US 20210030843A1 IN ( 19 ) United States ( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2021/0030843 A1 Mohanlal et al . ( 43 ) Pub . Date : Feb. 4 , 2021

( 54 ) COMPOSITION AND METHOD FOR on Oct. 22 , 2018 , provisional application No. 62/713 , REDUCING CHEMOTHERAPY - INDUCED 486 , filed on Aug. 1 , 2018 , provisional application NEUTROPENIA VIA THE ADMINISTRATION No. 62 / 625,290 , filed on Feb. 1 , 2018 . OF PLINABULIN AND A G - CSF AGENT ( 71 ) Applicant: BEYONDSPRING Publication Classification PHARMACEUTICALS , INC . , New ( 51 ) Int. Cl . York , NY (US ) A61K 38/19 ( 2006.01 ) ( 72 ) Inventors : Ramon Mohanlal , New York , NY A61K 31/496 ( 2006.01 ) ( US ) ; Lan Huang , New York , NY A61P 37/04 ( 2006.01 ) ( US ) ; George Kenneth Lloyd , New ( 52 ) U.S. CI . York , NY (US ) CPC A61K 38/193 ( 2013.01 ) ; A61K 45/06 ( 2013.01 ) ; A61P 37/04 ( 2018.01 ) ; AIK ( 21 ) Appl. No .: 16 /966,156 31/496 ( 2013.01 ) ( 22 ) PCT Filed : Jan. 30 , 2019 ( 57 ) ABSTRACT ( 86 ) PCT No .: PCT / US2019 / 015867 Plinabulin and one or more G - CSF drugs are used for $ 371 ( C ) ( 1 ) , treating a chemotherapy induced neutropenia, stimulating ( 2 ) Date : Jul . 30 , 2020 neutrophil survival, reducing bone pain induced by the G - CSF drug and alleviating immune suppression effect Related U.S. Application Data induced by the G - CSF drug. For example , docetaxel - in ( 60 ) Provisional application No. 62 / 757,648 , filed on Nov. duced neutropenia can be reduced by - co - administering 8 , 2018 , provisional application No. 62 / 749,060 , filed plinabulin and one or more G - CSF compounds.

20.0 Mean Neutrophil Counts vs. Day Plinabulin 5 mg Plinabulin 10 mg Plinabulin 20 mg

Plinabulin 20 mg Pegfilgrastim NeutrophilCount(x10E9/L) 10.0

Plinabulin 5 mg Plinabulin 10 mg

0.5 2 5 6 7 8 9 Day Patent Application Publication Feb. 4 , 2021 Sheet 1 of 7 US 2021/0030843 A1

Plinabulin5mg Plinabulin10mg Plinabulin20mg -Pegfilgrastim

15

10

9 Plinabulin10mg 8 FIG,1 MeanNeutrophilCountsvs.Day Pegfilgrastim 7 Day

652

1 Plinabulin20mg Plinabulin5mg 1

1 20.0 10.0- 0.5 ) L / 10E9 x ( Count Neutrophil Patent Application Publication Feb. 4 , 2021 Sheet 2 of 7 US 2021/0030843 A1

*Grade3/4neutropennialine Lawamanan 10

9

FIG.2 Plinabulin20mg/m2+Neulasta6mg(n=16) 8 1Dayincycle

Neulasta6mg(n=21) 7

6

7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 ) L / cells 109 ( ANC Median Patent Application Publication Feb. 4 , 2021 Sheet 3 of 7 US 2021/0030843 A1

Plinabulin20mg/m2+ 86% Neulasta1.5mg (n=14)

Plinabulin20mgm2/+ 57% Neulasta3mg 21)(n=

FIG.3

Plinabulin20mg/m2+ 50% Neulasta6mg 16)(n= 0.0456=p %incidenceofgrade3/4neutropeniaincycle1afterTACforbreastcancer

Note:'AgainstNeulasta6mg. 81% Neulasta 6mg 21)(n= Patent Application Publication Feb. 4 , 2021 Sheet 4 of 7 US 2021/0030843 A1

Plinabulin20mg/m2+ 36% Neulasta1.5mg (n=14)

Plinabulin20mgm2/+ 33% Neulasta3mg 21)(n=

FIG.4

Plinabulin20mg/m2+ 0.0001"

%incidenceofbonepainincycle1afterTACforbreastcancer

Note:'AgainstNeulasta6mg. 95% Neulasta 6mg 21)(n= Patent Application Publication Feb. 4 , 2021 Sheet 5 of 7 US 2021/0030843 A1

Plinabulin20mg/m2+Neulast1.5mg(n=14) Plinabulin20mg/m2+Neulast6mg(n= 8

7

6

FIG.5 5 AtleastXdaysofbonepain

Plinabulin20mg/m2+Neulast3mg(n=21) afterTACforbreastcancerAtleastXdaysofbonepainincycle1 3

Neulasta6mg(n=21) 2

1

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%

patients of % Patent Application Publication Feb. 4 , 2021 Sheet 6 of 7 US 2021/0030843 A1

Plinabulin20mg/m2+ 7% Neulasta1.5mg (n=14)

Plinabulin20mg/m2+ 35% Neulasta3mg (n=21)

FIG.6

forbreastcancer)>5incycle1afterTACNeutrophiltolymphocyteratio(NLR%ofpatientswith Plinabulin20mg/m2+ 50% Neulasta6mg )(n=16

%76 Neulasta 6mg 21)(n= Patent Application Publication Feb. 4 , 2021 Sheet 7 of 7 US 2021/0030843 A1 To

Cycle1Daysin FIG.ZB LMR Pegfilgrastim Plinabulin+Pegfilgrastim 123456789101112131415 Plinabulin *p<0.073

50- 10- 60 40 30 20 0 ) %( Patients

T Cycle1Daysin FIG.7A NLR Pegfilgrastim Plinabulin+Pegfilgrastim 123456789101112131415 Plinabulin *p<0.0076

80 60 40 20 0 ) % ( Patients US 2021/0030843 A1 Feb. 4 , 2021 1

COMPOSITION AND METHOD FOR co - administering plinabulin and one or more G - CSF com REDUCING CHEMOTHERAPY - INDUCED pounds , wherein plinabulin is administered at a dose in the NEUTROPENIA VIA THE ADMINISTRATION range of about 1 mg /m² to about 50 mg / m² . OF PLINABULIN AND A G - CSF AGENT [ 0010 ] Some embodiments relate to a method of treating docetaxel induced neutropenia in a subject having advanced CROSS - REFERENCE TO RELATED breast cancer ( e.g. , early or metastatic breast cancer ), com APPLICATIONS prising: identifying a patient having advanced or metastatic breast cancer ; and co - administering plinabulin and one or [ 0001 ] This application is a 371 of international PCT more G - CSF compounds, wherein plinabulin is adminis Application No. PCT /US2019 /015867 , filed on Jan. 30 , tered at a dose in the range of about 1 mg/ m² to about 50 2019 , which claims benefit of U.S. Provisional Application mg /m² . No. 62 / 757,648 , filed on Nov. 8 , 2018 , and U.S. Provisional [ 0011 ] Some embodiments relate to a method of treating Application No. 62 / 749,060 , filed Oct. 22 , 2018 , and U.S. docetaxel induced neutropenia in a subject having non - small Provisional Application No. 62 / 713,486 , filed on Aug. 1 , cell lung cancer , comprising identifying a patient having 2018 , and U.S. Provisional Application No. 62 / 625,290 , non - small cell lung cancer ; and co - administering plinabulin filed on Feb. 1 , 2018 , the disclosures of which are incorpo and one or more G - CSF compounds, wherein plinabulin is rated herein by reference in their entireties . administered at a dose in the range of about 1 mg /m² to BACKGROUND about 50 mg /m2 . [ 0012 ] Some embodiments relate to a method of treating Field docetaxel induced neutropenia in a subject having hormone refractory metastatic prostate cancer, comprising: identify [ 0002 ] The present invention relates to the field of chem ing a patient having hormone refractory metastatic prostate istry and medicine . More particularly, the present invention cancer ; and co - administering plinabulin and one or more relates to method of reducing or ameliorating neutropenia G - CSF compounds, wherein plinabulin is administered at a using Plinabulin . dose in the range of about 1 mg /m² to about 50 mg/ m² . [ 0013 ] Some embodiments relate to a method of stimu Description of the Related Art lating neutrophil survival, comprising co - administering [ 0003 ] Myelosuppression is the primary toxicity of many plinabulin and one or more G - CSF compounds, wherein chemotherapy regimens which often limits applicability . plinabulin is administered at a dose in the range of about 1 Both the duration of Grade 4 neutropenia and the depth of mg/ m² to about 50 mg/ m² . the neutrophil nadir have been correlated to severe and [ 0014 ] Some embodiments relate to a pharmaceutical life - threatening infections. As a result , the prevention of composition comprising about 1 mg to about 150 mg , 1 mg neutropenia is a major goal for oncology practitioners for to about 100 mg or about 1 mg to about 40 mg of plinabulin . both safety and cost - efficiency and quality of life . [ 0015 ] Some embodiments relate to a sterile container [ 0004 ] Neutropenia is a frequent and potentially life comprising a docetaxel , and about 1 mg to about 150 mg , 1 threatening complication of cytotoxic myelosuppressive mg to about 100 mg or about 1 mg to about 40 mg of chemotherapy. Research has shown that patients who plinabulin , wherein the docetaxel and the plinabulin are develop neutropenia are more susceptible to infections provided in two separate sterile containers. which often required treatment with antibiotics and in severe cases require hospitalization . Moreover, severe neutropenia BRIEF DESCRIPTION OF THE DRAWINGS often necessitates modification of the chemotherapy regi [ 0016 ] FIG . 1 is a graph showing the change of neutrophil men , thereby compromising the ultimate success of the count through time with the treatment of plinabulin versus anticancer treatment plan . pegfligrastim . [ 0017 ] FIG . 2 is a graph measuring the change of median SUMMARY average neutrophil count ( ANC ) during the first 10 days of [ 0005 ] Some embodiments relate to a method of treating a cycle 1 chemotherapy treatment for patients receiving the chemotherapy induced neutropenia , comprising co - admin plinabulin and G - CSF combination or just G - CSF drug. istering plinabulin and one or more G - CSF compounds. [ 0018 ] FIG . 3 is a bar graph showing the incidence of [ 0006 ] Some embodiments relate to a method of reducing grade 3/4 neutropenia in cycle 1 of TAC treatment for breast bone pain , comprising administering an effective amount of cancer patients who received the plinabulin and G - CSF plinabulin . In some embodiments, the bone pain is induced combination or just G - CSF . by G - CSF drug. In some embodiments, the bone pain is [ 0019 ] FIG . 4 is a bar graph showing the incidence of bone induced by pegfilgrastim . pain in cycle 1 of TAC treatment for breast cancer patients [ 0007 ] Some embodiments relate to a method of stimu who received the plinabulin and G - CSF combination or just lating neutrophil survival, comprising co - administering G- CSF drug. plinabulin and one or more G - CSF compounds. [ 0020 ] FIG . 5 is a graph showing the duration of bone pain [ 0008 ] Some embodiments relate to a method of treating a in cycle 1 of TAC treatment for breast cancer patients who patient being administered with a docetaxel in an amount received the plinabulin and G - CSF combination or just sufficient to cause neutropenia, the method comprising co G - CSF . administering plinabulin and one or more G - CSF com [ 0021 ] FIG . 6 is a graph showing the percentage of pounds to alleviate or prevent neutrophil reduction in the patients having a neutrophil to lymphocyte ratio ( NLR ) patient. value of greater than 5 in the various treatment groups . [ 0009 ] Some embodiments relate to a method of treating [ 0022 ] FIG . 7A shows the percentage of patients with docetaxel induced neutropenia in a subject, comprising NLR over 5 in plinabulin ( 20 mg / m2 ) alone , plinabulin ( 20 US 2021/0030843 A1 Feb. 4 , 2021 2 mg /m2 ) + neulasta 6 mg , and Neulasta ( 6 mg ) . FIG . 7B shows would act to change some characteristic of the G - CSF the percentage of patients with lymphocyte to monocyte molecule as described above, such as increasing serum or ratio ( LMR ) less than 3.2 in plinabulin ( 20 mg/ m2 ) alone , other half - life or decreasing antigenicity ; ( 2 ) prepare a plinabulin ( 20 mg/ m2 ) + neulasta 6 mg , and Neulasta ( 6 mg ) . hybrid molecule , such as combining G - CSF with part or all of another protein such as another or another DETAILED DESCRIPTION OF THE protein which effects signal transduction via entry through PREFERRED EMBODIMENT the cell through a G - CSF - G - CSF receptor transport mecha [ 0023 ] Plinabulin , (3Z ,6Z ) -3 - Benzylidene - 6 - { [ 5-( 2 nism ; or ( 3 ) increase the biological activity as in , for methyl- 2 - propanyl) -1H - imidazol- 4 -yl ] methylene } -2,5 -pip example , the ability to selectively stimulate neutrophils ( as erazinedione, is a synthetic analog of the natural compound compared to a non -modified G - CSF molecule ) . G - CSF phenylahistin . Plinabulin can be readily prepared according includes derivatives, mimetics, variants and chemically to methods and procedures detailed in U.S. Pat. Nos . 7,064 , modified compounds or hybrids thereof as described in U.S. 201 and 7,919,497 , which are incorporated herein by refer Pat. Nos . 5,399,345 ; 5,416,195 ; 5,981,551 ; 6,166,183 and ence in their entireties . In some embodiments, Plinabulin 6,261,550 , the contents of which are incorporated by refer can efficiently promote antigen uptake and migration of ence in entireties . G - CSF compounds include but are not dendritic cells to lymph nodes where tumor - specific antigens limited to and pegfilgrastim . Examples of G - CSF are presented by dendritic cells to prime immune effector cells . Exposure of dendritic cells to Plinabulin can induce include but are not limited to Neupogen® (Amgen ), Teva maturation of dendritic cells and significantly increase their grastim® ( Teva ), Biograstim® ( CT Arzneimittel ), Ratio capacity to prime T cells . In some embodiments, Plinabulin grastim (Ratiopharm GmbH ) ), Zarxio® ( Sandoz GmbH ), can mediate tumor size reduction through immune modula Filgrastim Hexal® ( Hexal AG ) , Neulasta® ( Amgen ), Gra tion of the tumor microenvironment to promote anti - tumor nocyte® and Neutrogin® (Chugai ), and Neu - up ( Kyowa immune enhancing effects . In some embodiments , substan Hakko ), Rolontis® ( Spectrum , eflapegrastim ), Aiduo (me tial therapeutic synergies can be achieved when combining capegfilgrastim , Hengrui ), FulphilaTM ( pegfilgrastim - jmdb , Plinabulin with G - CSF . Mylan ). G - CSF is often given to manage chemotherapy [ 0024 ] Plinabulin is a small molecule with tumor- inhibit induced severe neutropenia . G - CSF such as pegfilgrastim is ing and immune - enhancing effects . Plinabulin induces den a colony - stimulating factor that acts on hematopoietic cells dritic cell maturation and - 1ß ( IL - 1B ) , by binding to specific cell surface receptors, thereby stimu IL - 6 , and IL - 12 production , all of which are important in lating proliferation , differentiation , commitment, and end neutrophil survival. Plinabulin also induces production of cell functional activation . MHCII , CD40 , CD80 and CD86 and related antigen - specific [ 0026 ] Febrile neutropenia ( FN ) is a potentially life T - cell activation . Plinabulin may induce maturation of den threatening condition characterized by the development of dritic cells , resulting in the release of the cytokines inter fever ( 238.3 ° C. ) and docetaxel- induced neutropenia (abso leukin ( IL ) -11 , IL - 6 and IL - 12 from monocytes /dendritic lute neutrophil count [ ANC ] < 0.5x109 /L ). The risk of severe cells , and the cytokines protect neutrophils against apopto neutropenia including FN is mitigated by reducing docetaxel sis . In particular IL - 6 can be mediated in the prevention of dosages or extending the dosing interval of the agents . neutrophil apoptosis and IL - 1ß with increased neutrophil However, research has shown these measures are directly count. Plinabulin can prevent docetaxel- or cyclophosph correlated to lower long - term survival rates because of the amide - induced neutropenia via a mechanism of action dif relative reduction in the dose intensity of the drug. There ferent from that of G - CSF analogues. When used for treating fore, granulocyte colony - stimulating factor ( G - CSF ) such as solid tumor, plinabulin showed protective effect against filgrastim (Neupogen® ) or pegfilgrastim (Neulasta® ), can neutropenia . In a Phase 2 ( Ph2 ) trial, the addition of Plinabu be given to manage chemotherapy - induced severe neutro lin to Docetaxel ( Plin + Doc ; n = 38 ) in NSCLC patients ( pts ) penia and to allow chemotherapy to be administered more with a measurable lesion , improved mOS with 4.6 mo vs effectively. According to these guidelines, prophylactic Doc alone ( n = 38 ). DOR ( a marker of immune effect ) was ~ 1 G - CSF use is recommended for patients at significant risk of yr longer ( P < 0.05 ) with Plinabulin + Docetaxel vs Docetaxel FN based on the chemotherapy regimen and patient specific alone . Plin exerted immune - enhancing effects ( DOR ) , with risk factors . However, the prophylactic use of G - CSF has out increasing Immune -Related AES ( IR - AES ) . some significant limitations in terms of safety, cost and [ 0025 ] Granulocyte -colony stimulating factor ( G - CSF ) convenience of use . Treatment should be administered refers to compounds or factors that stimulate proliferation, within 14 days of chemotherapy initiation . Moreover, differentiation , commitment and end cell functional activa G - CSF therapy cannot be initiated until 24 hours after the tion of granulocytes in an animal , including a human sub last dose of chemotherapy for each treatment cycle and is ject . The term G - CSF or G - CSF variant includes all natu generally administered once per chemotherapy cycle ( re rally occurring variants of G - CSF ( with or without a leader quires baseline complete blood count ( CBC ] and platelet sequence ), G - CSF biosimilars , as well as G - CSF proteins count during therapy ). The concern with administering derived therefrom which are modified by recombinant DNA G - CSF on the day of chemotherapy is that increasing growth technology, in particular fusion proteins which contain fur of myeloid cells may increase sensitivity to cytotoxic che ther polypeptide sequences apart from the G - CSF moiety . motherapy agents . Since cytotoxic chemotherapy causes the For example, one may : ( 1 ) increase half - life ( or prepare an most damage to rapidly growing cells , giving an agent that oral dosage form , for example ) of the G - CSF molecule by, causes myeloid cells to grow faster while chemotherapy is for example , decreasing the ability of proteases to act on the present may cause more toxicity. Duration of G - CSF therapy G - CSF molecule or adding chemical modifications to the is to attenuate chemotherapy - induced neutropenia and is G - CSF molecule , such as one or more polyethylene glycol dependent on the myelosuppressive potential of chemo molecules or enteric coatings for oral formulation which therapy regimen employed . Patients are required to either US 2021/0030843 A1 Feb. 4 , 2021 3 self - administer the drug or return to the center for treatment induced neutropenia ( sepsis , infections, hospitalizations , and evaluation which is often difficult and costly for the need for docetaxel dose reductions, and G - CSF use ) . Bone patient. pain was reported in 4 % of patients receiving plinabulin . [ 0027 ] Warnings and precautions for pegfilgrastim include Plinabulin has a favorable safety profile; the most prominent splenic rupture , acute respiratory distress syndrome, allergic finding was Grade 3 transient hypertension in 20 % and 5 % reactions including anaphylaxis, fatal sickle cell crisis, of patients receiving 30 mg /m² and 20 mg/ m² plinabulin , glomerulonephritis , capillary leak syndrome, and leukocy respectively . tosis . The most common adverse reactions are bone pain and [ 0032 ] Plinabulin can be effective for the mitigation of pain in an extremity which occurred in 31 % and 9 % of docetaxel - induced neutropenia . Administered by IV infusion patients, respectively . Additional notable adverse events on the same day of ( approximately 30 mins or 1 hour after) include acute febrile neutrophilic dermatosis, cutaneous docetaxel administration , plinabulin can be given in a single vaculitis and injection site reactions . dose to be determined per cycle . Plinabulin has the potential [ 0028 ] Plinabulin can be effective in ameliorating doc to be an effective, safe ( with much less bone pain ) , cost etaxel- related severe neutropenia ( including FN ) and has a effective , and convenient alternative to G - CSF for the pre better safety profile (much less bone pain ) and is more vention of docetaxel - induced neutropenia . convenient for the patient by reducing the number of [ 0033 ] Plinabulin and G - CSF ( e.g. pegfilgrastim or fil required patient visits and potentially also reducing the grastim ) can work synergistically to treat or prevent neutro burden to the healthcare system . Most importantly, plinabu penia occurred during the chemotherapy . The chemotherapy lin can be given after a docetaxel cycle ( e.g. , 30 mins or 1 can include treatment using chemotherapeutic agents or hour ) as opposed to 24 hours after the completion of the radiation therapy. The combination of plinabulin and G - CSF cycle ( as prescribed by pegfilgrastim , G - CSF and its bio ( e.g. pegfilgrastim or filgrastim ) can help manage chemo similars ) . therapy - induced severe neutropenia , maintain the patent's [ 0029 ] Patients with solid tumors who have received neutrophil count during treatment, and allow chemotherapy plinabulin monotherapy treatment in the absence of che to be administered more effectively. In addition , adminis motherapy ), did not experience any clinically significant tration of plinabulin and G - CSF drug can help shorten the deleterious changes in hematology or chemistry laboratory duration of severe neutropenia and maintain the absolute parameters; however, there was a significantly lower inci neutrophil count within normal range. dence of neutropenia in patients receiving plinabulin plus docetaxel compared with the docetaxel monotherapy arm . Definitions [ 0030 ] Clinical complications of neutropenia ( febrile neu [ 0034 ] Unless defined otherwise , all technical and scien tropenia, infections, sepsis , and mortality ) occur with Grade tific terms used herein have the same meaning as is com 4 Neutropenia , as compared to with Grade 2 or 3 Neutro monly understood by one of ordinary skill in the art to which penia. For regulatory approval, the FDA and Health Authori this disclosure belongs . All patents , applications , published ties focus on Grade 4 Neutropenia data . Grade 4 Neutrope applications , and other publications are incorporated by nia / Severe Neutropenia is an Absolute Neutrophil Count of reference in their entirety . In the event that there is a plurality < 0.5x10 ° / L . In animal model studies, Plinabulin has been of definitions for a term herein , those in this section prevail shown to prevent neutropenia caused by number of chemo unless stated otherwise . therapies with different mechanisms: docetaxel , cisplatin , [ 0035 ] “ Subject ” as used herein , means a human or a adriamycin , cyclosphosphamide, topotecan , and gemcit non -human mammal, e.g. , a dog , a cat , a mouse , a rat, a cow , abine . Table 1 shows many advantages plinabulin has over a sheep , a pig , a goat, a non -human primate or a bird , e.g. , G - CSF drug for treating or attenuating neutropenia . a chicken , as well as any other vertebrate or invertebrate . [ 0036 ] The term “ mammal” is used in its usual biological TABLE 1 sense . Thus, it specifically includes , but is not limited to , Plinabulin has a superior product profile vs. G -CSF /neulasta primates, including simians ( chimpanzees , apes, monkeys ) and humans, cattle, horses , sheep , goats, swine , rabbits, G - CSF Plinabulin dogs , cats, rodents, rats , mice guinea pigs , or the like . Therapy Type Growth Factor Anti - cancer [ 0037 ] An “ effective amount” or a “ therapeutically effec agent tive amount ” as used herein refers to an amount of a Bone Pain > 20 % < 4 % ( % of patients ) therapeutic agent that is effective to relieve , to some extent, Hospitalization 20 % 6 % or to reduce the likelihood of onset of, one or more of the ( % of patients) symptoms of a disease or condition , and includes curing a Dose 24 hours after 0.5-1 hour after disease or condition . Administration chemotherapy chemotherapy [ 0038 ] “ Treat, ” “ treatment, ” or “ treating , " as used herein Therapy Type Biologic Small molecule refers to administering a compound or pharmaceutical com position to a subject for prophylactic and / or therapeutic [ 0031 ] Compared to docetaxel treatment alone , the addi purposes . The term “ prophylactic treatment” refers to treat tion of plinabulin to docetaxel significantly ( p < 0.0003 ) ing a subject who does not yet exhibit symptoms of a disease reduced the proportion of patients with Grade 4 neutropenia or condition , but who is susceptible to , or otherwise at risk from 33.3 % to 4.6 % in Cycle 1. Data shows decrease in the of, a particular disease or condition , whereby the treatment proportions of patients with Grade 4 neutropenia ( absolute reduces the likelihood that the patient will develop the neutrophil count [ANC ] < 0.5x10 ° /L ) on Day 8 , the approxi disease or condition . The term “ therapeutic treatment ” refers mate day after docetaxel administration corresponding to the to administering treatment to a subject already suffering largest reduction in neutrophil count. Plinabulin also from , developing , or likely developing a disease or condi reduced the clinical sequelae associated with docetaxel tion . US 2021/0030843 A1 Feb. 4 , 2021 4

[ 0039 ] The term “ pharmaceutically acceptable salt ” refers caused by docetaxel . Consistent with the benefit of neutro to salts that retain the biological effectiveness and properties penia prevention , patients receiving plinabulin may require of a compound and , which are not biologically or otherwise less G - CSF treatment. The co - administration of plinabulin undesirable for use in a pharmaceutical. In many cases , the and G - CSF can work synergistically to continuously main compounds disclosed herein are capable of forming acid tain the patient's neutrophil count and reduce the risk of and / or base salts by virtue of the presence of amino and / or terminating the chemotherapy due to severe adverse effect. carboxyl groups or groups similar thereto . Pharmaceutically [ 0044 ] Some embodiments include co - administering a acceptable acid addition salts can be formed with inorganic composition , and / or pharmaceutical composition described acids and organic acids . Inorganic acids from which salts can herein , with an additional medicament. For example, as be derived include , for example, hydrochloric acid , hydro described above , some embodiments include co -administer bromic acid , sulfuric acid , nitric acid , phosphoric acid , and ing plinabulin and one or more G - CSF drugs. By “ co the like . Organic acids from which salts can be derived administration ,” it is meant that the two or more agents are include , for example, acetic acid , propionic acid , glycolic administered in such a manner that administration of one or acid , pyruvic acid , oxalic acid , maleic acid , malonic acid , more agent has a broad effect at the same time as the one or succinic acid , fumaric acid , tartaric acid , citric acid , benzoic more other agent, regardless of when or how they are acid , cinnamic acid , mandelic acid , methanesulfonic acid , actually administered . In one embodiment, the agents are ethanesulfonic acid , p - toluenesulfonic acid , salicylic acid , administered simultaneously . In one such embodiment, and the like . Pharmaceutically acceptable salts can also be administration in combination is accomplished by combin formed using inorganic and organic bases . Inorganic bases ing the agents in a single dosage form . In another embodi from which salts can be derived include , for example , bases ment, the agents are administered sequentially . In one that contain sodium , potassium , lithium , ammonium , cal embodiment the agents are administered through the same cium , magnesium , iron , zinc, copper, manganese , alumi route , such as orally or intravenously. In another embodi num , and the like ; particularly preferred are the ammonium , ment, the agents are administered through different routes, potassium , sodium , calcium and magnesium salts . In some such as one being administered orally and another being embodiments, treatment of the compounds disclosed herein administered i.v. In some embodiments, the time period with an inorganic base results in loss of a labile hydrogen between administration of one or more agent and adminis from the compound to afford the salt form including an tration of the co - administered one or more agent can be inorganic cation such as Li + , Na + , K + , Mg2 + and Ca2+ and about 5 min , 10 min , 20 min , 30 min , 40 min , 45 min , 50 the like . Organic bases from which salts can be derived min , 55 min , 1 hour, 65 min , 70 min , 75 min , 90 min , 2 include , for example, primary, secondary, and tertiary ami hours , 3 hours , 5 hours , 8 hours , 10 hours, 12 hours, 15 nes , substituted amines including naturally occurring sub hours , 18 hours , 20 hours, 24 hours , 36 hours , 48 hours, 3 stituted amines , cyclic amines , basic ion exchange resins, days, 4 days , 5 days, 6 days , 7 days , 10 days, 14 days , 21 and the like, specifically such as isopropylamine , trimeth days, 28 days , or 30 days . In some embodiments, the time ylamine, diethylamine , triethylamine , tripropylamine, and period between administration of one or more agent and ethanolamine . Many such salts are known in the art, as administration of the co - administered one or more agent can described in WO 87/05297 , Johnston et al . , published Sep. be in the range of about 1 min - 5 min , 1 min - 10 min , 1 11 , 1987 ( incorporated by reference herein in its entirety ) . min - 20 min , 1 min - 30 min , 1 min - 40 min , 1 min - 50 min , 1 min - 1 h , 1 min - 2 h , 1 min - 4 h , 1 min - 6 h , 1 min - 8 h , 1 Method of Treatment min - 10 h , 1 min - 12 h , 1 min - 24 h , 1 min - 36 h , 1 min - 48 h , [ 0040 ] Plinabulin can be effective in amel ing or treat 1 min - 60 h , 1 min - 72 h , 5 min - 10 min , 5 min - 20 min , 5 ing chemotherapy related ( e.g. , docetaxel, TAC , or TC min - 30 min , 5 min - 40 min , 5 min - 50 min , 5 min - 1 h , 5 related ) severe neutropenia ( including FN ) and has a better min - 75 min , 5 min - 2 h , 5 min - 4 h , 5 min - 6 h , 5 min - 8 h , 5 safety profile . Patients receiving Plinabulin treatment min - 10 h , 5 min - 12 h , 5 min - 24 h , 5 min - 36 h , 5 min - 48 h , showed less bone pain , lower hospitalization frequency, and 5 min - 60 h , 5 min - 72 h , 10 min - 20 min , 10 min - 30 min , 10 lower frequency of grade 4 neutropenia in cycle 1 when min - 40 min , 10 min - 50 min , 10 min - 1 h , 10 min - 75 min , 10 compared with other treatment methods ( e.g. , G - CSF ) . In min - 2 h , 10 min - 4 h , 10 min - 6 h , 10 min - 8 h , 10 min - 10 h , addition, Plinabulin treatment also resulted in minimum or 10 min - 12 h , 10 min - 24 h , 10 min - 36 h , 10 min - 48 h , 10 less febrile neutropenia when compared with other treatment min - 60 h , 10 min - 72 h , 30 min - 40 min , 30 min - 50 min , 30 methods ( e.g. , G - CSF ) . The patient can have better quality min - 1 h , 30 min - 75 min , 30 min - 2 h , 30 min - 4 h , 30 min - 6 of life due to the superior properties of Plinabulin . h , 30 min - 8 h , 30 min - 10 h , 30 min - 12 h , 30 min - 24 h , 30 [ 0041 ] For some embodiments, G - CSF can be adminis min - 36 h , 30 min - 48 h , 30 min - 60 h , 30 min - 72 h , 1 h - 2 h , tered with plinabulin in treating chemotherapy induced 1 h - 4 h , 1 h - 6 h , 1 h - 8 h , 1 h - 10 h , 1 h - 12 h , 1 h - 24 h , 1 h - 36 neutropenia as described herein . h , 1 h - 48 h , 1 h - 60 h , 1 h - 72 h , 6 h - 8 h , 6 h - 10 h , 6 h - 12 h , [ 0042 ] In some embodiments, the chemotherapy includes 6 h - 24 h , 6 h - 36 h , 6 h - 48 h , 6 h - 60 h , 6 h - 72 h , 12 h - 24 h , only docetaxel and no other additional chemotherapeutic 12 h - 36 h , 12 h - 48 h , 12 h - 60 h , or 12 h - 72 h . agent. In some embodiments, the chemotherapy does not [ 0045 ] Patients receiving plinabulin and G - CSF combina include docetaxel. tion treatment are less likely to require chemotherapy ( e.g. , [ 0043 ] In some embodiments, plinabulin can be co -admin docetaxel , TAC , or TC ) dose reduction . The safety profile of istered with G - CSF to reduce , ameliorate , or prevent neu plinabulin is better than other drugs that are used to treat or tropenia induced by a chemotherapy or radiation therapy. In ameliorate docetaxel induced neutropenia ( e.g. , G - CSF some embodiments , plinabulin can be co - administered with treatment ). G - CSF to stimulate neutrophil production or proliferation . [ 0046 ] Patients receiving plinabulin and G - CSF combina In some embodiments, plinabulin can be co - administered tion treatment can show at least one of the following with G - CSF to reduce , ameliorate , or prevent neutropenia conditions : 1 ) lower incidence of Grade 4 neutropenia US 2021/0030843 A1 Feb. 4 , 2021 5

( absolute neutrophil count [ANC ] < 0.5x109 /L ); 2 ) lower cisplatin , MVAC (methotrexate , vinblastine , doxorubicin incidence of febrile neutropenia ( FN ) ( ANC < 0.5x10 ° / L and and cisplatin ), docetaxel , trastuzumab , cyclophosphamide, body temperature 238.3 ° C. ) ; 3 ) higher neutrophil count paclitaxel , dose - dense AC followed by T ( i.e. , doxorubicin , during the treatment cycle ; 4 ) lower incidence of docu cyclophosphamide, paclitaxel ), TAC ( docetaxel, doxorubi mented infections in Cycles 1 to 4 ; 5 ) lower incidence and cin , cyclophosphamide ), fluorouracil, bleomycin , etoposide , shorter duration of hospitalizations, and lower mortality due vincristine , procarbazine, prednisone, BEACOPP (bleomy to FN during the treatment cycle ; 6 ) better health - related cin , etoposide, doxorubicin , cyclophosphamide, vincristine, Quality of Life; 7 ) shorter duration of severe neutropenia; 7 ) maintaining the neutrophil count within normal range and procarbazine, prednisone ), gemcitabine, ifosfamide , carbo preventing the neutrophil count from overshooting above platin , ICE ( ifosfamide, carboplatin , etoposide ) , rituximab , normal range . When compared with the G - CSF treatment RICE ( rituximab, ifosfamide , carboplatin , etoposide ), ( e.g. , pegfilgrastim or filgrastim ), plinabulin treatment CHOP - 14 ( cyclophosphamide, doxorubicin , vincristine , showed lower incidence of antibiotic use , lower incidence of prednisone ), mesna , novantrone , MINE ( mesna, ifosfamide, docetaxel dose delay , dose reduction , and / or dose discon novantrone, etoposide ) , dexamethasone , cytarabine DHAP tinuation, lower Incidence, occurrence , and severity of ( dexamethasone, cisplatin , cytarabine ), methylprednisolone , adverse events (AES ) /serious adverse events ( SAEs ) , lower ESHAP ( etoposide, methylprednisolone, cisplatin , cytara incidence , occurrence and severity of bone pain , better bine ) , HyperCVAD and rituximab ( cyclophosphamide , systemic tolerance ( physical examination and safety labo vincristine , doxorubicin , dexamethasone, rituximab ), dacar bazine , vinblastine, dacarbazine - based combination (dacar ratory assessments ). bazine , cisplatin , vinblastine ), dacarbazine - based combina [ 0047] In some embodiments, treating neutropenia tion with IL - 2 and alfa ( dacarbazine, cisplatin , includes reducing the likelihood or the incidence of neutro vinblastine, IL - 2 , ), topotecan , MAID (mesna , penia, reducing the duration of neutropenia , and / or main doxorubicin , ifosfamine , dacarbazine ), VelP ( vinblastine, taining the average neutrophil count of the subject to be ifosfamide, cisplatin ), VIP ( etoposide , ifosfamide , cisplatin ), within a range acceptable for chemotherapeutic treatment. TIP ( paclitaxel, ifosfamide, cisplatin ), gemcitabine , CMF [ 0048 ] In some embodiments , plinabulin can be used to classic ( cyclophosphamide, methotrexate , fluorouracil) , AC reduce incidence of developing bone pain . In some embodi ( doxorubicin , cyclophosphamide ), FEC ( fluorouracil, epiru ments , plinabulin can be used to shorten the duration of bone bicin , cyclophosphamide ), TC (docetaxel , cyclophosph pain . In some embodiments, the bone pain is induced by a amide ) , cisplatin / topotecan , paclitaxel / cisplatin , irincotecan , G- CSF drug. FOLFOX ( fluorouracil, leucovorin , oxaliplatin ) , irincote [ 0049 ] In some embodiments , plinabulin can be used to can / cisplatin , epirubicin /cisplatin / 5 - fluorouracil, epirubicin / alleviate the immune suppression effect of G - CSF . In some cisplatin / capecitabine, DT - PACE (dexamethasone / thalido embodiments, the immune suppression effect is caused by a mide / cisplatin /doxorubicin / cyclophosphamide / etoposide ), G - CSF drug . In some embodiments , plinabulin can be used ET - PACE and bortezomib , EPOCH ( etoposide, prednisone, to alleviate a G - CSF drug induced immune suppression vincristine , cyclophosphamide, doxorubicin ), GDP ( gemeit effect during a chemotherapy or radiation therapy. abine , dexamethasone, cisplatin ), GDP and rituximab , FMR [ 0050 ] In some embodiments , plinabulin can be used to ( fludarabine, mitoxantrone, rituximab , CHOP and rituximab reduce the NLR value ( ratio between absolute neutrophil ( cyclophosphamide, doxorubicin , vincristine , prednisone , count and absolute lymphocyte count) in a patient receiving rituximab ), cisplatin /paclitaxel , cisplatin / vinorelbine, cis a chemotherapy. In some embodiments, plinabulin can be platin / docetaxel, ciaplatin / etoposide, carboplatin /paclitaxel , used to reduce the NLR value in a patient receiving a G - CSF carboplatin / docetaxel, FOLFIRINOX ( 5 - FU / leucovorin , iri drug during a chemotherapy. In some embodiments , the notecan and oxaliplatin ) , cabazitaxel, etoposide / carboplatin , NLR value in a patient is lower than 5. In some embodi etoposide / cisplatin . In some embodiments , the chemo ments , the method described here can reduce the incidence therapy can independently include one or more agents of the patient having a NLR value greater than 5. NLR selected from the group consisting of methotrexate, vinblas greater than 5 is a negative predictor for poor survival. In tine , doxorubicin , cisplatin , docetaxel, trastuzumab , cyclo some embodiments , the method described here can reduce phosphamide, paclitaxel, fluorouracil , bleomycin , etoposide, the incidence of the patient having an NLR value greater vincristine , procarbazine , prednisone , gemcitabine , ifosf than 5 , and the incidence is reduced by at least 10 % . In some amide , carboplatin , mesna , novantrone, cytarabine methyl embodiments, the method described here can reduce the prednisolone , rituximab dacarbazine, vinblastine, topotecan , incidence of the patient having a NLR value greater than 5 , gemcitabine , irincotecan , epirubicin , 5 - fluorouracil, capecit and the incidence is reduced by at least 10 % , 20 % , 30 % , abine, bortezomib , and cabazitaxel. In some embodiments, 40 % , or 50 % . the chemotherapy does not comprises taxane . In some [ 0051 ] In some embodiments, plinabulin can be used to embodiments, the chemotherapy does not comprise doc reduce the LMR value ( ratio between absolute lymphocyte etaxel alone . In some embodiments, when the chemotherapy count and absolute monocyte count) in a patient receiving a includes administering more than one chemotherapeutic chemotherapy . In some embodiments, the patient is also agent, at least one of the chemotherapeutic agent is not administered a G - CSF drug. LMR value less than 3.6 is a taxane . In some embodiments, when the chemotherapy negative predictor for poor survival. includes administering more than one chemotherapeutic [ 0052 ] In some embodiments, the method described herein agent, at least one of the chemotherapeutic agent is not includes identifying a patient developing or at risk of docetaxel . In some embodiments, when the chemotherapy developing a bone pain after receiving G - CSF treatment. involves only one chemotherapeutic agent, the chemo [ 0053 ] In some embodiments , the chemotherapy can inde therapy is not taxane . In some embodiments, when the pendently include one or more agents selected from the chemotherapy involves only one chemotherapeutic agent, group consisting of methotrexate, vinblastine, doxorubicin , the chemotherapy is not docetaxel . In some embodiments , US 2021/0030843 A1 Feb. 4 , 2021 6 the chemotherapy comprises administering docetaxel, doxo reducing or preventing neutropenia induced by docetaxel , rubicin and cyclophosphamide ( TAC ); docetaxel and cyclo the method comprising co -administering plinabulin and one phosphamide ( TC ) ; doxorubicin and cyclophosphamide or more G - CSF compounds to the patient undergoing doc ( AC ) ; docetaxel and doxorubicin ( TA ); docetaxel ; doxoru etaxel treatment. bicin ; or cyclophosphamide. In some embodiments, the [ 0056 ] Chemotherapy such as Taxotere, Adriamycin and chemotherapy comprises administering docetaxel, doxoru Cyclophosphamide ( TAC ), and Taxotere and Cyclophosph bicin and cyclophosphamide ( TAC ) . amide ( TC ) can also cause severe neutropenia . TAC has a [ 0054 ] In some embodiments , the chemotherapy can high risk ( > 20 % ) of causing FN . In some embodiments , include one or more agents selected from the group con during the TAC chemotherapy, the doxorubicin component sisting of methotrexate , vinblastine , doxorubicin , cisplatin , is omitted and the TA chemotherapy is administered . For MVAC (methotrexate , vinblastine , doxorubicin and cispla example, during the TAC treatment, in cycles 2 to 4 , the tin ) , trastuzumab , cyclophosphamide, dose - dense AC fol doxorubicin component may be omitted at the discretion of lowed by T ( i.e. , doxorubicin , cyclophosphamide, pacli the investigator, i.e. , TC may be administered instead of taxel ) , fluorouracil, bleomycin , etoposide , vincristine, TAC . Some embodiments relate to a method of reducing or procarbazine, prednisone , BEACOPP ( bleomycin , etopo preventing neutropenia induced by TAC or TC , the method side , doxorubicin , cyclophosphamide, vincristine, procarba comprising administering plinabulin to the patient undergo zine , prednisone ), gemcitabine, ifosfamide, carboplatin , ICE ing docetaxel treatment . In some embodiments, the chemo ( ifosfamide, carboplatin, etoposide ), rituximab , RICE ( rit therapy includes only TAC and no other additional chemo uximab , ifosfamide, carboplatin , etoposide ), CHOP - 14 ( cy therapeutic agent. In some embodiments, the chemotherapy clophosphamide, doxorubicin , vincristine , prednisone ), includes only TC and no other additional chemotherapeutic mesna , novantrone , MINE (mesna , ifosfamide, novantrone , agent. In some embodiments, the administration schedule of etoposide ) , dexamethasone , cytarabine DHAP (dexametha TAC includes Day 1 : Doxorubicin 50 mg /m2 IV , followed sone , cisplatin , cytarabine ), methylprednisolone, ESHAP by cyclophosphamide 500 mg/ m2 IV , followed by docetaxel ( etoposide , methylprednisolone , cisplatin , cytarabine ), 75 mg /m2 IV after a 1 - hr interval . In some embodiments, the HyperCVAD and rituximab ( cyclophosphamide, vincristine, administration schedule of TC includes : Day 1 : Docetaxel doxorubicin , dexamethasone , rituximab ), dacarbazine, vin 75 mg/ m2 IV followed by cyclophosphamide 600 mg/ m2 blastine , dacarbazine - based combination ( dacarbazine, cis IV . platin , vinblastine ), dacarbazine - based combination with [ 0057 ] Plinabulin is useful in preventing, treating, or ame IL - 2 and interferon alfa ( dacarbazine, cisplatin , vinblastine , liorating neutrophil reduction arising from chemotherapy IL - 2 , interferon alfa ), topotecan , MAID ( mesna , doxorubi ( e.g. , docetaxel , TAC , or TC ) treatment . cin , ifosfamine , dacarbazine ), VeIP ( vinblastine, ifosfamide, [ 0058 ] Some embodiments relate to a method of treating a cisplatin ) , VIP ( etoposide, ifosfamide , cisplatin ) , TIP (pacli patient being administered with docetaxel in an amount taxel , ifosfamide, cisplatin ) . In some embodiments, the sufficient to cause neutropenia , the method comprising: gemcitabine, CMF classic ( cyclophosphamide , methotrex co - administering plinabulin and one or more G - CSF com ate , fluorouracil ), AC ( doxorubicin , cyclophosphamide ), pounds to alleviate or prevent neutrophil reduction in the FEC ( fluorouracil, epirubicin , cyclophosphamide ), cisplatin / patient. topotecan , paclitaxel/ cisplatin , irincotecan , FOLFOX ( fluo [ 0059 ] Some embodiments relate to a method of treating a rouracil, leucovorin , oxaliplatin ), irincotecan / cisplatin , epi patient being administered with chemotherapy in an amount rubicin / cisplatin / 5 - fluorouracil, epirubicin /cisplatin / sufficient to cause neutropenia, the method comprising : capecitabine, DT - PACE ( dexamethasone /thalidomide / co - administering plinabulin and G - CSF to alleviate or pre cisplatin / doxorubicin / cyclophosphamide/ etoposide ), vent neutrophil reduction in the patient. ET - PACE and bortezomib , EPOCH ( etoposide, prednisone, [ 0060 ] Some embodiments relate to co - administering vincristine, cyclophosphamide, doxorubicin ), GDP ( gemcit plinabulin and G - CSF to relieve the degree of neutropenia abine , dexamethasone, cisplatin ) , GDP and rituximab , FMR and to shorten the severe duration of neutropenia . ( fludarabine , mitoxantrone, rituximab , CHOP and rituximab [ 0061 ] In some embodiments, the patient has an advanced ( cyclophosphamide , doxorubicin , vincristine , prednisone, or metastatic breast cancer , early stage breast cancer, non rituximab ), cisplatin / paclitaxel, cisplatin / vinorelbine, small cell lung cancer , refractory metastatic prostate cancer . ciaplatin / etoposide, carboplatin /paclitaxel , FOLFIRINOX In some embodiments , the patient has head and neck cancer, ( 5 -FU / leucovorin , irinotecan and oxaliplatin ), cabazitaxel, lung cancer , stomach cancer , colon cancer , pancreatic can etoposide/ carboplatin, etoposide /cisplatin . In some embodi cer, prostate cancer, breast cancer, kidney cancer , bladder ments, the chemotherapy can include one or more agents cancer , ovary cancer, cervical cancer , melanoma , glioblas selected from the group consisting of methotrexate, vinblas toma , myeloid leukemia , myeloma, lymphoma, or leukemia . tine , doxorubicin , cisplatin , trastuzumab , cyclophosph In some embodiments, the patient has renal cell carcinoma, amide , fluorouracil, bleomycin , etoposide, vincristine, pro malignant melanoma, non - small cell lung cancer ( NSCLC ) , carbazine , prednisone, gemcitabine , ifosfamide, carboplatin , ovarian cancer , Hodgkin's lymphoma or squamous cell mesna , novantrone, cytarabine methylprednisolone , ritux carcinoma. In some embodiments , the patient has breast imab dacarbazine , vinblastine, topotecan , gemcitabine , irin cancer , colon cancer , rectal cancer, lung cancer, prostate cotecan , epirubicin , 5 - fluorouracil, capecitabine , and bort cancer, melanoma , leukemia, ovarian cancer , gastric cancer , ezomib . renal cell carcinoma, liver cancer, pancreatic cancer, lym [ 0055 ] Some embodiments relate to a method of reducing phomas and myeloma. In some embodiments, the patient has or preventing neutropenia induced by chemotherapy , the a solid tumor or hematological cancer . In some embodi method comprising co - administering plinabulin and one or ments, the patient has Acute Lymphocytic Leukemia ( ALL ) , more G - CSF compounds to the patient undergoing chemo Acute Myeloid Leukemia ( AML ), Adrenal Cancer, Basal therapy treatment . Some embodiments relate to a method of and Squamous Cell Skin Cancer, Bile Duct Cancer, Bladder US 2021/0030843 A1 Feb. 4 , 2021 7

Cancer, Bone Cancer, Brain and Spinal Cord Tumors, Breast neutrophil count and administering G - CSF drug when the Cancer, Cervical Cancer, Chronic Lymphocytic Leukemia patient has an absolute neutrophil count that is lower than ( CLL ) , Chronic Myeloid Leukemia ( CML ) , Chronic Myelo about 1.5x10 ° / L , about 1.0x109 / L , or about 0.5x10 ° / L . monocytic Leukemia ( CMML ), Colorectal Cancer, Endo [ 0069 ] In some embodiments , when plinabulin is co metrial Cancer, Esophagus Cancer, eye Cancer ( Ocular administered with G - CSF to treat neutropenia , the patient Melanoma and Lymphoma ), Gallbladder Cancer, Gastroin has an absolute neutrophil count ( ANC ) of less than 500 testinal Carcinoid Tumors, Gastrointestinal Stromal Tumor neutrophils/ mcl or an ANC of less than 1000 neutrophils/ ( GIST ) , Gestational Trophoblastic Disease , Hodgkin Lym mcl and a predicted decline of less than or equal to 500 phoma , Kaposi Sarcoma, Kidney Cancer, Laryngeal and neutrophils /mcl over the following 48 hours . In some Hypopharyngeal Cancer, Leukemia , Liver Cancer, Lung embodiments, plinabulin is co - administered with G - CSF to Cancer, Lung Carcinoid Tumor, Lymphoma, Malignant treat neutropenia in a patient having ANC of less than 100 Mesothelioma, Melanoma Skin Cancer, Merkel Cell Skin neutrophils /mcl . In some embodiments, plinabulin is co Cancer, Multiple Myeloma, Myelodysplastic Syndromes, administered with G - CSF to treat neutropenia in a patient Nasal Cavity and Paranasal Sinuses Cancer, Nasopharyn having ANC of less than 500 neutrophils /mcl . In some geal Cancer, Neuroblastoma, Non - Hodgkin Lymphoma, embodiments, plinabulin is co -administered with G - CSF to Non - Small Cell Lung Cancer, Oral Cavity and Oropharyn treat neutropenia in a patient having ANC of less than 1000 , geal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic 900 , 800 , 700 , 600 , 500 , 400 , 300 , 200 , 100 or 50 neutro Cancer , Prostate Cancer, Retinoblastoma , Rhabdomyosar phils /mcl . In some embodiments , plinabulin is co - adminis coma , Salivary Gland Cancer, Skin Cancer, Small Cell Lung tered with G -CSF to treat neutropenia in a patient having Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Stom ANC in the range of about 1000-100 , 900-100 , 800-100 , ach Cancer, Testicular Cancer, Thymus Cancer, Thyroid 700-100 , 600-100 , 500-100 , 400-100 , 300-100 , 200-100 , Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, 1000-200 , 900-200 , 800-200 , 700-200 , 600-200 , 500-200 , Waldenstrom Macroglobulinemia , or Wilms Tumor . 400-200 , 300-200 , 1000-300 , 900-300 , 800-300 , 700-300 , [ 0062 ] Some embodiments relate to treating a chemo 600-300 , 500-300 , 400-300 , 1000-400 , 900-400 , 800-400 , therapy ( e.g. , docetaxel, TAC , or TC ) induced neutropenia in 700-400 , 600-400 , 500-400 , 1000-500 , 900-500 , 800-500 , a subject having advanced for metastatic breast cancer , 700-500 , or 600-500 neutrophils /mcl . comprising identifying a patient having advanced or meta [ 0070 ] In some embodiments , the plinabulin is adminis static breast cancer , and co - administering a pharmaceuti tered at a dose in the range of about 1-50 mg /m² of the body cally effective amount of plinabulin and a pharmaceutically surface area . In some embodiments, the plinabulin is admin effective amount of G - CSF compound . istered at a dose of less than about 20 mg/ m² of the body [ 0063 ] Some embodiments relate to a method of treating surface area . In some embodiments, the plinabulin is admin chemotherapy ( e.g. , docetaxel , TAC , or TC ) induced neu istered at a dose in the range of about 10-30 or about 15-25 tropenia in a subject having non - small cell lung cancer , mg/ m ? of the body surface area . In some embodiments, the comprising : identifying a patient having non - small cell lung plinabulin is administered at a dose in the range of about 1-2 , cancer; and co - administering a pharmaceutically effective 1-3 , 1-4 , 1-5 , 1-6 , 1-7 , 1-8 , 1-9 , 1-10 , 1-11 , 1-12 , 1-13 , amount of plinabulin and a pharmaceutically effective 1-13.75 , 1-14 , 1-15 , 1-16 , 1-17 , 1-18 , 1-19 , 1-20 , 1-22.5 , amount of G - CSF compound. 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 , [ 0064 ] Some embodiments relate to a method of treating 1.5-8 , 1.5-9 , 1.5-10 , 1.5-11 , 1.5-12 , 1.5-13 , 1.5-13.75 , 1.5 chemotherapy ( e.g. , docetaxel , TAC , or TC ) induced neu 14 , 1.5-15 , 1.5-16 , 1.5-17 , 1.5-18 , 1.5-19 , 1.5-20 , 1.5-22.5 , tropenia in a subject having hormone refractory metastatic 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 , prostate cancer, comprising : identifying a patient having 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 , hormone refractory metastatic prostate cancer ; and co - ad 2.5-14 , 2.5-15 , 2.5-16 , 2.5-17 , 2.5-18 , 2.5-19 , 2.5-20 , 2.5 ministering a pharmaceutically effective amount of plinabu 22.5 , 2.5-25 , 2.5-27.5 , 2.5-30 , 2.5-7.5 , 3-4 , 3-5 , 3-6 , 3-7 , lin and a pharmaceutically effective amount of G - CSF 3-8 , 3-9 , 3-10 , 3-11 , 3-12 , 3-13 , 3-13.75 , 3-14 , 3-15 , 3-16 , compound . 3-17 , 3-18 , 3-19 , 3-20 , 3-22.5 , 3-25 , 3-27.5 , 3-30 , 3.5-6.5 , [ 0065 ] In some embodiments, the neutropenia is a febrile 3.5-13.75 , 3.5-15 , 2.5-17.5 , 4-5 , 4-6 , 4-7 , 4-8 , 4-9 , 4-10 , neutropenia . In some embodiments, the neutropenia is a 4-11 , 4-12 , 4-13 , 4-13.75 , 4-14 , 4-15 , 4-16 , 4-17 , 4-18,4-19 , drug - induced neutropenia . In some embodiments, the neu 4-20 , 4-22.5 , 4-25 , 4-27.5 , 4-30 , 5-6 , 5-7 , 5-8 , 5-9 , 5-10 , tropenia is a taxane - induced neutropenia . 5-11 , 5-12 , 5-13 , 5-13.75 , 5-14 , 5-15 , 5-16 , 5-17,5-18 , 5-19 , [ 0066 ] Some embodiments relate to a method of stimu 5-20 , 5-22.5 , 5-25 , 5-27.5 , 5-30 , 6-7 , 6-8 , 6-9 , 6-10 , 6-11 , lating neutrophil survival, comprising co - administering 6-12 , 6-13 , 6-13.75 , 6-14 , 6-15 , 6-16 , 6-17 , 6-18 , 6-19 , 6-20 , plinabulin and G - CSF , wherein the plinabulin is adminis 6-22.5 , 6-25 , 6-27.5 , 6-30 , 7-8 , 7-9 , 7-10 , 7-11 , 7-12 , 7-13 , tered at a dose in the range of about 1 mg/ m² to about 50 7-13.75 , 7-14 , 7-15 , 7-16 , 7-17 , 7-18 , 7-19 , 7-20 , 7-22.5 , mg /m² . Some embodiments relate to a method of stimulat 7-25 , 7-27.5 , 7-30 , 7.5-12.5 , 7.5-13.5 , 7.5-15 , 8-9 , 8-10 , ing neutrophil survival , comprising co - administering 8-11 , 8-12 , 8-13 , 8-13.75 , 8-14 , 8-15 , 8-16 , 8-17 , 8-18 , 8-19 , plinabulin and one or more G - CSF compounds. 8-20 , 8-22.5 , 8-25 , 8-27.5 , 8-30 , 9-10 , 9-11 , 9-12 , 9-13 , [ 0067 ] In some embodiments, the G - CSF drug is admin 9-13.75 , 9-14 , 9-15 , 9-16 , 9-17 , 9-18 , 9-19 , 9-20 , 9-22.5 , istered using an on -body injector ( e.g. , Onpro® on -body 9-25 , 9-27.5 , 9-30 , 10-11 , 10-12 , 10-13 , 10-13.75 , 10-14 , Injector) . In some embodiments, the G - CSF drug is admin 10-15 , 10-16 , 10-17 , 10-18 , 10-19 , 10-20 , 10-22.5 , 10-25 , istered subcutaneously. 10-27.5 , 10-30 , 11.5-15.5 , 12.5-14.5 , 7.5-22.5 , 8.5-32.5 , [ 0068 ] In some embodiments, the method described herein 9.5-15.5 , 15.5-24.5 , 5-35 , 17.5-22.5 , 22.5-32.5 , 25-35 , 25.5 further comprises monitoring the patient's absolute neutro 24.5 , 27.5-32.5 , 2-20 , t 2.5-22.5 , or 9.5-21.5 mg/ m² , of the phil count . In some embodiments, the method described body surface area . In some embodiments , the plinabulin is herein further comprises monitoring the patient's absolute administered at a dose of about 0.5 , 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 4 , US 2021/0030843 A1 Feb. 4 , 2021 8

4.5,5,5.5 , 6 , 6.5 , 7 , 7.5 , 8 , 8.5 , 9,9.5 , 10 , 10.5 , 11 , 11.5 , 12 , istered in a 21 - day cycle is about 0.5 , 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 12.5 , 13 , 13.5 , 14 , 14.5 , 15 , 15.5 , 16 , 16.5 , 17 , 17.5 , 18 , 18.5 , 4 , 4.5 , 5 , 5.5 , 6 , 6.5 , 7 , 7.5 , 8 , 8.5 , 9 , 9.5 , 10 , 10.5 , 11 , 11.5 , 19 , 19.5 , 20 , 20.5 , 21 , 21.5 , 22 , 22.5 , 23 , 23.5 , 24 , 24.5 , 25 , 12 , 12.5 , 13 , 13.5 , 14 , 14.5 , 15 , 15.5 , 16 , 16.5 , 17 , 17.5 , 18 , 25.5 , 26 , 26.5 , 27 , 27.5 , 28 , 28.5 , 29 , 29.5 , 30 , 30.5 , 31 , 32 , 18.5 , 19 , 19.5 , 20 , 20.5 , 21 , 21.5 , 22 , 22.5 , 23 , 23.5 , 24 , 24.5 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 mg/ m² of the body surface area . 25 , 25.5 , 26 , 26.5 , 27 , 27.5 , 28 , 28.5 , 29 , 29.5 , 30 , 30.5 , 31 , In some embodiments, the plinabulin is administered at a 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 mg /m² of the body surface dose less than about 0.5 , 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 4 , 4.5 , 5 , 5.5 , area . In some embodiments, the total dosage of plinabulin 6 , 6.5 , 7 , 7.5 , 8 , 8.5 , 9 , 9.5 , 10 , 10.5 , 11 , 11.5 , 12 , 12.5 , 13 , administered in a 21 -day cycle is less than about 0.5 , 1 , 1.5 , 13.5 , 14 , 14.5 , 15 , 15.5 , 16 , 16.5 , 17 , 17.5 , 18 , 18.5 , 19 , 19.5 , 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 , 20 , 20.5 , 21 , 21.5 , 22 , 22.5 , 23 , 23.5 , 24 , 24.5 , 25 , 25.5 , 26 , 10.5 , 11 , 11.5 , 12 , 12.5 , 13 , 13.5 , 14 , 14.5 , 15 , 15.5 , 16 , 16.5 , 26.5 , 27 , 27.5 , 28 , 28.5 , 29 , 29.5 , 30 , 30.5 , 31 , 32 , 33 , 34 , 35 , 17 , 17.5 , 18 , 18.5 , 19 , 19.5 , 20 , 20.5 , 21 , 21.5 , 22 , 22.5 , 23 , 36 , 37 , 38 , 39 , 40 mg /m of the body surface area . In some 23.5 , 24 , 24.5 , 25 , 25.5 , 26 , 26.5 , 27 , 27.5 , 28 , 28.5 , 29 , 29.5 , embodiments , the plinabulin is administered at a dose 30 , 30.5 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 mg/ m² of the greater than about 0.5 , 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 4 , 4.5 , 5 , 5.5 , 6 , body surface area . In some embodiments, the total dosage of 6.5 , 7 , 7.5 , 8 , 8.5 , 9 , 9.5 , 10 , 10.5 , 11 , 11.5 , 12 , 12.5 , 13 , 13.5 , plinabulin administered in a 21 - day cycle is greater than 14 , 14.5 , 15 , 15.5 , 16 , 16.5 , 17 , 17.5 , 18 , 18.5 , 19 , 19.5 , 20 , about 0.5 , 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 4 , 4.5 , 5 , 5.5 , 6 , 6.5 , 7 , 7.5 , 20.5 , 21 , 21.5 , 22 , 22.5 , 23 , 23.5 , 24 , 24.5 , 25 , 25.5 , 26 , 26.5 , 8 , 8.5 , 9 , 9.5 , 10 , 10.5 , 11 , 11.5 , 12 , 12.5 , 13 , 13.5 , 14 , 14.5 , 27 , 27.5 , 28 , 28.5 , 29 , 29.5 , 30 , 30.5 , 31 , 32 , 33 , 34 , 35 , 36 , 15 , 15.5 , 16 , 16.5 , 17 , 17.5 , 18 , 18.5 , 19 , 19.5 , 20 , 20.5 , 21 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 mg /m² 21.5 , 22 , 22.5 , 23 , 23.5 , 24 , 24.5 , 25 , 25.5 , 26 , 26.5 , 27 , 27.5 , of the body surface area . 28 , 28.5 , 29 , 29.5 , 30 , 30.5 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , [ 0071 ] In some embodiments, the plinabulin is adminis 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 mg / m ? of the tered at a single dose per treatment cycle . In some embodi body surface area . ments , the plinabulin is administered at two or more doses [ 0073 ] In some embodiments , when a single dose of per treatment cycle . In some embodiments, the treatment plinabulin is administered once per chemotherapy ( e.g. , cycle is a 21 -day treatment cycle . docetaxel , TAC , or TC ) treatment cycle ( e.g. , 21 day ) , the [ 0072 ] In some embodiments, the total dosage of plinabu total amount of plinabulin administered per treatment cycle lin administered in a 21 - day cycle is in the range of about of the chemotherapy is in the range of about 1-2 , 1-3 , 1-4 , 1-50 mg/ m ? of the body surface area . In some embodiments, 1-5 , 1-6 , 1-7 , 1-8 , 1-9 , 1-10 , 1-11 , 1-12 , 1-13 , 1-13.75 , 1-14 , the total dosage of plinabulin administered in a 21 - day cycle 1-15 , 1-16 , 1-17 , 1-18 , 1-19 , 1-20 , 1-22.5 , 1-25 , 1-27.5 , is less than about 20 mg/ m² of the body surface area . In some 1-30 , 1.5-2 , 1.5-3 , 1.5-4 , 1.5-5 , 5-6 , 1.5-7 , 1.5-9 . embodiments , the total dosage of plinabulin administered in 1.5-10 , 1.5-11 , 1.5-12 , 1.5-13 , 1.5-13.75 , 1.5-14 , 1.5-15 , a 21 - day cycle is in the range of about 10-30 or about 15-25 1.5-16 , 1.5-17 , 1.5-18 , 1.5-19 , 1.5-20 , 1.5-22.5 , 1.5-25 , mg /m² of the body surface area . In some embodiments, the 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 , total dosage of plinabulin administered in a 21 - day cycle is 2.5-8 , 2.5-9 , 2.5-10 , 2.5-11 , 2.5-12 , 2.5-13 , 2.5-13.75 , 2.5 in the range of about 1-2 , 1-3 , 1-4 , 1-5 , 1-6 , 1-7 , 1-8 , 1-9 , 14 , 2.5-15 , 2.5-16 , 2.5-17 , 2.5-18 , 2.5-19 , 2.5-20 , 2.5-22.5 , 1-10 , 1-11 , 1-12 , 1-13 , 1-13.75 , 1-14 , 1-15 , 1-16 , 1-17 , 1-18 , 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 , 1-19 , 1-20 , 1-22.5 , 1-25 , 1-27.5 , 1-30 , 1.5-2 , 1.5-3 , 1.5-4 , 3-10 , 3-11 , 3-12 , 3-13 , 3-13.75 , 3-14 , 3-15 , 3-16 , 3-17 , 3-18 , 1.5-5 , 1.5-6 , 1.5-7 , 1.5-8 , 1.5-9 , 1.5-10 , 1.5-11 , 1.5-12 , 3-19 , 3-20 , 3-22.5 , 3-25 , 3-27.5 , 3-30 , 3.5-6.5 , 3.5-13.75 , 1.5-13 , 1.5-13.75 , 1.5-14 , 1.5-15 , 1.5-16 , 1.5-17 , 1.5-18 , 3.5-15 , 2.5-17.5 , 4-5 , 4-6 , 4-7 , 4-8 , 4-9 , 4-10 , 4-11 , 4-12 , 1.5-19 , 1.5-20 , 1.5-22.5 , 1.5-25 , 1.5-27.5 , 1.5-30 , 2.5-2 , 4-13 , 4-13.75 , 4-14 , 4-15 , 4-16 , 4-17 , 4-18 , 4-19 , 4-20 , 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 , 4-22.5 , 4-25 , 4-27.5 , 4-30 , 5-6 , 5-7 , 5-8 , 5-9 , 5-10 , 5-11 , 2.5-12 , 2.5-13 , 2.5-13.75 , 2.5-14 , 2.5-15 , 2.5-16 , 2.5-17 , 5-12,5-13 , 5-13.75 , 5-14,5-15 , 5-16 , 5-17,5-18 , 5-19,5-20 , 2.5-18 , 2.5-19 , 2.5-20 , 2.5-22.5 , 2.5-25 , 2.5-27.5 , 2.5-30 , 5-22.5 , 5-25 , 5-27.5 , 5-30 , 6-7 , 6-8 , 6-9 , 6-10 , 6-11 , 6-12 , 2.5-7.5 , 3-4 , 3-5 , 3-6 , 3-7 , 3-8 , 3-9 , 3-10 , 3-11 , 3-12 , 3-13 , 6-13 , 6-13.75 , 6-14 , 6-15 , 6-16 , 6-17 , 6-18 , 6-19 , 6-20 , 3-13.75 , 3-14 , 3-15 , 3-16 , 3-17 , 3-18 , 3-19 , 3-20 , 3-22.5 , 6-22.5 , 6-25 , 6-27.5 , 6-30 , 7-8 , 7-9 , 7-10 , 7-11 , 7-12 , 7-13 , 3-25 , 3-27.5 , 3-30 , 3.5-6.5 , 3.5-13.75 , 3.5-15 , 2.5-17.5 , 4-5 , 7-13.75 , 7-14 , 7-15 , 7-16 , 7-17 , 7-18 , 7-19 , 7-20 , 7-22.5 , 4-6 , 4-7 , 4-8 , 4-9 , 4-10 , 4-11 , 4-12 , 4-13 , 4-13.75 , 4-14 , 7-25 , 7-27.5 , 7-30 , 7.5-12.5 , 7.5-13.5 , 7.5-15 , 8-9 , 8-10 , 4-15 , 4-16 , 4-17 , 4-18 , 4-19 , 4-20 , 4-22.5 , 4-25 , 4-27.5 , 8-11 , 8-12 , 8-13 , 8-13.75 , 8-14 , 8-15 , 8-16 , 8-17 , 8-18 , 8-19 , 4-30 , 5-6 , 5-7 , 5-8 , 5-9 , 5-10 , 5-11 , 5-12 , 5-13 , 5-13.75 , 8-20 , 8-22.5 , 8-25 , 8-27.5 , 8-30 , 9-10 , 9-11 , 9-12 , 9-13 , 5-14 , 5-15 , 5-16 , 5-17 , 5-18 , 5-19 , 5-20 , 5-22.5 , 5-25 , 9-13.75 , 9-14 , 9-15 , 9-16 , 9-17 , 9-18 , 9-19 , 9-20 , 9-22.5 , 5-27.5 , 5-30 , 6-7 , 6-8 , 6-9 , 6-10 , 6-11 , 6-12 , 6-13 , 6-13.75 , 9-25 , 9-27.5 , 9-30 , 10-11 , 10-12 , 10-13 , 10-13.75 , 10-14 , 6-14 , 6-15 , 6-16 , 6-17 , 6-18 , 6-19 , 6-20 , 6-22.5 , 6-25 , 10-15 , 10-16 , 10-17 , 10-18 , 10-19 , 10-20 , 10-22.5 , 10-25 , 6-27.5 , 6-30 , 7-8 , 7-9,7-10 , 7-11 , 7-12,7-13 , 7-13.75 , 7-14 , 10-27.5 , 10-30 , 11.5-15.5 , 12.5-14.5 , 7.5-22.5 , 8.5-32.5 , 7-15 , 7-16 , 7-17 , 7-18 , 7-19 , 7-20 , 7-22.5 , 7-25 , 7-27.5 , 9.5-15.5 , 15.5-24.5 , 5-35 , 17.5-22.5 , 22.5-32.5 , 25-35 , 25.5 7-30 , 7.5-12.5 , 7.5-13.5 , 7.5-15 , 8-9 , 8-10 , 8-11 , 8-12 , 8-13 , 24.5 , 27.5-32.5 , 2-20 , 2.5-22.5 , or 9.5-21.5 mg /m² , of the 8-13.75 , 8-14 , 8-15 , 8-16 , 8-17 , 8-18 , 8-19 , 8-20 , 8-22.5 , body surface area . In some embodiments, the total amount 8-25 , 8-27.5 , 8-30 , 9-10 , 9-11 , 9-12 , 9-13 , 9-13.75 , 9-14 , of plinabulin administered per chemotherapy treatment 9-15 , 9-16 , 9-17 , 9-18 , 9-19 , 9-20 , 9-22.5 , 9-25 , 9-27.5 , cycle is about 0.5 , 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 4 , 4.5 , 5 , 5.5 , 6 , 6.5 , 9-30 , 10-11 , 10-12 , 10-13 , 10-13.75 , 10-14 , 10-15 , 10-16 , 7 , 7.5 , 8 , 8.5 , 9 , 9.5 , 10 , 10.5 , 11 , 11.5 , 12 , 12.5 , 13 , 13.5 , 10-17 , 10-18 , 10-19 , 10-20 , 10-22.5 , 10-25 , 10-27.5 , 10-30 , 14 , 14.5 , 15 , 15.5 , 16 , 16.5 , 17 , 17.5 , 18 , 18.5 , 19 , 19.5 , 20 , 11.5-15.5 , 12.5-14.5 , 7.5-22.5 , 8.5-32.5 , 9.5-15.5 , 15.5-24.5 , 20.5 , 21 , 21.5 , 22 , 22.5 , 23 , 23.5 , 24 , 24.5 , 25 , 25.5 , 26 , 26.5 , 5-35 , 17.5-22.5 , 22.5-32.5 , 25-35 , 25.5-24.5 , 27.5-32.5 , 27 , 27.5 , 28 , 28.5 , 29 , 29.5 , 30 , 30.5 , 31 , 32 , 33 , 34 , 35 , 36 , 2-20 , t 2.5-22.5 , or 9.5-21.5 mg /m² , of the body surface area . 37 , 38 , 39 , 40 mg/ m² of the body surface area . In some In some embodiments , the total dosage of plinabulin admin embodiments, the total amount of plinabulin administered US 2021/0030843 A1 Feb. 4 , 2021 9 per chemotherapy treatment cycle is less than about 0.5 , 1 , mg - 42 mg , 15 mg - 44 mg , 15 mg - 46 mg , 15 mg - 48 mg , 15 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 , mg - 50 mg , 15 mg - 52 mg, 15 mg -54 mg , 15 mg - 56 mg, 15 10 , 10.5 , 11 , 11.5 , 12 , 12.5 , 13 , 13.5 , 14 , 14.5 , 15 , 15.5 , 16 , mg -58 mg , 15 mg - 60 mg , 17 mg - 18 mg , 17 mg - 20 mg , 17 16.5 , 17 , 17.5 , 18 , 18.5 , 19 , 19.5 , 20 , 20.5 , 21 , 21.5 , 22 , 22.5 , mg - 22 mg , 17 mg - 24 mg , 17 mg - 26 mg , 17 mg - 28 mg , 17 23 , 23.5 , 24 , 24.5 , 25 , 25.5 , 26 , 26.5 , 27 , 27.5 , 28 , 28.5 , 29 , mg - 30 mg , 17 mg - 32 mg , 17 mg - 34 mg , 17 mg - 36 mg , 17 29.5 , 30 , 30.5 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 mg /m² mg - 38 mg , 17 mg - 40 mg , 17 mg - 42 mg , 17 mg - 44 mg , 17 of the body surface area . In some embodiments , the total mg - 46 mg , 17 mg - 48 mg , 17 mg - 50 mg , 17 mg - 52 mg , 17 amount of plinabulin administered per chemotherapy treat mg - 54 mg , 17 mg- 56 mg , 17 mg - 58 mg , 17 mg - 60 mg , 20 ment cycle is greater than about 0.5 , 1 , 1.5 , 2 , 2.5 , 3 , 3.5 , 4 , mg - 22 mg , 20 mg - 24 mg , 20 mg - 26 mg , 20 mg - 28 mg , 20 4.5 , 5 , 5.5 , 6 , 6.5 , 7 , 7.5 , 8 , 8.5 , 9 , 9.5 , 10 , 10.5 , 11 , 11.5 , 12 , mg - 30 mg , 20 mg - 32 mg , 20 mg - 34 mg , 20 mg - 36 mg , 20 12.5 , 13 , 13.5 , 14 , 14.5 , 15 , 15.5 , 16 , 16.5 , 17 , 17.5 , 18 , 18.5 , mg - 38 mg , 20 mg - 40 mg , 20 mg - 42 mg , 20 mg - 44 mg , 20 19 , 19.5 , 20 , 20.5 , 21 , 21.5 , 22 , 22.5 , 23 , 23.5 , 24 , 24.5 , 25 , mg - 46 mg , 20 mg - 48 mg , 20 mg - 50 mg , 20 mg - 52 mg , 20 25.5 , 26 , 26.5 , 27 , 27.5 , 28 , 28.5 , 29 , 29.5 , 30 , 30.5 , 31 , 32 , mg - 54 mg , 20 mg - 56 mg , 20 mg - 58 mg , 20 mg - 60 mg , 22 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , mg - 24 mg , 22 mg - 26 mg , 22 mg - 28 mg , 22 mg - 30 mg , 22 49 , 50 mg/ m² of the body surface area . In some embodi mg- 32 mg , 22 mg-3-34 mg , 22 mg - 36 mg , 22 mg - 38 mg , 22 ments , the total amount of plinabulin administered per mg - 40 mg , 22 mg - 42 mg , 22 mg - 44 mg , 22 mg - 46 mg , 22 chemotherapy treatment cycle is about 20 mg/ m² of the body mg - 48 mg , 22 mg - 50 mg , 22 mg - 52 mg , 22 mg - 54 mg , 22 surface area . mg - 56 mg , 22 mg - 58 mg , 22 mg - 60 mg , 25 mg - 26 mg , 25 [ 0074 ] In some embodiments , the plinabulin dose is about mg - 28 mg , 25 mg - 30 mg , 25 mg - 32 mg , 25 mg - 34 mg , 25 5 mg - 300 mg , 5 mg - 200 mg , 7.5 mg - 200 mg , 10 mg - 100 mg , mg - 36 mg , 25 mg - 38 mg , 25 mg - 40 mg , 25 mg - 42 mg , 25 15 mg - 100 mg , 20 mg - 100 mg , 30 mg - 100 mg , 40 mg - 100 mg -44 mg , 25 mg - 46 mg, 25 mg -48 mg , 25 mg - 50 mg, 25 mg , 10 mg - 80 mg , 15 mg - 80 mg , 20 mg - 80 mg , 30 mg - 80 mg - 52 mg , 25 mg - 54 mg , 25 mg - 56 mg , 25 mg - 58 mg , 25 mg , 40 mg - 80 mg, 10 mg - 60 mg , 15 mg - 60 mg , 20 mg - 60 mg - 60 mg, 27 mg3-28 mg , 27 mg - 30 mg , 27 mg - 32 mg , 27 mg , 30 mg - 60 mg , about 40 mg - 60 mg , 1 mg - 40 mg , 1 mg - 34 mg , 27 mg - 36 mg , 27 mg - 38 mg , 27 mg - 40 mg , 27 mg - 35 mg , 1 mg - 30 mg , 10 mg - 40 mg , 10 mg - 35 mg , or 20 mg - 42 mg , 27 mg - 44 mg , 27 mg - 46 mg , 27 mg - 48 mg , 27 mg - 35 mg . In some embodiments, the plinabulin adminis mg - 50 mg , 27 mg - 52 mg , 27 mg - 54 mg , 27 mg - 56 mg , 27 tered is about 20 mg - 60 mg , 27 mg - 60 mg , 20 mg - 45 mg , or mg - 58 mg , 27 mg-3-60 mg , 30 mg - 32 mg , 30 mg - 34 mg , 30 27 mg - 45 mg . In some embodiments , the plinabulin admin mg- 36 mg , 30 mg - 38 mg , 30 mg - 40 mg , 30 mg - 42 mg , 30 istered is about 5 mg - 7.5 mg , 5 mg - 9 mg , 5 mg - 10 mg , 5 mg - 44 mg , 30 mg - 46 mg , 30 mg - 48 mg , 30 mg - 50 mg , 30 mg - 12 mg , 5 mg - 14 mg , 5 mg - 15 mg, 5 mg - 16 mg , 5 mg - 18 mg - 52 mg , 30 mg - 54 mg , 30 mg - 56 mg , 30 mg - 58 mg , 30 mg , 5 mg - 20 mg, 5 mg -22 mg, 5 mg - 24 mg , 5 mg - 26 mg , mg - 60 mg , 33 mg - 34 mg , 33 mg - 36 mg , 33 mg - 38 mg , 33 5 mg - 28 mg , 5 mg - 30 mg , 5 mg - 32 mg , 5 mg - 34 mg , 5 mg - 40 mg , 33 mg - 42 mg , 33 mg - 44 mg , 33 mg - 46 mg , 33 mg - 36 mg , 5 mg - 38 mg , 5 mg - 40 mg , 5 mg - 42 mg , 5 mg - 44 mg - 48 mg , 33 mg - 50 mg , 33 mg - 52 mg , 33 mg - 54 mg , 33 mg , 5 mg - 46 mg , 5 mg - 48 mg , 5 mg - 50 mg , 5 mg - 52 mg , mg - 56 mg , 33 mg - 58 mg , 33 mg - 60 mg , 36 mg - 38 mg , 36 5 mg - 54 mg , 5 mg - 56 mg , 5 mg - 58 mg , 5 mg - 60 mg , 7 mg - 40 mg , 36 mg - 42 mg , 36 mg - 44 mg , 36 mg - 46 mg , 36 mg - 7.7 mg , 7 mg - 9 mg , 7 mg - 10 mg , 7 mg - 12 mg , 7 mg - 14 mg - 48 mg , 36 mg - 50 mg , 36 mg - 52 mg , 36 mg - 54 mg , 36 mg , 7 mg - 15 mg, 7 mg - 16 mg 7 mg - 18 mg , 7 mg - 20 mg , mg - 56 mg , 36 mg - 58 mg , 36 mg - 60 mg , 40 mg - 42 mg , 40 7 mg - 22 mg , 7 mg - 24 mg , 7 mg - 26 mg , 7 mg - 28 mg , 7 mg - 44 mg , 40 mg - 46 mg , 40 mg - 48 mg , 40 mg - 50 mg , 40 mg - 30 mg , 7 mg - 32 mg , 7 mg - 34 mg , 7 mg - 36 mg , 7 mg - 38 mg - 52 mg , 40 mg - 54 mg , 40 mg - 56 mg , 40 mg - 58 mg , 40 mg , 7 mg - 40 mg , 7 mg - 42 mg , 7 mg - 44 mg , 7 mg - 46 mg , mg - 60 mg , 43 mg - 46 mg , 43 mg - 48 mg , 43 mg - 50 mg , 43 7 mg - 48 mg , 7 mg - 50 mg , 7 mg - 52 mg , 7 mg - 54 mg , 7 mg - 52 mg , 43 mg - 54 mg , 43 mg - 56 mg , 43 mg - 58 mg , 42 mg - 56 mg , 7 mg - 58 mg , 7 mg - 60 mg, 9 mg - 10 mg , 9 mg - 12 mg - 60 mg , 45 mg - 48 mg , 45 mg - 50 mg , 45 mg - 52 mg , 45 mg , 9 mg - 14 mg , 9 mg - 15 mg , mg- 16 mg , 9 mg - 18 mg , mg - 54 mg , 45 mg- 56 mg , 45 mg - 58 mg , 45 mg - 60 mg , 48 9 mg - 20 mg , 9 mg - 22 mg , 9 mg - 24 mg , 9 mg - 26 mg , 9 mg - 50 mg , 48 mg - 52 mg , 48 mg - 54 mg , 48 mg - 56 mg , 48 mg - 28 mg, 9 mg - 30 mg, 9 mg - 32 mg , 9 mg - 34 mg, 9 mg - 36 mg - 58 mg , 48 mg - 60 mg , 50 mg - 52 mg , 50 mg - 54 mg , 50 mg , 9 mg - 38 mg , 9 mg - 40 mg , 9 mg - 42 mg , 9 mg - 44 mg , mg - 56 mg , 50 mg - 58 mg , 50 mg - 60 mg , 52 mg - 54 mg , 52 9 mg - 46 mg , 9 mg - 48 mg , 9 mg - 50 mg , 9 mg - 52 mg , 9 mg - 56 mg , 52 mg - 58 mg , or 52 mg - 60 mg . In some mg - 54 mg , 9 mg - 56 mg , 9 mg - 58 mg , 9 mg - 60 mg , 10 embodiments, the plinabulin dose is greater than about 5 mg , mg - 12 mg , 10 mg - 14 mg , 10 mg - 15 mg , 10 mg - 16 mg , 10 about 10 mg , about 12.5 mg , about 13.5 mg , about 15 mg , mg - 18 mg , 10 mg - 20 mg , 10 mg - 22 mg , 10 mg - 24 mg , 10 about 17.5 mg , about 20 mg , about 22.5 mg , about 25 mg , mg - 26 mg , 10 mg - 28 mg , 10 mg - 30 mg , 10 mg - 32 mg , 10 about 27 mg , about 30 mg , about 35 mg , about 40 mg , about mg - 34 mg , 10 mg- 36 mg, 10 mg - 38 mg , 10 mg - 40 mg , 10 50 mg , about 60 mg , about 70 mg , about 80 mg , about 90 mg - 42 mg , 10 mg - 44 mg , 10 mg - 46 mg , 10 mg - 48 mg , 10 mg , about 100 mg , about 125 mg , about 150 mg , or about mg - 50 mg , 10 mg - 52 mg , 10 mg - 54 mg , 10 mg - 56 mg , 10 200 mg . In some embodiments, the plinabulin dose is about mg - 58 mg , 10 mg - 60 mg , 12 mg - 14 mg , 12 mg - 15 mg , 12 less than about 5 mg , about 10 mg , about 12.5 mg , about mg - 16 mg , 12 mg - 18 mg , 12 mg - 20 mg , 12 mg - 22 mg , 12 13.5 mg, about 15 mg , about 17.5 mg , about 20 mg , about mg - 24 mg , 12 mg- 26 mg, 12 mg5-28 -2 mg , 12 mg- 30 mg, 12 22.5 mg , about 25 mg , about 27 mg , about 30 mg , about 35 mg - 32 mg , 12 mg - 34 mg , 12 mg - 36 mg , 12 mg - 38 mg , 12 mg , about 40 mg , about 50 mg , about 60 mg , about 70 mg , mg - 40 mg , 12 mg - 42 mg , 12 mg - 44 mg , 12 mg - 46 mg , 12 about 80 mg , about 90 mg , about 100 mg , about 125 mg , mg - 48 mg , 12 mg - 50 mg , 12 mg - 52 mg , 12 mg - 54 mg , 12 about 150 mg , or about 200 mg . mg - 56 mg , 12 mg - 58 mg , 12 mg - 60 mg , 15 mg - 16 mg , 15 [ 0075 ] In some embodiments , the neutropenia is induced mg - 18 mg , 15 mg - 20 mg , 15 mg - 22 mg , 15 mg - 24 mg , 15 by a chemotherapy. The administration period can be a mg - 26 mg , 15 mg - 28 mg , 15 mg - 30 mg , 15 mg - 32 mg , 15 multi -week treatment cycle as long as the tumor remains mg - 34 mg , 15 mg - 36 mg , 15 mg - 38 mg , 15 mg - 40 mg , 15 under control and the regimen is clinically tolerated . In some US 2021/0030843 A1 Feb. 4 , 2021 10 embodiments, the chemotherapy and plinabulin can be administration of plinabulin once per treatment cycle , and administered once every three weeks . In some embodiments , then followed by administration of G -CSF , wherein the the chemotherapy and plinabulin can be administered once G - CSF drug can be either administered once per treatment every week , once every two weeks , once every three weeks , cycle when a long acting G - CSF is used or multiple times once every four weeks, once evert five weeks , or once every per treatment cycle when a short acting G - CSF is used . The six weeks . In some embodiments, the chemotherapy and administration of the G - CSF drug is performed 224 hours Plinabulin can be administered once a week , and preferably after the administration of the chemotherapy. In some once on each of day 1 and day 8 of a three -week ( 21 day ) embodiments, during the chemotherapy treatment cycle , the treatment cycle . In some embodiments, the chemotherapy chemotherapeutic agent( s) is administered one day 1 of the and Plinabulin can be administered once a week , twice a treatment cycle , followed by administration of plinabulin week , three times per week , four times per week , five times once on day 1 per treatment cycle , and then followed by per week , six times per week , or daily during a one -week , administration of G - CSF on day 2 per treatment cycle . In two - week , three -week , four -week , or five - week treatment some embodiments, when the chemotherapy treatment cycle . The administration can be on the same or different day involves more than one chemotherapeutic agents, the che of each week in the treatment cycle . In some embodiments , motherapeutic agents are administered on day 1 and 2 of the the plinabulin is administered prior to the chemotherapy treatment cycle , plinabulin is administered on day 1 after the administration . In some embodiments, the plinabulin is first chemotherapeutic agent is administered , and then fol administered concurrently with the chemotherapy adminis lowed by administration of G - CSF on day 3 per treatment tration . In some embodiments, the plinabulin is administered cycle . In some embodiments, when the chemotherapy treat after the chemotherapy administration . ment involves more than one chemotherapeutic agents, the [ 0076 ] The G - CSF drug described herein includes both chemotherapeutic agents are administered on day 1 , 2 , and short acting or long acting G - CSF drugs. In some embodi 3 of the treatment cycle , plinabulin is administered on day ments, the long acting G - CSF can include both drugs having 1 after the first chemotherapeutic agent is administered , and pegylated linker or other linkers to achieve extended release then followed by administration of G - CSF on day 4 per effect. In some embodiments , the G - CSF drug is a short treatment cycle . In some embodiments , the G - CSF drug can acting drug that requires daily administration for up to two be either administered once per treatment cycle when a long weeks or until the ANC has reached a level acceptable for a acting G - CSF is used or multiple times per treatment cycle patient undergoing chemotherapy. In some embodiments, when a short acting G - CSF is used . The administration of the the G - CSF drug is a long acting drug that does not require G - CSF drug is performed 24 hours after the administration daily administration . In some embodiments, the G - CSF drug of the chemotherapy. is a long acting drug that requires one dose per treatment [ 0078 ] In some embodiments , the neutropenia is induced cycle . In some embodiments , the long acting G - CSF drug by a docetaxel . The administration period can be a multi can be pegfilgrastim , eflapegrastim , macafilgrastim . In some week treatment cycle as long as the tumor remains under embodiments, the short acting G - CSF can be filgrastim . In control and the regimen is clinically tolerated . In some some embodiments, the G - CSF drug can be selected from embodiments , docetaxel and plinabulin can be administered Neupogen ( Amgen ), Tevagrastim ( Teva) , Biograstim once every three weeks . In some embodiments, docetaxel ( CT Arzneimittel ), Ratiograstim ( Ratiopharm GmbH ) ), and plinabulin can be administered once every week , once Zarxio® ( Sandoz GmbH ), Filgrastim Hexal® ( Hexal AG ) , every two weeks , once every three weeks, once every four Neulasta ( Amgen ), Granocyte® and Neutrogin ( Chu weeks, once evert five weeks , or once every six weeks. In gai ) , and Neu - up® (Kyowa Hakko ), Rolontis® ( Spectrum , some embodiments, docetaxel and Plinabulin can be admin eflapegrastim ), Aiduo (mecapegfilgrastim , Hengrui ), and istered once a week , and preferably once on each of day 1 FulphilaTM ( pegfilgrastim - jmdb, Mylan ). and day 8 of a three -week ( 21 day ) treatment cycle . In some [ 0077 ] In some embodiments, during the chemotherapy embodiments, docetaxel and Plinabulin can be administered treatment cycle , the chemotherapeutic agent ( s ) is only once a week , twice a week , three times per week , four times administered once at the beginning of the treatment cycle , per week , five times per week , six times per week , or daily followed by the co - administration of plinabulin and G - CSF during a one -week , two -week , three -week , four -week , or once , twice, three times , four times , five times , or six times five - week treatment cycle . The administration can be on the during the treatment cycle . In some embodiments , during the same or different day of each week in the treatment cycle . In chemotherapy treatment cycle , the chemotherapeutic agent some embodiments, the plinabulin is administered prior to ( s ) is only administered once at the beginning of the treat the docetaxel administration . In some embodiments , the ment cycle , followed by the co - administration of plinabulin plinabulin is administered concurrently with the docetaxel and G - CSF once every week , once every two weeks , once administration . In some embodiments, the plinabulin is every three weeks, once every four weeks, once evert five administered after the docetaxel administration . weeks, or once every six weeks . In some embodiments, [ 0079 ] In some embodiments , plinabulin and G - CSF is during the chemotherapy treatment cycle , the chemothera co - administered after the chemotherapy administration . peutic agent( s ) is only administered once at the beginning of When plinabulin and / or G - CSF is administered after the the treatment cycle , followed by co - administration of administration of a chemotherapy, it refers to administering plinabulin and G - CSF once a week , twice a week , three plinabulin and /or G - CSF after the last chemotherapeutic times per week , four times per week , five times per week , six agent (s ) of the chemotherapy has been completely admin times per week , or daily during a one -week , two -week , istered to the patients. For example, administering plinabulin three -week , four - week , or five -week treatment cycle . In about 30 mins after the administration of a TAC chemo some embodiments , during the chemotherapy treatment therapy refers to begin the plinabulin administration about cycle , the chemotherapeutic agent ( s ) is only administered 30 mins after the administration of the last chemotherapeutic once at the beginning of the treatment cycle , followed by agent ( e.g. , docetaxel ) has been completed . In some embodi US 2021/0030843 A1 Feb. 4 , 2021 11 ments, the plinabulin is administered about 1 min , 5 min , 10 the administration of the chemotherapy . In some embodi min , 15 min , 20 min , 25 min , 30 min , 45 min , 50 min , 1 h , ments , plinabulin is administered about 30 mins after the 75 min , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 chemotherapy administration . In some embodiments , h , 11 h , or 12 h after the administration of the chemotherapy . plinabulin is administered in less than 1 hour after the In some embodiments , the plinabulin is administered in less chemotherapy administration . than about 1 min , 5 min , 10 min , 15 min , 20 min , 25 min , [ 0081 ] In some embodiments , G - CSF is administered after 30 min , 45 min , 50 min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , the chemotherapy administration . In some embodiments, 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , 12 h , 13 h , 14 h , 15 G - CSF ( if short acting G - CSF is used , then the first dose of h , 16 h , 17 h , 18 h , 19 h , 20 h , 21 h , 22 h , 23 h , or 24 h after G - CSF ) is administered about 5 h , 10 h , 12 h , 15 h , 20 h , 24 the administration of the chemotherapy. In some embodi h , 30 h , 36 h , 41 h , 48 h , or 54 h after the administration of ments , the plinabulin is administered in more than about 1 the chemotherapy . In some embodiments, G - CSF ( if short min , 5 min , 10 min , 15 min , 20 min , 25 min , 30 min , 45 min , acting G - CSF is used , then the first dose of G - CSF ) is 50 min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 administered in less than about 24 h , 30 h , 36 h , 42 h , 48 h , h , 8 h , 9 h , 10 h , 11 h , 12 h , 13 h , 14 h , 15 h , 16 h , 17 h , 18 54 h , or 60 h after the administration of the chemotherapy. h , 19 h , 20 h , 21 h , 22 h , 23 h , or 24 h after the administration In some embodiments, G - CSF ( if short acting G - CSF is of the chemotherapy . In some embodiments , the plinabulin used , then the first dose of G - CSF ) is administered in more is administered in about 1 min - 5 min , 1 min - 10 min , 1 than about 10 h , 12 h , 15 h , 20 h , 24 h , 30 h , 36 h , 41 h , 48 min - 15 min , 1 min - 20 min , 1 min - 25 min , 1 min - 30 min , 1 h , or 54 h after the administration of the chemotherapy. In min - 45 min , 1 min - 1 h , 1 min - 75 min , 1 min - 90 min , 1 some embodiments, G - CSF ( if short acting G - CSF is used , min - 120 min , 0.25 h - 0.5 h , 0.25-0.75 h , 15 min - 45 min , 15 then the first dose of G - CSF ) is administered in about 10 min - 75 min , 15 min - 90 min , 15 min - 120 min , 0.25-1 h , 30 h - 36 h , 10 h - 48 h , 10 h - 54 h , 24 h - 36 h , 24 h - 48 h , 24 h - 54 min - 45 min , 30 min - 75 min , 30 min - 90 min , 0.5 h - 1 h , 0.5 h , or 24 h - 60 h after the administration of the chemotherapy . h - 2 h , 0.5 h - 2.5 h , 1 h - 2 h , 1 h - 3 h , 1 h - 5 h after the In some embodiments, G - CSF ( if short acting G - CSF is administration of the chemotherapy. In some embodiments, used , then the first dose of G - CSF ) is administered at least plinabulin is administered 30 mins after the chemotherapy 24 h after the chemotherapy administration . administration . In some embodiments, plinabulin is admin [ 0082 ] In some embodiments, the plinabulin and G - CSF istered in less than 1 hour after the chemotherapy adminis are administered after the docetaxel administration . In some tration . embodiments, the plinabulin is administered about 1 min , 5 [ 0080 ] In some embodiments, plinabulin and G - CSF can min , 10 min , 15 min , 20 min , 25 min , 30 min , 45 min , 50 be administered after the chemotherapy administration . min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 h , When plinabulin and / or G - CSF is administered after the 8 h , 9 h , 10 h , 11 h , or 12 h after the administration of administration of a chemotherapy , it refers to administering docetaxel . In some embodiments, the plinabulin is admin plinabulin and / or G - CSF after the last chemotherapeutic istered in less than about 1 min , 5 min , 10 min , 15 min , 20 agent (s ) of the chemotherapy has been completely admin min , 25 min , 30 min , 45 min , 50 min , 1 h , 75 min , 1.5 h , 2 istered to the patients. For example, administering plinabulin h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , 12 h , about 30 mins after the administration of a TAC chemo 13 h , 14 h , 15 h , 16 h , 17 h , 18 h , 19 h , 20 h , 21 h , 22 h , 23 therapy refers to begin the plinabulin administration about h , or 24 h after the administration of docetaxel. In some 30 mins after the administration of the last chemotherapeutic embodiments, the plinabulin is administered in more than agent ( e.g. , docetaxel ) has been completed . In some embodi about 1 min , 5 min , 10 min , 15 min , 20 min , 25 min , 30 min , ments , the plinabulin is administered about 1 min , 5 min , 10 45 min , 50 min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , min , 15 min , 20 min , 25 min , 30 min , 45 min , 50 min , 1 h , 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , 12 h , 13 h , 14 h , 15 h , 16 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 17 h , 18 h , 19 h , 20 h , 21 h , 22 h , 23 h , or 24 h after the h , 11 h , or 12 h after the administration of the chemotherapy. administration of docetaxel . In some embodiments , the In some embodiments , the plinabulin is administered in less plinabulin is administered in about 1 min - 5 min , 1 min - 10 than about 1 min , 5 min , 10 min , 15 min , 20 min , 25 min , min , 1 min - 15 min , 1 min 20 min , 1 min - 25 min , 1 min - 30 30 min , 45 min , 50 min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , min , 1 min - 45 min , 1 min - 1 h , 1 min - 75 min , 1 min - 90 min , 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , 12 h , 13 h , 14 h , 15 1 min - 120 min , 0.25 h - 0.5 h , 0.25-0.75 h , 15 min - 45 min , 15 h , 16 h , 17 h , 18 h , 19 h , 20 h , 21 h , 22 h , 23 h , or 24 h after min - 75 min , 15 min - 90 min , 15 min - 120 min , 0.25-1 h , 30 the administration of the chemotherapy. In some embodi min - 45 min , 30 min - 75 min , 30 min - 90 min , 0.5 h - 1 h , 0.5 ments , the plinabulin is administered in more than about 1 h - 2 h , 0.5 h - 2.5 h , 1 h - 2 h , 1 h - 3 h , 1 h - 5 h after the min , 5 min , 10 min , 15 min , 20 min , 25 min , 30 min , 45 min , administration of docetaxel. In some embodiments, plinabu 50 min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 lin is administered 30 mins after the docetaxel administra h , 8 h , 9 h , 10 h , 11 h , 12 h , 13 h , 14 h , 15 h , 16 h , 17 h , 18 tion . In some embodiments, plinabulin is administered in h , 19 h , 20 h , 21 h , 22 h , 23 h , or 24 h after the administration less than 1 hour after the docetaxel administration . of the chemotherapy . In some embodiments, the plinabulin [ 0083 ] In some embodiments , when plinabulin and G - CSF is administered in about 1 min - 5 min , 1 min - 10 min , 1 is co - administered prior to the chemotherapy administration , min - 15 min , 1 min - 20 min , 1 min - 25 min , 1 min - 30 min , 1 the plinabulin is administered about 1 min - 5 min , 1 min - 10 min - 45 min , 1 min - 1 h , 1 min - 75 min , 1 min - 90 min , 1 min , 1 min - 15 min , 1 min - 20 min , 1 min - 25 min , 1 min - 30 min - 120 min , 0.25 h - 0.5 h , 0.25-0.75 h , 15 min - 45 min , 10 min , 0.25 h - 0.5 h , 0.25-0.75 h , 0.25-1 h , 0.5 h - 1 h , 0.5 h - 2 min - 20 min , 10-30 min , 10-40 min , 10-50 min , 15 min - 75 h , 0.5 h - 2.5 h , 1 h - 2 h , 1 h - 3 h , 1 h - 5 h before the min , 15 min - 90 min , 15 min - 120 min , 20 min - 30 min , 20 administration of the chemotherapy. In some embodiments, min - 40 min , 20 min - 50 min , 25 min - 35 min , 28 min - 32 min , the plinabulin is administered about 1 min , 5 min , 10 min , 0.25-1 h , 30 min - 45 min , 30 min - 75 min , 30 min - 90 min , 0.5 15 min , 20 min , 25 min , 30 min , 1 h , 1.5 h , 2 h , 2.5 h , 3 h , h - 1 h , 0.5 h - 2 h , 0.5 h - 2.5 h , 1 h - 2 h , 1 h - 3 h , 1 h - 5 h after 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , or 12 h before the US 2021/0030843 A1 Feb. 4 , 2021 12 administration of the chemotherapy. In some embodiments, chemotherapy followed by the administration of plinabulin the plinabulin is administered in less than about 1 min , 5 about 30 mins after the chemotherapy administration , and min , 10 min , 15 min , 20 min , 25 min , 30 min , 1 h , 1.5 h , 2 the plinabulin is administered once every 3 weeks in a h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , 12 h , treatment cycle . In some embodiments , the treatment sched 13 h , 14 h , 15 h , 16 h , 17 h , 18 h , 19 h , 20 h , 21 h , 22 h , 23 ule includes administration of the chemotherapy followed by h , or 24 h before the administration of the chemotherapy. In the administration of plinabulin once every week , 2 weeks , some embodiments, the plinabulin is administered in more 3 weeks, 4 weeks , 5 weeks, 6 weeks , 7 weeks, or 8 weeks . than about 1 min , 5 min , 10 min , 15 min , 20 min , 25 min , In some embodiments , the treatment schedule includes 30 min , 1 h , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 h , 8 h , 9 administration of the chemotherapy followed by the admin h , 10 h , 11 h , 12 h , 13 h , 14 h , 15 h , 16 h , 17 h , 18 h , 19 h , istration of plinabulin two times every 1 week , 2 weeks, 3 20 h , 21 h , 22 h , 23 h , or 24 h before the administration of weeks, 4 weeks , 5 weeks , 6 weeks, 7 weeks , or 8 weeks . In the chemotherapy. some embodiments , the treatment schedule includes admin [ 0084 ] In some embodiments , when plinabulin and G - CSF istration of the chemotherapy followed by the administration is co -administered prior to docetaxel administration , the of plinabulin once every week in a treatment cycle of 1 plinabulin is administered about 1 min - 5 min , 1 min - 10 min , week , 2 weeks , 3 weeks, 4 weeks, 5 weeks, 6 weeks , 7 1 min - 15 min , 1 min 20 min , 1 min - 25 min , 1 min - 30 min , weeks, or 8 weeks . In some embodiments, the treatment 0.25 h - 0.5 h , 0.25-0.75 h , 0.25-1 h , 0.5 h - 1 h , 0.5 h - 2 h , 0.5 schedule includes administration of the chemotherapy fol h - 2.5 h , 1 h - 2 h , 1 h - 3 h , 1 h - 5 h before the administration lowed by the administration of plinabulin twice every 1 of docetaxel. In some embodiments , the plinabulin or week in a treatment cycle of 1 week , 2 weeks , 3 weeks , 4 G - CSF is administered about 1 min , 5 min , 10 min , 15 min , weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks . In some 20 min , 25 min , 30 min , 1 h , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , embodiments , the treatment schedule includes administra 6 h , 7 h , 8 h , 9h , 10 h , 11 h , or 12 h before the administration tion of the chemotherapy followed by the administration of of docetaxel. In some embodiments, the plinabulin or plinabulin on day 1 , day 8 , and day 15 of a 21 - day treatment G - CSF is administered in less than about 1 min , 5 min , 10 cycle . In some embodiments, the treatment schedule min , 15 min , 20 min , 25 min , 30 min , 1 h , 1.5 h , 2 h , 2.5 h , includes administering plinabulin following every dose of 3 h , 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , 12 h , 13 h , 14 the chemotherapy administration . In some embodiments, the h , 15 h , 16 h , 17 h , 18 h , 19 h , 20 h , 21 h , 22 h , 23 h , or 24 treatment schedule includes administering plinabulin fol h before the administration of docetaxel . In some embodi lowing the initial dose / cycle of the chemotherapy adminis ments, the plinabulin or G - CSF is administered in more than tration and then administering plinabulin following every about 1 min , 5 min , 10 min , 15 min , 20 min , 25 min , 30 min , two doses , three doses, four doses, five doses , or six doses 1 h , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 h , of the chemotherapy administration . In some embodiments, 11 h , 12 h , 13 h , 14 h , 15 h , 16 h , 17 h , 18 h , 19 h , 20 h , 21 the treatment schedule includes administering plinabulin h , 22 h , 23 h , or 24 h before the administration of docetaxel . following every other dose of the chemotherapy adminis [ 0085 ] In some embodiments, the infusion time for tration . In some embodiments, the plinabulin is administered plinabulin is about 1 min , 5 min , 10 min , 15 min , 20 min , 25 after every two doses , every three doses , every four doses , min , 30 min , 45 min , 50 min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , every five doses, or every six doses of the chemotherapy 3 h , 4 h , 5 h , 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , or 12 h . In some administration . embodiments, the infusion time for plinabulin is less than [ 0087 ] In some embodiments, the first dose of plinabulin about 1 min , 5 min , 10 min , 15 min , 20 min , 25 min , 30 min , or G - CSF is administered as soon as suspected or confirmed 45 min , 50 min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h , neutropenia development. 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , 12 h , 13 h , 14 h , 15 h , 16 h , [ 0088 ] In some embodiments , when plinabulin is co 17 h , 18 h , 19 h , 20 h , 21 h , 22 h , 23 h , or 24 h after. In some administered with G - CSF , the treatment schedule includes embodiments, the infusion time for plinabulin is greater than administration of the chemotherapy ( e.g. , docetaxel, TAC , or about 1 min , 5 min , 10 min , 15 min , 20 min , 25 min , 30 min , TC ) followed by the administration of plinabulin once every 45 min , 50 min , 1 h , 75 min , 1.5 h , 2 h , 2.5 h , 3 h , 4 h , 5 h, 3 weeks . In some embodiments , the treatment schedule 6 h , 7 h , 8 h , 9 h , 10 h , 11 h , 12 h , 13 h , 14 h , 15 h , 16 h , includes administration of the chemotherapy ( e.g., doc 17 h , 18 h , 19 h , 20 h , 21 h , 22 h , 23 h , or 24 h . In some etaxel , TAC , or TC ) followed by the administration of embodiments, the infusion time for plinabulin is about 1 plinabulin about 30 mins after the chemotherapy adminis min - 5 min , 1 min - 10 min , 1 min - 15 min , 1 min - 20 min , 1 tration , and the plinabulin is administered once every 3 min - 25 min , 1 min - 30 min , 1 min - 45 min , 1 min - 1 h , 1 weeks in a treatment cycle . In some embodiments, the min - 75 min , 1 min - 90 min , 1 min - 120 min , 0.25 h - 0.5 h , treatment schedule includes administration of the chemo 0.25-0.75 h , 15 min - 45 min , 15 min - 75 min , 15 min - 90 min , therapy ( e.g. , docetaxel, TAC , or TC ) followed by the 15 min - 120 min , 0.25-1 h , 30 min - 45 min , 30 min - 75 min , administration of plinabulin once every 1 week , 2 weeks , 3 30 min - 90 min , 0.5 h - 1 h , 0.5 h - 2 h , 0.5 h - 2.5 h , 1 h - 2 h , 1 weeks, 4 weeks , 5 weeks , 6 weeks, 7 weeks , or 8 weeks . In h - 3 h , 1 h - 5 h . In some embodiments, the infusion time for some embodiments, the treatment schedule includes admin plinabulin is 30 mins for a single dose ( e.g. , 5 , 10 , 20 , or less istration of the chemotherapy ( e.g. , docetaxel, TAC , or TC ) than 30 mg/ m² ) . In some embodiments, the infusion time for followed by the administration of plinabulin two times every plinabulin is about 1 hour ( e.g. , 20 , 30 , or greater than 30 1 week , 2 weeks , 3 weeks , 4 weeks , 5 weeks , 6 weeks , 7 mg /m² ). weeks, or 8 weeks . In some embodiments, the treatment [ 0086 ] In some embodiments , when plinabulin is co schedule includes administration of the chemotherapy ( e.g. , administered with G - CSF , the treatment schedule includes docetaxel , TAC , or TC ) followed by the administration of administration of the chemotherapy followed by the admin plinabulin once every 1 week in a treatment cycle of 1 week , istration of plinabulin once every 3 weeks. In some embodi 2 weeks, 3 weeks , 4 weeks, 5 weeks , 6 weeks, 7 weeks , or ments , the treatment schedule includes administration of the 8 weeks . In some embodiments , the treatment schedule US 2021/0030843 A1 Feb. 4 , 2021 13 includes administration of the chemotherapy ( e.g. , doc plinabulin following every two doses , three doses , four etaxel , TAC , or TC ) followed by the administration of doses , five doses, or six doses of the chemotherapy admin plinabulin twice every 1 week in a treatment cycle of 1 istration . In some embodiments, the treatment schedule week , 2 weeks , 3 weeks , 4 weeks, 5 weeks, 6 weeks, 7 includes co - administering plinabulin and G - CSF following weeks, or 8 weeks. In some embodiments, the treatment every other dose of the chemotherapy ( e.g. , docetaxel , TAC , schedule includes administration of the chemotherapy ( e.g. , or TC ) administration . In some embodiments, the plinabulin docetaxel , TAC , or TC ) followed by the administration of and G - CSF are administered after every two doses , every plinabulin on day 1 , day 8 , and day 15 of a 21 - day treatment three doses , every four doses , every five doses , or every six cycle . In some embodiments, the treatment schedule doses of the chemotherapy ( e.g. , docetaxel, TAC , or TC ) includes co - administering plinabulin and G - CSF following administration . every dose of the chemotherapy ( e.g. , docetaxel, TAC , or [ 0090 ] In some embodiments, co - administering plinabulin TC ) administration . In some embodiments, the treatment and G - CSF includes administering only one dose G - CSF schedule includes co - administering plinabulin and G - CSF after the initial dose of plinabulin is administered and no following the initial dose of the chemotherapy ( e.g. , doc G - CSF administration after the second dose of plinabulin etaxel , TAC , or TC ) administration and then co - administer per chemotherapy treatment cycle . In some embodiments, ing plinabulin and G - CSF following every two doses , three co - administering plinabulin and G - CSF includes adminis doses , four doses , five doses , or six doses of the chemo tering one dose G - CSF after each dose plinabulin is admin therapy administration . In some embodiments , the treatment istered . In some embodiments, co - administering plinabulin schedule includes co - administering plinabulin and G - CSF and G - CSF includes administering plinabulin once and then following every other dose of the chemotherapy ( e.g. , doc administering G - CSF daily for up to one week , two weeks , etaxel , TAC , or TC ) administration . In some embodiments , or three weeks, or until the patient's ANC returns to a level the plinabulin and /or G - CSF is administered after every two acceptable for the chemotherapy. doses , every three doses , every four doses , every five doses, [ 0091 ] In some embodiments, the treatment schedule or every six doses of the chemotherapy ( e.g. , docetaxel, includes co - administering plinabulin and G - CSF following TAC , or TC ) administration . every cycle of the chemotherapy ( e.g. , docetaxel , TAC , or [ 0089 ] In some embodiments, the treatment schedule TC ) administration . In some embodiments, the treatment includes administration of the chemotherapy ( e.g. , doc schedule includes administering plinabulin following the etaxel , TAC , or TC ) followed by the co - administration of initial cycle of the chemotherapy ( e.g. , docetaxel , TAC , or plinabulin and G - CSF once every 3 weeks . In some embodi TC ) administration and then administering plinabulin fol ments, the treatment schedule includes administration of the lowing every two cycles , three cycles , four cycles , five chemotherapy ( e.g. , docetaxel, TAC , or TC ) followed by the cycles , or six cycles of the chemotherapy administration . In co - administration of plinabulin and G - CSF , and the plinabu some embodiments, the treatment schedule includes admin lin is administered once every 3 weeks in a treatment cycle . istering plinabulin following every other cycle of the che In some embodiments , the treatment schedule includes motherapy ( e.g. , docetaxel , TAC , or TC ) administration . In administration of the chemotherapy ( e.g. , docetaxel, TAC , or some embodiments, the plinabulin is administered after TC ) followed by the co - administration of plinabulin and every two cycles , every three cycles , every four cycles , G - CSF once every 1 week , 2 weeks, 3 weeks , 4 weeks , 5 every five cycles , or every six cycles of the chemotherapy weeks, 6 weeks , 7 weeks , or 8 weeks . In some embodiments , ( e.g. , docetaxel, TAC , or TC ) administration . the treatment schedule includes administration of the che [ 0092 ] The treatment cycle can be repeated as long as the motherapy ( e.g. , docetaxel, TAC , or TC ) followed by the regimen is clinically tolerated . In ome embodiments, the administration of co - administration of plinabulin and treatment cycle for docetaxel or other chemotherapy is G - CSF two times every 1 week , 2 weeks , 3 weeks , 4 weeks , repeated for n times , wherein n is an integer in the range of 5 weeks, 6 weeks, 7 weeks, or 8 weeks . In some embodi 2 to 30. In some embodiments, n is 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , or ments , the treatment schedule includes administration of the 10. In some embodiments, a new treatment cycle can occur chemotherapy ( e.g. , docetaxel, TAC , or TC ) followed by the immediately after the completion of the previous treatment co - administration of plinabulin and G - CSF once every 1 cycle . In some embodiments, a new treatment cycle can week in a treatment cycle of 1 week , 2 weeks , 3 weeks, 4 occur a period of time after the completion of the previous weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks . In some treatment cycle . embodiments, the treatment schedule includes administra [ 0093 ] In some embodiments , the co - administration of tion of the chemotherapy ( e.g. , docetaxel, TAC , or TC ) plinabulin and G - CSF can reduce the incidence of Grade 3 followed by the co - administration of plinabulin and G - CSF and /or 4 neutropenia by at least about 1 % , 2 % , 3 % , 4 % , 5 % , twiceevery 1 week in a treatment cycle of 1 week , 2 weeks , 10 % , 12.5 % , 15 % , 17.5 % , 20 % , 22.5 % , 25 % , 27.5 % , 30 % , 3 weeks , 4 weeks , 5 weeks, 6 weeks , 7 weeks, or 8 weeks . 32.5 % , 35 % , 37.5 % , 40 % , 42.5 % , 45 % , 47.5 % , 50 % , In some embodiments , the treatment schedule includes 52.5 % , 55 % , 57.5 % , 60 % , 62.5 % , 65 % , 67.5 % , 70 % , administration of the chemotherapy ( e.g. , docetaxel, TAC , or 72.5 % , 75 % , 77.5 % , 80 % , 82.5 % , 85 % , 87.5 % , 90 % , 95 % , TC ) followed by the co - administration of plinabulin and or 100 % . In some embodiments, the co - administration of G - CSF on day 1 , day 8 , and day 15 of a 21 -day treatment plinabulin and G - CSF can reduce the incidence of Grade 3 cycle . In some embodiments, the treatment schedule and / or 4 neutropenia by at least about 5 % , 10 % , 12.5 % , includes co - administering plinabulin and G - CSF following 15 % , 17.5 % , 20 % , 22.5 % , 25 % , 27.5 % , 30 % , 32.5 % , 35 % , every dose of the chemotherapy ( e.g. , docetaxel, TAC , or 37.5 % , 40 % , 42.5 % , 45 % , 47.5 % , 50 % , 52.5 % , 55 % , TC ) administration . In some embodiments, the treatment 57.5 % , 60 % , 62.5 % , 65 % , 67.5 % , 70 % , 72.5 % , 75 % , schedule includes co - administering plinabulin and G - CSF 77.5 % , 80 % , 82.5 % , 85 % , 87.5 % , 90 % , 95 % , or 100 % . In following the initial dose of the chemotherapy ( e.g. , doc some embodiments , the co - administration of plinabulin and etaxel , TAC , or TC ) administration and then administering G - CSF can reduce the incidence of Grade 3 and / or 4 US 2021/0030843 A1 Feb. 4 , 2021 14 neutropenia by less than about 5 % , 10 % , 12.5 % , 15 % , 500 % , 600 % , 700 % , 800 % , 900 % , 10 times , 11 times , 12 17.5 % , 20 % , 22.5 % , 25 % , 27.5 % , 30 % , 32.5 % , 35 % , times , 13 times , 14 times , 15 times , or 16 times . In some 37.5 % , 40 % , 42.5 % , 45 % , 47.5 % , 50 % , 52.5 % , 55 % , embodiments , the co - administration of plinabulin and 57.5 % , 60 % , 62.5 % , 65 % , 67.5 % , 70 % , 72.5 % , 75 % , G - CSF can reduce the duration of severe neutropenia by less 77.5 % , 80 % , 82.5 % , 85 % , 87.5 % , 90 % , 95 % , or 100 % . In than about 5 % , 10 % , 12.5 % , 15 % , 17.5 % , 20 % , 22.5 % , some embodiments, the co - administration of plinabulin and 25 % , 27.5 % , 30 % , 32.5 % , 35 % , 37.5 % , 40 % , 42.5 % , 45 % , G - CSF can reduce the incidence of Grade 3 and / or 4 47.5 % , 50 % , 52.5 % , 55 % , 57.5 % , 60 % , 62.5 % , 65 % , neutropenia in the range of about 1 % -5 % , 1 % -10 % , 67.5 % , 70 % , 72.5 % , 75 % , 77.5 % , 80 % , 82.5 % , 85 % , 1 % -15 % , 1 % -20 % , 1 % -30 % , 1 % -40 % , 1 % -50 % , 2.5 % 87.5 % , 90 % , 95 % , 100 % , 110 % , 120 % , 130 % , 140 % , 10 % , 2.5 % -15 % , 2.5 % -20 % , 2.5 % -30 % , 5 % -10 % , 150 % , 160 % , 170 % , 180 % , 190 % , 200 % , 225 % , 250 % , 5 % -15 % , 5 % -20 % , 5 % -30 % , 5 % -40 % , 10 % -40 % , 12.5 % 275 % , 300 % , 350 % 400 % , 450 % , 500 % , 600 % , 700 % , 40 % , 5 % -50 % , 10 % -50 % , 12.5 % -50 % , 15 % -50 % , 17.5 % 800 % , 900 % , 10 times , 11 times , 12 times , 13 times , 14 50 % , 20 % -50 % , 25 % -50 % , 27.5 % -50 % , 30 % -50 % , times , 15 times , or 16 times . In some embodiments , the 5 % -60 % , 10 % -60 % , 12.5 % -60 % , 15 % -60 % , 17.5 % -60 % , co - administration of plinabulin and G - CSF can reduce the 20 % -60 % , 25 % -60 % , 27.5 % -60 % , 30 % -60 % , 35 % -60 % , duration of severe neutropenia in the range of about 37.5 % -60 % , 40 % -60 % , 45 % -70 % , or 50 % -80 % . 5 % -10 % , 5 % -20 % , 5 % -30 % , 5 % -40 % , 5 % -50 % , 5 % -60 % , [ 0094 ] In some embodiments , the co - administration of 5 % -70 % , 5 % -80 % , 5 % -100 % , 5 % -2 times , 5 % -5 times , plinabulin and G - CSF can be about 10 % , 20 % , 30 % , 40 % , 5 % -15 times , 20 % -10 times , or 50 % -500 % . 50 % , 60 % , 70 % , 80 % , 90 % , 100 % , 110 % , 120 % , 130 % , [ 0096 ] In some embodiments, the co -administration of 140 % , 150 % , 160 % , 170 % , 180 % , 190 % , 200 % , 225 % , plinabulin and G - CSF can be about 5 % , 10 % , 12.5 % , 15 % , 250 % , 275 % , 300 % , 350 % 400 % , 450 % , or 500 % more 17.5 % , 20 % , 22.5 % , 25 % , 27.5 % , 30 % , 32.5 % , 35 % , effective than the use of G - CSF ( e.g. , pegfilgrastim ) in 37.5 % , 40 % , 42.5 % , 45 % , 47.5 % , 50 % , 52.5 % , 55 % , reducing the incidence of Grade 3 and / or 4 neutropenia. In 57.5 % , 60 % , 62.5 % , 65 % , 67.5 % , 70 % , 72.5 % , 75 % , some embodiments, the co - administration of plinabulin and 77.5 % , 80 % , 82.5 % , 85 % , 87.5 % , 90 % , 95 % , 100 % , 110 % , G - CSF can be greater than about 10 % , 20 % , 30 % , 40 % , 120 % , 130 % , 140 % , 150 % , 160 % , 170 % , 180 % , 190 % , 50 % , 60 % , 70 % , 80 % , 90 % , 100 % , 110 % , 120 % , 130 % , 200 % , 225 % , 250 % , 275 % , 300 % , 350 % 400 % , 450 % , 140 % , 150 % , 160 % , 170 % , 180 % , 190 % , 200 % , 225 % , 500 % , 600 % , 700 % , 800 % , 900 % , 10 times , 11 times , 12 250 % , 275 % , 300 % , 350 % 400 % , 450 % , or 500 % more times , 13 times , 14 times , 15 times , or 16 times more effective than the use of G - CSF ( e.g. , pegfilgrastim ) in effective than G -CSF ( e.g. , pegfilgrastim ) in reducing the reducing the incidence of Grade 3 and / or 4 neutropenia. In duration of severe neutropenia . In some embodiments, the some embodiments, the co - administration of plinabulin and co -administration of plinabulin and G - CSF can be greater G - CSF can be less than about 10 % , 20 % , 30 % , 40 % , 50 % , than about 5 % , 10 % , 12.5 % , 15 % , 17.5 % , 20 % , 22.5 % , 60 % , 70 % , 80 % , 90 % , 100 % , 110 % , 120 % , 130 % , 140 % , 25 % , 27.5 % , 30 % , 32.5 % , 35 % , 37.5 % , 40 % , 42.5 % , 45 % , 150 % , 160 % , 170 % , 180 % , 190 % , 200 % , 225 % , 250 % , 47.5 % , 50 % , 52.5 % , 55 % , 57.5 % , 60 % , 62.5 % , 65 % , 275 % , 300 % , 350 % 400 % , 450 % , or 500 % more effective 67.5 % , 70 % , 72.5 % , 75 % , 77.5 % , 80 % , 82.5 % , 85 % , than the use of G - CSF ( e.g. , pegfilgrastim ) in reducing the 87.5 % , 90 % , 95 % , 100 % , 110 % , 120 % , 130 % , 140 % , incidence of Grade 3 and / or 4 neutropenia . In some embodi 150 % , 160 % , 170 % , 180 % , 190 % , 200 % , 225 % , 250 % , ments, the co - administration of plinabulin and G - CSF can 275 % , 300 % , 350 % 400 % , 450 % , 500 % , 600 % , 700 % , be greater than about 10 % , 20 % , 30 % , 40 % , 50 % , 60 % , 800 % , 900 % , 10 times , 11 times , 12 times , 13 times , 14 70 % , 80 % , 90 % , 100 % , 110 % , 120 % , 130 % , 140 % , 150 % , times , 15 times , or 16 times more effective than G - CSF ( e.g. , 160 % , 170 % , 180 % , 190 % , 200 % , 225 % , 250 % , 275 % , pegfilgrastim ) in reducing the duration of severe neutrope 300 % , 350 % 400 % , 450 % , or 500 % more effective than the nia . In some embodiments , the co - administration of plinabu use of G - CSF ( e.g. , pegfilgrastim ) in reducing the incidence lin and G - CSF can be less than about 5 % , 10 % , 12.5 % , 15 % , of Grade 3 and /or 4 neutropenia. 17.5 % , 20 % , 22.5 % , 25 % , 27.5 % , 30 % , 32.5 % , 35 % , [ 0095 ] In some embodiments , the co - administration of 37.5 % , 40 % , 42.5 % , 45 % , 47.5 % , 50 % , 52.5 % , 55 % , plinabulin and G - CSF can reduce the duration of severe 57.5 % , 60 % , 62.5 % , 65 % , 67.5 % , 70 % , 72.5 % , 75 % , neutropenia by about 1 % , 2 % , 3 % , 4 % , 5 % , 10 % , 12.5 % , 77.5 % , 80 % , 82.5 % , 85 % , 87.5 % , 90 % , 95 % , 100 % , 110 % , 15 % , 17.5 % , 20 % , 22.5 % , 25 % , 27.5 % , 30 % , 32.5 % , 35 % , 120 % , 130 % , 140 % , 150 % , 160 % , 170 % , 180 % , 190 % , 37.5 % , 40 % , 42.5 % , 45 % , 47.5 % , 50 % , 52.5 % , 55 % , 200 % , 225 % , 250 % , 275 % , 300 % , 350 % 400 % , 450 % , 57.5 % , 60 % , 62.5 % , 65 % , 67.5 % , 70 % , 72.5 % , 75 % , 500 % , 600 % , 700 % , 800 % , 900 % , 10 times , 11 times , 12 77.5 % , 80 % , 82.5 % , 85 % , 87.5 % , 90 % , 95 % , 100 % , 110 % , times , 13 times , 14 times , 15 times , or 16 times more 120 % , 130 % , 140 % , 150 % , 160 % , 170 % , 180 % , 190 % , effective than G - CSF ( e.g. , pegfilgrastim ) in reducing the 200 % , 225 % , 250 % , 275 % , 300 % , 350 % 400 % , 450 % , duration of severe neutropenia . In some embodiments , the 500 % , 600 % , 700 % , 800 % , 900 % , 10 times , 11 times , 12 co - administration of plinabulin and G - CSF can be in the times , 13 times , 14 times , 15 times , or 16 times . In some range of about 5 % -15 times, 20 % -10 times , or 50 % -500 % embodiments, the co - administration of plinabulin and more effective than G - CSF ( e.g. , pegfilgrastim ) in reducing G - CSF can reduce the duration of severe neutropenia by the duration of severe neutropenia . greater than about 1 % , 2 % , 3 % , 4 % , 5 % , 10 % , 12.5 % , 15 % , [ 0097 ] Plinabulin and G - CSF can be co - administered fol 17.5 % , 20 % , 22.5 % , 25 % , 27.5 % , 30 % , 32.5 % , 35 % , lowing the chemotherapy to treat or ameliorate neutropenia . 37.5 % , 40 % , 42.5 % , 45 % , 47.5 % , 50 % , 52.5 % , 55 % , In some embodiments, a single dose of G - CSF ( e.g. , peg 57.5 % , 60 % , 62.5 % , 65 % , 67.5 % , 70 % , 72.5 % , 75 % , filgrastim or eflapegrastim , or other long acting G - CSF ) can 77.5 % , 80 % , 82.5 % , 85 % , 87.5 % , 90 % , 95 % , 100 % , 110 % , be in the range of 0.1 mg to about 10 mg , about 0.3 mg to 120 % , 130 % , 140 % , 150 % , 160 % , 170 % , 180 % , 190 % , about 6 mg , about 0.1 mg to about 6 mg , 0.1 mg to about 7 200 % , 225 % , 250 % , 275 % , 300 % , 350 % 400 % , 450 % , mg , 0.5 mg to about 10 mg , from about 0.5 mg to about 8 US 2021/0030843 A1 Feb. 4 , 2021 15 mg , from about 0.5 mg to about 7 mg , from about 0.5 mg to about 1 mg , about 1.5 mg , about 2 mg , about 2.5 mg , about about 6 mg , from about 0.5 mg to about 5 mg , from about 3 mg , about 3.5 mg , about 4 mg , about 4.5 mg, about 5 mg , 0.5 mg to about 4 mg , from about 0.5 mg to about 3 mg , 1 about 5.5 mg , about 6 mg , about 7 mg , about 8 mg , about 9 mg to about 100 mg , from about 1 mg to about 50 mg , from mg , or about 10 mg . In some embodiments, a single dose of about 1 mg to about 25 mg , from about 1 mg to about 15 mg , G - CSF ( e.g. , pegfilgrastim , eflapegrastim , or other long from about 1 mg to about 10 mg , from about 1 mg to about acting G - CSF ) may be less than about 1 mg , about 1.5 mg , 8 mg , from about 1 mg to about 7 mg , from about 1 mg to about 2 mg , about 2.5 mg , about 3 mg , about 3.5 mg , about about 6 mg , from about 1 mg to about 5 mg , from about 1 4 mg , about 4.5 mg , about 5 mg , about 5.5 mg , about 6 mg, mg to about 4 mg , from about 1 mg to about 3 mg , from about 7 mg , about 8 mg , about 9 mg , about 10 mg , about about 2 mg to about 50 mg , from about 2 mg to about 25 mg , 12.5 mg , or about 15 mg . In some embodiments , a single from about 2 mg to about 15 mg , from about 2 mg to about dose of G - CSF ( e.g. , pegfilgrastim , eflapegrastim , or other 10 mg , from about 2 mg to about 10 mg , from about 2 mg long acting G - CSF ) may be about 0.5 mg , about 1 mg , about to about 8 mg , from about 2 mg to about 7 mg , from about 1.5 mg , about 2 mg , about 2.5 mg , about 3 mg , about 3.5 mg , 2 mg to about 6 mg , from about 2 mg to about 5 mg , from about 4 mg , about 4.5 mg , about 5 mg , about 5.5 mg , about about 2 mg to about 4 mg , from about 2 mg to about 3 mg , 6 mg , about 7 mg , about 8 mg , about 9 mg , or about 10 mg . from about 3 mg to about 50 mg , from about 3 mg to about In some embodiments , a single dose of G - CSF ( e.g. , peg 25 mg , from about 3 mg to about 15 mg , from about 3 mg filgrastim , eflapegrastim , or other long acting G - CSF ) may to about 10 mg , from about 3 mg to about 10 mg , from about be about 6 mg . 3 mg to about 8 mg , from about 3 mg to about 7 mg , from [ 0098 ] In some embodiments, the total dosage of G - CSF about 3 mg to about 6 mg , from about 3 mg to about 5 mg , ( e.g., pegfilgrastim or eflapegrastim , or other long acting from about 3 mg to about 4 mg , from about 4 mg to about G - CSF ) administered in a 21 -day treatment cycle can be in 50 mg , from about 4 mg to about 25 mg , from about 4 mg the range of 0.1 mg to about 10 mg , about 0.3 mg to about to about 15 mg , from about 4 mg to about 10 mg , from about 6 mg , about 0.1 mg to about 6 mg , 0.1 mg to about 7 mg , 4 mg to about 6 mg , from about 4 mg to about 5 mg , from 0.5 mg to about 10 mg , from about 0.5 mg to about 8 mg , about 5 mg to about 25 mg , from about 5 mg to about 15 mg , from about 0.5 mg to about 7 mg , from about 0.5 mg to from about 5 mg to about 10 mg , or from about 5 mg to about 6 mg , from about 0.5 mg to about 5 mg , from about about 8 mg . In some embodiments, a single dose of G - CSF 0.5 mg to about 4 mg , from about 0.5 mg to about 3 mg , 1 ( e.g. , pegfilgrastim or eflapegrastim , or other long acting mg to about 100 mg , from about 1 mg to about 50 mg , from G - CSF ) can have an amount equivalent to filgrastim in the about 1 mg to about 25 mg , from about 1 mg to about 15 mg , range of 0.5 mg to about 10 mg , from about 0.5 mg to about from about 1 mg to about 10 mg , from about 1 mg to about 8 mg , from about 0.5 mg to about 7 mg , from about 0.5 mg 8 mg , from about 1 mg to about 7 mg , from about 1 mg to to about 6 mg , from about 0.5 mg to about 5 mg , from about about 6 mg , from about 1 mg to about 5 mg , from about 1 0.5 mg to about 4 mg , from about 0.5 mg to about 3 mg , 1 mg to about 4 mg , from about 1 mg to about 3 mg , from mg to about 100 mg , from about 1 mg to about 50 mg , from about 2 mg to about 50 mg , from about 2 mg to about 25 mg , about 1 mg to about 25 mg , from about 1 mg to about 15 mg , from about 2 mg to about 15 mg , from about 2 mg to about from about 1 mg to about 10 mg , from about 1 mg to about 10 mg , from about 2 mg to about 10 mg , from about 2 mg 8 mg , from about 1 mg to about 7 mg , from about 1 mg to to about 8 mg , from about 2 mg to about 7 mg , from about about 6 mg , from about 1 mg to about 5 mg , from about 1 2 mg to about 6 mg , from about 2 mg to about 5 mg , from mg to about 4 mg , from about 1 mg to about 3 mg , from about 2 mg to about 4 mg , from about 2 mg to about 3 mg , about 2 mg to about 50 mg , from about 2 mg to about 25 mg , from about 3 mg to about 50 mg , from about 3 mg to about from about 2 mg to about 15 mg , from about 2 mg to about 25 mg , from about 3 mg to about 15 mg , from about 3 mg 10 mg , from about 2 mg to about 10 mg , from about 2 mg to about 10 mg , from about 3 mg to about 10 mg , from about to about 8 mg , from about 2 mg to about 7 mg , from about 3 mg to about 8 mg , from about 3 mg to about 7 mg , from 2 mg to about 6 mg , from about 2 mg to about 5 mg , from about 3 mg to about 6 mg , from about 3 mg to about 5 mg , about 2 mg to about 4 mg , from about 2 mg to about 3 mg , from about 3 mg to about 4 mg , from about 4 mg to about from about 3 mg to about 50 mg , from about 3 mg to about 50 mg , from about 4 mg to about 25 mg , from about 4 mg 25 mg , from about 3 mg to about 15 mg , from about 3 mg to about 15 mg , from about 4 mg to about 10 mg , from about to about 10 mg , from about 3 mg to about 10 mg , from about 4 mg to about 6 mg , from about 4 mg to about 5 mg , from 3 mg to about 8 mg , from about 3 mg to about 7 mg , from about 5 mg to about 25 mg , from about 5 mg to about 15 mg , about 3 mg to about 6 mg , from about 3 mg to about 5 mg , from about 5 mg to about 10 mg , or from about 5 mg to from about 3 mg to about 4 mg , from about 4 mg to about about 8 mg . In some embodiments , the total dosage of 50 mg , from about 4 mg to about 25 mg , from about 4 mg G - CSF ( e.g. , pegfilgrastim or eflapegrastim , or other long to about 15 mg , from about 4 mg to about 10 mg , from about acting G - CSF ) per 21 - day cycle can have an amount equiva 4 mg to about 6 mg , from about 4 mg to about 5 mg , from lent to filgrastim in the range of 0.5 mg to about 10 mg , from about 5 mg to about 25 mg , from about 5 mg to about 15 mg , about 0.5 mg to about 8 mg , from about 0.5 mg to about 7 from about 5 mg to about 10 mg , or from about 5 mg to mg , from about 0.5 mg to about 6 mg , from about 0.5 mg to about 8 mg . In some embodiments, a single dose of G - CSF about 5 mg , from about 0.5 mg to about 4 mg , from about ( e.g. , pegfilgrastim , eflapegrastim , or other long acting 0.5 mg to about 3 mg , 1 mg to about 100 mg , from about 1 G - CSF ) may be from about 3 mg to about 10 mg , or from mg to about 50 mg , from about 1 mg to about 25 mg , from about 4 mg to about 8 mg , or equivalent to an amount of about 1 mg to about 15 mg , from about 1 mg to about 10 mg , filgrastim in the ranges herein described . In some embodi from about 1 mg to about 8 mg , from about 1 mg to about ments , a single dose of G - CSF ( e.g. , pegfilgrastim , eflape 7 mg , from about 1 mg to about 6 mg , from about 1 mg to grastim , or other long acting G - CSF ) may be greater than about 5 mg , from about 1 mg to about 4 mg , from about 1 about 0.1 mg , about 0.2 mg , about 0.3 mg , about 0.5 mg , mg to about 3 mg , from about 2 mg to about 50 mg , from US 2021/0030843 A1 Feb. 4 , 2021 16 about 2 mg to about 25 mg , from about 2 mg to about 15 mg , [ 0100 ] Administration of Plinabulin and G - CSF can help from about 2 mg to about 10 mg , from about 2 mg to about prevent or treat severe neutropenia induced by the chemo 10 mg , from about 2 mg to about 8 mg , from about 2 mg to therapy treatment. In some embodiments , the G - CSF ( e.g. , about 7 mg , from about 2 mg to about 6 mg , from about 2 pegfilgrastim or filgrastim ) is administered once per chemo mg to about 5 mg , from about 2 mg to about 4 mg , from therapy cycle . In some embodiments, the G - CSF ( e.g. , about 2 mg to about 3 mg , from about 3 mg to about 50 mg , pegfilgrastim or filgrastim ) is not administered between 14 from about 3 mg to about 25 mg , from about 3 mg to about hours and 24 hours after the administration of cytotoxic 15 mg , from about 3 mg to about 10 mg , from about 3 mg chemotherapy. In some embodiments , the G - CSF ( e.g. , to about 10 mg , from about 3 mg to about 8 mg , from about pegfilgrastim or filgrastim ) is not administered before 24 3 mg to about 7 mg , from about 3 mg to about 6 mg , from about 3 mg to about 5 mg , from about 3 mg to about 4 mg , hours after the administration of cytotoxic chemotherapy In from about 4 mg to about 50 mg , from about 4 mg to about some embodiments , two doses of G - CSF ( e.g. , pegfilgrastim 25 mg , from about 4 mg to about 15 mg , from about 4 mg or filgrastim ) are administered one week apart. In some to about 10 mg , from about 4 mg to about 6 mg , from about embodiments , the G - CSF ( e.g. , pegfilgrastim or filgrastim ) 4 mg to about 5 mg , from about 5 mg to about 25 mg , from is administered once , twice , three times , four times , five about 5 mg to about 15 mg , from about 5 mg to about 10 mg , times , six times , seven times a week for one week or two or from about 5 mg to about 8 mg . In some embodiments , weeks . In some embodiments, the G - CSF ( e.g. , pegfil the total dosage of G - CSF ( e.g. , pegfilgrastim , eflape grastim or filgrastim ) is administered once a week , every grastim , or other long acting G - CSF ) per 21 - day cycle may two weeks, every three weeks, every four weeks , every five be from about 3 mg to about 10 mg , or from about 4 mg to weeks, or ever six weeks. In some embodiments , the first about 8 mg , or equivalent to an amount of filgrastim in the dose of G - CSF ( e.g. , pegfilgrastim or filgrastim ) is admin ranges herein described . In some embodiments, the total istered as soon as the suspected or confirmed exposure to dosage of G - CSF ( e.g. , pegfilgrastim , eflapegrastim , or other myelosuppressive chemotherapy or myelosuppressive dose long acting G - CSF ) in a 21 - day cycle may be greater than of radiation . In some embodiments , the G - CSF ( e.g. , peg about 0.1 mg , about 0.2 mg , about 0.3 mg , about 0.5 mg , filgrastim or filgrastim ) is administered subcutaneously . about 1 mg , about 1.5 mg , about 2 mg , about 2.5 mg , about [ 0101 ] In some embodiments , during the chemotherapy 3 mg , about 3.5 mg , about 4 mg , about 4.5 mg , about 5 mg, treatment cycle , the chemotherapeutic agent (s ) is only about 5.5 mg , about 6 mg , about 7 mg , about 8 mg , about 9 administered once at the beginning of the treatment cycle , mg , or about 10 mg . In some embodiments, a total dosage followed by the co - administration of plinabulin and G - CSF of G - CSF ( e.g. , pegfilgrastim , eflapegrastim , or other long once , twice , three times , four times , five times , or six times acting G - CSF ) in a 21 - day cycle may be less than about 1 during the treatment cycle . In some embodiments, during the mg , about 1.5 mg , about 2 mg , about 2.5 mg , about 3 mg , chemotherapy treatment cycle , the chemotherapeutic agent about 3.5 mg , about 4 mg , about 4.5 mg , about 5 mg , about ( s ) is only administered once at the beginning of the treat 5.5 mg , about 6 mg , about 7 mg , about 8 mg , about 9 mg , ment cycle , followed by the co - administration of plinabulin about 10 mg , about 12.5 mg , or about 15 mg . In some and G - CSF once every week , once every two weeks, once embodiments, a total dosage of G - CSF ( e.g. , pegfilgrastim , every three weeks , once every four weeks , once evert five eflapegrastim , or other long acting G - CSF ) in a 21 - day cycle weeks, or once every six weeks . In some embodiments, may be about 0.5 mg , about 1 mg , about 1.5 mg , about 2 mg , during the chemotherapy treatment cycle , the chemothera about 2.5 mg , about 3 mg , about 3.5 mg , about 4 mg , about peutic agent( s ) is only administered once at the beginning of 4.5 mg, about 5 mg , about 5.5 mg , about 6 mg , about 7 mg , the treatment cycle , followed by the co - administration of about 8 mg , about 9 mg , or about 10 mg . In some embodi plinabulin and G - CSF once a week , twice a week , three ments , a total dosage of G - CSF ( e.g. , pegfilgrastim , eflape times per week , four times per week , five times per week , six grastim , or other long acting G - CSF ) in a 21 - day cycle may times per week , or daily during a one -week , two - week , be about 6 mg . three - week , four -week , or five -week treatment cycle . [ 0099 ] In some embodiments , G - CSF ( e.g. , filgrastim or [ 0102 ] In some embodiments , the G - CSF and plinabulin other short acting G - CSF ) can be administered in an amount can be co - administered or administered separately once of about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , every three weeks . In some embodiments, the G - CSF and 17 , 18 , 19 , 20 ug /kg / day. In some embodiments , G - CSF plinabulin can be co - administered or administered sepa ( e.g. , filgrastim or other short acting G - CSF ) can be admin rately once every week , once every two weeks , once every istered in an amount greater than about 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , three weeks , once every four weeks , once evert five weeks , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ug /kg /day . In or once every six weeks. In some embodiments, the G - CSF some embodiments, G - CSF ( e.g. , filgrastim or other short and plinabulin can be co - administered or administered sepa acting G - CSF ) can be administered in an amount less than rately once a week . In some embodiments , G - CSF and about 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , plinabulin can be co - administered or administered sepa 30 , 40 , or 50 ug /kg / day. In some embodiments, G - CSF ( e.g. , rately once a week , twice a week , three times per week , four filgrastim or other short acting G - CSF ) can be administered times per week , five times per week , six times per week , or in an amount of about 1-5 , 1-10 , 1-15 , 1-20 , 1-30 , 2.5-5 , daily during a one -week , two -week , three -week , four- week , 2.5-7.5 , 2.5-10 , 2.5-15 , 2.5-20 , 5-10 , 5-15 , 5-20 , 5-25 , or or five -week treatment cycle . The administration can be on 5-30 ug / kg /day . In some embodiments , the G - CSF is admin the same or different day of each week in the treatment istered in an amount of about 0.05 , 0.75 , 0.1 , 0.2 , 0.3 , 0.4 , cycle . In some embodiments, the plinabulin is administered 0.48 , 0.5 , 0.6 , 0.7 , 0.8 , 0.9 , 1.0 , 1.2 , 1.5 , 1.75 , or 2 mg per prior to the G - CSF administration . In some embodiments, dose . In some embodiments, the G - CSF is administered in the plinabulin is administered concurrently with the G - CSF the range of about 0.05-0.5 mg , 0.05-1.0 mg , 0.1-1.0 mg , or administration . In some embodiments, the plinabulin is 0.05-2.0 mg per dose . administered after the G - CSF administration . US 2021/0030843 A1 Feb. 4 , 2021 17

[ 0103 ] In some embodiments, the G - CSF is administered [ 0106 ] Administration of the pharmaceutical composi prior to the plinabulin administration . In some embodi tions described herein can be via any of the accepted modes ments , the G - CSF is administered concurrently with the of administration for agents that serve similar utilities plinabulin administration . In some embodiments, the G - CSF including , but not limited to , orally, sublingually, buccally, is administered after the plinabulin administration . In some subcutaneously, intravenously, intranasally, topically, trans further embodiments , the G - CSF is administered about 10 dermally, intradermally, intraperitoneally , intramuscularly, hours to about 72 hours , about 20 hours to about 72 hours , intrapulmonarilly, vaginally, rectally, or intraocularly . Oral about 20 hours to about 70 hours , about 20 hours to about and parenteral administrations are customary in treating the 60 hours , about 20 hours to about 50 hours , about 20 to indications that are the subject of the preferred embodiments about 48 hours, about 20 hours to about 40 hours, about 20 hours to about 36 hours , about 20 hours to about 30 hours , Pharmaceutical Composition or about 20 hours to about 24 hours after the plinabulin administration . In some yet further embodiments, the G - CSF [ 0107 ] Some embodiments relate to a pharmaceutical is administered within 48 hours , within 24 hours , or within composition including plinabulin . Some embodiments relate 12 hours after the administration of the plinabulin . to a pharmaceutical composition comprising about 1 mg to [ 0104 ] In some embodiments , the G - CSF ( if a short acting about 100 mg of plinabulin . G - CSF is used , then the first dose of G - CSF ) is administered [ 0108 ] In some embodiments, the compositions described after about 6 h , 12 h , 18 h , 24 h , 36 g , 48 h , or 72 h after the herein can be administered or used in combination with administration of the chemotherapy. In some embodiments , docetaxel treatment. the G - CSF ( if a short acting G - CSF is used , then the first [ 0109 ] Other embodiments include co - administering dose of G - CSF ) is administered in less than about 12 h , 18 Plinabulin , G - CSF , and docetaxel in separate compositions h , 24 h , 36 h , 48 h , 60 h , 72 h , 84 h , 96 h , 5 days, 6 days, or the same composition . Thus, some embodiments include or 7 days after the administration of the chemotherapy . In a first pharmaceutical compositions comprising: ( a ) a safe some embodiments , the G - CSF ( if a short acting G - CSF is and therapeutically effective amount of docetaxel or phar used , then the first dose of G - CSF ) is administered in about maceutically acceptable salts thereof and ( b ) a pharmaceu 1 h - 24 h , 12 h - 36 h , 10 h - 40 h , 24 hour to 36 hour, 1 day - 2 tically acceptable carrier , diluent, excipient or combination days, 1 day - 5 days, 1 day -1 week after the administration of thereof; a second pharmaceutical composition comprising : the chemotherapy . In some embodiments, the G - CSF ( if a ( a ) a safe and therapeutically effective amount of plinabulin short acting G - CSF is used , then the first dose of G - CSF ) is and ( b ) a pharmaceutically acceptable carrier , diluent, administered at least about 24 h after the chemotherapy excipient or combination thereof, and a third pharmaceutical administration . In some embodiments , the G - CSF ( if a short composition comprising: ( a ) a safe and therapeutically effec acting G - CSF is used , then the first dose of G - CSF ) is tive amount of G - CSF and ( b ) a pharmaceutically acceptable administered at least about 48 h after the chemotherapy carrier, diluent, excipient or combination thereof. Some administration . In some embodiments, the G - CSF ( if a short embodiments include a pharmaceutical composition com acting G - CSF is used , then the first dose of G - CSF ) is prising: ( a ) a safe and therapeutically effective amount of administered about 24 h after the chemotherapy administra docetaxel or pharmaceutically acceptable salts thereof; ( b ) a tion . In some embodiments, the G - CSF ( if a short acting safe and therapeutically effective amount of plinabulin ; ( c ) G - CSF is used , then the first dose of G - CSF ) is administered a safe and therapeutically effective amount of G - CSF, and about 48 h after the chemotherapy administration . ( d ) a pharmaceutically acceptable carrier, diluent, excipient [ 0105 ] Some embodiments include administering one , or combination thereof. two, three, four, five , six , or more cycles of a chemotherapy regimen , each cycle of the chemotherapy regimen indepen [ 0110 ] In some embodiments, the pharmaceutical compo dently comprising administering one or more chemothera sition described herein can further include one or more peutic agents on day 1 , day 2 , day 3 , day 4 , day 5 , or a pharmaceutically acceptable diluents . In some embodi combination thereof, administering plinabulin on day 1 , day ments, the pharmaceutically acceptable diluent can include 2 , day 3 , day 4 , day 5 , day 6 , day 7 or a combination thereof, Kolliphor ( Polyethylene glycol ( 15 ) -hydroxystearate ). In and administering one or more G - CSF drugs on day 2 , day some embodiments, the pharmaceutically acceptable diluent 3 , day 4 , day 5 , day 6 , day 7 , day 8 , day 9 , day 10 , day 11 , can include propylene glycol . In some embodiments, the day 12 , day 13 , day 14 , or a combination thereof . In some pharmaceutically acceptable diluents can include kolliphor embodiments , the one or more chemotherapeutic agents may ( Kolliphor HS 15 ) and propylene glycol . In some embodi be administered , independently in each cycle of the chemo ments , the pharmaceutically acceptable diluents can include therapy, according to the foregoing description or of any kolliphor and propylene glycol , wherein the kolliphor is description elsewhere herein . In some embodiments, the about 40 % by weight and propylene glycol is about 60 % by plinabulin may be administered , independently in each cycle weight based on the total weight of the diluents . In some of the chemotherapy, according to the foregoing description embodiments, the composition can further include one or or of any description elsewhere herein . In some embodi more other pharmaceutically acceptable excipients . ments, the one or more G - CSF drugs may be administered , [ 0111 ] Standard pharmaceutical formulation techniques independently in each cycle of the chemotherapy , according can be used to make the pharmaceutical compositions to the foregoing description or of any description elsewhere described herein , such as those disclosed in Remington's herein . In some embodiments , each cycle of the chemo The Science and Practice of Pharmacy , 21st Ed . , Lippincott therapy regimen lasts up to 30 days , lasts up to 21 days , lasts Williams & Wilkins ( 2005 ) , incorporated herein by refer up to 14 days, or lasts up to 7 days. In some embodiments , ence in its entirety. Accordingly, some embodiments include each cycle of the chemotherapy regimen lasts 30 days, lasts pharmaceutical compositions comprising : ( a ) a safe and 21 days , lasts 14 days , or lasts 7 days . therapeutically effective amount of Plinabulin or pharma US 2021/0030843 A1 Feb. 4 , 2021 18 ceutically acceptable salts thereof; and ( b ) a pharmaceuti cally - acceptable carriers include, for example, solid or liquid cally acceptable carrier, diluent, excipient or combination fillers, diluents , hydrotropies, surface - active agents, and thereof. encapsulating substances. Optional pharmaceutically - active [ 0112 ] The term “ pharmaceutically acceptable carrier " or materials may be included , which do not substantially inter " pharmaceutically acceptable excipient” includes any and fere with the activity of the compound or composition. The all solvents, dispersion media , coatings, antibacterial and amount of carrier employed in conjunction with the com antifungal agents , isotonic and absorption delaying agents pound or composition is sufficient to provide a practical and the like . The use of such media and agents for pharma quantity of material for administration per unit dose of the ceutically active substances is well known in the art . Except compound. Techniques and compositions for making dosage insofar as any conventional media or agent is incompatible forms useful in the methods described herein are described with the active ingredient, its use in the therapeutic compo in the following references, all incorporated by reference sitions is contemplated . In addition , various adjuvants such herein : Modern Pharmaceutics, 4th Ed . , Chapters 9 and 10 as are commonly used in the art may be included . Consid (Banker & Rhodes , editors , 2002 ) ; Lieberman et al . , Phar erations for the inclusion of various components in pharma maceutical Dosage Forms: Tablets ( 1989 ) ; and Ansel, Intro ceutical compositions are described , e.g. , in Gilman et al . duction to Pharmaceutical Dosage Forms 8th Edition ( Eds . ) ( 1990 ) ; Goodman and Gilman's : The Pharmacologi ( 2004 ). cal Basis of Therapeutics, 8th Ed . , Pergamon Press, which is [ 0116 ] Various oral dosage forms can be used , including incorporated herein by reference in its entirety. such solid forms as tablets , capsules ( e.g. , liquid gel capsule [ 0113 ] Some examples of substances , which can serve as and solid gel capsule ) , granules and bulk powders. Tablets pharmaceutically -acceptable carriers or components thereof, can be compressed , tablet triturates, enteric - coated , sugar are sugars , such as lactose , glucose and sucrose ; starches , coated , film - coated , or multiple -compressed , containing such as corn starch and potato starch ; cellulose and its suitable binders, lubricants, diluents, disintegrating agents, derivatives, such as sodium carboxymethyl cellulose , ethyl coloring agents, flavoring agents, flow - inducing agents, and cellulose , and methyl cellulose ; powdered tragacanth ; malt ; melting agents. Liquid oral dosage forms include aqueous gelatin ; talc ; solid lubricants, such as stearic acid and magnesium stearate ; calcium sulfate ; vegetable oils , such as solutions, emulsions, suspensions, solutions and / or suspen peanut oil , cottonseed oil , sesame oil , olive oil , corn oil and sions reconstituted from non - effervescent granules , and oil of theobroma; polyols such as propylene glycol , glycer effervescent preparations reconstituted from effervescent ine , sorbitol, mannitol, and polyethylene glycol; alginic granules, containing suitable solvents , preservatives, emul acid ; emulsifiers, such as the TWEENS; wetting agents , sifying agents, suspending agents, diluents, sweeteners , such sodium lauryl sulfate; coloring agents ; flavoring melting agents, coloring agents and flavoring agents. agents; tableting agents, stabilizers ; antioxidants ; preserva [ 0117 ] The pharmaceutically -acceptable carriers suitable tives ; pyrogen - free water; isotonic saline ; and phosphate for the preparation of unit dosage forms for peroral admin buffer solutions . istration is well -known in the art . Tablets typically comprise [ 0114 ] The compositions described herein are preferably conventional pharmaceutically - compatible adjuvants as provided in unit dosage form . As used herein , a “ unit dosage inert diluents , such as calcium carbonate , sodium carbonate , form ” is a composition containing an amount of a compound mannitol, lactose and cellulose ; binders such as starch , or composition that is suitable for administration to an gelatin and sucrose ; disintegrants such as starch , alginic acid animal, preferably a mammalian subject, in a single dose , and croscarmelose ; lubricants such as magnesium stearate , according to good medical practice . The preparation of a stearic acid and talc . Glidants such as silicon dioxide can be single or unit dosage form however, does not imply that the used to improve flow characteristics of the powder mixture . dosage form is administered once per day or once per course Coloring agents , such as the FD & C dyes , can be added for of therapy. Such dosage forms are contemplated to be appearance . Sweeteners and flavoring agents, such as aspar administered once , twice , thrice or more per day and may be tame , saccharin , menthol, peppermint, sucrose , and fruit administered as infusion over a period of time ( e.g. , from flavors , are useful adjuvants for chewable tablets . Capsules about 30 minutes to about 2-6 hours ), or administered as a typically comprise one or more solid diluents disclosed continuous infusion , and may be given more than once above . The selection of carrier components depends on during a course of therapy , although a single administration secondary considerations like taste , cost , and shelf stability , is not specifically excluded . The skilled artisan will recog which are not critical , and can be readily made by a person nize that the formulation does not specifically contemplate skilled in the art . the entire course of therapy and such decisions are left for [ 0118 ] Peroral compositions also include liquid solutions , those skilled in the art of treatment rather than formulation . emulsions , suspensions , and the like . The pharmaceutically [ 0115 ] The compositions useful as described above may acceptable carriers suitable for preparation of such compo be in any of a variety of suitable forms for a variety of routes sitions are well known in the art . Typical components of for administration , for example, for oral , sublingual , buccal , carriers for syrups, elixirs , emulsions and suspensions nasal , rectal, topical ( including transdermal and intrader include ethanol, glycerol, propylene glycol , polyethylene mal ) , ocular, intracerebral, intracranial, intrathecal, intra glycol , liquid sucrose , sorbitol and water . For a suspension , arterial, intravenous, intramuscular, or other parental routes typical suspending agents include methyl cellulose , sodium of administration . The skilled artisan will appreciate that carboxymethyl cellulose , AVICEL RC - 591 , tragacanth and oral and nasal compositions include compositions that are sodium alginate ; typical wetting agents include lecithin and administered by inhalation , and made using available meth polysorbate 80 ; and typical preservatives include methyl odologies . Depending upon the particular route of adminis paraben and sodium benzoate . Peroral liquid compositions tration desired , a variety of pharmaceutically - acceptable may also contain one or more components such as sweet carriers well - known in the art may be used . Pharmaceuti eners , flavoring agents and colorants disclosed above . US 2021/0030843 A1 Feb. 4 , 2021 19

[ 0119 ] Such compositions may also be coated by conven [ 0128 ] Other excipient components, which may be tional methods, typically with pH or time -dependent coat included in the ophthalmic preparations, are chelating ings , such that the subject composition is released in the agents. A useful chelating agent is edetate disodium gastrointestinal tract in the vicinity of the desired topical (EDTA ), although other chelating agents may also be used application, or at various times to extend the desired action . in place or in conjunction with it . Such dosage forms typically include, but are not limited to , [ 0129 ] For topical use , creams , ointments, gels , solutions one or more of cellulose acetate phthalate, polyvinylacetate or suspensions, etc., containing the composition disclosed phthalate, hydroxypropyl methyl cellulose phthalate, ethyl herein are employed . Topical formulations may generally be cellulose , Eudragit coatings, waxes and shellac . comprised of a pharmaceutical carrier, co - solvent, emulsi [ 0120 ] Compositions described herein may optionally fier, penetration enhancer, preservative system , and emol include other drug actives . lient. [ 0121 ] Other compositions useful for attaining systemic [ 0130 ] For intravenous administration , the compositions delivery of the subject compounds include sublingual , buc described herein may be dissolved or dispersed in a phar cal and nasal dosage forms. Such compositions typically maceutically acceptable diluent, such as a saline or dextrose comprise one or more of soluble filler substances such as solution . Suitable excipients may be included to achieve the sucrose , sorbitol and mannitol; and binders such as acacia , desired pH , including but not limited to NaOH , sodium microcrystalline cellulose , carboxymethyl cellulose and carbonate , sodium acetate , HCl , and citric acid . In various hydroxypropyl methyl cellulose . Glidants, lubricants , sweet embodiments, the pH of the final composition ranges from eners , colorants , antioxidants and flavoring agents disclosed 2 to 8 , or preferably from 4 to 7. Antioxidant excipients may above may also be included . include sodium bisulfite , acetone sodium bisulfite , sodium [ 0122 ] A liquid composition , which is formulated for formaldehyde , sulfoxylate, thiourea , and EDTA . Other non topical ophthalmic use , is formulated such that it can be limiting examples of suitable excipients found in the final administered topically to the eye . The comfort may be intravenous composition may include sodium or potassium maximized as much as possible , although sometimes for phosphates, citric acid , tartaric acid , gelatin , and carbohy mulation considerations ( e.g. drug stability ) may necessitate drates such as dextrose , mannitol, and dextran . Further less than optimal comfort . In the case that comfort cannot be acceptable excipients are described in Powell , et al . , Com maximized , the liquid may be formulated such that the liquid pendium of Excipients for Parenteral Formulations, PDA J is tolerable to the patient for topical ophthalmic use . Addi Pharm Sci and Tech 1998 , 52 238-311 and Nema et al . , tionally, an ophthalmically acceptable liquid may either be Excipients and Their Role in Approved Injectable Products : packaged for single use , or contain a preservative to prevent Current Usage and Future Directions, PDAJ Pharm Sci and contamination over multiple uses . Tech 2011 , 65 287-332 , both of which are incorporated [ 0123 ] For ophthalmic application , solutions or medica herein by reference in their entirety. Antimicrobial agents ments are often prepared using a physiological saline solu may also be included to achieve a bacteriostatic or fungi tion as a major vehicle . Ophthalmic solutions may prefer static solution , including but not limited to phenylmercuric ably be maintained at a comfortable pH with an appropriate nitrate, thimerosal, benzethonium chloride , benzalkonium buffer system . The formulations may also contain conven chloride , phenol, cresol, and chlorobutanol . tional, pharmaceutically acceptable preservatives, stabiliz [ 0131] The compositions for intravenous administration ers and surfactants . may be provided to caregivers in the form of one or more [ 0124 ] Preservatives that may be used in the pharmaceu solids that are reconstituted with a suitable diluent such as tical compositions disclosed herein include, but are not sterile water, saline or dextrose in water shortly prior to limited to , benzalkonium chloride , PHMB , chlorobutanol, administration . In other embodiments, the compositions are thimerosal, phenylmercuric , acetate and phenylmercuric provided in solution ready to administer parenterally. In still nitrate . A useful surfactant is , for example , Tween 80 . other embodiments , the compositions are provided in a Likewise , various useful vehicles may be used in the oph solution that is further diluted prior to administration . In thalmic preparations disclosed herein . These vehicles embodiments that include administering a combination of a include , but are not limited to , polyvinyl alcohol , povidone , compound described herein and another agent, the combi hydroxypropyl methyl cellulose, poloxamers , carboxym nation may be provided to caregivers as a mixture, or the ethyl cellulose , hydroxyethyl cellulose and purified water. caregivers may mix the two agents prior to administration, [ 0125 ] Tonicity adjustors may be added as needed or or the two agents may be administered separately. convenient. They include, but are not limited to , salts [ 0132 ] The actual dose of plinabulin described herein particularly sodium chloride, potassium chloride , mannitol depends on the chemotherapeutic agent used ; and on the and glycerin , or any other suitable ophthalmically accept condition to be treated ; the selection of the appropriate dose able tonicity adjustor. is well within the knowledge of the skilled artisan . In some [ 0126 ] Various buffers and means for adjusting pH may be embodiments, a single dose of Plinabulin may be from about used so long as the resulting preparation is ophthalmically 5 mg/ m² to about 150 mg / m² of body surface area , from acceptable . For many compositions, the pH will be between about 5 mg/ m² to about 100 mg/ m² of body surface area , 4 and 9. Accordingly, buffers include acetate buffers , citrate from about 10 mg /m² to about 100 mg/ m ? of body surface buffers, phosphate buffers and borate buffers. Acids or bases area , from about 10 mg /m² to about 80 mg /m² of body may be used to adjust the pH of these formulations as surface area , from about 10 mg /m² to about 50 mg/ m² of needed . body surface area, from about 10 mg /m² to about 40 mg/ m² [ 0127 ] Ophthalmically acceptable antioxidants include, of body surface area , from about 10 mg/ m2 to about 30 but are not limited to , sodium metabisulfite, sodium thio mg/ m² of body surface area , from about 13.5 mg/ m² to about sulfate, acetylcysteine, butylated hydroxyanisole and buty 100 mg / m² of body surface area , from about 13.5 mg /m² to lated hydroxytoluene. about 80 mg /m² of body surface area , from about 13.5 US 2021/0030843 A1 Feb. 4 , 2021 20 mg/ m² to about 50 mg/ m ? of body surface area , from about [ 0135 ] Some embodiments relate to a sterile container 13.5 mg /m² to about 40 mg/ m of body surface area , from comprising the pharmaceutical composition of plinabulin about 13.5 mg/ m² to about 30 mg /m² of body surface area , described herein . Some embodiments relate to a kit includ from about 15 mg/ m² to about 80 mg /m² of body surface ing a chemotherapeutic agent, about 1 mg to about 80 mg of area , from about 15 mg/ m² to about 50 mg/ m² of body plinabulin , and about 0.1 mg to about 20 mg of G - CSF , surface area , or from about 15 mg /m² to about 30 mg/ m² of wherein the chemotherapy, G -CSF , and the plinabulin are the body surface area . In some embodiments, a single dose provided in separate sterile containers. of Plinabulin may be from about 13.5 mg/ m² to about 30 [ 0136 ] In some embodiments, the amount of plinabulin in mg/ m ? of body surface area . In some embodiments , a single the kit is less than 50 mg . In some embodiments, the amount dose of Plinabulin may be greater than about 5 mg/ m² , about of plinabulin in the sterile container is about 10 mg . In some 10 mg/ m² , about 12.5 mg/ m² , about 13.5 mg /m² , about 15 embodiments, the amount of plinabulin in the sterile con mg /m² , about 17.5 mg /m² , about 20 mg/ m² , about 22.5 tainer is about 20 mg . In some embodiments, the amount of mg/ m² , about 25 mg/ m² , about 27.5 mg/ m² , about 30 plinabulin in the sterile container is about 30 mg . In some mg/ m² , about 40 mg/ m² , about 50 mg /m² , about 60 mg/ m² , embodiments , the amount of plinabulin in the sterile con about 70 mg / m² , about 80 mg /m² , about 90 mg /m² , or about tainer is about 40 mg . In some embodiments, the amount of 100 mg /m² , of the body surface area . In some embodiments, G - CSF in the sterile container is less than 10 mg . In some a single dose of Plinabulin may be less than about 5 mg /m² , embodiments, the amount of G - CSF in the sterile container about 10 mg / m² , about 12.5 mg /m² , about 13.5 mg/ m² , is about 6 mg . In some embodiments, the amount of G - CSF about 15 mg/ m² , about 17.5 mg / m² , about 20 mg /m² , about in the sterile container is about 3 mg . In some embodiments, 22.5 mg/ m² , about 25 mg /m² , about 27.5 mg/ m² , about 30 the amount of G - CSF in the sterile container is about 1.5 mg . mg /m² , about 40 mg/ m² , about 50 mg /m² , about 60 mg/ m² , [ 0137 ] Some embodiments include a kit comprising a about 70 mg / m² , about 80 mg /m² , about 90 mg /m² , or about plinabulin , G - CSF , and docetaxel. In one embodiment, 100 mg /m² , of body surface area . In some embodiments, a plinabulin , G - CSF , and docetaxel are provided in separate single dose of Plinabulin may be about 5 mg/ m² , about 10 sterile containers . In the case of solids for reconstitution, the mg /m² , about 12.5 mg /m² , about 13.5 mg /m² , about 15 agents may be added to the container simultaneously or may mg/ m² , about 17.5 mg/ m² , about 20 mg / m² , about 22.5 be dry -powder filled into the container in separate steps. In mg/ m² , about 25 mg/ m² , about 27.5 mg/ m² , about 30 some embodiments, the solids are sterile crystalline prod mg /m² , about 40 mg/ m² , about 50 mg/ m² , about 60 mg/ m² , ucts . In other embodiment, the solids are lyophiles . about 70 mg / m2 , about 80 mg /m² , about 90 mg/ m² , or about 100 mg/ m2 , of the body surface area. EXAMPLE [ 0133 ] Some embodiments relate to a composition com prising about 1 mg to 100 mg of plinabulin . In some Example 1 embodiments, the composition includes about 5 mg to about 300 mg , from about 5 mg to about 200 mg , from about 7.5 [ 0138 ] A randomized , double blind study to evaluate dura mg to about 200 mg , from about 10 mg to about 100 mg , tion of severe neutropenia with plinabulin versus pegfil from about 15 mg to about 100 mg , from about 20 mg to grastim in patients with solid tumors receiving docetaxel about 100 mg , from about 30 mg to about 100 mg , from myelosuppressive chemotherapy was performed . Patients about 40 mg to about 100 mg , from about 10 mg to about 80 were randomly assigned to the following arms ( with the mg , from about 15 mg to about 80 mg , from about 20 mg to respective sample sizes ) : Arm 1 : Docetaxel ( 75 mg / m² ) + about 80 mg , from about 30 mg to about 80 mg , from about Pegfilgrastim ( 6 mg ) ( n = 14 ); Arm 2 : Docetaxel ( 75 mg / mº ) + 40 mg to about 80 mg , from about 10 mg to about 60 mg , Plinabulin ( 20 mg / m² ) ( n = 14 ); Arm 3 : Docetaxel ( 75 from about 15 mg to about 60 mg , from about 20 mg to mg/ m² ) + Plinabulin ( 10 mg/ m ? ) ( n = 14 ); and Arm 4 : Doc about 60 mg , from about 30 mg to about 60 mg , or from etaxel ( 75 mg /m² ) + Plinabulin ( 5 mg /m² ) ( n = 13 ). The testing about 40 mg to about 60 mg of plinabulin . In some embodi results are shown in FIG . 1 . ments, a single dose of Plinabulin or other therapeutic agent [ 0139 ] As shown in FIG . 1 , the neutrophil count in the may be from about 20 mg to about 60 mg , from about 27 mg pegfilgrastim group began to drop after 10 days, while the to about 60 mg , from about 20 mg to about 45 mg , or from neutrophil count in the plinabulin groups started to rise again about 27 mg to about 45 mg . In some embodiments, a single on day 10. The results showed that plinabulin was effective dose of Plinabulin or other therapeutic agent may be greater in treating neutropenia induced by chemotherapeutic agent. than about 5 mg , about 10 mg , about 12.5 mg , about 13.5 Plinabulin and Pegfilgrastim had different profile of reduc mg , about 15 mg , about 17.5 mg , about 20 mg , about 22.5 ing neutropenia, and the nadir time point was different for mg , about 25 mg , about 27 mg , about 30 mg , about 40 mg , plinabulin versus pegfilgrastim , suggesting the two drugs about 50 mg , about 60 mg , about 70 mg , about 80 mg , about can be used in combination to maintain the neutrophil count 90 mg , about 100 mg , about 125 mg , about 150 mg , or about level continuously. Plinabulin prevented the overshot of the 200 mg . In some embodiments , a single dose of Plinabulin ANC during recovery . The results also suggested that the or other therapeutic agent may be less than about 5 mg , amount of G - CSF drug or plinabulin required for the neu about 10 mg , about 12.5 mg , about 13.5 mg , about 15 mg , tropenia treatment may be decreased due to the supplemen about 17.5 mg , about 20 mg , about 22.5 mg , about 25 mg , tal effect of the combination . 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 Example 2 mg , about 125 mg , about 150 mg , or about 200 mg . [ 0140 ] A multicenter, randomized study, involving G - CSF [ 0134 ] Some embodiments relate to a pharmaceutical and plinabulin was performed . The Phase 2 portion was composition including plinabulin and one or more G - CSF randomized and open label . The decision to complete the drugs . Phase 2 portion of the study as open label was made to US 2021/0030843 A1 Feb. 4 , 2021 21 reduce the complexities of study conduct and to allow for the [ 014 ] Patients have been randomized to receive TAC ( or assessment, via Qol , of same - day plinabulin dosing ( i.e on TC for Cycles 2 to 4 ) + pegfilgrastim or a combination of the day of chemotherapy dosing ) versus next day dosing plinabulin and pegfilgrastim in each of Arms 1 , 2 , 3 , and 4 . with G - CSF . Patients with first line breast cancer were [ 0147 ] In Phase 2 ( Open Label ) , Cycles 1 to 4 consisted of enrolled in the study. TAC ( or TC for Cycles 2 to 4 ) administered IV on Day 1 , [ 0141 ] Patients received up to 4 cycles of a docetaxel / doxorubicin / cyclophosphamide based chemotherapy regi every 21 days. Patients in Arms 2 and 3 received a single men , every 3 weeks ( 21 days ) . On Day 1 of Cycle 1 , all dose of plinabulin over 30 minutes ( +5 minutes ), 30 minutes patients receive docetaxel ( 75 mg/ m² ) , doxorubicin ( 50 after the end of the TAC ( or TC for Cycles 2 to 4 ) infusion mg /m ), and cyclophosphamide ( 500 mg/ mº ) -Taxotere, on Day 1. On Day 2 of each cycle ( 224 hours after Adriamycin and cyclophosphamide ( TAC ). completing chemotherapy ) patients in Arm 1 received a [ 0142 ] During Cycles 2 to 4 , the doxorubicin component single dose of pegfilgrastim ( 6.0 mg ) ( subcutaneous injec may be omitted at the discretion of the investigator, i.e. , TC tion ) in an open label treatment. can be administered instead of TAC . [ 0148 ] Docetaxel : Docetaxel was administered at a dose of [ 0143 ] The eligibility of all patients was determined dur 75 mg /m2 . Administration was carried out with a 1 -hour IV ing a 28 - day screening period. infusion per institutional protocol at the dose prescribed by [ 0144 ] Since plinabulin has demonstrated efficacy against this clinical study protocol ( 75 mg/ m2 ). Dexamethasone ( 16 docetaxel- induced neutropenia in humans , and since the mg per day administered as 8 mg twice daily, or as per beneficial effects of plinabulin also were demonstrated in institution standard ) was given on the day before , the day of non - clinical studies with the two other components of the ( Day 1 ) , and the day following docetaxel infusion (Day 2 ) . TAC regimen , plinabulin helped ameliorate neutropenia [ 0149 ] Doxorubicin : Doxorubicin was administered at a induced by TAC . dose of 50 mg / m2 . Doxorubicin is potentially cardiotoxic . [ 0145 ] Phase 2 ( Open Label ): In Phase 2 , patients were Risk for doxorubicin cardiotoxicity increases with the cumu randomly assigned to one of the treatment arms, with the lative lifetime dose of doxorubicin . At the doxorubicin dose arm designation and planned intervention as shown in Table and schedule in this study, patients received a cumulative 2 . doxorubicin dose of 240 mg /m2 of body surface area , below TABLE 2 Treatments Administered for Phase 2 Cycles 1 to 4 , Day 1 21 Day Cycle 30 ( 12 ) Cycles 1 to 4 , minutes from Day 2 21 Day Cycles 1 to 4 , Day 1 21 Day the end of the Cycle 224 hours Cycle ( TAC ) Docetaxel infusion post Day 1 Arm 1 Pre - medication ( up to 30 minutes ) No drug Pegfilgrastim Doxorubicin ( 50 mg/ m² ) = administered ( 6.0 mg) SC Approximately 15 minute IV treatment single dose Cyclophosphamide ( 500 mg/ m² ) = Approximately 30 minute IV treatment Docetaxel ( 75 mg/ m² ) = Approximately 60 minute IV treatment Arm 2 Pre -medication ( up to 30 minutes ) Plinabulin pegfilgrastim Doxorubicin ( 50 mg/ m² ) ( 20 mg/ m² ) ( 6.0 mg ) Approximately 15 minute IV treatment 30 minute IV Cyclophosphamide ( 500 mg/ m² ) = infusion Approximately 30 minute IV treatment Docetaxel ( 75 mg /m² ) Approximately 60 minute IV treatment Arm 3 Pre -medication ( up to 30 minutes ) Plinabulin pegfilgrastim Doxorubicin ( 50 mg /m² ) = ( 20 mg/ m² ) ( 3.0 mg) Approximately 15 minute IV treatment 30 minute IV Cyclophosphamide ( 500 mg/m² ) = infusion Approximately 30 minute IV treatment Docetaxel ( 75 mg/ m² ) Approximately 60 minute IV treatment Arm 4 Pre -medication ( up to 30 minutes ) Plinabulin pegfilgrastim Doxorubicin ( 50 mg/ m² ) ( 20 mg/ m2 ) ( 1.5 mg) Approximately 15 minute IV treatment 30 minute IV Cyclophosphamide ( 500 mg /m² ) = infusion Approximately 30 minute IV treatment Docetaxel ( 75 mg /m² ) Approximately 60 minute IV treatment Abbreviations: IV = intravenous; SC = subcutaneous Note : During Cycles 2 to 4 , the doxorubicin component may be omitted at the discretion of the investigator, i.e. , TC will be administered instead of TAC . US 2021/0030843 A1 Feb. 4 , 2021 22 the threshold for symptomatic cardiac dysfunction . Patients bone pain and also shortened the duration of bone pain . In were monitored , per institutional standard , for doxorubicin FIG . 4 , the group with pegfilgrastim ( 6 mg ) showed 95 % cardiotoxicity. incidence of bone pain in cycle 1 after TAC treatment for [ 0150 ] During Cycles 2 to 4 , the doxorubicin component breast cancer, while the group with plinabulin ( 20 mg /m² ) may be omitted at the discretion of the investigator, i.e. , TC and pegfilgrastim ( 6 mg ) showed 6 % incidence of bone pain , can be administered instead of TAC . the group with plinabulin ( 20 mg /m² ) and pegfilgrastim ( 3 [ 0151 ] Cyclophosphamide: Cyclophosphamide was administered at a dose of 500 mg /m² . mg ) showed 33 % incidence of bone pain , and the group with [ 0152 ] TAC Regimen : All patients received 3 week cycles plinabulin ( 20 mg /m² ) and pegfilgrastim ( 1.5 mg ) showed of TAC chemotherapy. In each cycle , doxorubicin ( 50 36 % incidence of bone pain in cycle 1 after TAC treatment mg /m2 ) given as a 15 -minute IV infusion was administered for breast cancer. In FIG . 5 , the group with pegfilgrastim ( 6 first, followed immediately by cyclophosphamide ( 500 mg ) showed over 90 % patients having at least one day of mg/ m2 ) given as a 30 -minute IV infusion, and then by bone pain , and over 80 % patients having at least two days docetaxel ( 75 mg/ m2 ) administered as 1 - hour IV infusion of bone pain , close to 40 % patients having at least three days ( the infusion times stated are approximate ). Patients receiv of bone pain in cycle 1 after TAC treatment for breast cancer. ing TAC chemotherapy as an adjuvant treatment for their In comparison , the group with plinabulin ( 20 mg /m² ) and early breast cancer , received 4 cycles of TAC chemotherapy pegfilgrastim ( 6 mg ) showed less than 10 % patients having and at the discretion of the investigator up to 6 cycles of at least one day of bone pain and no patients reporting TAC chemotherapy ( i.e. , after completion of the 4 cycles on having at least three days of bone pain . The group with the protocol, these patients continue to receive TAC che plinabulin ( 20 mg/ m² ) and pegfilgrastim ( 3 mg ) showed less motherapy but with open label pegfilgrastim to prevent than 40 % of patients having at least one day of bone pain , neutropenia ). and the group with plinabulin ( 20 mg /mº ) and pegfilgrastim [ 0153 ] TAC has a high risk ( > 20 % ) of causing FN . The ( 1.5 mg ) also showed less than 40 % patients having bone NCCN guidelines recommend routine, primary prophylaxis pain in cycle 1 after TAC treatment for breast cancer . with myeloid growth factor support in the treatment patients with high risk regimens such as TAC . During Cycles 2 to 4 , [ 0157 ] The study results also showed that plinabulin was the doxorubicin component may be omitted at the discretion effective to alleviate the immune suppression effect of of the investigator, i.e. , TC may be administered instead of pegfilgrastim as measured using the neutrophil to lympho TAC . cyte ratio (NLR ) and LMR ( lymphocyte to monocyte ratio ). [ 0154 ] The combination of plinabulin and G - CSF ( e.g. , FIG . 6 shows the percentage of patients having a NLR value pegfilgrastim ) were surprisingly effective in reducing neu of greater than 5 in the various treatment groups . An tropenia . FIG . 2 shows the median ANC in the pegfilgrastim elevated NLR value is often associated with immune sup group and the plinabulin ( 20 mg /m2 ) and pegfilgrastim ( 6 pression and a poor prognosis in cancer treatment. In FIG . mg ) group . In FIG . 2 , the plinabulin ( 20 mg/ m2 ) and 6 , the group with pegfilgrastim ( 6 mg ) showed 76 % of pegfilgrastim ( 6 mg ) combination kept the ANC nadir within patients with NRL greater than 5 in cycle 1 after TAC normal range, while the pegfilgrastim group showed the treatment for breast cancer , while the group with plinabulin ANC nadir to be within the grade 3/4 neutropenia range . ( 20 mg /m² ) and pegfilgrastim ( 6 mg ) showed 50 % of [ 0155 ] The study results also showed that the plinabulin patients with NRL greater than 5 , the group with plinabulin and pegfilgrastim combination significantly reduced the incidence of severe neutropenia. In FIG . 3 , the group with ( 20 mg/ m ?) and pegfilgrastim ( 3 mg ) showed 35 % of pegfilgrastim ( 6 mg ) showed 81 % incidence of developing patients with NRL greater than 5 , and the grou with grade 3/4 neutropenia in cycle 1 after TAC treatment for plinabulin ( 20 mg /m ?) and pegfilgrastim ( 1.5 mg ) showed breast cancer , while the group with plinabulin ( 20 mg / m ) 7 % of patients with NRL greater than 5 in cycle 1 after TAC and pegfilgrastim ( 6 mg ) showed 50 % incidence of devel treatment for breast cancer . oping grade 3/4 neutropenia , and the group with plinabulin [ 0158 ] FIG . 7A shows the percentage of patients with ( 20 mg /m² ) and pegfilgrastim ( 3 mg ) showed 57 % incidence NLR over 5 in plinabulin ( 20 mg /m2 ) alone, plinabulin ( 20 of developing grade 3/4 neutropenia in cycle 1 after TAC mg/ m2 ) + neulasta 6 mg , and Neulasta ( 6 mg ) . FIG . 7B shows treatment for breast cancer. the percentage of patients with LMR less than 3.2 in ( 0156 ] In addition , the plinabulin and pegfilgrastim com plinabulin ( 20 mg /m2 ) alone , plinabulin ( 20 mg/m2 ) + neu bination significantly reduced the incidence of developing lasta 6 mg , and Neulasta ( 6 mg ) . TABLE 3 summarizes the study results in cycle 1 after TAC treatment for breast cancer Plinabulin Plinabulin Plinabulin 20 mg /m² + 20 mg/ m² + 20 mg /m² + pegfilgrastim pegfilgrastim pegfilgrastim pegfilgrastim 6 mg ( n = 21 ) 6 mg ( n = 16 ) 3 mg ( n = 21 ) 1.5 mg ( n = 14 ) DSN ( grade 3/4 ) 1.4 + 1.0 0.9 + 1.1 1.6 I 1.6 2.6 + 1.6 ( 36 % decrease ) % neutropenia 57 % 38 % 52 % 57 % ( grade 4 ) ( 33 % decrease ) % neutropenia 81 % 50 % 57 % 86 % ( grade 3/4 ) US 2021/0030843 Al Feb. 4 , 2021 23

TABLE 3 - continued summarizes the study results in cycle 1 after TAC treatment for breast cancer Plinabulin Plinabulin Plinabulin 20 mg /m² + 20 mg/ m² + 20 mg/ m² + pegfilgrastim pegfilgrastim pegfilgrastim pegfilgrastim 6 mg ( n = 21 ) 6 mg ( n = 16 ) 3 mg ( n = 21 ) 1.5 mg ( n = 14 ) % bone pain ( at 95 % 6 % 33 % 36 % least one day )

groups : Arm ( 1 ) administration of a combination of G - CSF TABLE 4 ( e.g. , pegfilgrastim or filgrastim ) in the range of about 1 Comparison of the plinabulin and pegfilgrastim ( 6 mg - 25 mg ( e.g. , 0.1 mg - 6 mg , 1 mg - 5.5 mg , 2 mg - 5.5 mg , mg) combination and pegfilgrastim standard of care 2 mg - 4 mg , 3 mg - 6 mg , 3 mg - 5.5 mg , 4 mg - 5.5 mg , or less Plinabulin than 6 mg ) and plinabulin in the range of about 1 mg/ m2-50 20 mg/ m² + mg /m² ( e.g. , 1-20 , 1-30 , 5-10 , 5-30 , 5 , 10 , 20 , 30 mg / m² ) ; pegfilgrastim Arm ( 2 ) administration of G - CSF ( e.g. , pegfilgrastim or pegfilgrastim 6 mg 6 mg filgrastim ) alone ; Arm ( 3 ) administration of plinabulin DSN ( grade 3/4 ) Well over 1 day Less than 1 day alone ; and Arm ( 4 ) administration of placebo . % neutropenia High ( > 80 % ) Low ( 50% ) ( grade 3/4 ) [ 0164 ] Plinabulin or Matching Placebo : Plinabulin is Median ANC Nadir 0.47 ( > 50 % grade 4 1.00 ( > 50 % administered at a selected dose ( ( e.g. , 1-20 , 1-30,5-10,5-30 , ( 10 ^ 9 cells / L ) neutropenia ) avoiding grade 5 , 10 , 20 , 30 mg /m² ). In one control group , matching 3/4 neutropenia ) placebo is administered in an equal volume . Pegfilgrastim or % bone pain Almost all Limited Matching Placebo : Pegfilgrastim is administered subcutane Anti - cancer No Yes ously at the selected dose ( e.g. , 0.1 mg - 6 mg , 1 mg - 5.5 mg , 2 mg - 5.5 mg , 2 mg - 4 mg , 3 mg - 6 mg , 3 mg - 5.5 mg , 4 [ 0159 ] Table 4 shows the superior profile of the plinabulin mg - 5.5 mg , or less than 6 mg ) as a single dose syringe. In and pegfilgrastim combination versus the pegfilgrastim another control group, matching placebo is administered in treatment. an equal volume . [ 0165 ] The population pharmacokinetics approach can be Example 3 used to characterize the pharmacokinetics of plinabulin and ( 0160 ] A multicenter, randomized study , with Phase 3 is pegfilgrastim following the administration of a chemo performed. The phase 3 portion is double blind . An esti therapy or radiotherapy . The pharmacodynamics assess mated total of 180 patients with breast cancer can be ments include blood pressure and DSN in various cycles of enrolled in Phase 3 part of this study . Patients are stratified the study. by region ( China and Japan vs rest of the world ) . [ 0166 ] It is expected that the combination of G - CSF ( e.g. , [ 0161 ] Patients receive up to 4 cycles of a docetaxel/ pegfilgrastim or filgrastim ) and plinabulin is effective in doxorubicin / cyclophosphamide based chemotherapy regi reducing incidence of neutropenia, particularly severe grade men , every 3 weeks ( 21 days ) . On Day 1 of Cycle 1 , all 3/4 neutropenia and the combination can maintain the patients receive docetaxel ( 75 mg /m² ) , doxorubicin ( 50 patient's neutrophil count to allow for continued chemo mg / m ), and cyclophosphamide ( 500 mg / m ? ) - Taxotere , therapy treatment. Adriamycin and cyclophosphamide ( TAC ). What is claimed is : [ 0162 ] In Phase 3 ( double blinded treatment) , Cycles 1 to 1. A method of treating a chemotherapy induced neutro 4 consist of TAC ( or TC for Cycles 2 to 4 ) administered IV penia , comprising co - administering plinabulin and one or on Day 1 , every 21 days. Patients receive a single dose of more G - CSF drugs . plinabulin or placebo IV over 30 minutes ( +5 minutes) in a 2. A method of stimulating neutrophil survival, compris double blinded manner , 30 minutes after the end of the TAC ing co -administering plinabulin and one or more G - CSF ( or TC for Cycles 2 to 4 ) infusion . On Day 2 of each cycle drugs. ( 224 hours after completing chemotherapy ) patients receive 3. The method of claim 1 or 2 , wherein the G - CSF drug a single dose of pegfilgrastim ( 6.0 mg ) or placebo ( subcu is pegfilgrastim . taneous injection ) in a double blinded manner . Plinabulin 4. The method of claim 1 or 2 , wherein the G - CSF drug and the matching placebo are administered in an equal is selected from Neupogen® , Tevagrastim® , Biograstim® , volume . Pegfilgrastim is administered at a dose of 6 mg as Ratiograstim®, Zarxio® , Filgrastim Hexal® , Neulasta® , a single dose syringe . The matching placebo is administered Granocyteß , Neutrogin®, Neu - up , Rolontis® , Aiduo (me in an equal volume. capegfilgrastim , Hengrui ), and Fulphila® . 5. The method of any one of claims 1-4 , wherein the total Example 4 dosage of the G - CSF drug used in a 21 - day cycle is in the [ 0163 ] The combination of G - CSF ( e.g. , pegfilgrastim or range of about 0.1 mg to about 20 mg . filgrastim ) and plinabulin is tested for its effect in reducing 6. The method of claim 5 , wherein the total dosage of the neutropenia induced by chemotherapy or radiation therapy. G - CSF drug used in a 21 - day cycle is less than about 6 mg . Patients having cancer receiving myelosuppresive chemo 7. The method of claim 5 , wherein the total dosage of the therapy or radiation therapy are assigned into the following G - CSF drug used in a 21 -day cycle is about 1.5 mg . US 2021/0030843 A1 Feb. 4 , 2021 24

8. The method of claim 5 , wherein the total dosage of the 30. The method of any one of claims 1-27 , wherein the G - CSF drug in a 21 -day cycle is about 3 mg . chemotherapy comprises administering docetaxel, doxoru 9. The method of claim 5 , wherein the total dosage of the bicin and cyclophosphamide ( TAC ); docetaxel and cyclo G - CSF drug in a 21 - day cycle is about 6 mg . phosphamide ( TC ) ; doxorubicin and cyclophosphamide 10. The method of any one of claims 1-9 , wherein the ( AC ); docetaxel and doxorubicin ( TA ); docetaxel ; doxoru G - CSF drug is administered in a single dose in a 21 - day bicin ; or cyclophosphamide . cycle . 31. The method of any one of claims 1-27 , wherein the 11. The method of any one of claims 1-9 , wherein the chemotherapy does not comprise docetaxel . G - CSF drug is administered in two or more doses in a 32. The method of any one of claims 1-31 , wherein the 21 - day cycle . patient has an advanced or metastatic breast cancer , early 12. The method of any one of claims 1-11 , wherein the breast cancer, non - small cell lung cancer , refractory meta G - CSF drug is administered using an on -body injector. static prostate cancer . 13. The method of any one of claims 1-12 , wherein the 33. The method of any one of claims 1-31 , wherein the G - CSF drug is administered subcutaneously . patient has head and neck cancer , lung cancer , stomach 14. The method of any one of claims 1-13 , comprising cancer, colon cancer , pancreatic cancer , prostate cancer , administering the G - CSF drug at least 24 hours after the breast cancer, kidney cancer , bladder cancer, ovary cancer , administration of the chemotherapy. cervical cancer , melanoma, glioblastoma , myeloid leuke 15. The method of any one of claims 1-13 , comprising mia , myeloma, lymphoma, or leukemia . administering the G - CSF drug within 24 hours after the 34. The method of any one of claims 1-33 , wherein the administration of the chemotherapy. plinabulin is administered less than 1 hour after the admin 16. The method of any one of claims 1-13 , comprising istration of the chemotherapy . administering the G - CSF drug when the patient has an 35. The method of any one of claims 1-34 , wherein the absolute neutrophil count that is lower than about 1.5x10 ° / L . plinabulin is administered about 30 mins after the adminis 17. The method of any one of claims 1-13 , comprising tration of the chemotherapy. administering two or more doses of the G - CSF drug wherein 36. The method of any one of claims 1-35 , wherein the a first dose of the G - CSF drug is administered between about neutropenia is a grade 3 or 4 neutropenia . 24 hours and 48 hours after the administration of the 37. The method of any one of claims 1-36 , wherein the chemotherapy. neutropenia is a grade 4 neutropenia . 18. The method of any one of claims 1-17 , comprising 38. The method of any one of claims 1-37 , comprising administering plinabulin within 24 hours after the adminis reducing an incidence of grade 3 or 4 neutropenia by at least tration of the chemotherapy. 5 % . 19. The method of any one of claims 1-18 , comprising 39. The method of any one of claims 1-38 , comprising administering plinabulin within 2 hours after the adminis reducing a duration of grade 3 or 4 neutropenia by at least tration of the chemotherapy. about 2 times . 20. The method of any one of claims 1-19 , comprising 40. A kit comprising a chemotherapeutic agent, about 1 administering plinabulin within 1 hour after the administra mg to about 80 mg of plinabulin , and about 0.1 mg to about tion of the chemotherapy. 20 mg of G - CSF, wherein the chemotherapy , G - CSF , and the 21. The method of any one of claims 1-20 , comprising plinabulin are provided in separate sterile containers . administering a single dose of plinabulin in a 21 - day treat 41. The kit of claim 40 , wherein the amount of plinabulin ment cycle. is less than 50 mg . 22. The method of any one of claims 1-21 , comprising 42. The kit of claim 40 , wherein the amount of plinabulin administering plinabulin at a total dosage in the range of is about 10 mg . about 1 mg /m² to about 50 mg/ m² in a 21 - day cycle . 43. The kit of claim 40 , wherein the amount of plinabulin 23. The method of any one of claims 1-22 , comprising is about 20 mg . administering plinabulin at a total dosage less than or equal 44. The kit of claim 40 , wherein the amount of plinabulin to 40 mg /m² in a 21 -day cycle . is about 30 mg . 24. The method of any one of claims 1-23 , comprising 45. The kit of claim 40 , wherein the amount of plinabulin administering plinabulin at a total dosage of about 10 mg/ m2 is about 40 mg . in a 21 -day cycle . 46. The kit container of any one of claims 40-45 , wherein 25. The method of any one of claims 1-23 , comprising the amount of G - CSF is less than 10 mg . administering plinabulin at a total dosage of about 20 mg /m² 47. The kit of any one of claims 40-46 , wherein the in a 21 -day cycle . amount of G - CSF is about 6 mg . 26. The method of any one of claims 1-23 , comprising 48. The kit of any one of claims 40-46 , wherein the administering plinabulin at a total dosage of about 30 mg / m² amount of G - CSF is about 3 mg . in a 21 -day cycle . 49. The kit of any one of claims 40-46 , wherein the 27. The method of any one of claims 1-23 , comprising amount of G - CSF is about 1.5 mg . administering plinabulin at a total amount in the range of 50. A method of reducing bone pain induced by a G - CSF about 10 mg to about 60 mg in a 21 - day cycle . drug, comprising administering an effective amount of 28. The method of any one of claims 1-23 , comprising plinabulin . administering plinabulin at a total amount of about 40 mg in 51. A method of alleviating immune suppression effect a 21 -day cycle . induced by a G - CSF drug, comprising administering an 29. The method of any one of claims 1-27 , wherein the effective amount of plinabulin . chemotherapy comprises administering docetaxel and no 52. A method of treating a chemotherapy induced neu other chemotherapeutic agent. tropenia or stimulating neutrophil survival, comprising one US 2021/0030843 A1 Feb. 4 , 2021 25 or more cycles of a chemotherapy regimen , each cycle of the 61. The method of claim 52 , wherein the one or more chemotherapy regimen independently comprising : G - CSF drugs is pegfilgrastim . administering one or more chemotherapeutic agents on 62. The method of claim 52 , wherein the one or more day 1 , G - CSF drugs are administered , independently in each cycle administering plinabulin on day 1 , and of the chemotherapy regimen , in a single or multiple doses administering one or more G - CSF drugs on day 2 , of up to about 6 mg at least about 24 hours after the wherein the plinabulin is administered within 12 hours , administration of the one or more chemotherapeutic agents . within 4 hours , within 2 hours, or within 1 hour after 63. The method of claim 52 , wherein the one or more the administration of the one or more chemotherapeutic G - CSF drugs are administered , independently in each cycle agents. of the chemotherapy regimen , in a single or multiple doses 53. The method of claim 52 , wherein the one or more of up to about 6 mg about 20 to about 50 hours after the G - CSF drugs are administered within 24 hours after the administration of plinabulin . administration of the plinabulin . 64. The method of claim 52 , wherein the one or more 54. The method of claim 52 , comprising two to four G - CSF drugs are administered , independently in each cycle cycles of the chemotherapy regimen . of the chemotherapy regimen , in a single dose of about 1.5 55. The method of claim 52 , wherein each cycle of the mg , about 3.0 mg , or about 6 mg about 20 to about 30 hours chemotherapy regimen independently lasts up to 30 days . after the administration of plinabulin. 56. The method of claim 55 , wherein each cycle of the chemotherapy regimen lasts 21 days . 65. Plinabulin for use in combination with one or more 57. The method of claim 52 , wherein the one or more G - CSF drugs for treating a chemotherapy induced neutro chemotherapeutic agents are selected , independently in each penia . cycle of the chemotherapy regimen , from the group consist 66. Plinabulin for use in combination with one or more ing of : docetaxel , doxorubicin , and cyclophosphamide. G - CSF drugs for stimulating neutrophil survival. 58. The method of claim 56 , wherein the plinabulin is 67. Plinaublin for use in reducing bone pain induced by a administered , independently in each cycle of the chemo G - CSF drug therapy regimen , in a single or multiple doses of up to about 68. Plinaublin for use in alleviating an immune suppres 40 mg/ m² about 10 to 50 minutes, or about 20 to 40 minutes sion effect induced by a G - CSF drug. after the administration of the one or more chemotherapeutic 69. Plinabulin for use in combination with one or more agents. G - CSF drugs for treating a chemotherapy induced neutro 59. The method of claim 56 , wherein the plinabulin is penia or stimulating neutrophil survival in one or more administered , independently in each cycle of the chemo cycles of a chemotherapy regimen , each cycle of the che therapy regimen , in a single dose of about 5 mg/ m² , about motherapy regimen independently comprising: 10 mg /m² , or about 20 mg/ m² about 25 to 35 minutes, or administering one or more chemotherapeutic agents on about 28 to 32 minutes, or about 30 minutes after the day 1 , administration of the one or more chemotherapeutic agents . 60. The method of claim 52 , wherein the one or more administering plinabulin on day 1 , and G - CSF drugs are selected , independently in each cycle of the administering one or more G - CSF drugs on day 2 , chemotherapy regimen , from the group consisting of: wherein the plinabulin is administered within 12 hours , Neupogen® , Tevagrastim® , Biograstim®, Ratiograstim®, within 4 hours, within 2 hours , or within 1 hour after Zarxio® , Filgrastim Hexal® , Neulasta® , Granocyte® , Neu the administration of the one or more chemotherapeutic trogin® , Neu - up , Rolontis , Aiduo (mecapegfilgrastim , agents . Hengrui ), and Fulphila .