Methods of treating glioblastoma with prodrugs of riluzole

Abstract

There is provided a method of treating glioblastoma in a patient in need of such treatment, the method comprising administering to the patient a first dosage form comprising a therapeutically active amount of triluzole or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] The present invention relates to the treatment of cancer with prodrugs of riluzole. In particular, the present invention relates to the treatment of glioblastoma with riluzole as a monotherapy or in combination with another anticancer agent and / or ionizing radiation. Background Art

[0002] Glioblastoma (GBM) is a fast-growing and aggressive brain tumor that invades nearby brain tissue but does not usually spread to distant organs. In adults, GBM most often occurs in the cerebral hemispheres, particularly in the frontal and temporal lobes of the brain. GBM is a devastating brain cancer that is incurable and can lead to death in six months or less. Therefore, new drugs are urgently needed to treat this aggressive type of cancer.

[0003] Troleukazole is a novel tripeptide prodrug of the glutamate modulator riluzole. Riluzole is a reference listed drug The active ingredient in riluzole, which is approved for the treatment of amyotrophic lateral sclerosis (ALS). In addition, clinical and translational studies have shown that riluzole may also be an effective therapeutic drug for many other indications. However, the optimal use of riluzole is limited by several factors. The bioavailability of riluzole tablets is approximately 60%, which is attributed to the high first-pass effect in the liver and the variable metabolism of the heterogeneously expressed CYP1A2 enzyme. These factors lead to a relatively high degree of pharmacokinetic (PK) variability after administration of riluzole. The absorption rate of riluzole is also reduced when taken with meals (i.e., negative food effect), which may lead to low systemic exposure. Therefore, it is recommended to administer riluzole one hour before or two hours after meals (i.e., fasting for 3 hours). Riluzole has a dose-dependent effect on liver function tests (LFTs). The riluzole drug itself also has other intrinsic limitations, including very low solubility in water, poor oral palatability, pH-dependent chemical stability, and strong oral numbness if applied directly to the oral mucosa.

[0004] Troriluzole was developed to alleviate the aforementioned limitations of riluzole. Troriluzole is a novel, rationally designed third-generation tripeptide prodrug of riluzole that potentially provides improved bioavailability, pharmacology, safety, and administration. Troriluzole is actively absorbed in the intestine (via a peptide transporter [PepT1]), is not subject to negative food effects, is rapidly cleaved by aminopeptidases in the systemic circulation to release active metabolites, is expected to produce predictable exposure of its active metabolites, bypasses first-pass metabolism, reduces the riluzole load on the liver, and allows exploration of higher active metabolite concentrations.

[0005] Troriluzole has been reported to be useful in treating some types of cancer. However, there is no evidence that troriluzole can treat glioblastoma. Summary of the invention

[0006] The present invention relates to methods of treating glioblastoma by administering a prodrug of riluzole, either as a monotherapy or in combination with another anticancer agent and / or ionizing radiation.

[0007] In one embodiment, a method of treating glioblastoma in a patient in need of such treatment is provided. The method comprises administering to the patient a first dosage form comprising a therapeutically active amount of troriluzole or a pharmaceutically acceptable salt thereof.

[0008] In another embodiment, the method may further comprise administering to the patient a second dosage form comprising a therapeutically active amount of temozolomide or a pharmaceutically acceptable salt thereof.

[0009] In yet another embodiment, the method may further comprise administering to the patient a third dosage form comprising a therapeutically active amount of lomustine or a pharmaceutically acceptable salt thereof.

[0010] In yet another embodiment, the method may further comprise irradiating the glioblastoma cells with a therapeutically effective dose of ionizing radiation. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] These and / or other aspects will become apparent and more readily understood from the following description of the embodiments taken in conjunction with the accompanying drawings, which illustrate the mechanism of action of troriluzole. DETAILED DESCRIPTION

[0012] The following detailed description is provided to help those skilled in the art to practice the present invention. Exemplary embodiments will be described in detail below. However, these embodiments are merely exemplary, and the present disclosure is not limited thereto, but is limited by the scope of the appended claims. Those of ordinary skill in the art may modify and change the embodiments described herein without departing from the spirit or scope of the present disclosure.

[0013] Therefore, the embodiments are described below only by reference to structures and schemes to explain various aspects of the specification. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The term "or" means "and / or". Expressions such as "at least one of", when following a list of elements, modify the entire list of elements without modifying the individual elements of the list.

[0014] It should be understood that when an element is referred to as being "on" another element, it can be in direct contact with the other element or intervening elements may be present therebetween. In contrast, when an element is referred to as being "directly on" another element, there are no intervening elements.

[0015] It should be understood that although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Therefore, the first element, component, region, layer or section discussed below may be referred to as the second element, component, region, layer or section without departing from the teachings of the embodiments of the present invention.

[0016] It should be understood that the terms “comprises and / or comprising” or “includes and / or including” when used in the present specification specify the presence of stated features, regions, integers, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components and / or groups thereof.

[0017] Unless otherwise defined, all technical and scientific terms used herein will have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. The terms used in the description are only used to describe specific embodiments and are not intended to be restrictive. It should also be understood that terms (such as those defined in common dictionaries) should be interpreted as having a meaning consistent with their meaning in the context of the relevant technology and the present disclosure, and unless clearly defined in this article, should not be interpreted in an idealized or overly formal sense.

[0018] As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application. Where a term is not expressly defined herein, the term is given its art-recognized meaning by a person of ordinary skill in the art applying the term in the context of its use to describe the present invention.

[0019] The articles "a" and "an" refer to one or to more than one (ie, to at least one) of the grammatical object of the article, unless the context clearly indicates otherwise. For example, "an element" means one element or more than one element.

[0020] Additional aspects will be set forth in part in the description which follows and, in part, will be apparent from the description.

[0021] In one embodiment, a method of treating glioblastoma in a patient in need of such treatment is provided. The method comprises administering to the patient a first dosage form comprising a therapeutically active amount of troriluzole or a pharmaceutically acceptable salt thereof.

[0022] Troriluzole is a compound having the following chemical formula:

[0023]

[0024] The first dosage form may include 10 to 500 mg of troriluzole or an equivalent amount of a pharmaceutically acceptable salt thereof. In some aspects, the first dosage form may include 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450 or 500 mg of troriluzole or an equivalent amount of a pharmaceutically acceptable salt thereof. For example, the first dosage form may include 100 mg or 200 mg of troriluzole or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0025] The first dosage form can be administered once a day, twice a day, three times a day, four times a day, or at any other frequency as needed. For example, the first dosage form can be administered once a day or twice a day.

[0026] The duration of treatment can be several days to several weeks to several months.For example, treatment can be applied one day, two days, three days, four days, five days, six days or seven days.In another example, treatment can be applied one week, two weeks, three weeks, four weeks, five weeks, six weeks or seven weeks.In another example, treatment can be applied one month, two months, three months, four months, five months, six months or seven months.In one embodiment, treatment can be applied one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days or 28 days.In another example, treatment can be applied for a cycle of 28 days.In another example, treatment can be applied for one, two, three, four, five, six, seven, eight, nine or ten 28-day cycles.

[0027] In one aspect, the duration of treatment may be four weeks, and troriluzole or a pharmaceutically acceptable salt thereof may be administered in an amount of 100 mg twice daily for the first two weeks and in an amount of 200 mg twice daily for the other two weeks.

[0028] In one aspect, the total amount of troriluzole or a pharmaceutically acceptable salt thereof administered to a patient during a day may be 50 to 1000 mg. For example, the total amount of troriluzole administered to a patient during a day may be 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 950 or 1000 mg. For example, the total amount of troriluzole administered to a patient during a day may be 200 mg, 300 mg or 400 mg.

[0029] In another embodiment, troriluzole can be paired with temozolomide to treat glioblastoma. Temozolomide is a drug used to treat brain tumors that has the following chemical structure:

[0030]

[0031] Troluzole and temozolomide may be included in the same or different dosage forms. In one aspect, the method for treating glioblastoma with Troluzole may also include applying a second dosage form to the patient, wherein the second dosage form comprises a therapeutically active amount of temozolomide or a pharmaceutically acceptable salt thereof. The second dosage form may comprise 10 to 300 mg of temozolomide or an equivalent amount of its pharmaceutically acceptable salt. For example, the second dosage form may comprise 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275 or 300 mg of temozolomide or an equivalent amount of its pharmaceutically acceptable salt. For example, the second dosage form may comprise 75 or 150 mg of temozolomide or an equivalent amount of its pharmaceutically acceptable salt.

[0032] The second dosage form can be administered once a day, twice a day, three times a day, or four times a day. For example, the second dosage form can be administered once a day or twice a day.

[0033] In one aspect, the total amount of temozolomide or its pharmaceutically acceptable salt administered to a patient during one day may be 50 to 300 mg. For example, the total amount of temozolomide or its pharmaceutically acceptable salt administered to a patient during one day may be 75 mg. In another example, the total amount of temozolomide or its pharmaceutically acceptable salt administered to a patient during one day may be 150 mg.

[0034] Glioblastoma can be a newly diagnosed 6 -methylguanine-DNA-methyltransferase (MGMT) methylated glioblastoma or O 6 -Methylguanine-DNA-methyltransferase (MGMT) is not methylated in glioblastoma.

[0035] In another embodiment, troriluzole can be paired with lomustine to treat glioblastoma. Lomustine is an alkylated nitrosourea compound used in chemotherapy, which has the following structure:

[0036]

[0037] Troriluzole and lomustine may be contained in the same or different dosage forms. In one aspect, the method of treating glioblastoma with troriluzole may further comprise administering to the patient a third dosage form comprising a therapeutically active amount of lomustine or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0038] In one aspect, the third dosage form may include 10 to 200 mg of temozolomide or its pharmaceutically acceptable salt of an equivalent amount. For example, the second dosage form may include 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175 or 200 mg of temozolomide or its pharmaceutically acceptable salt of an equivalent amount. In one aspect, the third dosage form may include 50 mg of lomustine or its pharmaceutically acceptable salt of an equivalent amount. In another aspect, the third dosage form may include 100 mg of lomustine or its pharmaceutically acceptable salt of an equivalent amount.

[0039] The third dosage form can be administered once a day, twice a day, three times a day, or four times a day. For example, the third dosage form can be administered once a day.

[0040] The total amount of lomustine or a pharmaceutically acceptable salt thereof administered to a patient during a day may be 50 to 200 mg. For example, the total amount of lomustine or a pharmaceutically acceptable salt thereof administered to a patient during a day may be 100 mg.

[0041] The glioblastoma may be a recurrent glioblastoma.

[0042] In another embodiment, troriluzole can be paired with an additional anticancer agent to treat glioblastoma. The additional anticancer agent can include regorafenib, paxalisib, VAL-083, VT1021, or any combination thereof.

[0043] In one embodiment, troriluzole can be paired with regorafenib to treat glioblastoma. Regorafenib is an oral multikinase inhibitor that targets angiogenic, stromal, and oncogenic receptor tyrosine kinases (RTKs). Regorafenib has the following chemical structure:

[0044]

[0045] Troriluzole and regorafenib may be contained in the same or different dosage forms. In one aspect, the method of treating glioblastoma with troriluzole in a patient in need of such treatment further comprises administering to the patient a fourth dosage form comprising a therapeutically active amount of regorafenib or a pharmaceutically acceptable salt thereof.

[0046] In another embodiment, troriluzole can be paired with pasalicilib to treat glioblastoma. Pasalicilib is a phosphatidylinositol 3-kinase (PI3K) inhibitor with potential anti-tumor activity, which has the following chemical structure:

[0047]

[0048] Troriluzole and pasalicilib may be contained in the same or different dosage forms. In one aspect, the method of treating glioblastoma with troriluzole in a patient in need of such treatment further comprises administering to the patient a fifth dosage form comprising a therapeutically active amount of pasalicilib or a pharmaceutically acceptable salt thereof.

[0049] In another embodiment, troriluzole can be paired with VAL-083 to treat glioblastoma. VAL-083 is a bifunctional DNA targeting agent that has been shown to be active against a variety of solid tumors and hematological tumors in preclinical studies. VAL-083 has the following chemical structure:

[0050]

[0051] Troriluzole and VAL-083 may be contained in the same or different dosage forms. In one aspect, the method of treating glioblastoma with troriluzole in a patient in need of such treatment further comprises administering to the patient a sixth dosage form comprising a therapeutically active amount of VAL-083 or a pharmaceutically acceptable salt thereof.

[0052] In another embodiment, troriluzole can be paired with VT1021 to treat glioblastoma. VT1021 is a dual modulatory compound developed by Vigeo Therapeutics Ltd. that blocks the CD47 immune checkpoint and activates CD36, which will induce apoptosis and increase the M1:M2 macrophage ratio.

[0053] Troriluzole and VT1021 may be contained in the same or different dosage forms. In one aspect, the method of treating glioblastoma with troriluzole in a patient in need of such treatment further comprises administering to the patient a seventh dosage form comprising a therapeutically active amount of VT1021 or a pharmaceutically acceptable salt thereof.

[0054] In another embodiment, the method of treating glioblastoma may further comprise irradiating the glioblastoma cells with a therapeutically effective dose of ionizing radiation.

[0055] In another embodiment, a pharmaceutical composition is provided, comprising troriluzole and an additional anticancer agent selected from the group consisting of temozolomide, lomustine, regorafenib, pasalicibub, VAL-083, VT1021, and any combination thereof, in an amount effective for treating glioblastoma. For example, the pharmaceutical composition may comprise troriluzole and temozolomide or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise troriluzole and lomustine or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise troriluzole and regorafenib or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise troriluzole and pasalicibub or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise troriluzole and VAL-083 or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise troriluzole and VT1021 or a pharmaceutically acceptable salt thereof.

[0056] Treatment method based on

[0057] A new drug, troriluzole, is being developed for the treatment of neurological and psychiatric disorders and other potential indications. Troriluzole is a novel orally administered prodrug of the glutamatergic agent riluzole. The FDA initially approved riluzole For the treatment of patients with amyotrophic lateral sclerosis (ALS) 1 Riluzole is only indicated for ALS and has a number of undesirable attributes that have limited its clinical development and use. Troriluzole is a tripeptide prodrug of the glutamate modulator riluzole that has been optimized to improve bioavailability, pharmacokinetics, and dosing.

[0058] The research presented in glioblastoma multiforme (GBM) builds on accumulating evidence that glutamatergic dysregulation is implicated in the pathophysiology of many different tumors. Additionally, preclinical and clinical evidence using troriluzole (or its active metabolite, riluzole) suggests that troriluzole has the potential to be an effective treatment for these tumors, complementary to existing standard of care (SOC) therapies. The large unmet need combined with the available data provide a compelling rationale for developing troriluzole as a complementary treatment for GBM.

[0059] Riluzole was initially developed as a centrally acting muscle relaxant and subsequently as an anticonvulsant and neuroprotectant. The primary mode of action of riluzole is to reduce synaptic glutamate levels. This occurs via two mechanisms: (1) riluzole increases glutamate uptake from synapses by glial cells, and (2) riluzole reduces glutamate release from presynaptic neurons. Riluzole reduces the release of glutamate from presynaptic neurons because it inactivates voltage-gated sodium channels on glutamatergic nerve terminals that mediate depolarization of presynaptic neurons. In addition, riluzole increases glutamate uptake from synapses by enhancing the expression and function of excitatory amino acid transporters (i.e., EAAT2) located on glial cells, which play a key role in clearing glutamate from synapses. 2-8 In addition, riluzole has a range of other therapeutically relevant pharmacological actions, including modulation of neurotransmitter signaling and ion channel function, and enhancement of neurotrophic and pro-survival cell signaling pathways.

[0060] As shown in FIG1 , troriluzole reduces extracellular glutamate levels by: (1) promoting extracellular glutamate reuptake by increasing the expression and function of excitatory amino acid transporters on glial cells, and (2) reducing presynaptic glutamate release by inhibiting voltage-gated sodium channels.

[0061] The therapeutic agents included in GBM AGILE were selected through a rigorous scientific evaluation process. For more information, see Reference 9.

[0062] Glutamate promotes the maintenance, proliferation, migration and invasion of GBM. GBM is characterized by changes in cellular metabolism, especially changes in glutamate homeostasis. Dysregulation of glutamate transporters (SXC [Cl-dependent cystine / glutamate exchanger], EAAT) can lead to excessive secretion into the microenvironment and reduced glutamate reabsorption. Excess glutamate acts in an autocrine / paracrine manner to activate glutamate receptors and promote tumor growth and invasion. Excess glutamate also has an inhibitory effect on T cell function and causes excitotoxic neuronal death. Tumor growth / invasion and excitotoxicity lead to GBM-related seizures. Neuronal activity can stimulate tumor progression via glutamatergic neuron-glioma synaptic communication. Non-clinical evidence supports the study of anti-glutamatergic agents as potential GBM therapies.

[0063] Troriluzole was chosen for inclusion in the trial because it is a potent glutamate modulator, a novel targeted therapy, and a potential treatment for glioblastoma that shows minimal toxicity.

[0064] Troriluzole works by reducing extracellular glutamate levels at synaptic junctions. This is achieved through two mechanisms: (1) promoting extracellular glutamate reuptake by increasing the expression and function of excitatory amino acid transporters (EAATs) on glial cells, and (2) reducing presynaptic glutamate release by inhibiting voltage-gated sodium channels.

[0065] In addition to its mechanism of action, there are other ostensible reasons to believe that troriluzole could provide benefit to GBM patients. Preclinical and clinical data have shown promising therapeutic effects.

[0066] Preclinical data in GBM models showed the following key conclusions about riluzole and troriluzole:

[0067] ● Combination of riluzole and radiation enhances radiation-induced cytotoxicity in the U87MG cell line in an anchorage-independent colony formation assay 10 .

[0068] ● In the CAM assay in 64SP stem-like cells, the combination of riluzole and radiation enhances sensitivity to radiation 11 .

[0069] ● Riluzole combined with temozolomide (TMZ) via O 6 -Inhibition of methylguanine-DNA-methyltransferase (MGMT) expression to enhance the effect of TMZ 12 .

[0070] Troriluzole treatment induced a survival benefit, promoted the proliferation of tumor-infiltrating T cells, and synergized with anti-PD-1 immunotherapy to further improve survival and reduce regulatory T cells in the glioma tumor microenvironment (TME) 13 .

[0071] ●Preclinical IF data showed that the concentration of CD4+ T cells in the TME increased after troriluzole treatment. In addition, troriluzole monotherapy and combination with anti-PD-1 therapy led to increased proliferation of CD3+ tumor-infiltrating lymphocytes 13 .

[0072] Preliminary clinical data from trials of troriluzole (or its active metabolite) also suggest that it has the potential for pharmacodynamic and clinical responses in non-GBM tumors.

[0073] In summary, glutamatergic signaling has been shown to promote glioblastoma proliferation, migration, and invasion. Recently, the interaction between neuronal signaling and glioma cells has led to increased interest in targeting glutamate receptors. Troriluzole is a glutamate modulator that has been shown to affect glioblastoma growth in animal models. It has an acceptable safety profile, and there is evidence that it can penetrate the blood-brain barrier. Combination studies with riluzole in glioma model systems have shown enhanced sensitivity to both radiation and TMZ. For these reasons, the arm selection committee felt that the inclusion of troriluzole in the GBM AGILE trial would provide an opportunity to more fully evaluate its efficacy in GBM.

[0074] Troluzole dose selection

[0075] This study will start by evaluating troriluzole administered at 200mg BID in the dose exploration phase and perform dose confirmation. The dose is selected based on accumulated experience, including nonclinical toxicology and safety / tolerance, pharmacokinetic and pharmacodynamic data. Importantly, the MTD of troriluzole is determined to be 140mg QAM+280mg PO QPM. The 200mg BID dose represents a simpler regimen for patients to follow (the same dose interval is administered approximately 12 hours) without significantly affecting the exposure of riluzole. A population PK model was developed that utilizes data from healthy subjects and patients with several indications (SCA, OCD, AD and GAD) being studied with troriluzole, and is used to simulate the exposure of riluzole after administering troriluzole 200mg BID and 140mg QAM+280mg QPM MTD. Table 1 presents the simulated riluzole C in healthy subjects and patients. max and AUC 0-24 .

[0076] Table 1 : Median (90% prediction interval) steady-state riluzole exposure parameters after troriluzole administration a

[0077]

[0078] a The simulation population was assumed to be 50% female, and age and weight were randomly sampled by sex with replacement from the data set. Simulations assumed no fluvoxamine was used, and the evening dose was assumed to be administered in the fed state. The fed state for the morning dose was assumed to be 50%.

[0079] As shown in Table 1, the simulated riluzole exposure after administration of troriluzole 200 mg BID was similar to the simulated riluzole exposure after administration of the MTD and is expected to be safe in the glioblastoma population. A dose-finding phase will be implemented to confirm this recommended dose of troriluzole when combined with radiotherapy and temozolomide and lomustine and ensure the safety of the patients.

[0080] Overview of the Troriluzole Arm

[0081] The troriluzole arm is open to patients with 1) NDU GBM, 2) NDM GBM, and 3) recurrent GBM of any methylation status. Troriluzole is being studied in combination with temozolomide and radiation in newly diagnosed patients and with lomustine in patients with first recurrent disease, therefore, a dose-finding phase is being conducted to confirm the dose of troriluzole to ensure the safety of these combinations in patients with glioblastoma. A rolling 6 design is being conducted to determine the starting dose.

[0082] Once patients are assigned to the troriluzole arm, they will receive additional safety assessments, including adverse events, dose modification profiles, hematology, full serum chemistry, and coagulation profiles collected every two weeks. These additional safety assessments, known as Enhanced Safety Management (ESM), will be performed in approximately 30 patients initially assigned to the troriluzole arm: 20 newly diagnosed patients (NDU and NDM) and 10 relapsed patients.

[0083] As part of GBM AGILE, the troriluzole arm will consist of 2 stages: The first stage will be a Bayesian adaptive randomization screening stage (Stage 1) to identify the effectiveness of troriluzole in improving survival. In Stage 1, a target maximum sample size of 200 patients will be randomly assigned to the troriluzole arm in all applicable disease subtypes. The second stage (Stage 2) will use fixed randomization to confirm the efficacy signal identified in Stage 1 and support drug approval. The target maximum sample size in Stage 2 is 50 patients in the experimental arm. The initial screening stage (Stage 1) uses a Bayesian adaptive randomization algorithm to assign patients to the experimental arm or the control arm based on their disease subtype (defined below).

[0084] Dose-finding phase

[0085] Troriluzole has been studied in a variety of diseases and oncology areas and is well tolerated. However, GBMAGILE is the first trial to study troriluzole in combination with temozolomide and radiation in newly diagnosed patients and with lomustine in patients with relapsed disease. To confirm the recommended dose of troriluzole when used in combination with radiation therapy and temozolomide and lomustine, and to ensure patient safety, troriluzole will undergo a dose-finding phase. This phase of the study will be conducted only at selected research centers in the United States and will be completed before initiating the arm in other regions.

[0086] Newly diagnosed patients. The first 6 patients in the newly diagnosed subtype will receive troriluzole 100 mg BID in the first two weeks, followed by 200 mg BID in the next two weeks, in combination with temozolomide and radiation therapy. If no DLT is observed in these 6 patients or 1 DLT is observed (1 / 6), these patients will continue to participate in the study and will continue to receive enhanced safety monitoring (ESM) (described in detail below), and this dose will be determined as dose level 0 or starting dose.

[0087] If there are 2 DLTs in the first 6 patients (2 / 6), the dose will be de-escalated to 100 mg once a day in the morning (qAM) and 200 mg once a day in the evening (qPM) for 4 weeks. Then 6 patients will receive 100 mg qAM, followed by 200 mg qPM for 4 weeks and observe for DLTs. If no DLTs are observed or 1 DLT is observed in these 6 patients (1 / 6), these patients will continue to participate in the study and will continue to receive ESM (described in detail below), and this dose of 100 mg qAM and 200 mg qPM will be determined as dose level 0 or starting dose.

[0088] If there are 2 DLTs in these 6 patients (2 / 6), the dose will be de-escalated to 100 mg BID. The 6 patients will then receive 100 mg BID for 4 weeks and observe for DLTs. If no DLTs are observed or 1 DLT is observed in the 6 patients (1 / 6), these patients will continue to participate in the study and will continue to receive ESM (described in detail below), and this 100 mg BID dose will be determined as dose level 0 or starting dose.

[0089] Patients with relapsed disease. Similarly, the first 6 patients in the relapsed disease subtype will receive troriluzole at 100 mg BID for the first two weeks, followed by 200 mg BID for the next two weeks, in combination with lomustine. These patients will be monitored for DLT for 4 weeks. If no DLT is observed in 6 patients or 1 DLT (1 / 6) is observed, these patients will continue to participate in the study and will continue to receive ESM (described in detail below), and the troriluzole dose of 200 mg BID will be determined as dose level 0 or starting dose.

[0090] If there are more than 2 / 6 DLTs in the first 6 patients, the dose will be de-escalated to 100 mg once a day in the morning (qAM) and 200 mg once a day in the evening (qPM) for 4 weeks. Then 6 patients will receive 100 mg qAM, followed by 200 mg qPM for 4 weeks and observe DLTs. If no DLTs are observed in 6 patients or 1 DLT (1 / 6) is observed, these patients will continue to participate in the study and will continue to receive ESM (described in detail below), and this dose of 100 mg qAM and 200 mg qPM will be determined as dose level 0 or starting dose.

[0091] If there are 2 DLTs in these 6 patients (2 / 6), the dose will be de-escalated to 100 mg BID. The 6 patients will then receive 100 mg BID for 4 weeks and observe for DLTs. If no DLTs are observed or 1 DLT is observed in the 6 patients (1 / 6), these patients will continue to participate in the study and will continue to receive ESM (described in detail below), and this 100 mg BID dose will be determined as dose level 0 or starting dose.

[0092] If there is dose de-escalation, patients who received a higher dose during the dose-finding phase and did not have any DLTs can continue in the trial and receive the confirmed starting dose. However, these patients will not be included in the final analysis.

[0093] DLTs should be reversible and can be monitored within 4 weeks. An evaluable DLT will be considered a DLT for which the patient has received 75% or more of the study drug during the dose-finding phase. If a patient has a DLT before receiving 75% of the study drug during this phase, a new patient will be added to the rolling 6 design to replace that patient in order to complete the evaluation. Patients will be evaluated for AEs every two weeks during the dose-finding phase. In addition, patients will also receive ESM evaluations during this phase.

[0094] After the sixth patient is enrolled in the dose-finding phase, enrollment in the troriluzole arm will be paused for 4 weeks to allow for DLT evaluation in this patient, according to a rolling 6 design. After completion of the DLT evaluation, the starting dose will be confirmed and enrollment will resume for both newly diagnosed and relapsed subtypes on the troriluzole arm.

[0095] Enhanced Security Management (ESM)

[0096] Enhanced Safety Management is a seamless process for new arms with combination agents from different classes that have limited safety data to complement and support their inclusion in the GBM AGILE trial. The decision to adopt ESM for these arms into GBM AGILE was based on the recommendation of the Arm Selection Committee. ESM provides agents with a well-tolerated safety profile the opportunity to be tested in all subgroups in GBM AGILE (newly diagnosed methylated patients, newly diagnosed unmethylated patients, and relapsed patients). ESM will be conducted only at selected research centers in the United States and will be completed prior to launching the arm in other regions.

[0097] Once patients are assigned to the troriluzole arm, they will receive additional safety assessments, including adverse events, dose adjustment profiles, hematology, serum chemistry panels, and coagulation profiles collected every two weeks. These additional safety assessments will be performed in approximately 30 patients initially assigned to the troriluzole arm. Although there is no minimum or maximum number of patients, it is estimated that there will be approximately 20 newly diagnosed patients and 10 relapsed patients.

[0098] These additional assessments will be input into monthly reports, reviewed by the global principal investigator (PI) and medical monitor (MM), and submitted to 1-2 clinical members of the Data and Safety Monitoring Board (DSMB).

[0099] Clinical leadership and the DSMB will monitor ESM in the following ways:

[0100] ● Real-time: Global PI and MM will monitor in real time for dose adjustments or temporary discontinuation based on AE assessment.

[0101] ●Monthly Reporting: The global PI and MM will review the monthly data and will seek the recommendation of 1 to 2 clinical members of the DSMB to continue or suspend ESM data collection or to discontinue a study arm.

[0102] ● Quarterly Reporting: Consolidated ESM data prior to this date will be submitted at quarterly DSMB meetings. Decisions made based on monthly reporting will be reviewed by all members of the DSMB. If the decision to suspend ESM data collection occurs between quarterly DSM meetings, an interim review by all DSMB members may be requested.

[0103] If the DSMB decides to discontinue the ESM, researchers will be notified and no additional safety measurements will be required.

[0104] If, during the ESM, the DSMB determined that there was a grade 5 event or any two grade 4 events were at least possibly related to troriluzole, patient recruitment would be paused until the DSMB performed a thorough safety review as recommended by the DSMB members, and then enrollment would resume.

[0105] Treatment Procedure

[0106] Required Tests or Evaluations. Unless otherwise specified below, the following procedures were performed at each visit for newly diagnosed patients and relapsed patients prior to administration of troriluzole (±3 days).

[0107] ● Neurological examination, i.e. clinical assessment of neurological function according to local practice. Note: For patients with relapse, if within 14 days after randomization and If the additional assessment is performed on Cycle 1 (C1) Day 1 (D1), patients do not need to undergo this additional assessment on C1D1.

[0108] ●Assess vital signs (including BP, temperature, and heart rate) according to local practice.

[0109] ECGs should be collected during the Screening Period and as follows:

[0110] ○ For newly diagnosed patients: Day 1 and Day 29 of the treatment phase and Day 1 of each cycle during the maintenance phase

[0111] ○ For relapsed patients: Day 1 of each cycle

[0112] ○ Additional ECG monitoring should be performed for all participants in the troriluzole arm as clinically indicated

[0113] Karnofsky performance status according to local practice (see Table 2 below).

[0114] ●Adverse event assessment.

[0115] ●Concomitant medication.

[0116] ●Use of corticosteroids.

[0117] QOL assessments (EORTC QLQ-C-30, EORTC QLQ-BN20, and EQ-5D-5L) should be performed on C1D1 before study treatment and then before patients receive any daily results (if feasible) and concurrently with radiographic response assessments as follows:

[0118] ○ For newly diagnosed patients: every 8 weeks (± 4 weeks).

[0119] ○ For recurrent patients: every 6 weeks (± 1 week).

[0120] Laboratory blood or urine tests (collected and assessed locally):

[0121] ○ hematology: Complete blood count with differential (absolute), including but not limited to:

[0122] ■Red blood cell count.

[0123] ■Hemoglobin.

[0124] ■Hematocrit.

[0125] ■White blood cell count.

[0126] ■Absolute neutrophil count.

[0127] ■Absolute lymphocyte count.

[0128] ■Platelet count.

[0129] ○ Serum Chemistry: The full range of chemistry includes but is not limited to:

[0130] ■Sodium.

[0131] Potassium.

[0132] ■Calcium.

[0133] ■Chlorine.

[0134] ■Blood urea nitrogen.

[0135] ■Creatinine.

[0136] ■Fasting blood sugar.

[0137] ■Total bilirubin (if total bilirubin is above the upper limit of normal, direct and indirect bilirubin tests should be performed).

[0138] ■Aspartate aminotransferase / serum glutamate oxaloacetate aminotransferase (AST / SGOT).

[0139] ■Alanine aminotransferase (ALT / SGPT).

[0140] ■Lipase.

[0141] ■Amylase.

[0142] ○ Perform urinalysis according to local practice.

[0143] ● Administer or distribute study treatment.

[0144] MRI to assess response / evaluate tumor:

[0145] ○ For newly diagnosed patients: every 8 weeks (± 4 weeks).

[0146] ○ For recurrent patients: every 6 weeks (± 1 week).

[0147] Note: For patients with relapse, if within 14 days after randomization and If the patient has an MRI scan on C1D1, then the patient does not need to undergo this additional MRI on C1D1. For newly diagnosed patients and patients with a relapse, MRI scans should be performed at the above frequency regardless of whether treatment is delayed. If the criteria for progressive disease are met “preliminarily”, a confirmatory MRI scan must be performed no earlier than 4 weeks later in accordance with section 14.2.3 of the master protocol.

[0148] • Study blood samples were collected from consenting patients on day 1 of each cycle.

[0149] Table 2. Karnofsky physical status scale definition assessment (%) standard.

[0150]

[0151]

[0152] For more information, see reference 17.

[0153] Timeline of Events in the Troriluzole Arm. In the Troriluzole arm, the above evaluations will be performed according to the study calendar.

[0154] A ±3-day (or longer if otherwise specified) administration window is allowed for all treatment visits (defined as including “required testing or evaluations”) throughout this protocol. Delays in treatment or visits due to public holidays or weather conditions or force majeure do not constitute a protocol violation and every effort should be made to adhere to the prescribed assessment schedule.

[0155] End-of-Treatment Assessment. All procedures described need to be completed within 14 days before discontinuation or completion of troriluzole or repeated at the End-of-Treatment Visit within 14 days after discontinuation or completion of troriluzole.

[0156] All patients will be evaluated for safety 28 days after their last dose of troriluzole.

[0157] Post-treatment follow-up evaluations. Post-treatment follow-up evaluations should be completed as described below.

[0158] Treatment of patients

[0159] Patient Dosing Instructions. Subjects randomized to the troriluzole experimental arm will receive the troriluzole dose identified for each cohort during the dose-finding phase.

[0160] All subjects were advised to take study medication twice daily, once in the morning and once in the evening (approximately 12 hours apart and at the same time each day), regardless of meals.

[0161] Newly diagnosed patients will receive TMZ 75 mg / m during the treatment period. 2 Oral (7 days per week), and during the maintenance phase, the first cycle of TMZ will be 150 mg / m 2 , on days 1-5 of a 28-day cycle. If there is no toxicity, the second and subsequent cycles of maintenance therapy will be 200 mg / m 2 , on days 1-5 of a 28-day cycle. In the maintenance phase, TMZ will be combined with troriluzole for up to 6 cycles. After 6 cycles, patients will continue to receive troriluzole alone.

[0162] Relapsed patients will receive lomustine 110 mg / m2 on day 1 of a 42-day cycle for up to 6 cycles. After 6 cycles, patients will continue to receive troriluzole only.

[0163] Concomitant medications. Prior and concomitant use of riluzole was prohibited.

[0164] Because of the potential for drug interactions, caution should be exercised when troriluzole is used with drugs that are inhibitors or inducers of the CYP1A2 enzyme system, and troriluzole should be avoided with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin). Subjects should be monitored appropriately while taking CYP1A2 inhibitors or inducers. The following drugs are prohibited for at least 5 half-lives before randomization and during the study:

[0165] 1. Strong to moderate CYP1A2 inhibitors, which may increase the risk of riluzole-related AEs, including the SSRI fluvoxamine; strong inhibitors are prohibited.

[0166] 2. Strong to moderate CYP1A2 inducers, which may lead to reduced efficacy.

[0167] 3. Hepatotoxic drugs (e.g., allopurinol, methyldopa, sulfasalazine), which may increase the risk of hepatotoxicity.

[0168] Oral contraceptives containing ethinyl estradiol (a moderate CYP1A2 inhibitor) are permitted.

[0169] Growth Factors. See below for growth factors permitted for use in supportive care.

[0170] Anticoagulants. There were no additional guidelines regarding anticoagulants for the troriluzole arm.

[0171] Herbal preparations / drugs. It is strongly recommended not to use medical or recreational marijuana and cannabidiol (CBD) oil within 30 days before randomization.

[0172] Other anticancer or experimental therapies. There were no additional guidelines regarding other anticancer or experimental therapies for the troriluzole arm.

[0173] Supportive Care. There were no additional guidelines regarding supportive care for the troriluzole arm.

[0174] Antiemetic Medication. Premedication with antiemetic therapy is permitted if clinically indicated.

[0175] Antiepileptic medications. No additional guidance was available regarding antiepileptic medications for the troriluzole arm.

[0176] Dose Modifications and Toxicity Management. The following Tables 3-5 summarize the dose modifications of troriluzole. Dose modifications will be the same in the newly diagnosed cohort and the relapsed cohort and will be based on the starting dose confirmed from the dose-finding phase. Toxicity will be graded according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5).

[0177] Table 3. Dose adjustment of troriluzole was indicated if 100 mg BID for two weeks followed by increase to 200 mg BID was confirmed as the starting dose.

[0178] Dosage Levels Troluzole daily Dose level 0 (starting dose) 100 mg BID for 2 weeks, then increase to 200 mg BID Dose Level-1 100 mg BID

[0179] If a clinically significant AE occurs while a participant is receiving troriluzole 200 mg BID and is judged to be related to troriluzole, the investigator may consider modifying the dosing regimen. Down-titration to 100 mg BID (dose level -1) is permitted after Week 2.

[0180] Trolizole may also be suspended at the investigator's discretion. Consultation with the medical supervisor is recommended. Once the issue is resolved, the dose may be titrated upward to 200 mg BID at the investigator's discretion.

[0181] Table 4. Dose adjustment of troriluzole if 100 mg qAM and 200 mg qPM are confirmed as starting doses.

[0182] Dosage Levels Troluzole daily Dose level 0 (starting dose) 100 qAM ​​and 200 mg qPM Dose Level-1 100 mg BID

[0183] Table 5. If 100 mg BID is confirmed as the starting dose, the dose of troriluzole should be adjusted.

[0184] Dosage Levels Troluzole daily Dose level 0 (starting dose) 100 mg BID

[0185] When there is＞ If a grade 3 DLT develops, troriluzole should be withheld. ＜ If the DLT is grade 1, troriluzole can be restarted at dose level -1. The DLT should resolve within 28 days to allow troriluzole to be restarted. ＞ For grade 3 DLT, the drug should be permanently discontinued.

[0186] Patients who develop toxicity described in the definition of DLT after dose reduction will be discontinued from the study. CTCAE defines dose-limiting toxicity (DLT) as toxicity that prevents further administration of the agent at that dose level.

[0187] An AE was considered a DLT if it was assessed as a clinically significant AE not related to tumor progression, intercurrent disease, temozolomide, radiation, or other concomitant medications (based on CTCAE v5.0).

[0188] DLTs should be defined as the following events that are not clearly attributable to the underlying disease or external causes:

[0189] Any death

[0190] Non-hematologic toxicity

[0191] ■Level 3 or higher

[0192] ■Hy's Law Case

[0193] Hematologic toxicity

[0194] Grade 4 neutropenia > 7 days

[0195] Grade 3 or higher thrombocytopenia with clinically significant bleeding

[0196] ■ Neutropenic fever

[0197] The DLT definition may exclude:

[0198] Grade 3 nausea / vomiting or diarrhea lasting less than 72 hours and receiving adequate antiemetic and other supportive care

[0199] Grade 3 fatigue lasting more than 1 week

[0200] Grade 3 or higher electrolyte abnormalities that persist for up to 72 hours, are clinically uncomplicated, and resolve spontaneously or respond to conventional medical interventions

[0201] Grade 3 or higher amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitis

[0202] Seizures of grade 3 or higher considered attributable to study drug (without further justification based on grade or baseline frequency), deep vein thrombosis, and pulmonary embolism will not be excluded as DLTs.

[0203] Dose modifications and discontinuation of TMZ should be as outlined in the guidelines provided in the locally approved regulatory prescribing information. Guidelines for hematologic toxicities (neutropenia and thrombocytopenia) should be followed as outlined in Table 6 below.

[0204] Table 6. Interruption or discontinuation of TMZ and troriluzole administration during the treatment and maintenance phases in newly diagnosed patients

[0205]

[0206] Dose adjustments and discontinuations of lomustine should be as outlined in the guidelines provided in the locally approved regulatory prescribing information. See Table 7 below for further details.

[0207] Table 7. Interruption or discontinuation of lomustine and troriluzole during the treatment phase in patients with relapse

[0208]

[0209]

[0210] Mild increases in liver enzymes are the most commonly observed adverse events with troriluzole. Guidelines for dose adjustments for liver enzymes are listed in Table 8 below. In general, mild liver enzyme elevations attributed to troriluzole occur due to enzyme induction and may resolve spontaneously within 12 weeks without any change in the dose of troriluzole. However, the investigator should evaluate the subject as appropriate.

[0211] For AST / ALT elevations greater than 3xULN, consultation with a medical supervisor is required within 72 hours. In these cases, clinical evaluation should include repeat laboratory assessments (ALT, AST, total and direct bilirubin, alkaline phosphatase, PT, aPTT, INR) within 1 week and continued until resolution. Additional testing (e.g., viral serology) may be performed as appropriate to investigate the cause of the liver enzyme increase. No specific management is required while TMZ and troriluzole are withheld, other than supportive care.

[0212] Guidelines for dose adjustments for changes in liver enzymes and bilirubin are listed below in Table 8.

[0213] Table 8. Dose adjustments for liver enzyme changes.

[0214]

[0215] *Unless the patient has a history of or is suspected of having Gilbert's syndrome.

[0216] References

[0217] 1. Covis Pharma. Rilutek (riluzole) US Prescribing Information. Revised March 2020. www.accessdata.fda.gov / drugsatfda_docs / label / 2020 / 020599s019lbl.pdf

[0218] 2. Sanderink GJ, Bournique B, Stevens J, Petry M, Martinet M. Involvement of human CYP1A isoenzymes in the metabolism and drug interactions of riluzolein in vitro. J Pharmacol Exp Ther. 1997; 282(3): 1465-1472. PMID: 9316860.

[0219] 3.Dunlop J,Beal McIlvain H,She Y,Howland DS.Impaired spinal cordglutamate transport capacity and reduced sensitivity to riluzole in atransgenic superoxide dismutase mutant rat model of amyotrophic lateralsclerosis.JNeurosci.2003;23(5):1688-1696.PMID:12629173.

[0220] 4.Sung B, Lim G, Mao J. Altered expression and uptake activity of spinalglutamate transporters after nerve injury contribute to the pathogenesis ofneuropathic pain in rats. J Neurosci. 2003; 23(7): 2899-2910. PMID: 12684477.

[0221] 5. Frizzo ME, Dall'Onder LP, Dalcin KB, Souza DO. Riluzole enhances glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol. 2004;24(1):123 - 128. PMID: 15049516

[0222] 6. Fumagalli E, Funicello M, Rauen T, Gobbi M, Mennini T. Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. Eur J Pharmacol. 2008;578(2 - 3):171 - 176. PMID: 18036519.

[0223] 7. Banasr M, Chowdhury GM, Terwilliger R, et al. Glial pathology in an animal model of depression: reversal of stress - induced cellular, metabolic and behavioral deficits by the glutamate - modulating drug riluzole. Mol Psychiatry. 2010;15(5):501 - 511. PMID: 18825147.

[0224] 8. Chowdhury GM, Banasr M, de Graaf RA, et al. Chronic riluzole treatment increases glucose metabolism in rat prefrontal cortex and hippocampus. J Cereb Blood Flow Metab. 2008;28(12):1892 - 1897. PMID: 18628780.

[0225] 9. Niciu MJ, Kelmendi B, Sanacora G. Overview of glutamatergic neurotransmission in the nervous system. Pharmacol Biochem Behav. 2012;100(4):656 - 664. PMID: 21889952.

[0226] 10. Khan AJ, LaCava S, Mehta et al. The glutamate release inhibitor riluzole increases DNA damage and enhances cytotoxicity in human glioma cells, in vitro and in vivo. Oncotarget. 2019;10(29):2824 - 2834. PMID: 31073373.

[0227] 11. Sperling S, Aung T, Martin S, Rohde V, Ninkovic M. Riluzole: a potential therapeutic intervention in human brain tumor stem - like cells. Oncotarget. 2017;8(57):96697 - 96709. PMID: 29228563.

[0228] 12. Yamada, T, Tsuji, S, Nakamura, S, et al. Riluzole enhances the antitumor effects of temozolomide via suppression of MGMT expression in glioblastoma, J Neurosurg. 2020;134(3):701 - 710. PMID: 32168477.

[0229] 13. Medikonda, R., Choi, J., Pant, et al. Synergy between glutamate modulation and anti–programmed cell death protein 1 immunotherapy for glioblastoma, J Neurosurg. 2021;13:1-10. PMID: 34388730.

[0230] 14. Ashizawa T, Figueroa KP, Perlman SL, et al. Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US; a prospective observational study. Orphanet J Rare Dis 2013;8:177. PMID: 24225362.

[0231] 15. Silk AW, Saraiya B, Groisberg R, et al. A phase Ib study of troriluzole (BHV-4157) in combination with nivolumab. J Clin Oncol. 2020;38:suppl 5; abstract 79.

[0232] 16. Merck. (temozolomide) US Prescribing Information. Revised Date: November 2019. https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2019 / 021029s033lbl.pdf

[0233] 17. Schag CC, Heinrich RL, Ganz PA. Karnofsky performance status revisited: reliability, validity, and guidelines. J Clin Oncol. 1984;2(3):187-193. PMID: 6699671.

[0234] Throughout this application, various publications are cited by author name and date or by patent number or patent publication number. The disclosures of these publications are hereby incorporated by reference in their entirety into this application in order to more fully describe the prior art known to those skilled in the art as of the date of the invention described and claimed herein. However, citation of references herein should not be construed as an admission that such references are prior art to the present invention.

[0235] Those skilled in the art will recognize or be able to determine many equivalents of the specific procedures described herein using no more than routine experiments. Such equivalents are considered to be within the scope of the present invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and embodiments herein may be used. In addition, it is contemplated that specific items within a list of items or item sub-cluster groups within a larger item group may be combined with other specific items, item sub-cluster groups, or larger item groups, regardless of whether there is a specific disclosure identifying such a combination herein.

Claims

1. A method of treating glioblastoma in a patient in need of such treatment, the method comprising administering to the patient a first dosage form comprising a therapeutically active amount of troriluzole or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the first dosage form comprises 100 mg of troriluzole or an equivalent amount of a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 or 2, wherein the first dosage form comprises 200 mg of troriluzole or an equivalent amount of a pharmaceutically acceptable salt thereof.

4. The method according to any one of claims 1 to 3, wherein the first dosage form is administered once a day.

5. The method according to any one of claims 1 to 4, wherein the first dosage form is administered twice daily.

6. The method according to any one of claims 1 to 5, wherein the duration of the treatment is four weeks and wherein troriluzole or a pharmaceutically acceptable salt thereof is administered in an amount of 100 mg twice a day for the first two weeks and in an amount of 200 mg twice a day for the other two weeks.

7. The method according to any one of claims 1 to 6, wherein the total amount of troriluzole or a pharmaceutically acceptable salt thereof administered to the patient during one day is 200 mg.

8. The method according to any one of claims 1 to 7, wherein the total amount of troriluzole or a pharmaceutically acceptable salt thereof administered to the patient during one day is 300 mg.

9. The method according to any one of claims 1 to 8, wherein the total amount of troriluzole or a pharmaceutically acceptable salt thereof administered to the patient during one day is 400 mg.

10. The method according to any one of claims 1 to 9, further comprising administering to the patient a second dosage form comprising a therapeutically active amount of temozolomide or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the second dosage form comprises 75 mg of temozolomide or an equivalent amount of a pharmaceutically acceptable salt thereof.

12. The method according to claim 10 or 11, wherein the second dosage form comprises 150 mg of temozolomide or an equivalent amount of a pharmaceutically acceptable salt thereof.

13. The method according to any one of claims 10 to 12, wherein the second dosage form is administered once a day.

14. The method according to any one of claims 10 to 13, wherein the second dosage form is administered twice daily.

15. The method according to any one of claims 10 to 14, wherein the total amount of temozolomide or a pharmaceutically acceptable salt thereof administered to the patient during one day is 75 mg.

16. The method according to any one of claims 10 to 15, wherein the total amount of temozolomide or a pharmaceutically acceptable salt thereof administered to the patient during one day is 150 mg.

17. The method according to any one of claims 1 to 16, wherein the glioblastoma is newly diagnosed. 6 -methylguanine-DNA-methyltransferase (MGMT) methylation in glioblastoma.

18. The method according to any one of claims 1 to 16, wherein the glioblastoma is newly diagnosed. 6 -Methylguanine-DNA-methyltransferase (MGMT) is not methylated in glioblastoma.

19. The method of claim 1, further comprising administering to the patient a third dosage form comprising a therapeutically active amount of lomustine or an equivalent amount of a pharmaceutically acceptable salt thereof.

20. The method of claim 19, wherein the third dosage form comprises 50 mg of lomustine or an equivalent amount of a pharmaceutically acceptable salt thereof.

21. The method of claim 19 or 20, wherein the third dosage form comprises 100 mg of lomustine or an equivalent amount of a pharmaceutically acceptable salt thereof.

22. The method of any one of claims 19 to 21, wherein the third dosage form is administered once a day.

23. The method according to any one of claims 19 to 22, wherein the third dosage form is administered twice daily.

24. The method according to any one of claims 19 to 23, wherein the total amount of lomustine or a pharmaceutically acceptable salt thereof administered to the patient during a day is 100 mg.

25. The method of any one of claims 19 to 24, wherein the glioblastoma is a recurrent glioblastoma.

26. The method of any one of claims 1 to 25, further comprising irradiating the glioblastoma cells with a therapeutically effective dose of ionizing radiation.

27. A kit for use in a method of treating a patient suffering from glioblastoma, the kit comprising: (a) troriluzole or a pharmaceutically acceptable salt thereof; (b) temozolomide or a pharmaceutically acceptable salt thereof; and (b) instructions for administering troriluzole and temozolomide according to the method of any one of claims 1 to 26.

28. A kit for use in a method of treating a patient suffering from glioblastoma, the kit comprising: (a) troriluzole or a pharmaceutically acceptable salt thereof; (b) lomustine or a pharmaceutically acceptable salt thereof; and (b) instructions for administering troriluzole and temozolomide according to the method of any one of claims 1 to 26.

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