Compounds for the treatment of glioblastoma

Abstract

The present invention includes cMET inhibitors for use in the treatment of glioblastoma, including disseminated glioblastoma harboring MET amplification.

Description

[Technical field]

[0001] FIELD OF THE PRESENT ART The present invention provides for the use of inhibitors of the receptor tyrosine kinase (TKI) mesenchymal-epithelial transition factor (cMET) in the treatment of glioblastoma, including disseminated glioblastoma harboring MET amplification. [Background technology]

[0002] 2. Background of the Invention cMET inhibitors Mesenchymal-epithelial transition factor (cMet) has emerged as a promising target in the development of anticancer therapeutics due to its low levels of expression in normal tissues and its idiosyncratic activation in many human cancers. Aberrant stimulation of numerous signaling pathways downstream of the receptor tyrosine kinase cMET promotes cell transformation, tumor motility and invasion. Therefore, cMET has become the focus of prognostic and therapeutic studies in different tumor types, including non-small cell lung cancer. Specifically, several cMET inhibitors have been developed as innovative therapeutic candidates as well as are currently being investigated in clinical trials (see, for example, van der Stee et al., 2016, Thoracic Onc 11(9): 1423). With regard to selectivity, there is specificity between type I and type II class c-Met inhibitors depending on the binding site on the kinase. Type I inhibitors can be further divided into type Ia and type Ib, with type Ib inhibitors being more specific to MET and having fewer off-target effects when compared to type Ia inhibitors. Type II inhibitors inhibit inactive MET and generally exhibit more off-target effects of other protein kinases, which may cause severe toxic effects. Tepotinib is a highly selective, blood-brain barrier-penetrating oral c-MET inhibitor, the hydrochloride salt hydrate of which was recently FDA approved for MET-exon 14-mutated non-small cell lung cancer (NSCLC). 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (tepotinib) was described in WO 2009 / 006959. Glioblastoma

[0003] Gliomas are a type of tumor that originate in the glial cells of the brain or spinal cord. Gliomas are classified according to cell type, grade, and location. High-grade gliomas (i.e., WHO grades III-IV) are undifferentiated or anaplastic, malignant, and have a poor prognosis. This group includes anaplastic astrocytomas and glioblastomas. Glioblastomas are also known as glioblastoma multiforme (GBM). The grading of gliomas has changed recently, and glioblastomas are now primarily classified according to their isocitrate dehydrogenase (IDH) mutation status (IDH wild-type or IDH mutant). Glioblastoma is an intrinsic malignant brain tumor likely derived from glial progenitor cells, characterized morphologically by infiltrative growth, focal necrosis, and angiogenesis, and at the molecular level by frequent genetic alterations involving receptor tyrosine kinase (RTK) / RAS / phosphatidylinositol 3-kinase (PI3K), p53, and retinoblastoma (RB) pathways. The MET oncogene encodes a receptor tyrosine kinase that promotes cell proliferation, invasion, and angiogenesis in several solid cancers, including glioblastoma. MET tumor pathological copy number amplifications and point mutations are drivers in glioblastoma, with the incidence of MET amplification ranging from 2 to 5%. MET activation promotes tumor growth, angiogenesis, and invasion, and is associated with poor prognosis in gliomas due to poor response to treatment, progression-free survival, and shorter overall survival. In mice bearing ligand-independent Hs746T and HGF-dependent U87MG tumors, tumor growth inhibition and tumor regression by tepotinib was observed transiently before the tumors became resistant and progressed (Bladt et al., 2013, Clin Cancer Res 19(11): 2941). The combination of tepotinib and 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide for treating cancer, particularly glioblastoma, in mouse models was described in WO 2016 / 091347.

[0004] Although there are potential therapies for use in the treatment of glioblastoma, clinical responses are not satisfactory. Glioblastoma remains one of the most lethal solid cancers. Since the introduction of temozolomide, no other pharmacological treatments have been shown to extend survival in addition to the standard treatment of surgery followed by radiation therapy. Efficacy tests of the HGF antibody AMG-102 (Wen et al., 2011, Neuro-oncology 13(4): 437), or the MET antibody onartuzumab (Cloughesy et al., 2017, Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 35(3): 343) had negative results in glioblastoma. Thus, there remains a need to develop novel therapeutic options for the treatment of glioblastoma. In addition, there is a need for therapies with higher efficacy than existing therapies. [Brief description of the drawings]

[0005] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1] Figure 1 shows HGF / MET pathway activity in mouse glioma cells. Figure 1A-1B. Hgf and Met mRNA expression was assessed by RT-PCR in vitro and ex vivo. Figure 1C-1D. HGF protein release and constitutive or HGF-stimulated p-MET levels were assessed in vitro by ELISA (HGF) (C) or immunoblotting (p-MET) (D).

[0006] [Diagram 2]Figure 2 shows synergistic survival extension with radiation and tepotinib-mediated MET inhibition in an in vivo SMA-560 glioma model. Figures 2A-2D. Syngeneic mice were implanted intracranially with SMA-560 glioma cells and treated with 100 mg / kg tepotinib daily starting on day 6, or with vehicle, or with a single dose of 12 Gy on day 7, or with the combination. Brains from animals euthanized at the first symptomatic mouse were studied in A and C. Figure 2A. Tumor lysates pooled from two pre-randomized animals per group were analyzed by immunoblotting for target inhibition (p-MET). Figure 2B. Kaplan-Meier survival curves. Figure 2C. Tumor sections from three pre-randomized animals per group were stained with H&E (top), Ki-67 (middle), or CD31 (bottom). Sections were counterstained with hematoxylin (blue). Quantification of immunoreactivity (right panel) (n=3, *p<0.05, t-test).

[0007] [Diagram 3] Figure 3 shows changes in cytokine levels in response to tepotinib, radiation, or combination treatment. Tumor lysates pooled from two pre-randomized animals per group were analyzed by Proteome Profiler arrays. In A, raw data are presented as pixel density measured by Image J. In B, fold changes indicate downregulation (left) or upregulation (right) relative to control tumors. A 2-fold difference above or below control was used as a cutoff to assign targets to arbitrary groups.

[0008] [Figure 4]Figure 4 shows the change in response to tepotinib and radiation alone or in combination due to loss of adaptive immunity. Figure 4A. Rag1-deficient mice were implanted intracranially with SMA-560 glioma cells and treated with tepotinib at 100 mg / kg daily from day 6, or with vehicle, or with a single dose of 10 Gy on day 7, or with the combination. Kaplan-Meier survival curves are shown. Figures 4B-4C. Syngeneic mice were implanted intracranially with GL-261 glioma cells and treated with tepotinib at 100 mg / kg daily from day 6, or with vehicle, or with a single dose of 10 Gy on day 7, or with the combination. Figure 4B. Kaplan-Meier survival curves were analyzed via log-rank test. Figure 4C. Mice surviving in (B) were rechallenged with GL-261 cells in the contralateral hemisphere 13 weeks after the initial tumor cell injection. Naïve mice transplanted with GL-261 cells were used as controls. Kaplan-Meier survival curves are shown. Figure 4D-4EGL-261 met knockout cells were intracranially implanted into wild-type C57 / Bl6 mice (D), or GL-261 wild-type cells were intracranially implanted into C57 / Bl6 Rag1-deficient mice (E). Mice were treated with tepotinib at 100 mg / kg daily from day 6, or vehicle, or a single dose of 10 Gy on day 7, or a combination thereof, and Kaplan-Meier survival curves are shown. Figure 4F. Analysis of median survival between treatment groups.

[0009] [Diagram 5] FIG. 5 shows the treatment course of one patient and includes MRI screenshots of various intraparenchymal, intraventricular, and spinal lesions that were present prior to treatment with tepotinib.

[0010] [Figure S1]Figure S1 shows the inhibition of MET phosphorylation but no cytotoxic effect of tepotinib in mouse glioma cell lines. Figure S1-A. SMA-497 or SMA-560 cells were exposed to tepotinib to determine the time- and concentration-dependent inhibition of MET phosphorylation. Figure S1-B-C. Cells were exposed to tepotinib in acute growth inhibition (B) or clonogenic viability (C) assays. Viability was assessed by MTT assay (n=3, mean and standard error of the mean).

[0011] [Figure S2] Figure S2 shows changes in the HGF / MET pathway due to radiation in vitro. Figure S2-A-B. Cells were either untreated or exposed to radiation, and then Hgf and Met mRNA expression (A), or MET and p-MET levels by immunoblotting (B) were assessed. Cells were exposed to radiation in the absence or presence of 100 nM tepotinib and / or 50 ng / ml HGF, and clonogenic survival (n=6, mean and standard error of the mean) was monitored. Summary of the Invention

[0012] SUMMARY OF THE PRESENT APPLICATION Each of the embodiments described below may be combined with any other embodiment described herein that is not inconsistent with the embodiment with which it is combined.Furthermore, each of the embodiments described herein contemplates within its scope pharma-ceutically acceptable salts, solvates, and / or hydrates of the compounds described herein.Thus, the phrase "or its pharma-ceutically acceptable salts, solvates, and / or hydrates" is implicit in the description of all compounds described herein.Embodiments within the aspects described below may be combined with other embodiments that are not inconsistent within the same or different aspects.

[0013] In a first aspect, the present invention provides a cMET inhibitor for use in treating glioblastoma in a subject in need thereof. The cMET inhibitor is administered in an amount effective in treating glioblastoma. In one aspect of this embodiment, the cMET inhibitor is used in treating a human subject. In one aspect of this embodiment, the cMET inhibitor is used for long-term treatment and is administered for at least 10 weeks. In one aspect of this embodiment, the cMET inhibitor is used for long-term treatment and is administered for at least 10 weeks in one treatment regimen. In one aspect of this embodiment, the cMET inhibitor for use in treating glioblastoma is not administered in combination with chemotherapy in the same treatment regimen. In one aspect of this embodiment, the cMET inhibitor for use in treating glioblastoma is administered in combination with radiation therapy in the same treatment regimen. In one embodiment, radiation therapy is administered as a single dose or after the first administration of the cMET inhibitor, or a combination thereof. In one aspect of this embodiment, the glioblastoma is disseminated glioblastoma. In another aspect of this embodiment, the glioblastoma harbors MET amplification. In a further aspect of this embodiment, the glioblastoma harbors IDH wild type, MGMT unmethylated, and / or MET amplification at 7q31.2. In a final aspect of this embodiment, the cMET inhibitor is tepotinib, or a pharmaceutically acceptable salt, solvate, and / or hydrate thereof.

[0014] A second aspect is a method of treating glioblastoma in a subject in need thereof, comprising administering to the subject an effective amount of a cMET inhibitor, or a pharma- ceutically acceptable salt, solvate and / or hydrate thereof. In one aspect of this embodiment, the subject being treated is a human. In one aspect of this embodiment, the cMET inhibitor is suitable for long-term treatment and is administered for at least 10 weeks. In one aspect of this embodiment, the cMET inhibitor is used for long-term treatment and is administered for at least 10 weeks in one treatment regimen. In one aspect of this embodiment, the cMET inhibitor is not administered in combination with chemotherapy in the same treatment regimen. In one aspect of this embodiment, administration of the cMET inhibitor results in a complete response, increases the likelihood of a complete response, reduces the likelihood of development of drug resistance, extends the time to tumor progression, and / or extends the time to tumor recurrence in the subject. Also provided is a method of inhibiting tumor growth or progression in a subject having malignant cells. Also provided is a method of inhibiting metastasis of malignant cells in a subject. Also provided is a method of inducing tumor regression in a subject with malignant cells. The treatment results in an objective response in the subject, preferably a complete or partial response. In one aspect of this embodiment, the method further comprises administering radiation therapy in the same treatment regimen, optionally as a single radiation dose, or after the first administration of the cMET inhibitor, or a combination thereof. In one aspect of this embodiment, the cMET inhibitor is administered in the first line treatment of glioblastoma. In another aspect of this embodiment, the cMET inhibitor is administered in the second line or higher treatment regimen of glioblastoma. The treatment of the present invention may be used in the treatment of glioblastoma in subjects who have previously been treated with one or more chemotherapy or immunotherapy, or who have received radiation therapy, but have failed such previous treatment. In a further aspect of this embodiment, the subject is administered a treatment selected from the group of surgery, radiation therapy, chemotherapy, and combinations thereof, prior to the first administration of the cMET inhibitor.In a further aspect of this embodiment, the subject is administered a treatment selected from the group consisting of surgery, radiation therapy, or a combination thereof, optionally followed by chemotherapy, prior to the first administration of the cMET inhibitor.Radiation therapy can be treatment with electrons, photons, protons, alpha emitters, other ions, radionucleotides, boron capture neutrons, and combinations thereof.In an additional aspect of this embodiment, the subject is administered tepotinib, or a pharma- ceutically acceptable salt, solvate, and / or hydrate thereof.In the final aspect of this embodiment, the cMET inhibitor is administered as a monotherapy.

[0015] A third aspect relates to the use of a cMET inhibitor for the manufacture of a medicament for the treatment of glioblastoma. In one aspect of this embodiment, the cMET inhibitor is used for the manufacture of a medicament for long-term treatment and administered for at least 10 weeks. In one aspect of this embodiment, the cMET inhibitor is used for the manufacture of a medicament for long-term treatment and administered for at least 10 weeks in one treatment regimen. In one aspect of this embodiment, the cMET inhibitor is used for the manufacture of a medicament for long-term treatment and not administered in combination with chemotherapy in the same treatment regimen. In one aspect of this embodiment, the cMET inhibitor is used for the manufacture of a medicament for long-term treatment and not administered in combination with radiation therapy in the same treatment regimen. In one aspect of this embodiment, the cMET inhibitor is used for the manufacture of a medicament for long-term treatment of humans. Detailed Description

[0016] The compounds for use according to the present invention advantageously target c-Met to inhibit glioblastoma. cMET inhibitors may be a potential strategy for treating glioblastoma, for example by crossing the blood-brain barrier. The administration of the compounds of the present invention may also result in reducing tumor burden, which in turn will reduce disease severity. Whatever the exact mechanism of action of the anti-cancer properties of the cMET inhibitors of the present invention, it is proposed that their administration will have one or more clinical benefits, as further described herein. Specifically, the present application describes and demonstrates cMET monotherapy for treating glioblastoma in subjects.

[0017] Treatment of glioblastoma using the methods of the present invention includes administering an effective amount of a cMET inhibitor of the present invention at any stage of glioblastoma to prevent or reduce symptoms associated therewith.Typically, a subject will be administered an effective amount of a cMET inhibitor of the present invention after a reliable diagnosis and presentation of symptoms consistent with glioblastoma, and administration will reduce tumor severity and / or prevent tumor progression to a more severe condition.The clinical utility of such administration is described in more detail in the following section. definition

[0018] "A," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a compound refers to one or more compounds, or at least one compound. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

[0019] "About" when used to modify a numerically defined parameter (e.g., the dose of a cMET inhibitor or the length of treatment period with a therapy described herein) means that the parameter may vary by as much as 10% below or above the numerical value stated for that parameter.

[0020] "Administering" or "administration" of a drug to a patient (and grammatical equivalents of this expression) refers to direct administration, which may be administration by a health care professional to the patient or self-administration, and / or indirect administration, which may be the act of prescribing the drug. By way of example, a physician who instructs a patient to self-administer a drug or provides a patient with a prescription for a drug is administering the drug to the patient.

[0021] "Biomarker" generally refers to a biological molecule that indicates a disease state, as well as its quantitative and qualitative measurements. "Prognostic biomarkers" correlate with disease outcome independent of treatment. For example, tumor hypoxia is a negative prognostic marker; the higher the tumor hypoxia, the more likely the disease outcome will be negative. "Predictive biomarkers" are those that indicate whether a patient is likely to respond positively to a particular treatment. For example, HER2 profiling is commonly used in breast cancer patients to determine whether a patient is likely to respond to Herceptin (trastuzumab, Genentech). "Response biomarkers" provide a measure of response to treatment and provide an indication of whether the treatment is working. For example, a decrease in the level of prostate specific antigen is generally an indication that anti-cancer treatment is working for prostate cancer patients. Where a marker can be used as a criterion for identifying or selecting a patient for the treatment described herein, the marker can be measured before and / or during treatment, and / or the obtained values ​​are used by the clinician to assess any of the following: (a) whether an individual is more suitable or more likely to be suitable for initially receiving the treatment(s); (b) whether an individual is more suitable or more likely to be suitable for initially receiving the treatment(s); (c) responsiveness to treatment; (d) whether an individual is more suitable or more likely to be suitable for continuing the treatment(s); (e) whether an individual is more suitable or more likely to be suitable for continuing the treatment(s); (f) dosage adjustment; (g) prediction of possible clinical benefit; or (h) toxicity. As will be well understood by those skilled in the art, the measurement of a biomarker in a clinical setting clearly indicates that this parameter is used as a basis for initiating, continuing, adjusting, and / or ceasing the administration of the treatment described herein.

[0022] "Chemotherapy" is treatment involving chemotherapeutic agents, which are chemical compounds useful in the treatment of cancer.

[0023] "Clinical outcome", "clinical parameter", "clinical response", or "clinical endpoint" refers to any clinical observation or measurement related to a patient's response to treatment. 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.

[0024] "cMET inhibitor" refers to a compound that has the biological effect of inhibiting or significantly reducing or downregulating the expression of the gene encoding cMET and / or the expression of cMET and / or the biological activity of cMET. In one embodiment, a cMET inhibitor specifically binds to cMET kinase. There are two classes of drugs with clinical activity against receptor tyrosine kinases: antibodies that target the extracellular domain of the receptor, and small molecule TKIs that target the intracellular portion by competing with ATP, thus inhibiting receptor autophosphorylation and preventing downstream signaling. Examples of cMET TKIs are tepotinib, crizotinib, capmatinib, savolitinib, cabozantinib, MGCD265, merestinib, and [ka] (GST-HG161) while onartuzumab and ARGX-111 are examples of cMET-targeted antibodies.

[0025] "Combination" refers to providing a first effective modality in addition to another effective modality. In the scope of the combination described herein, any combination modality or partner (e.g., active compound, ingredient, or drug) in a single or multiple compositions is intended. It is understood that any modality in a single composition, formulation, or unit dosage form (i.e., fixed dose combination) must have the same dosage mode and delivery route. It is not intended to imply that multiple modalities must be formulated to be delivered together (e.g., in the same composition, formulation, or unit dosage form). The combined modalities may be manufactured and / or formulated by the same or different manufacturers. Thus, the combination partners may be, for example, completely separate pharmaceutical dosage forms or pharmaceutical compositions that are sold independently of each other.

[0026] "Combination therapy", "in combination with" or "in conjunction with" refers to any form of joint, parallel, simultaneous, sequential or intermittent treatment with at least two separate treatment modalities (e.g., compounds, ingredients or therapeutic agents). Thus, the term refers to administering one treatment modality before, during or after administering the other treatment modality to a subject. The modalities in the combination can be administered in any order. The therapeutically effective modalities are administered together (e.g., simultaneously in the same or separate compositions, formulations or unit dosage forms) or separately (e.g., following the appropriate administration protocol for separate compositions, formulations or unit dosage forms, on the same or different days, and in any order), in a manner and administration regime prescribed by a medical professional or in accordance with a regulatory agency. Generally, each treatment modality will be administered at a dosage and / or time schedule established for that treatment modality. Optionally, three or more modalities may be used in combination therapy. In addition, combination therapy may be used in conjunction with other types of treatment. For example, the other anti-cancer treatment may be selected from the group consisting of chemotherapy, surgery, radiotherapy (radiation) and / or hormonal therapy, among other treatments associated with the current standard of care for the subject.

[0027] "Complete response" or "complete remission" refers to the disappearance of all signs of cancer, including glioblastoma, in response to treatment. This does not necessarily mean that the glioblastoma has been cured.

[0028] "Comprising" is intended to mean that the compositions and methods include the recited elements but do not exclude other elements. When used to define compositions and methods, "consisting essentially of" is intended to mean excluding other elements of any essential significance to the composition or method. "Consisting of" is intended to mean that the claimed compositions and substantial method steps exclude more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of the invention. Thus, the methods and compositions may include (comprise) additional steps and ingredients or, alternatively, include (consist essentially of) insignificant steps and compositions or, alternatively, are intended to contemplate (consist of) only the recited method steps or compositions.

[0029] "Dose" and "dosage" refer to a specific amount of an active or therapeutic agent, including a cMET inhibitor, for administration. Such amounts are encompassed by "dosage forms," ​​which refer to physically discrete units suitable as unitary administration for human subjects and other mammals, each unit containing a predetermined quantity of active agent calculated to produce the desired expression, tolerability and therapeutic effect, in association with one or more suitable pharmaceutical excipients, such as carriers.

[0030] A "medicament" in the sense of the present invention is any drug in the pharmaceutical field, which comprises one or more compounds of the present invention or preparations thereof (e.g. pharmaceutical compositions or pharmaceutical formulations) and can be used for the prevention, treatment, follow-up or aftercare of patients suffering from clinical symptoms and / or known risks for glioblastoma.

[0031] "Objective response" refers to a measurable response, including a complete response (CR) or partial response (PR).

[0032] "Overall survival" (OS) refers to the time from patient enrollment to removal at the date of death or last known survival. OS encompasses the increase in life expectancy compared to an untreated or untreated individual or patient. Overall survival refers to the state in which a patient survives for a defined period of time, such as, for example, 1 year, 5 years, etc., from the time of diagnosis or treatment.

[0033] "Partial response" refers to a reduction in the size of one or more tumors or lesions, or the extent of cancer in the body, in response to treatment, as defined by the RECIST v1.1 guideline.

[0034] "Patient" or "subject" refers to an animal, preferably a human. However, "subject" can include companion animals such as dogs and cats. In one embodiment, the subject is an adult human patient. In another embodiment, the subject is a pediatric patient. A pediatric patient includes any human under the age of 18 at the start of treatment. An adult patient includes any human 18 years of age or older at the start of treatment. In one embodiment, the subject is a member of a high-risk group, such as a human aged 65 years or older, carrying MET amplification, or having other comorbidities.

[0035] "Pharmaceutically acceptable" indicates that the compound, inhibitor, substance or composition must be chemically and / or toxicologically compatible with other ingredients contained in the formulation and / or with the subject being treated therewith. In other words, the substance or composition must be chemically and / or toxicologically suitable for treating the subject.

[0036] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable diluent" refers to any solvent, dispersion medium, coating agent, antibacterial and antifungal agent, isotonic and absorption delaying agent that are compatible with pharmaceutical administration. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, as well as combinations thereof. The use of such media and agents for pharmaceutically active substances is well known in the art. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include, without limiting the scope of the invention, the following: additional buffering agents; preservatives; cosolvents; antioxidants, including ascorbic acid and methionine; chelating agents, such as EDTA; metal complexes (e.g., zinc-protein complexes); biodegradable polymers, such as polyesters; salt-forming counterions, such as sodium; polyhydric sugar alcohols; amino acids, such as alanine, glycine, glutamine, asparagine, histidine, arginine, lysine, ornithine, leucine, 2-phenylalanine, glutamic acid, and threonine; lactate, stearate, or the like. Organic sugars or sugar alcohols such as glycerol, stachyose, mannose, sorbose, xylose, ribose, ribitol, myo-initose, myo-inititol, galactose, galactitol, glycerol, cyclitols (e.g., inositol), and polyethylene glycol; sulfur-containing reducing agents such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, [alpha]-monothioglycerol, and sodium thiosulfate; low molecular weight proteins such as human serum albumin, bovine serum albumin, gelatin, or other immunoglobulins; and hydrophilic polymers such as polyvinylpyrrolidone. Other pharma- ceutically acceptable carriers, excipients, or stabilizers may also be included in the pharmaceutical compositions described herein, provided they do not adversely affect the desired characteristics of the pharmaceutical composition.

[0037] "Progression-free survival" (PFS) refers to the time from enrollment to disease progression or death. PFS is commonly measured using the Kaplan-Meier method and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 standards. In general, progression-free survival refers to the state in which a patient is alive without their cancer, including glioblastoma, getting worse.

[0038] "RECIST" means Response Evaluation Criteria in Solid Tumors. RECIST guidelines, criteria, or standards describe a standard approach to solid tumor measurement and definition for objectively assessing changes in tumor size for use in adult and pediatric cancer clinical trials. RECIST v1.1 means the revised RECIST guidelines, version 1.1, published in 2009, European Journal of Cancers 45: 228.

[0039] "Recurrent" cancers, including "recurrent" glioblastoma, are those that have regrowth at the original site or at a distant site after responding to initial treatment such as surgery. Locally "recurrent" cancers are cancers that return after treatment in the same location as the previously treated cancer.

[0040] "Reduction" of a symptom or symptoms (and grammatical equivalents of this expression) refers to a decrease in the severity or frequency of the symptom or symptoms, or the elimination of the symptom or symptoms.

[0041] A "resistant" tumor or cancer is a tumor or cancer, including glioblastoma, that cannot or is no longer amenable to treatment with an anticancer drug. Resistance may already exist before the first treatment with an anticancer drug is attempted. Resistance may also be acquired after the first treatment with an anticancer drug, sometimes as a result of the treatment.

[0042] "Suitable for therapy" or "suitable for treatment" shall mean that the patient is more likely to show one or more favorable clinical outcomes compared to patients with the same cancer and receiving the same treatment, but possessing different characteristics considered for comparison purposes. In one aspect, the considered characteristics are gene polymorphisms or somatic mutations. In another aspect, the considered characteristics are gene or polypeptide expression levels. In one aspect, the more favorable clinical outcome is a relatively high likelihood or relatively good tumor response, such as reduced tumor burden. In another aspect, the more favorable clinical outcome is a relatively long overall survival. In yet another aspect, the more favorable clinical outcome is a relatively long progression-free survival or time to tumor progression. In yet another aspect, the more favorable clinical outcome is a relatively long disease-free survival. In another aspect, the more favorable clinical outcome is a relatively reduced or delayed tumor recurrence. In another aspect, the more favorable clinical outcome is a relatively reduced metastasis. In another aspect, the more favorable clinical outcome is a relatively low relative risk. In yet another aspect, the more favorable clinical outcome is a relative reduction in toxicity or side effects. In some embodiments, more than one clinical outcome is considered simultaneously. In one such aspect, a patient who carries a characteristic, such as the genotype of a gene polymorphism, may show one or more more favorable clinical outcomes compared to a patient who has the same cancer and receives the same treatment but does not have the characteristic. The patient is considered suitable for treatment as defined herein. In another such aspect, a patient who carries a characteristic may show one or more favorable clinical outcomes, but at the same time, show one or more less favorable clinical outcomes. The clinical results are then considered overall, and a decision is made as to whether the patient is suitable for treatment, taking into account the patient's particular situation and the relevance of the clinical outcomes. In some embodiments, progression-free survival or overall survival is weighted more heavily than tumor response in the overall decision-making.

[0043] A "therapeutically effective amount" of a cMET inhibitor refers to an amount effective, at the dosage and duration required, that when administered to a patient with cancer, including glioblastoma, according to a method, combination, or combination therapy, the method, combination, or combination therapy will have the intended therapeutic effect (e.g., alleviation, amelioration, reduction, or elimination of one or more symptoms of cancer in the patient), or any other clinical result in the course of treating the cancer patient. The therapeutic effect does not necessarily occur with one dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more doses. Such a therapeutically effective amount may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of the cMET inhibitor to elicit a desired response in the individual. A therapeutically effective amount is also an amount in which any toxic or detrimental effects of the cMET inhibitor are outweighed by therapeutically beneficial effects.

[0044] "Treatment," "treat," and "treating" refer to reversing, alleviating, delaying onset, or inhibiting progression of glioblastoma, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to susceptible individuals before symptoms develop (e.g., taking into account comorbidities or other susceptibility factors that are predictive of severe disease).

[0045] As applied to a subject diagnosed with or suspected of having cancer, "tumor" refers to a malignant or potentially malignant neoplasm or mass of tissue of any size, including primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that does not usually contain cysts or liquid areas. Different types of solid cancers are named for the type of cells that form them. compound

[0046] One embodiment provides a method for the treatment of glioblastoma comprising administering to the patient: [ka] or a pharma- ceutically acceptable salt, and / or solvate or hydrate thereof.

[0047] This compound may also be referred to as the first compound. The first compound may also be referred to as 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (INN: tepotinib). It is disclosed and further characterized as compound "A257" in WO 2009 / 006959. In an exemplary embodiment, the hydrochloride hydrate form of this first compound is used, which is referred to as 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate. In another exemplary embodiment, the hydrochloride monohydrate form of this first compound is used, which is referred to as 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate. It is disclosed and further characterized in WO 2009 / 007074 as compound "A7". In an exemplary embodiment, the hydrochloride monohydrate crystal form H2 of this first compound is used, which is referred to as 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate crystal modification H2. It is disclosed and further characterized in Example 12 in WO 2010 / 078897.

[0048] References to the first compound below shall be read as including references to 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, and the crystalline modification H2 of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate. In a preferred embodiment, the cMET inhibitor for use in the methods of the invention is 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile The crystalline modification H2 of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate is selected from the group consisting of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate. All of the above compounds are highly selective and potent cMET inhibitors.

[0049] One aspect relates to a method for treating glioblastoma comprising administering to a subject a compound of the following: [ka] (GST-HG161) or a pharma- ceutically acceptable salt, and / or solvate or hydrate thereof. The cMET inhibitor GST-HG161 is disclosed and further characterised in EP 3 533 787 as "embodiment 1-2".

[0050] The above compounds may be used either in their free form or as pharma- ceutically acceptable salts.Free compounds may be converted to the relevant acid addition salts by reaction with acids, for example, by reacting equivalent amounts of base and acid in an inert solvent, such as ethanol, and then evaporating.Suitable acids for this reaction are, among others, salts that give physiologically acceptable salts, such as hydrogen halides (e.g., hydrogen chloride, hydrogen bromide, or hydrogen iodide), other mineral acids and their corresponding salts (e.g., sulfates, nitrates, or phosphates, etc.), sulfonic acid alkyl- and monoarylsulfonates (e.g., ethanedisulfonate (edisyl), toluenesulfonate, naphthalene-2-sulfonate (napsyl), benzenesulfonate) and other organic acids and their corresponding salts (e.g., fumarate, oxalate, acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate), etc.

[0051] Exemplary embodiments of pharma- ceutically acceptable salts of the first compound include the hydrochloride salt, as described above.

[0052] Unless otherwise stated, structures depicted herein are also meant to encompass all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure (e.g., R and S configurations of each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers). Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.

[0053] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure including the replacement of a carbon with a C-enriched carbon are within the scope of this invention. In some embodiments, the group contains one or more deuterium atoms.

[0054] Specifically, the cMET inhibitor is not administered in combination with chemotherapy in the same treatment regimen. In one embodiment, the administration of the cMET inhibitor is excluded in combination with any other therapeutic agent, particularly with another chemotherapy agent, in any treatment regimen (e.g., before, simultaneously with, or after the administration of the cMET inhibitor). In one embodiment, the administration of the cMET inhibitor is excluded in combination with a p70S6k inhibitor, particularly with 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide. In one embodiment, the cMET inhibitor is not administered in combination therapy. In one embodiment, the cMET inhibitor is administered in combination with radiation therapy, particularly in the same treatment regimen. Use, Formulation, and Administration

[0055] The compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. Preferably, the compositions are administered orally. More preferably, the cMET inhibitor is administered via oral administration. In one embodiment, the oral formulation of the compound of the present invention is in tablet or capsule form. In another embodiment, the oral formulation is a solution or suspension that will be given to a subject in need thereof via the mouth or nasogastric tube. Any oral formulation of the present invention may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition of the present invention is administered separately from food. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food.

[0056] The pharma- ceutically acceptable composition of this invention is orally administered in any orally acceptable dosage form. Exemplary oral dosage forms are capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspension is required for oral use, active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners, flavorings or colorings are also optionally added.

[0057] The amount of the compounds of the present invention, optionally combined with a carrier material to produce a composition in a single dosage form, will vary depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0058] The pharmaceutical composition is in the form of one or more dosage units, which may be provided as a single daily dose or as two or more consecutive doses per day such that the total daily dose is the same as the single daily dose. In certain embodiments, the cMET inhibitor is administered in a dosage strength of about 15 mg, 25 mg, 100 mg, 215 mg, 225 mg, 250 mg, 300 mg, 450 mg, 500 mg, or 1000 mg, preferably about 15 mg, 25 mg, 100 mg, 225 mg, 250 mg, 450 mg, or 500 mg, more preferably about 225 mg or 250 mg.

[0059] In certain embodiments, the total amount of cMET inhibitor administered to a subject in need thereof is between about 0.5 mg and about 1400 mg per day, preferably between about 300 mg and about 1400 mg per day, more preferably between about 225 mg and about 1000 mg per day. In certain embodiments, the total amount of cMET inhibitor administered to a subject in need thereof is between about 1 mg and 1000 mg per day, more preferably between about 1 mg and 700 mg per day, most preferably between about 100 mg and 500 mg per day, and very preferably between about 225 mg and 500 mg per day. In one embodiment, the total amount of cMET inhibitor administered to a subject in need thereof is between about 225 mg and about 900 mg per day, preferably between 225 mg and about 450 mg per day, more preferably 450 mg. In one embodiment, the total amount of cMET inhibitor administered to a subject in need thereof is about 900 mg per day. In one embodiment, the total amount of cMET inhibitor administered to a subject in need thereof is between about 250 mg and 1000 mg per day, preferably between 250 mg and 500 mg per day, more preferably 500 mg. In one embodiment, the total amount of cMET inhibitor administered to a subject in need thereof is about 1000 mg per day. In certain embodiments, the total amount of cMET inhibitor administered to a subject in need thereof is between about 30 mg and 400 mg per day, more preferably between about 30 mg and 230 mg per day. In one embodiment, the total amount of cMET inhibitor administered to a subject in need thereof is about 60 mg to 315 mg per day.

[0060] In any of the above embodiments, the cMET inhibitor is administered daily. In any of the above embodiments, the cMET inhibitor is administered once daily. In one embodiment, the cMET inhibitor is administered once daily at a dosage strength of about 450 mg to 500 mg. In one embodiment, the dosage of tepotinib is 450 mg once daily orally (equivalent to 500 mg of tepotinib hydrochloride hydrate). In one embodiment, the dosage of tepotinib is 225 mg once daily orally. 225 mg of tepotinib is equivalent to 250 Mg of tepotinib hydrochloride hydrate. In one embodiment, the dosage of tepotinib is 900 mg once daily orally. 900 mg of tepotinib is equivalent to 1000 Mg of tepotinib hydrochloride hydrate.

[0061] In any of the above embodiments, the cMET inhibitor is administered twice daily. In one embodiment, the cMET inhibitor is administered twice daily at a dosage strength of 250 mg. In one embodiment, the cMET inhibitor is administered twice daily at a dosage strength of 500 mg. In one embodiment, the dosage of tepotinib is 450 mg orally twice daily.

[0062] In any of the above embodiments, the cMET inhibitor is administered three times daily. In one embodiment, the cMET inhibitor is administered three times daily at a dosage strength of about 100 mg.

[0063] In any of the above embodiments, the cMET inhibitor is administered four times a day. In one embodiment, the cMET inhibitor is administered four times a day at a dosage strength of 250 mg. In one embodiment, the dosage of tepotinib is 225 mg orally four times a day.

[0064] In any of the above embodiments, the cMET inhibitor is administered three times per week. In one embodiment, the cMET inhibitor is administered three times per week at a dosage strength of between about 60 mg and 315 mg.

[0065] In any of the above embodiments, the cMET inhibitor is administered for a period of at least 10 weeks. In one aspect of any of the above embodiments, the cMET inhibitor is administered for a period of at least about 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 ​​weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks. In one aspect of any of the above embodiments, the cMET inhibitor is administered for a period of at least about 11 weeks to about 52 weeks, preferably at least about 11 to 25 weeks, more preferably at least about 15 to 21 weeks, most preferably at least about 18 to 20 weeks, and most preferably at least about 19 weeks.

[0066] In another aspect of any of the above embodiments, the cMET inhibitor is administered for at least about 10-52 weeks, particularly at least about 10-19 weeks. In one embodiment, the cMET inhibitor is administered at a dosage strength of about 300 mg to 1400 mg once daily for at least about 10-52 weeks, particularly at least about 10-19 weeks. In one embodiment, the cMET inhibitor is administered at a dosage strength of about 450 mg to 500 mg twice daily for at least about 10-52 weeks, particularly at least about 10-19 weeks. In one embodiment, tepotinib hydrochloride hydrate is administered at a dosage strength of about 500 mg twice daily for at least about 10-52 weeks, particularly at least about 10-19 weeks.

[0067] In one embodiment of the present invention, the subject suffers from disseminated glioblastoma. In one embodiment of the present invention, the disseminated glioblastoma is treated. In one embodiment of the present invention, the subject suffers from glioblastoma, particularly one carrying MET amplification at 7q31.2. In one embodiment of the present invention, the glioblastoma carrying MET amplification is treated. In one embodiment of the present invention, the subject suffers from disseminated glioblastoma, and / or glioblastoma carrying MET amplification. In one embodiment of the present invention, disseminated glioblastoma, glioblastoma carrying MET amplification, or a combination thereof is treated. MET amplification is caused by an increase in the copy number of the MET gene and has been identified as a resistance mechanism in EGFR gene mutation-positive NSCLC (Socinski et al., 2021, JCO Precision Oncology 5: 653). In one embodiment of the present invention, the subject suffers from glioblastoma carrying IDH wild type, MGMT unmethylated and / or MET amplification at 7q31.2. In one embodiment of the invention, glioblastomas carrying IDH wild type, MGMT unmethylation, or MET amplification at 7q31.2, or a combination thereof, are treated. In another aspect of this embodiment, the glioblastomas carrying MET-exon 14 skipping.

[0068] These biomarkers can be determined by standard methods. In various embodiments, biomarker protein levels are determined by methods including quantitative Western blot, multiple immunoassay formats, ELISA, immunohistochemistry, histochemistry, or using FACS analysis of tumor lysates, fluorescent immunostaining, bead-based suspension immunoassay, Luminex technology, or proximity ligation assay. In another embodiment, biomarker RNA levels are determined by methods including microarray chip, RT-PCR, qRT-PCR, multiplex qPCR, or in situ hybridization. In another embodiment, markers are detected by next-generation sequencing, liquid biopsy, and / or tissue biopsy. For example, MET exon 14 skipping can be detected by DNA-based methods (e.g., next-generation sequencing or Sanger sequencing) as well as RNA-based methods (e.g., next-generation sequencing or quantitative PCR assay), in each case using samples from liquid biopsy (e.g., using Guardant360 CDx Test Version 2.10 (73 genes) assay) or tissue biopsy.

[0069] Any suitable sample can be used in this method. Non-limiting examples of such include one or more of serum samples, plasma samples, whole blood, pancreatic juice samples, tissue samples, tumor lysates, or tumor samples, which can be isolated, for example, from needle biopsy, core biopsy, or needle aspiration. For example, tissue, plasma, or serum samples are taken from patients before and optionally during treatment with the cMET inhibitor of the present invention. The information obtained can indicate whether the patient will respond favorably or unfavorably to cancer treatment.

[0070] In one embodiment of the invention, the subject is an inpatient undergoing treatment. In another embodiment, the subject is an outpatient undergoing treatment. In one aspect of the preceding embodiment, the subject may continue to receive a cMET inhibitor after transitioning from being treated as an inpatient to being treated as an outpatient.

[0071] In one embodiment, administration of a cMET inhibitor results in one or more clinical benefits. In one aspect of this embodiment, the one or more clinical benefits are selected from the group including complete response, increased likelihood of complete response, reduced likelihood of developing drug resistance, increased time to tumor progression, and increased time to tumor recurrence in the subject; preferably a complete response.

[0072] The present invention also provides a method of treating glioblastoma in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention. An effective amount for treating or inhibiting glioblastoma is an amount that will cause a reduction in one or more symptoms of glioblastoma, such as tumor burden and mortality, compared to an untreated control subject.

[0073] One embodiment of the present invention is a method of treating glioblastoma in a subject in need thereof, comprising administering to the subject an effective amount of a cMET inhibitor, or a pharma- ceutically acceptable salt, and / or solvate or hydrate thereof. In one aspect of this embodiment, the subject is a human. In one aspect of this embodiment, the cMET inhibitor is administered to the subject for at least 10 weeks. In one aspect of this embodiment, the cMET inhibitor is tepotinib, or a pharma- ceutically acceptable salt, solvate and / or hydrate thereof. In one aspect of this embodiment, the cMET inhibitor is not administered in combination with 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide. In one aspect of this embodiment, the cMET inhibitor is administered in a single treatment regimen for at least 10 weeks. In one aspect of this embodiment, the cMET inhibitor is not administered in combination with chemotherapy in the same treatment regimen.

[0074] A preferred embodiment of the present invention is a method for treating glioblastoma in a human in need thereof, comprising administering to the human an effective amount of tepotinib, or a pharma- ceutically acceptable salt, solvate and / or hydrate thereof, for at least 10 weeks, wherein tepotinib is not administered in combination with chemotherapy in one treatment regimen. More particularly, a preferred embodiment of the present invention is a method for long-term treatment of glioblastoma in a human subject in need thereof, comprising administering to the subject an effective amount of a cMET inhibitor in one treatment regimen for at least 10 weeks, wherein the cMET inhibitor is selected from the group consisting of: [ka] Or, the pharma- ceutically acceptable salts, solvates and / or hydrates thereof, and the cMET inhibitor are not administered in combination with chemotherapy in the same treatment regimen.

[0075] In another aspect of this embodiment, administration of a cMET inhibitor results in anti-tumor activity in a subject over the long term.

[0076] The terms "same treatment plan," "one and the same treatment plan," "a particular treatment plan," and "single treatment plan" are used interchangeably herein, unless the context dictates otherwise, to refer to a defined treatment plan, i.e., a first-line treatment plan, a second-line treatment plan, or a higher-level treatment plan, but not to combinations thereof.

[0077] In various embodiments, the method of the present invention is used as a first-line, second-line, third-line, or subsequent treatment regimen. Treatment regimen refers to the order in which a patient undergoes treatment with different drugs or other therapies. A first-line treatment regimen is the treatment that is performed first, and a second-line treatment or a third-line treatment is performed after the first-line treatment or after the second-line treatment, respectively. Thus, a first-line treatment is the first treatment against a disease or illness. In patients with cancer, including glioblastoma, a first-line treatment, sometimes called a primary treatment or primary treatment, can be surgery, chemotherapy, radiation therapy, or a combination of these treatments. Typically, a patient undergoes a subsequent chemotherapy regimen (second-line or third-line treatment) because the patient did not show a positive clinical outcome or showed only a subclinical response to the first-line or second-line treatment, or showed a positive clinical response but later experienced a relapse, and in some cases became resistant to the previous treatment that elicited the previous positive response.

[0078] In another aspect of this embodiment, the cMET inhibitor is administered in the first-line treatment of glioblastoma. In one aspect of this embodiment, the cMET inhibitor is administered in the first-line treatment of glioblastoma, and the method further comprises administering a treatment or treatment course selected from the group consisting of surgery, radiation therapy, chemotherapy, and combinations thereof after the initial administration of the cMET inhibitor. The safety and clinical usefulness proposed by the cMET inhibitor of the present invention warrants its first-line setting in glioblastoma patients. In particular, tepotinib may become the new standard treatment for patients suffering from glioblastoma. In another aspect of this embodiment, the cMET inhibitor is administered in the second-line treatment or higher treatment course of glioblastoma.

[0079] In another aspect of this embodiment, the cMET inhibitor is administered in a second-line or higher treatment course for glioblastoma, and the method further comprises administering a treatment or treatment course selected from the group of surgery, radiation therapy, chemotherapy, and combinations thereof, prior to the first administration of the cMET inhibitor. There is no limit to the number of previous treatments, as long as the subject has undergone at least one previous cancer treatment. A previous cancer treatment round refers, for example, to a defined schedule / stage for treating the subject with a chemotherapeutic agent (excluding the cMET inhibitor according to the present invention), radiation therapy, or chemoradiotherapy, where the subject has failed such previous treatment and completed or discontinued it earlier than planned. One of the reasons may be that the cancer was or has become resistant to the previous treatment. The use of the cMET inhibitor suppresses this resistance mechanism and restores the efficacy of the treatment. A population of resistant patients can be treated and shows improved response. In one aspect, the subject has undergone at least one round or line of previous glioblastoma treatment; optionally, the glioblastoma has been or has become resistant to the previous treatment. One round of previous glioblastoma treatment and one line of previous glioblastoma treatment are used interchangeably herein. In one aspect of this embodiment, the subject has been previously treated with surgery, radiation therapy and / or chemotherapy.

[0080] In any of the above embodiments, administration of the cMET inhibitor provides one or more clinical benefits to the subject. In one aspect of this embodiment, the one or more clinical benefits are complete response, increased likelihood of complete response, reduced likelihood of developing drug resistance, increased time to tumor progression, and increased time to tumor recurrence.

[0081] The compound of the present invention can be administered before or after the onset of glioblastoma, or after glioblastoma is diagnosed in a subject.The aforementioned compounds and pharmaceutical products of the use of the present invention are specifically used for therapeutic treatment.The therapeutically relevant effect is to alleviate to some extent one or more symptoms of the disorder, or to restore one or more physiological or biochemical parameters related to or causing the disease or pathology, either partially or completely, to normal.Monitoring is considered as a type of treatment when the compound is administered at separate intervals, for example, to boost response and eradicate disease symptoms.The method of the present invention can also be used to reduce the likelihood of developing the disorder, or even prevent the onset of glioblastoma-related disorders prior to mild to moderate disease symptoms, or to treat the onset and ongoing symptoms of glioblastoma.

[0082] The present invention furthermore relates to a medicament comprising at least one compound for use according to the invention, or a pharma- ceutically acceptable salt, solvate and / or hydrate thereof. Monotherapy

[0083] The present invention relates to the successful long-term treatment of glioblastoma in subjects.In various embodiments, cMET inhibitor is administered alone, i.e. as monotherapy.In one embodiment, cMET inhibitor is administered as monotherapy in a specific treatment plan.It does not exclude administering other treatments in another treatment plan before or after the monotherapy with cMET inhibitor.In one embodiment, cMET inhibitor is administered entirely as monotherapy.It is the single active ingredient treatment and is the only treatment plan (i.e., first-line treatment).

[0084] In various embodiments, the cMET inhibitor is not administered in combination with 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide. Preferably, the cMET inhibitor is administered without any p70S6k inhibitor, more preferably without any chemotherapeutic agent, most preferably without any chemotherapy or radiation therapy, and most preferably without any other therapeutic agent (hereinafter jointly referred to as limited combination therapy).

[0085] The present inventors have surprisingly found that when cMET inhibitors are administered as monotherapy (or limited combination therapy) for at least 10 weeks or more, preferably up to 19 weeks or more, more preferably up to 52 weeks or more, long-term treatment without resistance is successful. The prior art does not teach or suggest that cMET inhibitors, particularly tepotinib, can be used to successfully treat glioblastoma as monotherapy (or limited combination therapy) without the occurrence of drug resistance and tumor progression. Combination Treatment

[0086] In various embodiments, the cMET inhibitor is administered in combination with surgery, radiation therapy, chemotherapy, and combinations thereof. They may be administered simultaneously, separately, or sequentially, and in any order. The individual combination partners of the combination therapy of the present invention may be administered separately at different times during treatment, or simultaneously in a divided or single combination form. The treatment regimens in the combination may have different but overlapping delivery regimens (e.g., daily, twice daily, versus single or weekly administration). In one aspect of these embodiments, the method further comprises administering a treatment or treatment course selected from the group of surgery, radiation therapy, chemotherapy, and combinations thereof, prior to the first administration of the cMET inhibitor. Optionally, surgery or radiation therapy, or combinations thereof, are administered first, followed by chemotherapy, prior to the first administration of the cMET inhibitor. In one aspect of these embodiments, the method comprises administering a treatment selected from the group consisting of surgery, radiation therapy, and combinations thereof, optionally followed by chemotherapy, prior to the first administration of the cMET inhibitor.

[0087] In one embodiment, the cMET inhibitor is administered in combination with surgery. In one aspect of this embodiment, the surgery is a lobectomy and / or resection.

[0088] In one embodiment, the cMET inhibitor is administered in combination with radiation therapy. The cMET inhibitor and radiation therapy can be administered in either one and the same treatment course, or in different treatment courses. In one aspect of these embodiments, radiation therapy is administered in a prior treatment course for glioblastoma, i.e., before the first administration of cMET inhibitor in a higher treatment course for glioblastoma. In one aspect of these embodiments, the cMET inhibitor and radiation therapy are administered in the same treatment course. In a preferred embodiment of the same treatment course, radiation therapy is administered as a single dose, or after the first administration of cMET inhibitor, or a combination thereof. In a more preferred embodiment of the same treatment course, radiation therapy is administered within 96 hours, preferably within 72 hours, more preferably within 48 hours, most preferably within 36 hours, and most preferably within 24 hours after the first administration of cMET inhibitor. In one embodiment, radiation therapy is administered within 36 hours of the first dose of the cMET inhibitor in the same treatment regimen.

[0089] Examples of radiation therapy are proton beam therapy, gamma radiation, neutron beam radiation therapy, electron beam radiation therapy, brachytherapy, low-dose radiation therapy, total body radioisotope, and intensity-modulated radiation therapy (IMRT). In one embodiment, the radiation therapy is proton beam radiation.

[0090] In some embodiments, radiation therapy is administered in either standard fractionation (e.g., 1.8-2 Gy per day, 5 days per week), or once daily for a total dose of up to 50-70 Gy. Other fractionation schedules may also be envisaged, such as twice daily with smaller doses per fraction, and cMET inhibitor also twice daily. It is also possible to give higher daily doses over a shorter period of time. In one embodiment, radiation therapy comprises 1000-6000 cGy, preferably 2000-5000 cGy, more preferably 3000-4000 cGy, and most preferably 3500-3700 cGy. In one aspect of this embodiment, radiation therapy is followed by a boost to the tumor bed of 1000-4000 cGy, preferably 2000-3000 cGy, and more preferably 2300-2500 cGy. In a preferred embodiment, radiation therapy, such as proton beam radiation therapy, comprises about 3000-4000 cGy, optionally followed by a boost to the tumor bed of 2000-3000 cGy.

[0091] In one embodiment, the cMET inhibitor is administered in combination with one or more additional therapeutic agents, with the proviso that the cMET inhibitor is not administered in combination with a chemotherapeutic agent in the same treatment regimen. A synergistic or increased effect may be achieved using two or more compounds in a pharmaceutical composition. The active ingredients may be used either simultaneously or sequentially. In one embodiment, the cMET inhibitor is administered in combination with an anticancer agent, with the proviso that the cMET inhibitor and the anticancer agent are administered in different treatment regimens. In one aspect of this embodiment, the cMET inhibitor is administered in a second-line or higher treatment regimen for glioblastoma, and chemotherapy is administered before the first administration of the cMET inhibitor. In one aspect of this embodiment, the cMET inhibitor is administered in a first-line treatment for glioblastoma, and chemotherapy is administered after the first administration of the cMET inhibitor. In one aspect of this embodiment, the chemotherapy or anticancer agent is temozolomide.

[0092] In some embodiments, the combination of a cMET inhibitor with one or more additional therapeutic agents reduces the effective amount (including but not limited to, dosage volume, dosage concentration, and / or total drug dose administered) of the cMET inhibitor and / or one or more additional therapeutic agents administered to achieve the same result compared to the effective amount administered when the cMET inhibitor or additional therapeutic agents are administered alone. In some embodiments, the combination of a cMET inhibitor with an additional therapeutic agent reduces the total treatment duration compared to administration of the additional therapeutic agent alone. In some embodiments, the combination of a cMET inhibitor with an additional therapeutic agent reduces the side effects associated with administration of the additional therapeutic agent alone. In some embodiments, the combination of an effective amount of a cMET inhibitor with an additional therapeutic agent is more effective compared to an effective amount of a cMET inhibitor or additional therapeutic agent alone. In one embodiment, the combination of an effective amount of a cMET inhibitor with one or more additional therapeutic agents provides one or more additional clinical benefits over administration of either agent alone. Invention items

[0093] The present invention also includes the following: 1. A method for the long-term treatment of glioblastoma in a human subject in need thereof, comprising administering to the subject an effective amount of a cMET inhibitor for at least 10 weeks, wherein the cMET inhibitor is: [ka] or a pharma- ceutically acceptable salt, solvate and / or hydrate thereof, which is not administered in combination with 4-[(S)-2-azetidin-1-yl-1-(4-chloro-3-trifluoromethyl-phenyl)-ethylamino]-quinazoline-8-carboxylic acid amide. 2 cMET inhibitors include 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate, 3-(1-{3-[5-( Item 1. The method according to item 1, wherein the compound is selected from the group consisting of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, ... 3. The method of any one of items 1 and 2, wherein disseminated glioblastoma is treated. 4. The method according to any one of items 1 to 3, wherein a glioblastoma carrying MET amplification is treated. 5. The method of any one of items 1 to 4, wherein glioblastoma harboring IDH wild type, MGMT unmethylated and / or MET amplification at 7q31.2 is treated. 6. The method of any one of items 1 to 5, wherein administration of a cMET inhibitor results in one or more clinical benefits selected from the group consisting of increased likelihood of complete response, reduced likelihood of development of drug resistance, increased time to tumor progression, and increased time to tumor recurrence. 7. The method of any one of items 1 to 6, wherein the cMET inhibitor is administered for at least about 11 to 25 weeks. 8. The method of any one of items 1 to 7, wherein the cMET inhibitor is administered daily. 9. The method according to any one of items 1 to 8, wherein the total amount of cMET inhibitor administered is between about 225 mg and about 1000 mg per day. 10. The method according to any one of items 1 to 9, wherein the cMET inhibitor is administered via oral administration. 11. The method according to any one of items 1 to 10, further comprising administering a treatment selected from the group consisting of surgery, radiation therapy, chemotherapy, and combinations thereof. 12. The method of claim 11, wherein radiation therapy is administered; optionally, the radiation therapy is proton radiation. 13. The method according to item 11 or 12, wherein the radiation therapy comprises about 3000-4000 cGy, optionally followed by a boost to the tumor bed at 2000-3000 cGy. 14. The method of claim 11, wherein chemotherapy is administered; optionally, the chemotherapy is temozolomide. 15. The method of any one of items 1 to 14, wherein the subject has undergone at least one prior round of glioblastoma treatment; optionally, the glioblastoma was resistant or has become resistant to the prior treatment. 16. The method according to any one of items 1 to 15, wherein the cMET inhibitor is administered in second line or higher treatment lines for glioblastoma. 17. The method of any one of items 1 to 16, further comprising administering a treatment selected from the group consisting of surgery, radiation therapy, and combinations thereof, optionally followed by chemotherapy, prior to the first administration of a cMET inhibitor. The method according to any one of items 1 to 14, wherein the cMET inhibitor is administered in the first line treatment of glioblastoma. 19. The method according to any one of items 1 to 10, wherein the cMET inhibitor is not administered in combination with radiation therapy or chemotherapy. The method of any one of items 1 to 10, wherein the cMET inhibitor is administered as monotherapy.

[0094] It is to be understood that the present invention is not limited to the specific compounds, pharmaceutical compositions, uses and methods described herein, since such matters may of course vary. It is to be understood that the terminology used herein is only for the purpose of describing specific embodiments, and is not intended to limit the scope of the present invention, which is defined solely by the appended claims. The techniques essential according to the present invention are described in detail in the specification. Other techniques not described in detail correspond to known standard methods well known to those skilled in the art, or the techniques are described in more detail in cited documents, patent applications, or standard documents. Unless otherwise indicated in this application, they are used only as examples and are not considered essential according to the present invention, but they may be replaced by other suitable tools and biological materials. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0095] Example As depicted in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. EXAMPLES

[0096] synthesis 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (free base), designated compound "A257", as described in Example 40 of WO2009 / 006959 and Example 3 of WO2009 / 007074, can be synthesized as follows: [ka]

[0097] To a suspension of 13.0 g (56.5 mmol) of 3-(5-hydroxy-pyrimidin-2-yl)-benzoic acid methyl ester and 13.4 g (62.1 mmol) of N-Boc-piperidinemethanol in 115 ml of THF, 17.7 g (67.8 mmol) of triphenyl-phosphine were added. The suspension was cooled to 5° C. To the suspension kept at this temperature, 13.3 ml (67.8 mmol) of diisopropyl azodicarboxylate were added dropwise under stirring within 45 minutes. The reaction mixture was stirred at room temperature for 1 hour. Then, another 22.2 g (84.7 mmol) of triphenylphosphine and 16.6 ml (84.7 mmol) of diisopropyl azodicarboxylate were added. The reaction mixture was stirred at room temperature for 18 hours and concentrated in vacuum. The resulting solid 4-[2-(3-methoxycarbonyl-phenyl)-pyrimidin-5-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester was pumped off, washed with diethyl ether and chromatographed (silica gel column with dichloromethane / methanol as eluent / mobile phase).

[0098] To a suspension of 1.71 g (3.99 mmol) of 4-[2-(3-methoxycarbonyl-phenyl)-pyrimidin-5-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester in 20 ml of THF was added dropwise under nitrogen 25 ml (25 mmol) of a 1 M solution of diisobutylaluminum hydride in THF. The reaction mixture was stirred at room temperature for 1 h and mixed with a saturated solution of sodium sulfate. The resulting precipitate was siphoned off and washed with THF and warm 2-propanol. The filtrate was concentrated and recrystallized from tert-butyl methyl ether resulting in {3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-phenyl}-methanol as beige crystals.

[0099] To a solution of 313 mg (1.00 mmol) of {3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-phenyl}-methanol in 2 ml of THF, 264 mg (1.30 mmol) of 3-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile and 397 mg (1.5 mmol) of triphenylphosphine were added in sequence. The reaction mixture was cooled in an ice bath and 294 μl (1.5 mmol) of diisopropyl azodicarboxylate were added dropwise. The reaction mixture was stirred at room temperature for 18 hours and then concentrated. The residue was chromatographed (silica gel column with dichloromethane / methanol as eluent / mobile phase). Product containing fractions were pooled and concentrated, and the residue of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile was boiled with tert-butyl methyl ether, pumped up and dried in vacuum.

[0100] By salt formation, compound "A257" can be obtained as hemisulfate, citrate, tartrate, sulfate, succinate, and hydrochloride salts.

[0101] Alternatively, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile (free base) can be synthesized as follows, as described in Example 43 of WO 2009 / 006959: [ka]

[0102] To a suspension of 4.15 g (20 mmol) of 3-(6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile in 40 ml of 1-methyl-2-pyrrolidone, 6.00 g (21 mmol) of 5-bromo-2-(3-chloromethyl-phenyl)-pyrimidine and 2.76 g (341 mmol) of potassium carbonate were added. The reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was then added to 200 ml of water. The resulting precipitate, 3-{1-[3-(5-bromopyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrile, was siphoned off, washed with water and dried in vacuum.

[0103] To a solution of 18.0 g (41.0 mmol) of 3-{1-[3-(5-bromopyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrile in 85 ml of DMF, 11.8 g (47 mmol) of bis(pinacolato)diboron and 11.9 g (122 mmol) of potassium acetate were added. The reaction mixture was heated to 80° C. under nitrogen. After stirring at this temperature for 15 minutes, 273 mg (1.22 mmol) of palladium(II) acetate was added and the reaction mixture was stirred at 80° C. under nitrogen for 2 hours. The reaction mixture was then cooled to room temperature, followed by the addition of water and dichloromethane, filtration over diatomite / kieselguhr and separation of the organic phase. The organic phase was dried over sodium sulfate and concentrated to yield 3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-benzyl}-1,6-dihydro-pyridazin-3-yl)-benzonitrile as a grey solid, which could be used in subsequent reactions without purification.

[0104] A suspension of 5.33 g (10.9 mmol) of 3-(6-oxo-1-{3-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]-benzyl}-1,6-dihydro-pyridazin-3-yl)-benzonitrile in 35 ml of THF and 35 ml of water was added in portions with 4.93 g (49.4 mmol) of sodium perborate under ice cooling and then stirred at room temperature for 2 hours. The reaction mixture was mixed with 300 ml of dichloromethane and 100 ml of saturated aqueous ammonium chloride solution. The organic phase was separated, dried over sodium sulfate and concentrated. The residue of 3-{1-[3-(5-hydroxy-pyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrile was recrystallized from methanol.

[0105] To a suspension of 25 g (65.6 mmol) of 3-{1-[3-(5-hydroxy-pyrimidin-2-yl)-benzyl]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzonitrile in 250 ml of THF, 15.6 g (68.8 mmol) of N-Boc-4-piperidine-methanol and 19.1 g (72.1 mmol) of triphenylphosphine were added in sequence. Then, 14.9 ml (72.1 mmol) of diisopropyl azodicarboxylate were added dropwise under ice cooling. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was further mixed with 750 ml of 2-propanol and 13.1 ml of a 0.5 M solution of potassium hydroxide in ethanol in ethanol. The resulting precipitate of 4-(2-{3-[3-(3-cyano-phenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}-pyrimidin-5-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester was pumped off, washed with diethyl ether and dried in vacuum.

[0106] To an aqueous solution of 16.0 g (28.0 mmol) of 4-(2-{3-[3-(3-cyano-phenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}-pyrimidin-5-yloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester in 80 ml of formic acid, 6.60 ml of 35% aqueous formaldehyde solution was added. The reaction mixture was stirred at a temperature of 110° C. for 2 hours, after which 300 ml of water was added. The reaction mixture was concentrated in vacuum to a volume of 150 ml and then extracted with 200 ml of dichloromethane. The organic phase was washed with aqueous bicarbonate, dried over sodium sulfate and concentrated. The residue of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile was recrystallized from 2-propanol.

[0107] The crystalline modification H2 of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate can be prepared as follows, as described in Example 12 of WO 2010 / 078897:

[0108] Approximately 511 mg of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile was dispersed in 75 mL of acetone and 1.12 mL of 1N aqueous HCl was added. No clear solution was obtained. However, the remaining solid residue was removed by filtration and then a clear solution was obtained. The resulting clear solution was then incubated overnight to obtain crystals. The crystals were either isolated by filtration and dried at 65° C. in a vacuum drying cabinet for 1 h (purification option 1) or isolated by filtration, washed with acetone and dried in a vacuum drying cabinet (purification option 2).

[0109] The powder X-ray diffraction pattern of compound "A7" was obtained by standard techniques as described in the European Pharmacopeia 6th Edition chapter 2.9.33 (Cu-Kα1 radiation, λ=1.5406 Å, Stoe StadiP 611 KL diffractometer). Compound "A7" is characterized by the following XRD data:

[0110] Powder X-ray diffractogram peak list (purification option 1): [Table 1-1] [Table 1-2]

[0111] Powder X-ray diffractogram peak list (purification option 2): [Table 2]

[0112] The powder X-ray diffraction pattern and corresponding X-ray diffraction data confirmed that compound "A7" was the H2 crystalline modification of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate. EXAMPLES

[0113] Anti-cancer testing of compounds Complete response to adjuvant tepotinib hydrochloride hydrate in a patient with newly diagnosed disseminated glioblastoma (GBM) harboring MET amplification

[0114] Here, we report a complete radiographic response to tepotinib hydrochloride hydrate in a patient with newly diagnosed disseminated GBM harboring MET amplification. A 29-year-old man presented with progressive headaches. Brain MRI showed a large heterogeneously enhancing intraventricular mass with an epicenter in the right lateral ventricular trigone, and enhancing nodules in the bilateral cerebellum. Spine MRI showed multifocal enhancement along the distal cervicothoracic spinal cord and cauda equina, with concern for leptomeningeal disease. He underwent right temporal lobectomy and partial resection of the mass. Due to dizziness, his KPS was 90 after surgery. Pathology was consistent with GBM, IDH wild-type, MGMT unmethylated, and MET amplification at 7q31.2. He completed proton craniospinal irradiation (CSI) at 3600 cGy followed by a boost to the tumor bed with intensity-modulated radiation therapy (IMRT) at 2400 cGy, but did not receive concomitant temozolomide (TMZ) due to the large radiation field. He completed two cycles of adjuvant TMZ, but it was withheld due to myelosuppression. He then began monotherapy with tepotinib hydrochloride hydrate at 1000 mg daily, obtained under a compassionate IND. MRI one month after treatment showed resolution of areas of enhancement in the brain and spine. Specifically, MRI of the brain, cervical spine, thoracic spine, and lumbar spine showed near complete resolution of contrast enhancing lesions and LMD after one cycle (=4 weeks) of tepotinib. He had grade 1 creatinine elevation and abdominal discomfort, and the dose was reduced to 500 mg daily after two cycles. Nineteen weeks after initiation of tepotinib hydrochloride hydrate, his complete response has persisted and he remains clinically stable with mild chronic dizziness. Adjuvant tepotinib monotherapy was well tolerated and resulted in complete and durable control in a patient with disseminated, MET-amplified GBM on updated MRI after 11 cycles (Figure 5). Although trials of targeted therapies in molecularly unselected GBM have been largely disappointing, this case demonstrates the promise of targeting MET using tepotinib, or its pharmacologic acceptable salts, solvates and / or hydrates, in GBM. EXAMPLES

[0115] Effects of MET pathway inhibition and radiation in a syngeneic mouse model material and method Reagents and cell lines

[0116] Tepotinib was dissolved in DMSO and further diluted in cell culture medium. For in vivo studies, tepotinib was prepared using 20% ​​Solutol and 80% sodium acetate buffer (pH 5.5). Recombinant human HGF (GeneTex, Lucerne, Switzerland) was dissolved in Dulbecco's phosphate-buffered saline (PBS). Mouse glioma cell lines SMA-497, SMA-540, and SMA-560 were obtained from Duke University Medical Center (Durham, NC), and GL-261 from the National Cancer Institute (Frederick, MD). Cells were cultured in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal calf serum (FCS) and 1% glutamine. Gene expression profiles of these cell lines were previously generated (Ahmad et al., 2014).

[0117] Real-time polymerase chain reaction (RT-PCR)

[0118] RT-PCR was performed on cDNA generated by reverse transcription from 1 μg of total RNA. Relative gene expression was measured as described (Papa et al., 2017) using a variation of the 2Δ (delta delta CT) method (Livak and Schmittgen, 2001). Hypoxanthine-guanine phosphoribosyltransferase 1 (Hprt1) was used as the reference gene. Mouse-specific primer sequences were as follows: Hprt1 fw:5'- CCT AAG ATG AGC GCA AGT TGA A -3', rev:5'- CCA CAG GAC TAG AAC ACC TGC TAA-3'; Hgf fw:5'- TCA AAA TGT CAC CTA AAA CAA TCC -3', rev:5'- ACA AAC AAT ACA ACA GAA AAC ACC -3'; Met fw:5'- TTT GGG GAA GTC TCA TTT TTG -3', rev:5'- CGA TTT TCA GTT GGC TTT TG -3'.

[0119] Immunoblot analysis

[0120] Lysates of cells or tumor specimens were prepared using radioimmunoprecipitation assay (RIPA) lysis buffer (pH 7.8) containing 5 mM EDTA supplemented with 25 mM Tris-HCl, 120 mM NaCl, phenylmethylsulfonyl fluoride (Sigma Aldrich, St. Louis, MO), 0.5% NP-40, 200 mM sodium orthovanadate, 0.5 M sodium fluoride, protease inhibitor cocktail, and phosphatase inhibitor cocktails 2 and 3 (Sigma Aldrich). Primary antibodies were as follows: rabbit anti-p-MET (Tyr1234 / 1235) (D26), mouse anti-MET (clone 25H2; both Cell Signaling Technology, Denvers, MA), or goat anti-actin (sc-47778; Santa Cruz Biotechnology, SC, Santa Cruz, CA). The membrane was exposed to an HRP-conjugated secondary species-specific antibody.

[0121] Proteome profiler array

[0122] For simultaneous determination of relative levels of mouse cytokines in vivo, the Mouse XL Cytokine Array Kit (ARY028, Minneapolis, MN) from R&D Systems was used. Tissue lysates were prepared by electric homogenization in ice-cold lysis buffer supplemented with a protease inhibitor cocktail and then centrifuged to remove cellular debris; 150 μg of protein was used for each tumor sample and nitrocellulose membrane (control, monotherapy, and combination therapy). To compare the percentage of protein levels in each tumor specimen, quantification of pixel density for each spot on the array was performed using Image J (version 1.32j) software (National Institutes of Health, Bethesda, MD, http: / / rsb.info.nih.gov / ij / ).

[0123] Enzyme-linked immunosorbent assay (ELISA)

[0124] 4 × 10 collected after 36 h 6 Serum-free supernatant from the cells was used to quantitate mouse HGF using a Mouse HGF ELISA Kit (#EMHGF, Thermo Scientific, Frederick, MD).

[0125] CRISPR / Cas9 knockout of MET

[0126] Knockout clones were generated as described (Ran et al., 2013; Machado et al., 2019). Briefly, 2 MET-specific guide RNAs (5'-GAGAGCACGACAAATACGTA-3', and 5'-GTATCGGACAGAGTTTACCA-3') were cloned into pSpCas9(BB)-2A-GFP and both plasmids were co-transfected using Lipofectamine (Thermo). After puromycin selection, single cells were sorted into 96-well plates using a BD FACSAria III. Knockout was confirmed by RT-PCR and Sanger sequencing after clonal expansion.

[0127] animal research

[0128] All experiments were performed according to the guidelines of the Swiss Federal Act on Animal Protection and in accordance with the Swiss Cantonal Veterinary Office under animal license permit numbers ZH-038 and ZH-098. mRNA was prepared from untreated gliomas that had begun to show symptoms in mice, or from the brains of mice without tumors. For treatment studies, 5,000 tumor cells were transfected into 6-12 week-old immunocompetent VM / Dk mice, immunocompetent C57BL / 6 mice, or "non-leaky" immunodeficient Rag1-deficient mice without mature B and T cells (B6.129S7-Rag1) on a C57BL / 6 background. tm1MomTepotinib was administered orally at 100 mg / kg using gavage. Local cranial radiotherapy was performed 10 days after tumor implantation at room temperature using a 200 kV X-ray unit from Gulmay at 1 Gy / min (Schneider et al., 2017). Neurological symptoms were assessed daily according to the guidelines of the Veterinary Office of the Canton of Zurich (grade 0: no visible defects, grade 1: reduced activity, slight balance and coordination defects, grade 2: reduced activity, 15% weight loss compared to peak weight, slight paralysis of a suspected leg, signs of moderate pain). To assess early histological changes, animals were euthanized when the first animal showed grade 2 signs of disease progression including neurological symptoms. Total mRNA or protein lysates were prepared from 20–25 mg of brain tissue taken from the left and right hemispheres and tumors at the time of sacrifice.

[0129] Histology and immunohistochemistry

[0130] Sections (8 μm thick) of tumor-bearing cryopreserved brains were prepared. The average tumor size was determined by the maximum tumor area in the horizontal plane on hematoxylin-eosin (H&E)-stained sections by multiplying the longest perpendicular diameter from low-magnification (2.5x) images. Brain sections were immunostained to determine proliferation using Ki-67 antibody (clone SP6, Epitomics, Burlingame, CA), anti-mouse CD31 antibody (clone MEC 13.3, BD Pharmingen, Franklin Lakes, NJ), anti-CD45 antibody (clone 30-F11; BioLegend), anti-CD3 (clone 17A2; BD Biosciences, San Jose, CA) or anti-CD11b (clone M1 / 70; BD Biosciences), and Histofine Simple Stain Mouse MAX-PRO Anti-Rabbit Secondary Antibody (Nichirei Biosciences, Tokyo, Japan). Anti-rat N-histofine Simple Stain Mouse MAX-PO (Nichirei Biosciences) and DAB chromogen were used to stain blood vessels. The percentage of Ki-67 positive tumor nuclei and the average number of CD31 positive intratumoral blood vessels in a high-power field (40x objective) were calculated using 3 randomly selected different microscopic fields of 3 mice per group. Alternatively, DAB positive signals were quantified using ImageJ software (https: / / imagej.nih.gov / ) (Crowe and Yue, 2019).

[0131] statistical analysis

[0132] All in vitro and in vivo experiments reported here were performed in biological replicates, i.e., in independent experiments, and with different cell line passages. Statistical significance was assessed by two-tailed unpaired t-tests, or two-way ANOVA with Bonferroni post-hoc test (GraphPad Prism). Tumor sizes were analyzed using the Mann-Whitney U nonparametric test. Survival times were analyzed using Kaplan-Meier survival plots followed by the log-rank (Mantel-Cox) test. Differences were considered statistically significant when p-values ​​were less than 0.05. result

[0133] Murine glioma cells expressed HGF and MET and responded to exogenous HGF with MET phosphorylation (p-MET). Glioma cell viability or proliferation was resistant to genetic or pharmacological MET inhibition using tepotinib or met gene knockout. MET inhibition failed to sensitize glioma cells to radiation in vitro. In contrast, the combination of tepotinib and radiotherapy extended survival of mice bearing orthotopic SMA-560 or GL-261 gliomas and was associated with suppression of glioma cell proliferation and delayed tumor growth compared with radiotherapy or tepotinib treatment alone. In the SMA-560 model, the combination treatment suppressed a series of proinflammatory cytokines that were upregulated by radiation alone and associated with poor outcome in glioblastoma. The synergistic effect was lost when SMA-560 gliomas were formed and treated in immunodeficient RAG-deficient mice. In the GL-261 model, the synergistic effect was also lost in Rag1-deficient mice, and importantly, also when MET expression was disrupted in the tumors.

[0134] Characterization of the HGF / MET axis in a mouse glioma model in vitro

[0135] We first examined HGF and MET expression levels, as well as constitutive MET activation, in GL-261, SMA-497, SMA-540, or SMA-560 mouse glioma models. All cell lines expressed Hgf and Met mRNA in vitro and ex vivo. Ex vivo tumor samples from all four models showed comparable levels of Hgf mRNA, which were similar to those in normal brain tissue. In contrast, Met mRNA expression was significantly upregulated in tumor tissue compared to brain tissue (Figures 1A, 1B). Among the four mouse cell lines, Hgf mRNA expression and HGF protein release in vitro showed a high correlation (r=0.998, p=0.002), with SMA-540 demonstrating the highest HGF expression (Figure 1C). Constitutive MET phosphorylation was detected in SMA-497 and SMA-560 cells. All cell lines accumulated p-MET in response to exogenous HGF (Fig. 1D). GL-261 showed the lowest basal MET activity state based on microarray-based transcriptional profiling of MET-promoting genes. We next confirmed that exposure of SMA-497 and SMA-560 cells to the MET inhibitor tepotinib suppressed MET phosphorylation in a time- and concentration-dependent manner (Fig. S1A). However, glioma cell lines were resistant to the inhibitory effects of tepotinib at concentrations up to 1 μM in acute growth inhibition or clonogenic assays (Fig. S1B, S1C).

[0136] Radiation induced HGF / MET signaling, but inhibition of HGF / MET signaling in vitro did not induce radiosensitivity

[0137] There was no significant change in Hgf or Met mRNA expression upon irradiation in GL-261, SMA-497, or SMA-540 cells. In contrast, there was a dose-dependent induction of Hgf and Met mRNA expression in SMA-560 cells (Fig. S2A), which translated into tepotinib-sensitive MET phosphorylation (Fig. S2B). However, at concentrations known to specifically inhibit MET phosphorylation (Fig. S1A), tepotinib failed to sensitize glioma cells to the inhibitory effects of radiation in vitro. To exclude that this negative effect was simply a result of low availability of HGF in culture, we performed similar experiments in the presence of exogenous HGF, but again no sensitivity to radiation by tepotinib was evident (Fig. S2C).

[0138] Tepotinib inhibits basal and radiation-induced activation of invasiveness in mouse glioma cells in vitro

[0139] Next, we evaluated the motogenic activity of HGF / MET in response to radiation in vitro. Low-dose irradiation (2 Gy) increased invasiveness in SMA-540 and SMA-560 cells, whereas high-dose irradiation (8 Gy) reduced invasiveness in SMA-497 and SMA-560 cells. Tepotinib suppressed invasiveness in all cell lines, regardless of whether they were irradiated or not, except for low-dose irradiated SMA-540 cells. A similar trend was also observed in a spheroid invasion assay using SMA-560 cells (Szabo et al., 2016).

[0140] Synergistic growth inhibition of murine SMA-560 glioma by radiation therapy and tepotinib in vivo

[0141] Based on high Met gene expression and constitutive MET phosphorylation in tumor tissue (Figure 1B), we selected the SMA-560 model to assess the effect of radiation therapy in combination with pharmacological inhibition of MET by tepotinib in vivo. We first confirmed the target inhibition by tepotinib by measuring p-MET levels by immunoblot ex vivo: p-MET was detected in the tumor and in the tumor-bearing right hemisphere. Although it was induced by radiation, p-MET was not detected in animals treated with tepotinib (Figure 2A). Neither tepotinib nor radiation therapy alone had a significant effect on survival, but the combination resulted in a strong synergistic survival extension from approximately 20 days with or without monotherapy to approximately 60 days with the combination. All mice were euthanized in the control group as well as in the radiation therapy group due to symptoms related to tumor growth. In contrast, one mouse in the tepotinib group and three in the combination group were alive and tumor-free at day 80 (Figure 2B). To gain knowledge of the mechanism of action mediating the synergistic effect in vivo, tissue analysis was performed using morphological and immunohistochemical assessment of mice according to a randomization list at the first symptomatic mouse in either group. Animals in all treatment groups showed a 30-40% reduction in tumor volume compared to the untreated control group. However, although the percentage of Ki-67 stained nuclei remained unaffected in both monotherapy groups, there was a marked reduction in Ki-67 positive cells in the combination group (Figure 2C). Such a combination effect was not observed when the same treatment was administered acutely in vitro. SMA-560 cells give rise to highly vascularized tumors reflected by a high density of CD31 positive blood vessels (Ahmad et al., 2014). Here, we observed a decrease in CD31 immunoreactivity in both monotherapy arms (1.8-fold), as well as more so in the combination arm (2.8-fold) (Figure 2D).

[0142] Cellular and molecular mechanisms mediating synergistic growth inhibition of experimental gliomas by radiation and tepotinib

[0143] Because we observed synergistic growth suppression in vivo but not in vitro, we concluded that the microenvironment may also contribute to the therapeutic effect. Therefore, we assessed differences in host cell infiltration in tumors from the four treatment groups, but did not observe consistent differences at early time points, i.e., when the first mice with symptoms appeared. We then compared cytokine profiles in ex vivo tumor tissue lysates among the four treatment groups. First, we noted that almost all cytokines were induced rather than reduced by either treatment modality; while tepotinib monotherapy only reduced the levels of some cytokines, irradiation alone produced the most striking induction of cytokines (Figure 3). The only cytokine that was induced by the combination but not by either monotherapy alone was WNT1-inducible signaling pathway protein (WISP / CCN4). The most relevant pattern was the induction by irradiation, which was attenuated by tepotinib. This group of molecules included mediators of angiogenesis and inflammatory cell adhesion molecules, including VEGF, intercellular adhesion molecule 1 (ICAM-1 / CD54), serpin E1 / PAI-1, P-selectin and matrix metalloproteinases (MMPs)-2 and -9, the antiangiogenic and antitumor factors serpin F1 / PEDF, lipocalin-2, colony-stimulating factor 1 M-CSF, and the innate pattern recognition molecules pentraxin 2 / 3 and C-reactive protein (CRP, pentraxin 1), the proinflammatory cytokines IL-1a / IL-1F1 and CXCL10; the anti-inflammatory cytokines IL-10 and IL-11, the Notch / Delta / Serrate protein family members pref-1 / DLK-1 / FA1, and the low-density lipoprotein receptor (LDL-R). Among these differentially regulated factors, expression of the IL1A gene is associated with poor prognosis in glioblastoma patients.

[0144] Synergistic inhibition of glioma growth by radiation and tepotinib requires adaptive immunity and tumor MET expression

[0145] To separate tumor microenvironment versus tumor-autonomous mechanisms in mediating the synergistic response of experimental gliomas to the combination of radiotherapy and tepotinib, we opted for a dual approach and studied a second model: to explore the combination therapy in immunodeficient animals, we disrupted the MET gene in GL-261 glioma cells. In contrast to wild-type cells, MET-deficient GL-261 did not respond to MET phosphorylation when exposed to exogenous HGF, but had no growth disadvantage in vitro, as determined by measurements of cell doubling time, cell cycle progression, or viability in vitro. Ex vivo analysis demonstrated that MET-deficient tumors exhibited similar growth characteristics in immunocompetent syngeneic mice, and comparable immune cell infiltration. In MET-deficient tumors, vascular density was significantly reduced, corresponding to the pattern seen with tepotinib treatment (Figure 2C). First, we noted that the synergistic effect of the combination treatment was strongly attenuated when SMA-560 cells were grown in RAG-deficient mice (Figure 4A). In the GL-261 model, when tumors were generated and treated in wild-type mice, the combination therapy resulted in a marked increase in survival. There were approximately 50% long-term survivors in the combination treatment group (Figure 4B). The long-term survivors were rechallenged with GL-261 cells at day 90, and all four animals remained asymptomatic until the end of the experiment after another 50 days (Figure 4C). When the same experiment was performed in RAG-deficient mice, radiation therapy retained its activity, but synergy with tepotinib was lost (Figure 4D). Finally, when MET was disrupted, radiation therapy was as effective against wild-type tumors, but again in this model the synergy was lost (Figure 4E). Comparative survival data are summarized in Figure 4F. Consider

[0146] Although the synergy between MET inhibition and radiotherapy has previously been proposed to be mediated by interfering with the cytoprotective role of the MET pathway in the context of DNA repair in human glioma, gastric adenocarcinoma, and lung cancer cells (Welsh et al., 2009; De Bacco et al., 2011; Medova et al., 2012), such a mechanism is unlikely to be at work in our model, since there was no synergy between radiotherapy and pharmacological MET inhibition in vitro (Figure S2). Conversely, we observed a strong synergy between radiotherapy and tepotinib in two syngeneic immunocompetent glioma models in vivo (Figures 2, 4), which was not predicted by the in vitro data. Compared with either treatment alone, the combination treatment induced an early inhibition of proliferation and angiogenesis in the SMA-560 model (Figure 2). The inhibition of angiogenesis may be the result of suppression of radiotherapy-induced increase in angiogenic molecules such as VEGF, MCSF, MMP2, or MMP9 during co-treatment with tepotinib (Figure 3). Glioblastoma develops radioresistance by multiple adaptive molecular strategies (Bao et al., 2006; De Bacco et al., 2011; Squatrito and Holland, 2011). In summary, we report that tepotinib attenuates the expression of several radiotherapy-induced cancer-associated inflammation and immunoregulatory cytokines as a potential mechanism by which tepotinib slows tumor growth when combined with radiotherapy. Complementary studies exploring the efficacy of combination therapy in either immunodeficient mice or in mice bearing tumors with disrupted expression of the MET gene confirmed that synergy requires at least two mechanisms: first, expression of MET in the tumor and second, a functional immune system (Figure 4). Our preclinical data would therefore suggest that MET pathway inhibition in human glioblastoma could be advantageously explored in combination with radiotherapy. References

[0147] Ahmad M , Frei K , Willscher E , Stefanski A , Kaulich K , Roth P , et al. Journal of neuropathology and experimental neurology 2014; 73(11):1062.

[0148] [ PMC free article ] [ PubMed ] Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Helmeland AB, et al. Nature 2006; 444(7120):756.

[0149] Crowe AR, Yue W. Bioprotocol 2019; 9(24).

[0150] De Bacco F, Luraghi P, Medical E, Reato G, Girolami F, Perera T, et al. Journal of the National Cancer Institute 2011; 103(8):645.

[0151] Livak KJ, Schmittgen TD. Methods (San Diego, Calif) 2001; 25(4):402.

[0152] Machado RAC, Schneider H, DeOcesano-Pereira C, Lichtenstein F, Andrade F, Fujita A, et al. Sci Rep 2019; 9(1):3952.

[0153] Medova M, Aebersold DM, Zimmer Y. [ PubMed ] [ Cross Ref ] Medova M, Aebersold DM, Zimmer Y; 130(3):728.

[0154] Papa E, Weller M, Weiss T, Ventura E, Burghardt I, Szabo E. Cell death & disease 2017; 8(12): 3210.

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[0156] Schneider H, Lohmann B, Wirsching HG, Hasenbach K, Rushing EJ, Frei K, et al. Oncotarget 2017; 8(50): 87124.

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Claims

1. A composition comprising a cMET inhibitor for use in a method in a human subject in need thereof for the long-term treatment of glioblastoma, wherein said method comprises administering to the subject an effective amount of the cMET inhibitor in a treatment regimen for at least 10 weeks, wherein the cMET inhibitor is: 【Chemical 1】 Or a pharmaceutically acceptable salt, solvate and / or hydrate thereof, and wherein the cMET inhibitor is not administered in combination with chemotherapy in the same treatment regimen, said composition.

2. The composition according to claim 1, wherein the cMET inhibitor is selected from the group consisting of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride hydrate, 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate, and crystalline modification H2 of 3-(1-{3-[5-(1-methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-pyridazin-3-yl)-benzonitrile hydrochloride monohydrate.

3. The composition according to claim 1, wherein disseminated glioblastoma, glioblastoma bearing MET amplification, or a combination thereof is treated.

4. The composition according to claim 1, wherein glioblastoma bearing IDH wild-type, MGMT non-methylated or MET amplification, or a combination thereof at 7q31.2 is treated.

5. The composition according to claim 1, wherein the administration of the cMET inhibitor has one or more clinical utilities selected from the group consisting of complete response, increased likelihood of complete response, reduced likelihood of drug resistance development, prolonged time to tumor progression, and prolonged time to tumor recurrence; preferably resulting in a complete response.

6. The composition according to claim 1, wherein the cMET inhibitor is administered for at least about 11 to 52 weeks.

7. further comprising administering radiotherapy in the same treatment regimen; wherein optionally, the radiotherapy is administered as a single dose, or after the first administration of the cMET inhibitor, or a combination thereof, the composition according to claim 1.

8. The composition according to claim 7, wherein the radiotherapy is administered within 96 hours, preferably within 36 hours, after the first administration of the cMET inhibitor.

9. The composition according to claim 1, wherein the cMET inhibitor is administered in a second-line treatment or higher-order treatment regimen for glioblastoma.

10. further comprising administering a treatment selected from the group consisting of surgery, radiotherapy, chemotherapy, and combinations thereof, prior to the first administration of the cMET inhibitor; wherein optionally, surgery or radiotherapy, or a combination thereof, is first administered prior to the first administration of the cMET inhibitor, followed by chemotherapy, the composition according to claim 1.

11. The composition according to claim 1, wherein the cMET inhibitor is administered in a first-line treatment for glioblastoma.

12. The composition according to claim 11, further comprising administering a treatment selected from the group consisting of surgery, radiotherapy, chemotherapy, and combinations thereof, after the first administration of the cMET inhibitor.

13. radiotherapy is administered; wherein optionally, the radiotherapy is proton irradiation, the composition according to any one of claims 7.

14. The composition according to any one of claims 7 to 13, wherein the radiotherapy comprises from about 3000 to 4000 cGy and optionally subsequently a boost to the tumor bed at 2000 to 3000 cGy.

15. The composition according to any one of claims 1 to 6, wherein the cMET inhibitor is administered as monotherapy.

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