10-15 mg/kg. In some embodiments, the plinabulin may be administered at a dose of about 10 mg-70 mg and the ADC may be administered at a dose of about 5-50 mg/kg. In some embodiments, the plinabulin may be administered at a dose of about 20 mg-60 mg and the ADC may be administered at a dose of about 5-20 mg/kg. In some embodiments, the plinabulin may be administered at a dose of about 30 mg-50 mg and the ADC may be administered at a dose of about 5-15 mg/kg.
[0136] In some embodiments, the plinabulin may be administered at a dose of about 1-100, 1-80, 1-60, 1-50, 2-50, 3-50, 5-50, 5-45, 5-40, 5-35, 5-30, 7-30, 7-20, 5-20, 5-15, 10- 40, 10-30. 15-30, 15-25, 20-100, 20-50, or 20-30 mg/m2; and the ADC may be administered at a dose of about 1-100, 2-100, 5-100, 5-75, 5-50, 5-40, 5-30, 5-20, 5-15, 10-100, 10-50, 10- 30, 10-20, or 10-15 mg/kg. In some embodiments, the plinabulin may be administered at a dose of about 105-50 mg/m2 and the ADC may be administered at a dose of about 5-50 mg/kg. In some embodiments, the plinabulin may be administered at a dose of about 10-30 mg/m2 and the ADC may be administered at a dose of about 5-20 mg/kg. In some embodiments, the plinabulin may be administered at a dose of about 15-25 mg/m2 and the ADC may be administered at a dose of about 5-15 mg/kg.
[0137] In some embodiments, the ADC is administered intravenously. In some such embodiments, the ADC is administered over a period of about 30, 60, 90, 120, 150, 180, 210, 240, 270, or 300 minutes, or more, or within a range defined by any two of the aforementioned times. In some embodiments, the ADC is administered over a period of about 30 minutes to about 240 minutes, about 60 minutes to about 300 minutes, about 120 minutes to about 240 minutes, or about 150 minutes to about 210 minutes. In some embodiments, the ADC is administered over a period of about 180 minutes.
[0138] 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.
[0139] In some embodiments, plinabulin is administered prior to the administration of the ADC. In some embodiments, plinabulin is administered concurrently with the ADC. In some embodiments, plinabulin is administered after the administration of the ADC.
[0140] In some embodiments, plinabulin is administered about 1 min, 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, Ih, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, lOh, l lh, 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 the ADC. 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 24h, 3 Oh, 36h, 40h, or 48h, or a range between any two of these values, before the administration of the ADC. 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 30h, 36h, 40h, or 48h, or a range between any two of these values, after the administration of the ADC. 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 30h, 36h, 40h, or 48h, or a range between any two of these values, after the administration of the ADC. 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 30h, 36h, 40h, or 48h, or a range between any two of these values, after the administration of the ADC. 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, l lh, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 3 Oh, 36h, 40h, or 48h, or a range between any two of these values, before the administration of the ADC. 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 days after the administration of the ADC. 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- Ih, 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 the ADC.
[0141] The treatment cycle can be repeated as long as the regimen is clinically tolerated. In some embodiments, the treatment cycle for the ADC 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.
[0142] In some embodiments, the method provided herein includes the administration of one or more immune checkpoint inhibitor. 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, 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,
-SO- 50mg-60mg, 52mg-54mg, 52mg-56mg, 52mg-58mg, 52mg-60mg, 100mg-200mg, 200mg- 300mg, 300mg-400mg, 400mg-500mg, 50mg-2000 mg, 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.
[0143] In some embodiments, the one or more immune checkpoint inhibitor is administered intravenously. In some such embodiments, the one or more immune checkpoint inhibitor is administered over a period of about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, or 120 minutes, or more, or within a range defined by any two of the aforementioned times. In some embodiments, the one or more immune checkpoint inhibitor is administered over a period of about 10 minutes to about 120 minutes, about 20 minutes to about 100 minutes, about 30 minutes to about 90 minutes, or about 30 minutes to about 60 minutes. In some embodiments, the one or more immune checkpoint inhibitor is administered over a period of about 30 minutes. In other embodiments, the one or more immune checkpoint inhibitor is administered over a period of about 60 minutes.
[0144] 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 additional chemotherapeutic agents, radiation therapy, and/or biologic therapies.
[0145] To further illustrate this invention, the following examples are included. The examples should not, of course, be construed as specifically limiting the invention. 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 invention 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 invention without exhaustive examples.
EXAMPLES
Example 1 - Combination of plinabulin with sacituzumab govitecan
[0146] This study assesses the effect of plinabulin when administered in combination with sacituzumab govitecan in NCr athymic nu/nu female mice with subcutaneously transplanted cell line-derived xenograft (CDX). The mice are placed into four testing groups of 8 mice each according to Table 1.
Table 1. Study Groupings
[0147]_ Plinabulin Administration. To groups 3 and 4, Plinabulin is administered biweekly starting on day 1 of the study via intraperitoneal injection at a dosage of 7.5 mg/kg. In study group 4, the plinabulin is administered one hour after administration of sacituzumab govitecan is complete.
[0148]_ Sacituzumab govitecan Administration: To groups 2 and 4, sacituzumab govitecan is administered biweekly via intravenous injection at a dosage of 1 mg/kg.
[0149]_ Measurement of Total Body Weight: The mice are weighed on day 1 prior to administration of treatment. The mice are subsequently weighed three times weekly through the end of the 4- week study. Tumor wet weight of the mice are obtained at the end of the four- week study. Example 2 - Combination of plinabulin with sacituzumab govitecan and immune checkpoint inhibito
[0150] This study assesses the effect of plinabulin when administered in combination with sacituzumab govitecan and/or Anti-PDl antibody RMP1-14 (an immune checkpoint inhibitor) in C57BL/6 female mice with subcutaneously transplanted B-hTROP2 MC38 plus cells. Human TROP2 is highly expressed on the surface of humanized B-hTROP2 MC38 tumor cells, indicating B-hTROP2 MC38 plus cells can be used for in vivo efficacy studies of TROP2 therapeutics. The mice are placed into eight testing groups of 8 mice each according to Table 2.
Table 2, Study Groupings
[0151]_ Plinabulin Administration. To groups 2, 5, 7, and 8, Plinabulin is administered biweekly starting on day 1 of the study via intraperitoneal injection at a dosage of 7.5 mg/kg. In study groups 5 and 8, the plinabulin is administered one hour after administration of sacituzumab govitecan is complete.
[0152]_ Sacituzumab govitecan Administration: To groups 3, 5, 6, and 8, sacituzumab govitecan is administered biweekly via intravenous injection at a dosage of 1 mg/kg.
[0153] RMP1 -14 Administration: To groups 4, 6, 7, and 8, MPR-14 is administered biweekly via intraperitoneal injection at a dosage of 1 mg/kg.
[0154]_ Measurement of Total Body Weight: The mice are weighed on day 1 prior to administration of treatment. The mice are subsequently weighed three times weekly through the end of the 4- week study. Tumor wet weight of the mice are obtained at the end of the four- week study.
Example 3 - Combination Effects on Cell Proliferation
[0155] This study assessed the combination effect of test compounds on a metastatic breast cancer cell line that overexpress HER2. The combination was assessed in reference to a cisplatin control. All solutions containing plinabulin were protected from direct exposure to white light for the duration of the study.
Single Agent ICso Test
[0156] Cells lines (NCI-H1975 and KPL-4) were cultured in a 37 °C incubator with 5% CO2 and 95% air in RPMI1640 (hyclone; Cat # SH30809.01) +10% FBS (ExCell Bio; Cat # FND500) cell culture medium. Cells were harvested during the logarithmic growth period. The harvested cells were resuspended in cell culture medium and counted using a Vi cell counter. Single agent IC50 tests were performed by diluting cells with RPMI1640+10% FBS cell culture medium and 90 pL of cell suspensions were added to 96 well polystyrene microplates (Corning; Cat # 3610). Two duplicate plates were set up: one for reading at TO and the other for culturing in an indicator for reading at the end point (5 days after incubation). The plates were incubated overnight in humidified incubator at 37° C with 5% CO2.
[0157] To the TO plate, 10 pL RPMI1640+10% FBS cell culture medium was added to each well for TO reading. The final medium volume in each well was 100 pL. CellTiter-Glo® Reagent (Promega; Cat # G7573) (60pL) was then added to each well and the contents were mixed for 2 minutes on an orbital shaker to facilitate cell lysis. The plates were allowed to incubate at room temperature for 10 minutes to stabilize luminescent signal. A Backseal black sticker (Perkin Elmer; Cat # 6005189) was then affixed to the bottom of each plate and luminescence was recorded using a Microplate reader.
[0158] For the drug screening plates, the culture medium of the wells was replaced with RPMI1640+11.9% FBS cell culture medium. Solutions of test compounds Trastuzumab deruxtecan, Sacituzumab govitecan, and cisplatin were prepared in phosphate buffered saline (PBS), while plinabulin solution was prepared in dimethyl sulfoxide (DMSO). The solutions were then further diluted to the concentrations for the study as shown in Table 3, with C1-C9 showing the nine concentration levels of test compounds.
Table 3: Testing concentrations for ICso tests
[0159] At the study endpoint, 60 pL of CellTiter-Glo® Reagent was added to each well and the contents were mixed for 2 minutes on an orbital shaker to facilitate cell lysis. The plate was then allowed to incubate at room temperature for 10 minutes to stabilize luminescent signal. A Backseal black was then affixed to the bottom of each plate and luminescence was recorded using a Microplate reader. The ICso data for the single compounds against the NCI- 111975 non-small cell lung cancer cells is provided in FIG. 1, while the ICso data for the single compounds against the NCI-H1975 metastatic breast cancer cells is provided in FIG. 2. The data shows significantly lower ICso values for each individual test compound at compared with cisplatin. Table 4 shows these vales for both tested cell lines.
Table 4: Single Agent ICso tests
Combination Testing
[0160] Testing was performed for the combination of sactuzumab govitecan and plinabulin and for the combination of performed for the combination of trastuzumab deruxtecan and plinabulin to determine the combination effect of the test compounds against NCI-H1975 and KPL-4 cell lines. The testing endpoint for the combination of sactuzumab govitecan and plinabulin was three days, while the testing endpoint for the combination of trastuzumab deruxtecan and plinabulin was five days.
[0161] The testing for each combination against was done in a 6x6 combination matrix for each cell line. The concentration of compound used was based on the ICso values obtained for single compound testing. Concentrations of compounds used for the study against NCI-H1975 cells are shown in Table 5A, with C1-C6 showing the six concentration levels of test compounds. Concentrations of compounds used for the study against KPL-4 cells are shown in Table 5B, with C1-C6 showing the six concentration levels of test compounds.
Table 5 A: Testing concentrations for combination tests against NCI-H1975 cells
Table 5B: Testing concentrations for combination tests against KPL-4 cells
[0162] The results for the testing of the combination of Sacituzumab govitecan and plinabulin against the NCI-H1975 cell line are shown in Table 6. The bolded cells in Table 6 shows an increased effect of the two compounds together as compared to each individual compound as a single agent.
Table 6: Combination testing of sacituzumab govitecan and plinabulin against NCI-H1975 cells [0163] The results for the testing of the combination of Trastuzumab deruxtecan and plinabulin against the KPL-4 cell line are shown in Table 7. The bolded cells in Table 7 shows an increased effect of the two compounds together as compared to each individual compound as a single agent.
Table 7: Combination testing of trastuzumab deruxtecan and plinabulin against KPL-4 cells
[0164] The combination testing data of trastuzumab deruxtecan and plinabulin against KPL-4 cells was also analyzed using the Bliss model (Bliss C. I. Ann. Appl. Biol. 1939, 26, 585-615, which is incorporated herein by reference in its entirety) and using the Loewe model (Loewe, S. ArzneimiettelForschung 1953, 3286-290, which is incorporated herein by reference in its entirety). The Bliss model is a reference model for evaluating the combination effect of two drugs. The basic assumption of this model is the expected effect of two drugs acting independently; i.e. when each target a different signaling pathway. The Loewe model is based on the assumption that both drugs have similar modes of action on the same targets or pathways.
[0165] The Bliss synergy plot for combination testing of plinabulin with trastuzumab deruxtecan on HER2-positve KPL-4 breast cancer cells shows a mean synergy score of +2.15 (FIG.3) and a maximum synergy score of +10.48. Additionally, the Loewe synergy plot for combination testing of plinabulin with trastuzumab deruxtecan on HER2- positve KPL-4 breast cancer cells (FIG. 4) also shows a positive mean synergy score, with a mean synergy score of +3.36 and a maximum synergy score of +11.98. Thus, both models show a positive synergy score for plinabulin with trastuzumab deruxtecan against HER2- positve KPL-4 breast cancer cells. The Bliss and Loewe synergy scores for particular combinations of concentration of plinabulin and trastuzumab deruxtecan are shown in Tables 8 and 9.
Table 8: Bliss synergy scores for trastuzumab deruxtecan and plinabulin against KPL-4 cells
Table 9: Loewe synergy scores trastuzumab deruxtecan and plinabulin against KPL-4 cells
[0166] The Bliss synergy plot for combination testing of plinabulin with sacituzumab govitecan on NCLH1975 cells shows a mean synergy score of -16.46 (FIG.5) and a maximum synergy score of -3.99. Additionally, the Loewe synergy plot for combination testing of plinabulin with sacituzumab govitecan on NCI -Hl 975 cells (FIG. 6) has a mean synergy score of -8.70 and a maximum synergy score of +9.29. The Bliss and Loewe synergy scores for particular combinations of concentration of plinabulin and sacituzumab govetican are shown in Tables 10 and 11. Table 10: Bliss synergy scores for Sacituzumab govetican and plinabulin against NCI-H1975 cells
Table 11: Loewe synergy scores for Sacituzumab govetican and plinabulin against NCI-H1975 cells
[0167] The combination effects of trastuzumab deruxtecan and plinabulin against KPL-4 cells was studied at three fixed molar ratios of trastuzumab deruxtecan to plinabulin (i.e., 1: 1, 2:1, and 4:1) using the Combination Index method described in Roell et al. Front Parmacol. 2017, 8, 158, which is incoprorated by reference herein in its entirety. This method is one of the most widely used methods for detecting and quantifying synergistic interactions between two or more drugs. The main equation forming the basis of this method is referred to as the median-effects equation: fa/fu=(D/Dm)m where fa is the fraction of cells affected (i.e., killed), ; is the fraction of cells unaffected (i.e., living), D is the dose of drug given, Dm is the median-effect dose and m is the sigmoidicity of the dose-effect curve. This equation can be simplified into the following linearized version: log (fa/fu) = m log (D) -m log (Dm) A linear regression can then be applied for the various doses (£>) and responses fa/fi). From this, values for Dm and m can be estimated. These values can then be used to calculate estimates for variables in the following equation giving the (generalized) combination index (CT):
CI=Di/Ei+ D2/E2 where £>i and £>2 are the actual drug doses used in the combinations during dosing experiments and Ei and 2 are theoretical individual drug levels that would be expected to be needed to achieve the experimentally measured response. While Di and £>2 are known from experimental design, £1 and £2 can be calculated using the Dm and in values previously computed. A CI value less than 1 indicates synergism, greater than 1 indicates antagonism, and equal to 1 indicating additivity.
[0168] Inhibition of KPL-4 cells was determined using a fixed molar ratio of trastuzumab deruxtecan to plinabulin of 1:1. These values are provided in Table 12. The Combination Index was determined for this concentration ratio of trastuzumab deruxtecan to plinabulin. Values of the fraction of cells affected and the CI are provided in Table 13. The median CI was found to be 0.49, indicating synergism.
Table 12: Combination effects for trastuzumab deruxtecan and plinabulin (1: 1 molar ratio) against KPL-4 cells
Table 13: Combination Index for trastuzumab deruxtecan and plinabulin (1:1 molar ratio) against KPL-4 cells [0169] Inhibition of KPL-4 cells was determined using a fixed molar ratio of trastuzumab deruxtecan to plinabulin of 2:1. These values are provided in Table 14. The Combination Index was determined for this concentration ratio of trastuzumab deruxtecan to plinabulin. Values of the fraction of cells affected and the CI are provided in Table 15. The median CI was found to be 0.45, indicating synergism.
Table 14: Combination effects for trastuzumab deruxtecan and plinabulin (2: 1 molar ratio) against KPL-4 cells
Table 15: Combination Index for trastuzumab deruxtecan and plinabulin (2:1 molar ratio) against KPL-4 cells
[0170] Inhibition of KPL-4 cells was determined using a fixed molar ratio of trastuzumab deruxtecan to plinabulin of 4:1. These values are provided in Table 16. The Combination Index was determined for this concentration ratio of trastuzumab deruxtecan to plinabulin. Values of the fraction of cells affected and the CI are provided in Table 17. The median CI was found to be 0.25, indicating synergism.
Table 16: Combination effects for trastuzumab deruxtecan and plinabulin (4: 1 molar ratio) against KPL-4 cells Table 17: Combination Index for trastuzumab deruxtecan and plinabulin (4:1 molar ratio) against KPL-4 cells
[0171] The present technology is not to be limited in terms of the particular aspects described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of this present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods within the scope of the present technology, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that this present technology is not limited to particular methods, reagents, compounds, compositions, labeled compounds or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting. Thus, it is intended that the specification be considered as exemplary only with the breadth, scope and spirit of the present technology indicated only by the appended claims, definitions therein and any equivalents thereof.
[0172] The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of’ will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of’ excludes any element not specified.
[0173] All publications, patent applications, issued patents, and other documents (for example, journals, articles and/or textbooks) referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Claims

WHAT IS CLAIMED IS:
1. A method of treating cancer in a subject, the method comprising administering plinabulin or a pharmaceutically acceptable salt thereof to the subject in combination with an antibody-drug conjugate (ADC).
2. The method of Claim 1 , wherein the antibody-drug conjugate is an anti-Trop2, anti- HER2, or anti-HER3 antibody conjugate.
3. The method of Claim 1 or 2, wherein the cancer overexpresses Trop-2.
4. The method of any one of Claims 1 to 3, wherein the cancer overexpresses HER2.
5. The method of any one of Claims 1 to 4, wherein the cancer over expresses HER3.
6. The method of any one of Claims 1 to 5, wherein the cancer is a breast cancer, a bladder cancer, a glioma, a glioblastoma, a head and neck cancer, a non-small cell lung cancer, a small cell lung cancer, recurrent small cell lung cancer (SCLC), a colorectal cancer, a gastrointestinal stromal tumor, a gastroesophageal carcinoma, a renal cell cancer, a prostate cancer, a liver cancer, a colon cancer, a pancreatic cancer, an ovarian cancer, a lymphoma, a cutaneous T-cell lymphoma, or a melanoma.
7. The method of any one of Claims 1 to 6, wherein the cancer is colorectal cancer, a breast cancer, a lung cancer, gastrointestinal stromal tumor, or a gastroesophageal carcinoma.
8. The method of Claim 7, wherein the cancer is triple negative breast cancer (TNBC).
9. The method of any one of Claims 1 to 8, wherein the dose of plinabulin is from about 10 mg/m2to about 50 mg/m2.
10. The method of Claim 9, wherein the dose of plinabulin is about 20 mg/m2.
11. The method of Claim 9, wherein the dose of plinabulin is about 30 mg/m2.
12. The method of Claim 9, wherein the dose of plinabulin is about 40 mg.
13. The method of any one of Claims 1 to 12, wherein the plinabulin is administered intravenously.
14. The method of any one of Claims 1 to 13, wherein the ADC comprises an anti- Trop-2 antibody selected from the group consisting of: LS-C126418, LS-C178765, LS- C126416, LS-C126417, 10428-MM01, 10428-MM02, 10428-R001, 10428-R030, MR54, sc- 376181, sc-376746, MM0588-49D6, ab79976, ab89928, BRI 10, hRS7, sacituzumab and datopotamab.
15. The method of any one of Claims 1 to 13, wherein the ADC comprises an anti- HER2 antibody selected from the group consisting of trastuzumab, margetuximab, pertuzumab, GB235, huMAb4D5-l, huMAb4D5-2, huMAb4D5-3, huMAb4D5-4, huMAb4D5-5, huMAb4D5-6, huMAb4D5-7 and huMAb4D5-8.
16. The method of any one of Claims 1 to 13, wherein the ADC comprises an anti- HER3 antibody selected from the group consisting of Patritumab, Seribantumab, Lumretuzumab, GSK2849330, CDX-3379, Barecetamab, AV-203, Elgemtumab, HMBD-001, U3P1287/01, and SIBP-03.
17. The method of any one of Claims 1 to 16, wherein the ADC comprises a topoisomerase inhibitor.
18. The method of any one of Claims 1 to 16, wherein the ADC comprises a drug selected from ozogamicin, vedotin, emtansine, camptothecins, exatecan, topotecan, irinotecan, belotecan, deruxtecan, govitecan, mafodotin, pasudotox tesirine, calicheamicin yl, or doxorubicin.
19. The method of Claim 18, the ADC comprises a drug selected from deruxtecan and govitecan.
20. The method of any one of Claims 1 to 19, wherein the antibody-drug conjugate is sacituzumab govitecan, datopotamab deruxtecan, trastuzumab emtansine, trastuzumab deruxtecan, Patritumab deruxtecan, ifinatamab deruxtecan, Raludotatug deruxtecan, DS-6000, SHR-A2009, RC-48 SKB264, LCB84, STI-3258, BAT8008, FDA018-ADC, BIO-106, JS108, PF-06664178, or a combination thereof.
21. The method of any one of Claims 1 to 20, wherein the antibody-drug conjugate is sacituzumab govitecan,
22. The method of any one of Claims 1 to 20, wherein the antibody-drug conjugate is trastuzumab deruxtecan,
23. The method of any one of Claims 1 to 22, wherein the dose of the antibody-drug conjugate is from about 0.1 mg/kg to about 15 mg/kg.
24. The method of any one of Claims 1 to 22, wherein the dose of the antibody-drug conjugate is from about 0.5 mg/kg to about 5 mg/kg.
25. The method of any one of Claims 1 to 22, wherein the dose of the antibody-drug conjugate is 1.0 mg/kg.
26. The method of any one of Claims 1 to 25, wherein the antibody-drug conjugate is administered intravenously.
27. The method of any one of Claims 1 to 26, wherein the method comprises a treatment cycle.
28. The method of Claim 27, wherein the treatment cycle is from 1 day to 30 days.
29. The method of Claim 28, wherein the treatment cycle is 21 days.
30. The method of Claim 28, wherein the treatment cycle is 28 days.
31. The method of any one of Claims 27 to 30, wherein the plinabulin is administered on day 1 of the treatment cycle.
32. The method of any one of Claims 27 to 30, wherein the plinabulin is administered on day 4 of the treatment cycle.
33. The method of any one of Claims 27 to 32, wherein the antibody-drug conjugate is administered on day 1 of the treatment cycle.
34. The method of any one of Claims 27 to 33, wherein the antibody-drug conjugate is administered on day 8 of the treatment cycle.
35. The method of any one of Claims 1 to 34, further including administration of: radiation therapy, an immune checkpoint inhibitor, a chemotherapeutic agent, or a combination thereof, to the subject.
36. The method of Claim 35, wherein the one or more immune checkpoint inhibitor is administered intravenously.
37. The method of Claim 36, wherein the one or more immune checkpoint inhibitor is administered to the subject in an amount of from 50 mg to 2000 mg.
38. The method of any one of Claims 35 to 37, wherein the one or more immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pidilizumab, ipilimumab, BMS 936559, RMP1-14, durvalumab, or a combination thereof.
39. The method of any one of Claims 35 to 38, wherein radiation therapy is administered in one to ten fractions.
40. The method of Claim 39, wherein radiation therapy is administered three to five fractions.
41. The method of Claim 39, wherein radiation therapy is administered in three fractions.
42. The method of Claim 39, wherein radiation therapy is administered in four fractions.
43. The method of Claim 39, wherein radiation therapy is administered in five fractions.
44. The method any one of Claims 35 to 43, wherein the total dose of radiation administered is from about 1 Gy to about 20 Gy.
45. The method of any one of Claims 35 to 43, wherein the total dose of radiation administered is from about 2 Gy to about 15 Gy.
46. The method of any one of Claims 35 to 43, wherein the total dose of radiation administered is from about 4 Gy to about 15 Gy.
47. The method of any one of Claims 35 to 43, wherein the total dose of radiation administered is about 4 Gy.
48. The method of any one of Claims 35 to 43, wherein the total dose of radiation administered is about 8 Gy.
49. The method of any one of Claims 35 to 43, wherein the total dose of radiation administered is about 12.5 Gy.
50. The method any one of Claims 35 to 49, wherein radiation therapy is administered on days 1, 2, and 3 of the treatment cycle.
51. The method any one of Claims 35 to 49, wherein radiation therapy is administered on days 1, 2, 3, and 4 of the treatment cycle.
52. The method any one of Claims 35 to 49, wherein radiation therapy is administered on days 1, 2, 3, 4, and 5 of the treatment cycle.
53. The method of any one of Claims 35 to 52, wherein when radiation therapy and plinabulin are administered on the same day, the plinabulin is administered from about 3 hours to about 12 hours after completion of administration of the radiation therapy.
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