Ibudilast in combination therapy for use in the treatment of glioblastoma

Abstract

Disclosed herein are compositions and methods for treating glioblastoma in a patient in need thereof by administration of ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 246,755, filed September 21, 2021, which is incorporated by reference in its entirety herein.

[0002] The present disclosure relates generally to methods for treating glioblastoma multiforme (GBM), also known as glioblastoma, comprising administering a therapeutically effective amount of ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) and a therapeutically effective amount of an immune checkpoint inhibitor, such as an anti-PD-1 agent or an anti-PD-L1 agent. [Background technology]

[0003] The small molecule ibudilast (3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine) is an inhibitor of macrophage inhibitory factor (MIF) (Cho et al PNAS-USA 2010 June 107:11313-8) and a selective inhibitor of cyclic nucleotide phosphodiesterases (PDEs) 3A, 4, 10A1 and 11A1 (Gibson et al., Eur J Pharmacol 538:39-42, 2006). Ibudilast is well distributed to the CNS (Sanftner et al., Xenobiotica 2009 39:964-977) at clinically relevant plasma or CNS concentrations, where ibudilast selectively inhibits macrophage migration inhibitory factor (MIF) and then selectively inhibits PDEs 3, 4, 10 and 11. Ibudilast also acts as a leukotriene D4 antagonist, anti-inflammatory agent, PAF antagonist and vasodilator (Thompson Current Drug Reports). Ibudilast is believed to play a neuroprotective role in the mammalian central nervous system, possibly by suppressing glial cell activation (Mizuno et al., Neuropharmacology 46:404-411, 2004).

[0004] Ibudilast is widely used in Japan to relieve symptoms associated with ischemic stroke or bronchial asthma. Recent clinical trials have examined its use in the treatment of multiple sclerosis (MS), an inflammatory disease of the central nervous system (News.Medical.Net; Pharmaceutical News, 2 Aug. 2005). As disclosed in the publication, the clinical trial was expected to treat "relapsing-remitting MS," but no mention was made of progressive multiple sclerosis. In U.S. Patent No. 6,395,747, ibudilast is disclosed as a treatment for multiple sclerosis, which is generally understood to mean relapsing and remitting multiple sclerosis, not progressive multiple sclerosis. U.S. Patent Application Publication No. 20060160843 discloses ibudilast for the treatment of intermittent and short-term pain, but not pain associated with progressive neurodegenerative diseases. However, U.S. Patent No. 9,314,452 discloses ibudilast as a treatment for amyotrophic lateral sclerosis, a progressive neurodegenerative disease. Similarly, U.S. Patent No. 8,138,201 discloses ibudilast as a treatment for primary progressive multiple sclerosis and / or secondary progressive multiple sclerosis.

[0005] Although the use of ibudilast for several different indications has been previously reported, to the applicant's knowledge, the use of ibudilast in combination with immune checkpoint inhibitors to treat glioblastoma multiforme (GBM) or its recurrent or refractory forms has previously remained largely unexplored. Summary of the Invention

[0006] In one aspect, provided herein is a method of treating glioblastoma in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 agent. In some embodiments, the anti-PD-1 agent is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 agent is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, spartalizumab, canrelizumab, sintilimab, tislelizumab, toripalimab, AMP-514, AMP-224, JTX-4014, dostallimab, retifanlimab, and AUNP-12. In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 agent. In some embodiments, the anti-PD-L1 agent is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 agent is selected from the group consisting of atezolizumab, avelumab, durvalumab, cosibelimab, CA-170 and BMS-986189. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 agent. In some embodiments, the anti-CTLA-4 agent is an anti-anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 agent is selected from the group consisting of ipilimumab and tremelimumab.

[0007] In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 3 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 6 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 1 year. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 2 years.

[0008] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered at least once a day.In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered orally.

[0009] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least 30 mg / day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 0.1 mg to 720 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 30 mg to 200 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 30 mg to 720 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 60 mg to 600 mg per day. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 100 mg to 480 mg per day.

[0010] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is selected from the group consisting of 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day.

[0011] In some embodiments, a therapeutically effective amount is administered as a single dose or divided into two, three, or four doses.

[0012] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof and the at least one additional therapy are both administered continuously, hi some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered continuously and the immune checkpoint inhibitor is administered cyclically. [Brief description of the drawings]

[0013] [Figure 1] Figure 1 shows the results of a mouse glioblastoma model (Ibudilast treatment in an allogeneic mouse model (20,000 SB28 cells) synergized with anti-PD1) in which mice were treated with ibudilast, anti-PD-1 antibody, or a combination of ibudilast and anti-PD-1 antibody. Isotype serves as a negative control for anti-PD-1 antibody, and vehicle serves as a negative control for ibudilast. Treatment was initiated 7 days after engraftment, with three intraperitoneal injections at 3-day intervals; n=10 mice / group (male); median survival time obtained for each group, *p<0.05, **p<0.01, ***p<0.001 as assessed by log-rank (colored asterisks indicate comparison with the respective control group). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The practice of the present disclosure employs conventional methods of chemistry, biochemistry, and pharmacology, within the skill of those of ordinary skill in the art, unless otherwise indicated. Such techniques are fully explained in the literature. See, for example, A. L. Lehninger, Biochemistry (Worth Publishers, Inc., current addition); Morrison and Boyd, Organic Chemistry (Allyn and Bacon, Inc., current addition); J. March, Advanced Organic Chemistry (McGraw Hill, current addition); Remington: The Science and Practice of Pharmacy, A. Gennaro, Ed., 20th Ed.; FDA's Orange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, L. L. Limbird, A. Gilman, 11th Ed., 2005, The Merck Manual, 18th edition, 2007, and The Merck Manual of Medical Information 2003.

[0015] All publications cited herein, including internet articles, the FDA Orange Book (available on the FDA website), books, handbooks, journal articles, patents, and patent applications, whether supra or infra, are hereby incorporated by reference in their entirety.

[0016] definition Before describing the present disclosure in detail, it is to be understood that this disclosure is not limited to particular modes of administration, patient populations, and the like, as such can vary, as will become apparent from the accompanying specification and drawings.

[0017] It should be noted that, as used herein and in the intended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "drug" includes a single drug as well as two or more of the same or different drugs, reference to an "optional excipient" refers to a single optional excipient as well as two or more of the same or different optional excipients, etc.

[0018] In describing and claiming this disclosure, the following terminology will be used in accordance with the definitions set out below.

[0019] As used herein, the terms "comprising" or "comprises" are intended to mean that the compositions and methods include the recited elements but do not exclude other elements. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements that are essential to the combination for the purposes described. Thus, a composition consisting essentially of the elements defined herein does not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. "Consisting of" is intended to mean excluding more than trace elements of other components and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.

[0020] A "pharmaceutically acceptable salt excipient or carrier" refers to an excipient that may optionally be included in a composition of the present disclosure and that causes no significant adverse toxicological effects to a patient.

[0021] "Pharmaceutically acceptable salts" include, but are not limited to, amino acid salts, salts prepared with inorganic acids, such as chlorides, sulfates, phosphates, diphosphates, bromides and nitrates, or salts prepared from the corresponding inorganic acid forms of any of the above, such as hydrochlorides, or salts prepared with organic acids, such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate.Similarly, salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium (including substituted ammonium).

[0022] As described herein, "active molecule" or "active agent" includes any agent, drug, compound, composition or mixture that provides some pharmacological, often beneficial, effect that can be demonstrated in vivo or in vitro. This includes foods, dietary supplements, nutrients, nutraceuticals, drugs, vaccines, antibodies, vitamins, and other beneficial agents. As used herein, the term further includes any physiologically or pharmacologically active substance that produces a local or systemic effect in a patient. In a specific embodiment, the active molecule or active agent includes ibudilast or a pharmaceutically acceptable salt thereof.

[0023] "Substantially" or "essentially" means nearly completely or completely, e.g., 95% or more of a given amount.

[0024] "Optional" or "optionally" means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not occur.

[0025] "Glial cells" refers to various cells of the central nervous system, also known as microglia, astrocytes and oligodendrocytes.

[0026] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, including, but not limited to, mice, rodents, rats, monkeys, humans, farm animals, dogs, cats, sport animals, and pets.

[0027] The term "pharmacologically effective amount" or "therapeutically effective amount" of a composition or agent provided herein refers to a non-toxic but sufficient amount of the composition or agent to provide a desired response, such as reduction or regression of clinical symptoms of glioblastoma. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the condition being treated, the specific drug(s) used, the mode of administration, etc. The appropriate "effective" amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein.

[0028] The term "about" is meant to encompass a deviation of plus or minus 5 percent, particularly with respect to a given amount.

[0029] As used herein, the term "normal glial cell" refers to a specific cell type.

[0030] As used herein, the terms "glioblastoma multiforme" or "glioblastoma" or "malignant glioma" are used interchangeably herein and refer to brain tumors arising from astrocytes. As used herein, glioblastoma includes recurrent glioblastoma.

[0031] As used herein, the term "treatment" or "treating" means any treatment of a disease or condition or related disorder in a patient, including: · Inhibiting a disease or condition, i.e. halting or suppressing the development of clinical symptoms such as cachexia in cancer; alleviating the disease or condition, i.e. causing regression of clinical symptoms, for example increasing overall survival or reducing tumor burden; · To improve clinical outcomes for patients suffering from glioblastoma; · or any combination of these.

[0032] The term "clinical outcome" refers to any clinical observation or measurement of a patient's response to a treatment. Non-limiting examples of improved clinical outcomes include longer survival, reduction in tumor size, non-growth of tumor size, and / or lack of worsening of neurological symptoms. Non-limiting examples of neurological symptoms include double vision, vomiting, loss of appetite, mood and personality changes, changes in thinking and learning ability, seizures, difficulty speaking, and cognitive impairment. Further, non-limiting examples of clinical outcomes include tumor response (TR), overall survival (OS), progression-free survival (PFS), disease-free survival, time to tumor recurrence (TTR), time to tumor progression (TTP), relative risk (RR), toxicity or side effects. "Overall survival" (OS) refers to the extension of life expectancy compared to a naive or untreated individual or patient. "Progression-free survival" (PFS) or "time to tumor progression" (TTP) refers to the length of time during and after treatment during which the cancer does not grow. Progression-free survival includes the time during which a patient experienced a complete or partial response, and the time during which a patient experienced stable disease. As used herein and defined by the National Cancer Institute, "tumor recurrence" is cancer that has recurred (come back), usually after a period during which the cancer could not be detected. The cancer may return to the same location as the original (primary) tumor or to another location in the body. It is also called recurrent cancer. "Time to tumor recurrence" (TTR) is defined as the time from the date of cancer diagnosis to the first recurrence, death, or last contact if the patient had no tumor recurrence at last contact. If the patient did not recur, the TTR was censored at the time of death or last follow-up. "Relative risk" (RR) in statistics and mathematical epidemiology refers to the risk of an event (or disease occurrence) relative to an exposure. Relative risk is the ratio of the odds of an event occurring in the exposed group versus the unexposed group.

[0033] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments of the present disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0034] Ibudilast The disclosed method for the treatment of glioblastoma is based on the administration of ibudilast in combination with an immune checkpoint inhibitor. Ibudilast is a small molecule drug (molecular weight 230.3) having the structure shown below. [ka]

[0035] Ibudilast is also found in ChemBank ID 3227, CAS # 50847-11-5, and Beilstein Handbook Reference No. 5-24-03-00396. Its molecular formula is 14 H 18 It corresponds to NO. Ibudilast is also known by various chemical names, including 2-methyl-1-(2-(1-methylethyl)pyrazolo(1,5-a)pyridin-3-yl)1-propanone, 3-isobutyryl-2-isopropylpyrazolo(1,5-a)pyridine]; and 1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-2-methyl-propan-1-one. Other synonyms of ibudilast include ibudilastam (Latin), BRN 0656579, KC-404 and MN-166. The trade name is Ketas®. As referred to herein, ibudilast is meant to include any and all pharma- ceutically acceptable salt forms, prodrug forms (e.g., corresponding ketals), solvates, etc. thereof, suitable for use in the intended formulation for administration.

[0036] Ibudilast is an inhibitor of macrophage inhibitory factor (MIF). Ibudilast is also a selective inhibitor of cyclic nucleotide phosphodiesterases (PDE) 3A, 4, 10A1 and 11A1 (Gibson et al., Eur J Pharmacol 538:39-42, 2006) and has been reported to have leukotriene D4 and PAF antagonist activity. Its profile appears to be effectively anti-inflammatory and unique compared to other PDE inhibitors and anti-inflammatory agents. PDEs catalyze the hydrolysis of the phosphoester bond on the 3'-carbon to generate the corresponding 5'-nucleotide monophosphate. Thus, they regulate the cellular concentration of cyclic nucleotides. Because extracellular receptors for many hormones and neurotransmitters utilize cyclic nucleotides as second messengers, PDEs also regulate cellular responses to these extracellular signals. There are at least eight classes of PDEs: Ca2+ / calmodulin-dependent PDEs (PDE1); cGMP-stimulated PDEs (PDE2); cGMP-inhibited PDEs (PDE3); cAMP-specific PDEs (PDE4); cGMP-binding PDEs (PDE5); photoreceptor PDEs (PDE6); high-affinity cAMP-specific PDEs (PDE7); and high-affinity cGMP-specific PDEs (PDE9). Ibudilast acts to suppress inflammation through its effects on inflammatory cells (e.g., glial cells), resulting in the suppression of both proinflammatory and neuroactive mediator release. Ibudilast can also suppress the production of proinflammatory cytokines (IL-1β, TNF-α) and enhance the production of anti-inflammatory cytokines (IL-4, IL-10).References:Obernolte,R.,et al.(1993)「The cDNA of a human lymphocyte phosphorylation phosphodiesterase pPDE IV)reveals a multigene family」 Gene 129:239-247;Rile,G.,et al.(2001)「Potentiation of ibudilast inhibition of platelet aggregation in the presence of endothelial cells」 Thromb.Res.102:239-246;Souness,J. al.(1994)「Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone」 Br.J.Pharmacol.111:1081-1088;Suzumura,A.,1999 et al.(Ibudilast). TNF.alpha.production by glial cells functioning mainly as type III phosphodiesterase inhibitor in CNS」 Brain Res.837:203-212;Takuma,K.,et al.(2001)「Ibudilast attenuates astrocyte apoptosis via cyclic GMP signaling pathway in a vital reperfusion model」 Br.J.Pharmacol.133:841-848。

[0037] The use of rolipram (a PDE4 inhibitor) to treat glioblastoma has been suggested. See Chen et al., Cancer Biol. Ther. 2002, 1(3):268-276. Although rolipram has shown positive results in cell assay studies and animal model studies, rolipram is not a strong candidate for the treatment of glioblastoma in humans due to poor penetration into the central nervous system (CNS). Ibudilast, on the other hand, shows good CNS penetration. (Sanftner et al Xenobiotica 2009 39:964-977)

[0038] Reference to any one or more of the drugs described herein, particularly ibudilast, is meant to encompass, where applicable, any and all enantiomers, racemic mixtures, prodrugs, pharma- ceutically acceptable salt forms, hydrates (e.g., monohydrates, dihydrates, etc.), solvates, mixtures of enantiomers including different physical forms (e.g., crystalline solids, amorphous solids), metabolites, and the like.

[0039] Immune checkpoint inhibitors Immune checkpoint inhibitors used in the methods of the present disclosure include anti-PD-1 agents, anti-PD-L1 agents, and / or anti-CTLA-4 agents. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 agent. In some embodiments, the immune checkpoint inhibitor is an anti-PD-L1 agent. In some embodiments, the immune checkpoint inhibitor is an anti-CTLA-4 agent.

[0040] In some embodiments, the anti-PD-1 agent is an anti-PD-1 antibody. Non-limiting examples of anti-PD-1 agents include nivolumab, pembrolizumab, pidilizumab, cemiplimab, spartalizumab, canrelizumab, sintilimab, tislelizumab, toripalimab, AMP-514, AMP-224, JTX-4014, dostallimab, retifanlimab, and AUNP-12. In some embodiments, the anti-PD-1 agent is pembrolizumab.

[0041] In some embodiments, the anti-PD-L1 agent is an anti-PD-L1 antibody. Non-limiting examples of anti-PD-L1 agents include atezolizumab, avelumab, embafolimab, durvalumab, cosibelimab, CA-170, and BMS-986189.

[0042] In some embodiments, the anti-CTLA-4 agent is an anti-anti-CTLA-4 antibody. Non-limiting examples of anti-CTLA-4 agents include ipilimumab and tremelimumab.

[0043] Treatment method As mentioned above, the present disclosure is directed to a method of treating glioblastoma in a patient, including a human patient, in need of treatment of glioblastoma, comprising administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anti-PD-1 agent. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anti-PD-L1 agent. In some embodiments, the method comprises administering to the patient a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an anti-CTLA-4 agent. Such administration is effective to reduce the amount of glioblastoma experienced by the patient, i.e., to cause a significant attenuation or even reversal of glioblastoma, as demonstrated in the accompanying examples. Ibudilast or a pharma- ceutically acceptable salt thereof is preferably administered in a daily dosage range of about 0.1 mg to 720 mg daily, about 30 mg to 720 mg daily, about 60 mg to 600 mg daily, or about 100 mg to 480 mg daily.

[0044] The methods of the disclosure may, in certain cases, include the step of selecting a patient suffering from glioblastoma prior to administering thereto a combination of ibudilast and an immune checkpoint inhibitor (e.g., an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent).

[0045] In some embodiments, both ibudilast or a pharma- ceutically acceptable salt thereof and the immune checkpoint inhibitor are administered continuously, hi some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered continuously and the immune checkpoint inhibitor is administered cyclically.

[0046] Preferred delivery methods of ibudilast-based therapeutic formulations for the treatment of glioblastoma include systemic and local delivery. Such administration routes include, but are not limited to, oral, intraarterial, intrathecal, intraspinal, intramuscular, intraperitoneal, intranasal and inhalation routes.

[0047] More specifically, the ibudilast-based formulation of the present disclosure can be administered for treatment by any suitable route, including but not limited to oral, rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, parenteral (including subcutaneous, intravenous, intramuscular and intradermal), intrathecal and pulmonary.In some embodiments, the ibudilast-based formulation is administered orally.In some embodiments, the ibudilast-based formulation is administered by injection.The preferred route will of course vary depending on the condition and age of the recipient, the particular syndrome being treated, and the particular combination of drugs being used.

[0048] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered orally.In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered by injection.

[0049] The combinations described herein may be administered as separate dosage forms. When the drugs comprising the therapeutic combinations of the present disclosure are administered as separate dosage forms and require simultaneous administration, ibudilast and the immune checkpoint inhibitor may be administered simultaneously, sequentially in any order, or separately.

[0050] Dosage: Ibudilast The therapeutic amount can be empirically determined and varies depending on the particular condition being treated, the subject, and the efficacy and toxicity of each active agent contained in the composition. The actual dose administered will vary depending on the age, weight, and general condition of the subject, as well as the severity of the condition being treated, the judgment of the medical professional, and the particular combination being administered.

[0051] The therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof may range from about 0.1 mg / day to about 720 mg / day, about 60 to about 600 mg / day, or about 100 to about 480 mg / day, or more preferably from about 1 to about 240 mg / day, about 30 to about 240 mg / day, about 30 to about 200 mg / day, about 30 to about 120 mg / day, about 1 to about 120 mg / day, about 50 to about 150 mg / day, about 60 to about 150 mg / day, about 60 to about 120 mg / day, or about 60 to about 100 mg / day in a total daily dose, administered either as a single dose or multiple doses. In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is about 30 to about 200 mg / day, administered either as a single dose or multiple doses. In some embodiments, multiple doses include two, three, or four doses per day.

[0052] Preferred dosages of ibudilast include doses of greater than about 20 mg BID or TID. That is, preferred dosage amounts are greater than about 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 70 mg / day, 80 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 130 mg / day, 140 mg / day, 150 mg / day, 160 mg / day, 170 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day or greater, or any value therebetween.

[0053] In some embodiments, a therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least 30 mg / day, at least 40 mg / day, at least 50 mg / day, at least 60 mg / day, at least 70 mg / day, at least 80 mg / day, at least 90 mg / day, at least 100 mg / day, at least 110 mg / day, at least 120 mg / day, at least 130 mg / day, at least 140 mg / day, at least 150 mg / day, at least 160 mg / day, at least 170 mg / day, at least 180 mg / day, at least 190 mg / day, at least 200 mg / day, at least 225mg / day, at least 250mg / day, at least 275mg / day, at least 300mg / day, at least 325mg / day, at least 350mg / day, at least 375mg / day, at least 400mg / day, at least 425mg / day, at least 450mg / day, at least 475mg / day, at least 500mg / day, at least 525mg / day, at least 550mg / day, at least 575mg / day, at least 600mg / day, at least 625mg / day, at least 650mg / day, at least 675mg / day, at least 700mg / day, or at least 720mg / day. In some embodiments, the therapeutically effective amount of ibudilast or its pharma- ceutically acceptable salt is at least 60mg / day. In some embodiments, the therapeutically effective amount of ibudilast or its pharma-ceutically acceptable salt is at least 100mg / day.

[0054] In some embodiments, the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is about 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, or 720 mg / day, or any value therebetween.

[0055] Depending on the dosage and the exact condition being treated, administration of ibudilast may be once, twice, three times, or four times daily over a time course of one day to several days, weeks, months, or even years, or even for the patient's lifetime. Exemplary dosing regimens last for at least about 1 week, about 1-4 weeks, 1-3 months, 1-6 months, 1-52 weeks, 1-24 months, or longer. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for 3 months or less. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 3 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 6 months. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 1 year. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 2 years. In some embodiments, ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 3 years.

[0056] In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in a single dose per day.In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in two doses per day.In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in three doses per day.In some embodiments, the therapeutically effective amount of ibudilast or its pharmaceutically acceptable salt is administered in four doses per day.

[0057] In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered at least once a day. In some embodiments, ibudilast or a pharma- ceutically acceptable salt thereof is administered at least twice a day.

[0058] In practical terms, any given composition or unit dose of active agent of the present disclosure can be administered in various dosing schedules, depending on the clinician's judgment, the patient's needs, etc. Specific dosing schedules are known to those skilled in the art or can be determined experimentally using routine methods. Exemplary dosing schedules include, but are not limited to, administration 5 times a day, 4 times a day, 3 times a day, 2 times a day, once a day, every other day, 3 times a week, twice a week, once a week, twice a month, once a month, etc.

[0059] Treatment: Anti-PD-1 agent In some embodiments, the immune checkpoint inhibitor is nivolumab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 2 mg / kg / dose up to 600 mg / dose.

[0060] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 2 mg / kg / dose up to 600 mg / dose.

[0061] In some embodiments, the immune checkpoint inhibitor is cemiplimab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 2 mg / kg / dose up to 600 mg / dose.

[0062] In some embodiments, the immune checkpoint inhibitor is spartalizumab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 2 mg / kg / dose up to 600 mg / dose.

[0063] In some embodiments, the immune checkpoint inhibitor is canrelizumab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 2 mg / kg / dose up to 600 mg / dose.

[0064] In some embodiments, the immune checkpoint inhibitor is sintilimab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 2 mg / kg / dose up to 600 mg / dose.

[0065] In some embodiments, the immune checkpoint inhibitor is ticelelizumab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 2 mg / kg / dose up to 600 mg / dose.

[0066] In some embodiments, the immune checkpoint inhibitor is toripalimab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 2 mg / kg / dose up to 600 mg / dose.

[0067] Treatment: Anti-PD-L1 agent In some embodiments, the immune checkpoint inhibitor is atezolizumab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 5 mg / kg / dose up to 2000 mg / dose.

[0068] In some embodiments, the immune checkpoint inhibitor is avelumab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 5 mg / kg / dose up to 2000 mg / dose.

[0069] In some embodiments, the immune checkpoint inhibitor is emvafolimab, which may be administered daily for about 2 to about 12 weeks at a minimum dose of 5 mg / kg / dose up to 2000 mg / dose.

[0070] In some embodiments, the immune checkpoint inhibitor is durvalumab, which may be administered daily for about 2 to about 6 weeks at a minimum dose of 5 mg / kg / dose up to 2000 mg / dose.

[0071] Administration: Anti-CTLA-4 agent In some embodiments, the immune checkpoint inhibitor is ipilimab, which may be administered daily at a dose of 2 mg / kg / dose to 15 mg / kg / dose for about 2 to about 12 weeks.

[0072] In some embodiments, the immune checkpoint inhibitor is tremelimumab. Cemiplimab may be administered daily at a dose of 2 mg / kg / dose to 15 mg / kg / dose for about 2 to about 12 weeks.

[0073] formulation In addition to containing ibudilast or a pharma- ceutically acceptable salt thereof, the therapeutic formulations of the present disclosure may optionally contain one or more excipients / carriers described below.

[0074] Excipients / Carriers In addition to ibudilast or its pharmaceutically acceptable salt, the composition of the present disclosure for treating glioblastoma may further comprise one or more pharmaceutically acceptable excipients or carriers.Exemplary excipients include, but are not limited to, polyethylene glycol (PEG), hydrogenated castor oil (HCO), cremophor, carbohydrates, starch (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders / fillers, surfactants, lubricants (e.g., calcium stearate or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, etc.

[0075] The composition of the present disclosure may include one or more carbohydrates, such as sugars, derivatized sugars, such as alditols, aldonic acids, esterified sugars, and / or sugar polymers.Specific carbohydrate excipients include, for example, monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc.; disaccharides, such as lactose, sucrose, trehalose, cellobiose, etc.; polysaccharides, such as raffinose, melezitose, maltodextrin, dextran, starch, etc.; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosylsorbitol, myoinositol, etc.

[0076] Also suitable for use in the compositions of the present disclosure are potato and corn based starches, such as sodium starch glycolate and directly compressible modified starches.

[0077] Further representative excipients include inorganic salts or buffers such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations.

[0078] The composition of the present disclosure may also contain one or more antioxidants.Antioxidants are used to prevent oxidation, thereby preventing the deterioration of drugs or other components of preparations.Suitable antioxidants for use in the present disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

[0079] Further exemplary excipients include surfactants, such as polysorbates, e.g., "Tween 20" and "Tween 80," and pluronics, e.g., F68 and F88 (both available from BASF, Mount Olive, NJ), sorbitan esters, lipids (e.g., phospholipids, such as lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty acid esters, steroids, e.g., cholesterol, and chelating agents, such as EDTA, zinc and other such suitable cations.

[0080] In addition, the composition of the present disclosure may optionally include one or more acids or bases.Non-limiting examples of acids that can be used include acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof.Non-limiting examples of suitable bases include, but are not limited to, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.

[0081] The amount of any individual excipient in the composition varies depending on the role of the excipient, the dosage requirements of the active agent component, and the specific needs of the composition. Typically, the optimal amount of any individual excipient is determined by routine experimentation, i.e., by preparing compositions containing various amounts of excipient (ranging from low to high), examining stability and other parameters, and then determining the range in which optimal performance is achieved without significant adverse effects.

[0082] Generally, however, the excipient is present in the composition in an amount of about 1% to about 99% by weight of the excipient, preferably about 5% to about 98% by weight, and more preferably about 15% to about 95% by weight. Generally, the amount of excipient present in the ibudilast compositions of the present disclosure is selected from at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

[0083] These aforementioned pharmaceutical excipients, along with other excipients, are described in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), the "Physician's Desk Reference", 52nd ed., Medical Economics, Montvale, NJ (1998), and Kibbe, AH, Handbook of Pharmaceutical Excipients, 3rd Edition, American Pharmaceutical Association, Washington, DC, 2000.

[0084] Sustained delivery formulations Preferably, the composition is formulated to improve the stability and extend the half-life of ibudilast or its pharmaceutically acceptable salt.For example, ibudilast or its pharmaceutically acceptable salt can be delivered in a controlled release formulation or sustained release formulation.Controlled release formulation or sustained release formulation is prepared by incorporating ibudilast or its pharmaceutically acceptable salt into a carrier or vehicle, such as liposomes, non-resorbable impermeable polymers, such as ethylene vinyl acetate copolymers and Hytrel® copolymers, swellable polymers, such as hydrogels, or resorbable polymers, such as collagen and certain polyacids or polyesters, such as those used to make resorbable sutures.In addition, ibudilast or its pharmaceutically acceptable salt can be encapsulated, adsorbed, or associated with particulate carriers.Examples of particulate carriers include those derived from polymethylmethacrylate polymers, and microparticles derived from poly(lactide) and poly(lactide-co-glycolide), known as PLG. See, e.g., Jeffery et al., Pharm. Res. (1993) 10:362-368; and McGee et al., J. Microencap. (1996).

[0085] Suitable sustained release polymers for this purpose are known in the art and include hydrophobic polymers such as cellulose ethers.Non-limiting examples of suitable cellulose ethers include ethyl cellulose, cellulose acetate, etc.; polyvinyl esters such as polyvinyl acetate, polyacrylic esters, methacrylic and acrylate polymers (pH independent); high molecular weight polyvinyl alcohols and waxes such as fatty acids and glycerides, methacrylic acid ester neutral polymers, polyvinyl alcohol-maleic anhydride copolymers, etc.; ethyl acrylate-methyl methacrylate copolymers; aminoalkyl methacrylate copolymers; and mixtures thereof.

[0086] Mode of delivery The compositions of ibudilast or its pharma- ceutically acceptable salts described herein include all types of formulations, particularly formulations suitable for systemic or intrathecal administration.Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules and pellets.In some embodiments, the oral dosage form is a tablet.In some embodiments, the tablet is a sustained release tablet.In some embodiments, the oral dosage form is a capsule.In some embodiments, the capsule is a sustained release tablet.

[0087] Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, powders or lyophilized agents that can be reconstituted, and liquids.Examples of suitable diluents for reconstituting solid compositions before injection include bacteriostatic water for injection, 5% dextrose in water, phosphate buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof.For liquid pharmaceutical compositions, solutions and suspensions are envisioned.Preferably, the compositions of ibudilast or its pharmaceutically acceptable salts of the present disclosure are suitable for oral administration.

[0088] Turning now to oral delivery formulations, tablets can be made by compression or molding, optionally with one or more auxiliary ingredients or additives.Compressed tablets are prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethylcellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethylcellulose) and / or surfactant or dispersant, using a suitable tablet press.

[0089] Molded tablets are prepared, for example, by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable tablet press. Tablets may be optionally coated or scored, and may be formulated to provide slow or controlled release of active ingredients, for example, using various percentages of hydroxypropylmethylcellulose to provide a desired release profile. Tablets may be optionally provided with coatings, such as thin films, sugar coatings, or enteric coatings, to release in parts of the intestine other than the stomach. The processes, equipment, and contract manufacturers for the manufacture of tablets and capsules are well known in the art.

[0090] Formulations for topical administration in the mouth include lozenges, which generally contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth, and pastilles, which contain the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia.

[0091] Pharmaceutical compositions for topical administration may also be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

[0092] Alternatively, the formulation may be in the form of a patch (e.g., a transdermal patch) or dressing, such as a bandage or adhesive plaster, impregnated with the active ingredient and optionally one or more excipients or diluents. Topical formulations may further include compounds that enhance absorption or penetration of the ingredient through the skin or other affected areas, such as dimethylsulfoxidem bisabolol, oleic acid, isopropyl myristate, and D-limonene, to name a few.

[0093] In emulsions, the oily phase is composed of known ingredients in a known manner. This phase may simply comprise an emulsifier (also known as an emulgent), but desirably comprises a mixture of at least one emulsifier with fat and / or oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifiers, with or without stabilizers, constitute the so-called emulsifying wax, which, together with the oil and / or fat, constitute the so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation. Exemplary emulsifiers and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0094] Formulations for rectal administration are typically in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0095] Formulations suitable for vaginal administration generally take the form of a suppository, tampon, cream, gel, paste, foam, or spray.

[0096] Formulations suitable for nasal administration in which the carrier is a solid include coarse powders having a particle size in the range of, for example, about 20 to about 500 microns. Such formulations are typically administered by rapid inhalation through the nasal passages, for example, from a container of the powder held close to the nose. Alternatively, formulations for nasal delivery may be in the form of a liquid, for example, a nasal spray or nasal drops.

[0097] The aerosolizable formulation for inhalation may be in dry powder form (e.g., suitable for administration by dry powder inhaler) or may be in liquid form, for example, for use in a nebulizer. Nebulizers for delivering aerosolized solutions include AERx® (Aradigm), Ultravent® (Mallinkrodt), and Acorn II® (Marquest Medical Products). The compositions of the present disclosure may also be delivered using a pressurized metered dose inhaler (MDI), such as a Ventolin® metered dose inhaler, that contains a solution or suspension of the drug combination described herein in a pharma- ceutical inert liquid propellant, such as a chlorofluorocarbon or fluorocarbon.

[0098] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions.

[0099] The parenteral formulations of the disclosure may optionally be contained in unit-dose or multi-dose sealed containers, for example ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type previously described.

[0100] The formulations of the present disclosure may also be sustained release formulations, such that each drug component is slowly released or absorbed over time, as compared to non-sustained release formulations.Sustained release formulations may use prodrug forms of the active agent, delayed release drug delivery systems, such as liposomes or polymer matrices, hydrogels, or covalent attachment of polymers, such as polyethylene glycol, to the active agent.

[0101] In addition to the ingredients particularly mentioned above, the formulations of the present disclosure may optionally include other agents conventional in the pharmaceutical art, and for example, the particular type of formulation used for oral dosage forms; compositions for oral administration may include additional agents as sweeteners, thickeners, or flavoring agents.

[0102] kit Also provided herein are kits containing at least one combination of the present disclosure, along with instructions for use.

[0103] For example, in cases where each drug is administered by itself as an individual or separate dosage form, the kit includes ibudilast in addition to the immune checkpoint inhibitors constituting the combination of the present disclosure, together with instructions for use. The drug components may be packaged in any manner suitable for administration, so long as the packaging, when considered together with the instructions for administration, clearly indicates the manner in which each drug component is to be administered.

[0104] For example, in an exemplary kit including ibudilast and an immune checkpoint inhibitor, the kit may be organized for any suitable period, such as by day. As an example, on day 1, a representative kit may include a unit dosage of each of ibudilast and the immune checkpoint inhibitor. If each drug is administered twice a day, the kit may contain two rows of unit dosage forms of each of ibudilast and the immune checkpoint inhibitor, corresponding to day 1, along with instructions on the timing of administration. Alternatively, if one or more drugs differ in the timing or amount of unit dosage forms administered compared to other drug members of the combination, such will be reflected in the packaging and instructions. Various embodiments according to the above can be easily envisioned, and these will of course depend on the particular combination of drugs, their corresponding dosage forms, recommended dosages, intended patient population, etc., in addition to the ibudilast used for treatment. The packaging may be in any form commonly used for packaging pharmaceutical products, and may utilize any of several features, such as different colors, wrapping, tamper-evident packaging, blister packs, desiccants, etc.

[0105] Animal models The ability of the combination of ibudilast and immune checkpoint inhibitor to treat glioblastoma can be evaluated by any standard glioblastoma model known in the art.Examples of such models are described in Animal Models of Neurological Disease:Neurodegenerative Diseases(Neuromethods)by Alan A.Boulton,Glen B.Baker,and Roger F.Butterworth(1992);Handbook of Laboratory Animal Science,Second Edition:Volumes I-III(Handbook of Laboratory Animal Science)by Jann Hau(Editor),Jr.,Gerald L.Van Hoosier(Editor).(2004);Animal Models of Movement Disorders by Mark LeDoux(Editor),(2005);And Animal Models of Cognitive Impairment(Frontiers in Neuroscience)(2006)by Edward D.Levin(Editor),Jerry J.Buccafusco(Editor).

[0106] While the present disclosure has been described in conjunction with preferred specific embodiments, it should be understood that the foregoing description and the following examples are intended to illustrate, but not to limit, the scope of the present disclosure. Other aspects, advantages and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which this disclosure pertains.

[0107] All references mentioned in this application, including any patents, published patent applications, books, handbooks, journal publications, or the FDA Orange Book, are hereby incorporated by reference in their entirety.

[0108] The following examples are provided for the purpose of illustrating various embodiments of the present disclosure, and are not meant to limit the present disclosure in any way. Those skilled in the art will easily understand that the present disclosure is well adapted to carry out the objects and obtain the stated goals and advantages, as well as the objects, goals and advantages inherent therein. The examples, together with the methods described herein, are representative of the current embodiments, are exemplary, and are not intended as limitations on the scope of the present disclosure. Modifications therein and other uses encompassed within the spirit of the present disclosure, as defined by the scope of the claims, will occur to those skilled in the art. EXAMPLES

[0109] Example 1: Mouse GBM Model Mice bearing GBM orthotopic tumors were treated with PD-1 antibodies in the presence or absence of ibudilast (or ibudilast alone) and evaluated for survival after treatment initiation. More specifically, ibudilast treatment (50 mg / kg) was performed in a syngeneic mouse model (20,000 SB28 cells) synergized with anti-PD1 (25 μg / dose). Treatment was initiated 7 days after engraftment, with three intraperitoneal injections at 3-day intervals. n=10 mice / group (male).

[0110] Treatment with anti-PD-1 antibody alone extended median survival to 17-28 days in this model compared to control vehicle or non-specific antibody treatment. However, the addition of ibudilast to anti-PD1 antibody treatment further extended survival, bringing the median survival to 66 days (Figure 1). Ibudilast treatment alone had no effect on median survival.

[0111] Example 2: Human Clinical Trials The study is an open-label surgical "treat opportunity" study in recurrent glioblastoma and a phase 1b study in newly diagnosed glioblastoma.

[0112] Part 1 Part 1 will involve a safety run-in in six patients with recurrent glioblastoma to evaluate the toxicity and tolerability of the combination of ibudilast 100 mg orally daily and pembrolizumab 200 mg intravenously every three weeks. If an initial ibudilast dose of 60 mg daily is not tolerated, lower doses of 40 mg daily and 30 mg daily will be investigated.

[0113] If the combination is tolerated, a surgical treatment opportunity trial will be performed to evaluate the effect of the combination on tumor immune responses. Forty evaluable patients with recurrent glioblastoma requiring reoperation will be randomized to receive 2-3 weeks prior to surgery to group 1: ibudilast alone (100 mg daily) (10 patients); group 2: pembrolizumab alone 200 mg intravenously (10 patients); group 3: ibudilast (100 mg daily) in combination with pembrolizumab (200 mg) (10 patients); or group 4: no treatment (control) (10 patients). At the time of surgery, the tumor will be removed for analysis of the immune response.

[0114] Tumor tissue will be analyzed by immunohistochemistry using next generation sequencing to quantify tumor infiltrating lymphocyte (TIL) density and T cell receptor (TCR) repertoire. Blood will be collected at baseline, surgery, and at each scheduled follow-up visit during the postoperative period until progression for measurement of systemic immune cell subsets, immunophenotyping of MDSCs, and soluble immune cytokines.

[0115] After recovery from surgery, all patients will receive ibudilast 100 mg orally daily and pembrolizumab 200 mg every 3 weeks until tumor progression, development of unacceptable side effects, or a maximum of 2 years.

[0116] Patients will undergo MRI every 6 weeks. RANO18 and modified RANO19 criteria will be used.

[0117] Finally, the efficacy of this combination may be greater in newly diagnosed glioblastoma patients after debulking surgery, when the immune system may be more robust than at the time of recurrent disease, and in combination with standard radiochemotherapy. The safety and tolerability of this combination will be examined in newly diagnosed glioblastoma in part 2.

[0118] Part 2 In part 2, the safety and efficacy of ibudilast and pembrolizumab in combination with standard chemoradiotherapy and the recommended phase II dose will be determined in patients with newly diagnosed glioblastoma.

[0119] Eligible patients were randomly assigned to receive temozolomide (75 mg / m 2 for 42 days) combined with 6 weeks of radiation therapy (60 Gy), followed by 4 weeks off treatment, and temozolomide at 150–200 mg / m 2 / day x 5 every 28 days for 6 cycles. Ibudilast 60 mg / day will be administered orally, pembrolizumab 200 mg intravenously every 3 weeks, and radiochemotherapy will be initiated and continued until disease progression, occurrence of unacceptable toxicity, or for up to 2 years. A 3+3 design will be used. Dose-limiting toxicities (DLTs) will be determined during the first 10 weeks of treatment. If there are 0 / 3 or 1 / 6 DLTs with ibudilast 60 mg daily, the ibudilast dose will be increased to 100 mg daily for the next 3-6 patients. If this increased dose is tolerated, 18 more patients will be enrolled at this dose to confirm tolerability. If the initial ibudilast dose of 60 mg daily is not tolerated, lower doses of 40 mg daily and 30 mg daily will be investigated.

[0120] Embodiment 1. A method of treating glioblastoma in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of ibudilast, or a pharma- ceutical acceptable salt thereof, and a therapeutically effective amount of an immune checkpoint inhibitor.

[0121] Embodiment 2. The method of embodiment 1, wherein the immune checkpoint inhibitor is an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent.

[0122] Embodiment 3. The method of embodiment 2, wherein the immune checkpoint inhibitor is an anti-PD-1 agent.

[0123] Embodiment 4. The method of embodiment 2 or embodiment 3, wherein the anti-PD-1 agent is an anti-PD-1 antibody.

[0124] Embodiment 5. The method of embodiment 2 or embodiment 3, wherein the anti-PD-1 agent is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, spartalizumab, canrelizumab, sintilimab, tislelizumab, toripalimab, AMP-514, AMP-224, JTX-4014, dostallimab, retifanlimab, and AUNP-12.

[0125] Embodiment 6. The method of embodiment 2, wherein the immune checkpoint inhibitor is an anti-PD-L1 agent.

[0126] Embodiment 7. The method of embodiment 2 or embodiment 6, wherein the anti-PD-L1 agent is an anti-PD-L1 antibody.

[0127] Embodiment 8. The method of embodiment 2 or embodiment 6, wherein the anti-PD-L1 agent is selected from the group consisting of atezolizumab, avelumab, embafolimab, durvalumab, cosibelimab, CA-170 and BMS-986189.

[0128] Embodiment 9. The method of embodiment 2, wherein the immune checkpoint inhibitor is an anti-CTLA-4 agent.

[0129] Embodiment 10 The method of embodiment 2 or embodiment 9, wherein the anti-CTLA-4 agent is an anti-CTLA-4 antibody.

[0130] Embodiment 11. The method of any one of embodiments 2, 9 or 10, wherein the anti-CTLA-4 agent is selected from the group consisting of ipilimumab and tremelimumab.

[0131] Embodiment 12. The method of any one of embodiments 1-11, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 3 months.

[0132] Embodiment 13 The method of any one of embodiments 1-11, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 6 months.

[0133] Embodiment 14. The method of any one of embodiments 1-11, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least one year.

[0134] Embodiment 15. The method of any one of embodiments 1-11, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered for at least 2 years.

[0135] Embodiment 16. The method of any one of embodiments 1-15, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered at least once a day.

[0136] Embodiment 17. The method of any one of embodiments 1-16, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered orally.

[0137] Embodiment 18. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is at least 30 mg / day.

[0138] Embodiment 19. The method of any one of embodiments 1 to 17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 0.1 mg to 720 mg per day.

[0139] Embodiment 20. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 30 mg to 200 mg per day.

[0140] Embodiment 21. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is between 30 mg and 720 mg daily.

[0141] Embodiment 22. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 60 mg to 600 mg daily.

[0142] Embodiment 23. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is 100 mg to 480 mg daily.

[0143] Embodiment 24. The method of any one of embodiments 1-17, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is selected from the group consisting of 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day, and 720 mg / day.

[0144] Embodiment 25. The method of any one of embodiments 1-24, wherein the therapeutically effective amount of ibudilast or a pharma- ceutically acceptable salt thereof is administered as a single dose or divided into two, three, or four doses.

[0145] Embodiment 26. The method of any one of embodiments 1 to 25, wherein both ibudilast or a pharma- ceutically acceptable salt thereof and the immune checkpoint inhibitor are administered sequentially.

[0146] Embodiment 27. The method of any one of embodiments 1 to 25, wherein ibudilast or a pharma- ceutically acceptable salt thereof is administered continuously and the immune checkpoint inhibitor is administered cyclically.

[0147] Equivalent While the present disclosure has been specifically disclosed by certain embodiments and optional features, it is understood that modifications, improvements, and variations of the disclosure embodied in the disclosure herein may be made by those skilled in the art, and such modifications, improvements, and variations are considered to be within the scope of the present disclosure. The materials, methods, and examples provided herein are representative of certain embodiments, are illustrative, and are not intended as limitations on the scope of the disclosure.

[0148] The present disclosure is described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also forms part of the present disclosure. This includes the generic description of the present disclosure with a condition or negative limitation that removes any subject matter from the genus, regardless of whether the excised material is specifically described herein.

[0149] Furthermore, where features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

[0150] Use of the term "or" in the claims is used to mean "and / or," unless expressly indicated to refer to alternatives only or the alternatives are not mutually exclusive, however, the present disclosure supports a definition that refers to alternatives only and "and / or."

[0151] Other embodiments are within the scope of the following claims.

Claims

1. A medicament for treating glioblastoma in a patient in need thereof, comprising a combination of a therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of an immune checkpoint inhibitor.

2. The pharmaceutical composition of claim 1, wherein the immune checkpoint inhibitor is an anti-PD-1 agent, an anti-PD-L1 agent, or an anti-CTLA-4 agent.

3. The pharmaceutical according to claim 2, wherein the immune checkpoint inhibitor is an anti-PD-1 agent.

4. The pharmaceutical according to claim 3, wherein the anti-PD-1 agent is an anti-PD-1 antibody.

5. The pharmaceutical agent according to claim 3, wherein the anti-PD-1 agent is selected from the group consisting of nivolumab, pembrolizumab, cemiplimab, spartalizumab, canrelizumab, sintilimab, tislelizumab, toripalimab, AMP-514, AMP-224, JTX-4014, dostallimab, retifanlimab, and AUNP-12.

6. The pharmaceutical according to claim 2, wherein the immune checkpoint inhibitor is an anti-PD-L1 agent.

7. The pharmaceutical according to claim 6, wherein the anti-PD-L1 agent is an anti-PD-L1 antibody.

8. The pharmaceutical agent of claim 6, wherein the anti-PD-L1 agent is selected from the group consisting of atezolizumab, avelumab, embafolimab, durvalumab, cosibelimab, CA-170, and BMS-986189.

9. The pharmaceutical according to claim 2, wherein the immune checkpoint inhibitor is an anti-CTLA-4 agent.

10. The pharmaceutical according to claim 9, wherein the anti-CTLA-4 agent is an anti-CTLA-4 antibody.

11. The pharmaceutical composition of claim 9, wherein the anti-CTLA-4 agent is selected from the group consisting of ipilimumab and tremelimumab.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the ibudilast or a pharmaceutically acceptable salt thereof is administered for at least 3 months, at least 6 months, at least 1 year, or at least 2 years.

13. 12. The method of claim 1, wherein the ibudilast or a pharmaceutically acceptable salt thereof is administered at least once a day.

14. The pharmaceutical composition of claim 1 , wherein the ibudilast or a pharmaceutically acceptable salt thereof is administered orally.

15. 12. The method of any one of claims 1 to 11, wherein the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is at least 30 mg / day.

16. 12. The method of any one of claims 1 to 11, wherein the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is 0.1 mg to 720 mg per day, 30 mg to 200 mg per day, 30 mg to 720 mg per day, 60 mg to 600 mg per day, or 100 mg to 480 mg per day.

17. 12. The medicament of any one of claims 1 to 11, wherein the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is selected from the group consisting of 30 mg / day, 40 mg / day, 50 mg / day, 60 mg / day, 90 mg / day, 100 mg / day, 110 mg / day, 120 mg / day, 150 mg / day, 180 mg / day, 190 mg / day, 200 mg / day, 210 mg / day, 240 mg / day, 270 mg / day, 300 mg / day, 360 mg / day, 400 mg / day, 440 mg / day, 480 mg / day, 520 mg / day, 580 mg / day, 600 mg / day, 620 mg / day, 640 mg / day, 680 mg / day and 720 mg / day.

18. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein the therapeutically effective amount of ibudilast or a pharmaceutically acceptable salt thereof is administered as a single dose or divided into two, three, or four doses.

19. The pharmaceutical composition of any one of claims 1 to 11, wherein the ibudilast or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor are both administered sequentially.

20. The pharmaceutical composition of any one of claims 1 to 11, wherein the ibudilast or a pharmaceutically acceptable salt thereof is administered continuously and the immune checkpoint inhibitor is administered cyclically.

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