Method for treating glioblastoma using a prodrug of riluzole

Abstract

A method of treating glioblastoma in a patient in need of treatment for glioblastoma, the method comprising administering to the patient a first dosage form comprising a therapeutically effective amount of tolrolizumab or a pharmaceutically acceptable salt thereof is provided.

Description

Technical Field

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

Background Art

[0002] Glioblastoma (GBM) is a rapidly growing and aggressive brain tumor that invades nearby brain tissue but usually does not spread to distant organs. In adults, GBM most frequently occurs in the cerebral hemispheres, particularly the frontal and temporal lobes of the brain. GBM is a devastating brain cancer with no cure and a high likelihood of death within six months. Therefore, there is an urgent need for new drugs to treat this aggressive type of cancer.

[0003] Troriluzole is a novel tripeptide prodrug of the glutamate modulator riluzole. Riluzole is the active ingredient of RILUTEK®, a reference listed drug approved for the treatment of amyotrophic lateral sclerosis (ALS). In addition, clinical trials and translational research have suggested that riluzole may be an effective treatment for several other indications. However, the optimal use of riluzole is limited by several factors. Riluzole tablets have a bioavailability of approximately 60%, which is due to high first-pass effect in the liver and variable metabolism by the non-uniformly expressed CYP1A2 enzyme. These factors result in relatively high pharmacokinetic (PK) variability after riluzole administration. Riluzole is also associated with decreased absorption when taken with food (i.e., food effect), which may lead to reduced systemic exposure. Therefore, it is recommended that riluzole be administered 1 hour before or 2 hours after a meal (i.e., 3-hour fasting). Riluzole has a dose-dependent effect on liver function tests (LFTs). The riluzole drug substance itself has other inherent limitations, including very low solubility in water, poor oral palatability, pH-dependent chemical stability, and a strong oral numbness sensation when administered directly to the oral mucosa.

[0004] Troriluzole was developed to mitigate the aforementioned limitations of riluzole. Troriluzole is a novel and rationally designed third-generation tripeptide prodrug that may offer improvements in bioavailability, pharmacology, safety, and administration. Troriluzole is actively absorbed in the intestine (via the peptide transporter [PepT1]), is not affected by food effects, is rapidly cleaved by aminopeptidases in the systemic circulation to release the active metabolite, and is expected to produce a predictable exposure of its active metabolite, bypass first-pass metabolism, reduce the hepatic load of riluzole, and enable the search for higher concentrations of the active metabolite.

[0005] Trolezol has been reported to be potentially useful in treating certain types of cancer. However, there is no evidence showing that trolezol is effective in treating glioblastoma.

Summary of the Invention

[0006] The present invention is directed to a method of treating glioblastoma by administering a prodrug of rilzol as either a monotherapy or in combination therapy with another anti-cancer 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 includes administering to the patient a first dosage form comprising a therapeutically effective amount of trolezol or a pharmaceutically acceptable salt thereof.

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

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

[0010] In still another embodiment, the method may further include irradiating glioblastoma cells with a therapeutically effective dose of ionizing radiation.

Brief Description of the Drawings

[0011]

Figure 1

Modes for Carrying Out the Invention

[0012] The following detailed description is provided to assist those skilled in the art in practicing the present invention. Exemplary embodiments are described in detail below. However, these embodiments are merely examples and the present disclosure is not limited thereto, but rather is defined by the appended claims. Those skilled in the art can modify and vary the embodiments described herein without departing from the spirit or scope of the present disclosure.

[0013] Accordingly, embodiments are described below only by reference to structures and schemes for purposes of illustrating aspects of this 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", when preceding a list of elements, modify the entire list of elements and not the individual elements of the list.

[0014] When an element is referred to as being "on" another element, it will be understood that it may 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, no intervening elements are present.

[0015] The terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers, and / or sections, but it will be understood that these elements, components, regions, layers, and / or sections are not to be limited by these terms. These terms are only used to distinguish one element, component, region, layer, or section from another. Thus, the first element, component, region, layer, or section discussed below could be termed a second element, component, region, layer, or section without departing from the teachings of this embodiment.

[0016] As used herein, the terms "comprise" and / or "comprising", or "include" and / or "including" specify the presence of the stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude 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 have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The terms used herein are for the purpose of describing particular embodiments only and are not intended to be limiting. Terms such as those defined in commonly used dictionaries should be interpreted to have a meaning that coincides with their meaning in the context of the relevant art and this disclosure, and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

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

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

[0020] Additional aspects will be described in part in the following description and will in part become apparent from the description.

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

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

Chemical formula

[0023] The first dosage form may contain a corresponding amount of 10 - 500 mg of tolylazole or a pharmaceutically acceptable salt thereof. In some embodiments, the first dosage form may contain a corresponding amount of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg of tolylazole, or a pharmaceutically acceptable salt thereof. For example, the first dosage form may contain a corresponding amount of 100 mg or 200 mg of tolylazole or a pharmaceutically acceptable salt thereof.

[0024] The first dosage form may 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 may be administered once a day or twice a day.

[0025] The treatment period can range from several days to several weeks or months. For example, the treatment may be administered for 1, 2, 3, 4, 5, 6, or 7 days. In another example, the treatment may be administered for 1, 2, 3, 4, 5, 6, or 7 weeks. In another example, the treatment may be administered for 1, 2, 3, 4, 5, 6, or 7 months. In one embodiment, the treatment may be administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 days. In another example, the treatment may be administered in cycles consisting of 28 days. In another example, the treatment may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cycles of 28 days.

[0026] In one aspect, the treatment period may be 4 weeks, and torilazol or a pharmaceutically acceptable salt thereof may be administered in an amount of 100 mg twice a day for the first 2 weeks and in an amount of 200 mg twice a day for the remaining 2 weeks.

[0027] In one aspect, the total amount of torilazol or a pharmaceutically acceptable salt thereof administered to the patient in a day may be 50 - 1000 mg. For example, the total amount of torilazol administered to the patient in 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 torilazol administered to the patient in a day may be 200 mg, 300 mg, or 400 mg.

[0028] In another embodiment, torilazol can be combined with temozolomide to treat glioblastoma. Temozolomide is an agent for treating brain tumors having the following chemical structure:

Chemical formula

[0029] Torilazol and temozolomide may be included in the same dosage form or different dosage forms. In one aspect, the method of treating glioblastoma using torilazol may further include administering to the patient a second dosage form containing a therapeutically effective amount of temozolomide or a pharmaceutically acceptable salt thereof. The second dosage form may contain a corresponding amount of 10 - 300 mg of temozolomide or a pharmaceutically acceptable salt thereof. For example, the second dosage form may contain 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 a corresponding amount of a pharmaceutically acceptable salt thereof. For example, the second dosage form may contain 75 or 150 mg of temozolomide or an equivalent amount of a pharmaceutically acceptable salt thereof.

[0030] The second dosage form can be administered once, twice, three times, or four times a day. For example, the second dosage form can be administered once or twice a day.

[0031] In one aspect, the total amount of temozolomide or a pharmaceutically acceptable salt thereof administered to a patient in a day may be 50 - 300 mg. For example, the total amount of temozolomide or a pharmaceutically acceptable salt thereof administered to a patient in a day may be 75 mg. In another example, the total amount of temozolomide or a pharmaceutically acceptable salt thereof administered to a patient in a day may be 150 mg.

[0032] Glioblastoma is newly diagnosed O 6 -methylguanine-DNA-methyltransferase (MGMT)-methylated glioblastoma or O 6 -methylguanine-DNA-methyltransferase (MGMT)-unmethylated glioblastoma.

[0033] In another embodiment, trolipazole can be combined with lomustine to treat glioblastoma. Lomustine is an alkylating nitrosourea compound used in chemotherapy having the following structure:

Chemical formula

[0034] Trolipazole and lomustine may be included in the same dosage form or different dosage forms. In one aspect, a method for treating glioblastoma using trolipazole may further include administering to a patient a third dosage form comprising a therapeutically effective amount of a corresponding amount of lomustine or a pharmaceutically acceptable salt thereof.

[0035] In one aspect, the third dosage form may contain a corresponding amount of 10 to 200 mg of temozolomide or a pharmaceutically acceptable salt thereof. For example, the second dosage form may contain a corresponding amount of 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 a pharmaceutically acceptable salt thereof. In one aspect, the third dosage form may contain a corresponding amount of 50 mg of romidepsin or a pharmaceutically acceptable salt thereof. In another aspect, the third dosage form may contain a corresponding amount of 100 mg of romidepsin or a pharmaceutically acceptable salt thereof.

[0036] The third dosage form may be administered once a day, twice a day, three times a day, or four times a day. For example, the third dosage form may be administered once a day.

[0037] The total amount of romidepsin or a pharmaceutically acceptable salt thereof administered to the patient in a day may be 50 to 200 mg. For example, the total amount of romidepsin or a pharmaceutically acceptable salt thereof administered to the patient in a day may be 100 mg.

[0038] Glioblastoma may be recurrent glioblastoma.

[0039] In another embodiment, torin1 can treat glioblastoma in combination with an additional anti-cancer agent. The additional anti-cancer agent may include regorafenib, paxalisib, VAL-083, VT1021, or any combination thereof.

[0040] In one embodiment, torin1 can treat glioblastoma in combination with regorafenib. Regorafenib is an oral multi-kinase inhibitor that targets angiogenesis, stromal, and oncogenic receptor tyrosine kinases (RTKs). Regorafenib has the following chemical structure:

Chemical formula

[0041] Trolezole and regorafenib may be included in the same dosage form or different dosage forms. In one aspect, in a patient in need of treatment with trolezole for glioblastoma, a method of such treatment further comprises administering to the patient a fourth dosage form comprising a therapeutically effective amount of regorafenib or a pharmaceutically acceptable salt thereof.

[0042] In another embodiment, trolezole can be used in combination with paxalisib to treat glioblastoma. Paxalisib is a phosphatidylinositol 3-kinase (PI3K) inhibitor that may have antitumor activity and has the following chemical structure:

Chemical formula

[0043] Trolezole and paxalisib can be included in the same dosage form or different dosage forms. In one aspect, in a patient in need of treatment with trolezole for glioblastoma, a method of such treatment further comprises administering to the patient a fifth dosage form comprising a therapeutically effective amount of paxalisib or a pharmaceutically acceptable salt thereof.

[0044] In another embodiment, trolezole can be used in combination with VAL-083 to treat glioblastoma. VAL-083 is a bifunctional DNA targeting agent that has demonstrated preclinical activity against multiple solid tumors and hematological tumors. VAL-083 has the following chemical structure:

Chemical formula

[0045] Trolezole and VAL-083 can be included in the same dosage form or different dosage forms. In one aspect, in a patient in need of treatment with trolezole for glioblastoma, a method of such treatment further comprises administering to the patient a sixth dosage form comprising a therapeutically effective amount of VAL-083 or a pharmaceutically acceptable salt thereof.

[0046] In another embodiment, tolyzole can be used in combination with VT1021 to treat glioblastoma. VT1021 is a dual regulatory compound developed by Vigeo Therapeutics Ltd., which blocks the CD47 immune checkpoint, activates CD36, induces apoptosis, and increases the M1:M2 macrophage ratio.

[0047] Tolyzole and VT1021 may be included in the same dosage form or different dosage forms. In one aspect, in a patient in need of treatment with tolyzole for glioblastoma, a method of such treatment further comprises administering to the patient a seventh dosage form comprising a therapeutically effective amount of VT1021 or a pharmaceutically acceptable salt thereof.

[0048] In another embodiment, a method for treating glioblastoma may further comprise irradiating glioblastoma cells with a therapeutically effective dose of ionizing radiation.

[0049] In another embodiment, provided is a pharmaceutical composition comprising tolyzole and an additional anti-cancer agent selected from the group consisting of temozolomide, romidepsin, regorafenib, paclitaxel, VAL-083, VT1021, and any combination thereof, in an amount effective to treat glioblastoma. For example, the pharmaceutical composition may comprise tolyzole and temozolomide or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise tolyzole and romidepsin or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise tolyzole and regorafenib or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise tolyzole and paclitaxel or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise tolyzole and VAL-083 or a pharmaceutically acceptable salt thereof. In another example, the pharmaceutical composition may comprise tolyzole and VT1021 or a pharmaceutically acceptable salt thereof.

[0050] Basis for the treatment method The new drug, troriluzole, is being developed for the treatment of neurological and psychiatric disorders, as well as other potential indications. Troriluzole is a novel orally administered prodrug of the glutamate agonist riluzole. The FDA initially approved riluzole (RILUTEK®) for the treatment of patients with amyotrophic lateral sclerosis (ALS). 1 . Riluzole is only indicated for ALS and has several undesirable properties that limit its clinical development and use. Troriluzole is a tripeptide prodrug of the glutamate modulator riluzole and is optimized to improve bioavailability, pharmacokinetics, and dosing.

[0051] The proposed study in glioblastoma multiforme (GBM) is based on the accumulating evidence that glutamate dysregulation is involved in the pathophysiology of various tumors. Furthermore, preclinical and clinical evidence regarding tro riluzole (or its active metabolite, riluzole) suggests that tro riluzole may be an effective treatment for these tumors that complements existing standard of care (SOC). The high unmet need, together with the available data, provides a compelling rationale for the development of tro riluzole as an adjuvant treatment for GBM.

[0052] Riluzole was originally developed as a central muscle relaxant and later as an anticonvulsant and neuroprotective agent. The main mechanism of action of riluzole is to reduce the level of glutamate in the synapse. This occurs through two mechanisms: (1) riluzole increases the uptake of glutamate from the synapse by glial cells, and (2) riluzole decreases the release of glutamate from presynaptic neurons. Riluzole decreases the release of glutamate from presynaptic neurons by inactivating voltage-dependent sodium channels on glutamate-activated nerve terminals that mediate presynaptic neuron depolarization. Furthermore, riluzole increases the uptake of glutamate from the synapse by enhancing the expression and function of excitatory amino acid transporters (i.e., EAAT2) located on glial cells, which play an important role in removing glutamate from the synapse. 2-8 Furthermore, riluzole has various other therapeutically relevant pharmacological effects, including the regulation of neurotransmitter signaling and ion channel function, and the enhancement of neurotrophic and survival-promoting cell signaling pathways.

[0053] As shown in Figure 1, trosarizole 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) decreasing presynaptic glutamate release by inhibiting voltage-dependent sodium channels.

[0054] The therapeutic agents included in GBM AGILE are selected through a rigorous scientific evaluation process. For details, please refer to Reference 9.

[0055] Glutamate promotes the maintenance, proliferation, migration, and invasion of GBM. GBM is characterized by changes in cellular metabolism, particularly glutamate homeostasis. Dysregulation of glutamate transporters (SXC [Cl−-dependent cystine / glutamate exchanger], EAAT) results in excessive secretion into the microenvironment, as well as decreased glutamate reuptake, and excessive glutamate acts in an autocrine / paracrine manner to activate glutamate receptors, promoting tumor growth and invasion. Excessive glutamate also has an inhibitory effect on T cell function and leads to excitotoxic neuronal death. Tumor growth / invasion and excitotoxicity result in GBM-related seizures. Neuronal activity may stimulate tumor progression via glutamatergic neuron-glioma synaptic transmission. Preclinical evidence supports investigating antiglutamine agents as potential GBM therapeutics.

[0056] Troriluzole has shown minimal toxicity and was selected to be included in the trial as a potent glutamate modulator with potential as a novel targeted therapy for glioblastoma.

[0057] Troriluzole acts by reducing extracellular glutamate levels at the synaptic junction. This is accomplished by two mechanisms: (1) promoting extracellular glutamate reuptake by increasing the expression and function of excitatory amino acid transporters (EAATs) on glial cells, and (2) decreasing presynaptic glutamate release by inhibiting voltage-dependent sodium channels.

[0058] There are other obvious reasons to believe that troriluzole may provide benefits to GBM patients beyond its mechanism of action. Preclinical and clinical data have shown beneficial therapeutic effects.

[0059] Preclinical data in GBM models have shown the following important conclusions for riluzole and troriluzole: · Rilzole in combination with radiation enhances radiation-induced cytotoxicity in the U87MG cell line in an anchorage-independent colony formation assay 10 。 · Rilzole in combination with radiation enhances sensitivity to radiation in the CAM assay in 64SP stem-like cells 11 。 · Rilzole in combination with temozolomide (TMZ) enhances the effect of TMZ through suppression of O 6 -methylguanine-DNA-methyltransferase (MGMT) expression 12 。 · Tolvaptan treatment induces a survival benefit, promotes the proliferation of tumor-infiltrating T cells, synergizes with anti-PD-1 immunotherapy to further improve survival, and reduces regulatory T cells in the glioma tumor microenvironment (TME) 13 。 · Preclinical IF data suggest an increase in the concentration of CD4+ T cells in the TME after tolvaptan treatment. Furthermore, tolvaptan monotherapy and combination with anti-PD-1 therapy resulted in an increase in CD3+ tumor-infiltrating lymphocyte proliferation 13 。

[0060] Preclinical data from tests of tolvaptan (or its active metabolite) also suggest the potential for pharmacodynamic and clinical responses in non-GBM tumors.

[0061] In summary, glutamate-mediated signaling has been shown to promote proliferation, migration, and invasion in glioblastoma. More recently, the interaction between neuronal signaling and glioblastoma cells has led to increased interest in targeting glutamate receptors. Tolvaptan is a glutamate modulator that has been shown to affect glioblastoma growth in animal models. It has an acceptable safety profile and evidence of blood-brain barrier penetration. Combinatorial studies with riluzole in glioblastoma model systems have shown improved sensitivity to both radiation and TMZ. For these reasons, the arm selection committee believes that incorporating tolvaptan into the GBM AGILE trial would provide an opportunity to more fully evaluate its efficacy in GBM.

[0062] Rationale for Tolvaptan Dose Selection The trial began by evaluating tolvaptan administered at 200 mg BID during the dose-setting phase and proceeded with dose confirmation. This dose was selected based on cumulative experience including non-clinical toxicity and safety / tolerability, pharmacokinetic, and pharmacodynamic data. Importantly, the MTD of tolvaptan was determined to be 140 mg QAM + 280 mg PO QPM. The 200 mg BID dose represents a simpler regimen for patients to follow (administering the same dose at approximately 12-hour intervals) without significantly affecting riluzole exposure. Population PK models were developed using data from healthy subjects and patients across several indications tested with tolvaptan (SCA, OCD, AD, and GAD) and used to simulate riluzole exposure after administration of tolvaptan 200 mg BID and the MTD of 140 mg QAM + 280 mg QPM. Simulated riluzole C max and AUC 0-24 are shown in Table 1.

Table 1

[0063] As shown in Table 1, the simulated riluzole exposure after administration of 200 mg of trolamine BID was similar to that after administration of the MTD and was expected to be safe in the glioblastoma population. The dose-setting phase is carried out to confirm this recommended dose of trolamine in combination with radiotherapy and temozolomide, and romustine, and to ensure patient safety.

[0064] Overview of the Trolamine Treatment Group The trolamine treatment group is open to patients with 1) NDU GBM, 2) NDM GBM, and 3) recurrent GBM of any methylation status. Trolamine has been studied for the first time in combination with temozolomide and radiation in newly diagnosed patients, and with romustine in patients with recurrent disease, and thus, in the dose-setting phase, it is being carried out to confirm the dose of trolamine to ensure the safety of the combination in glioblastoma patients. A rolling 6 design is being implemented to determine the starting dose.

[0065] Once a patient is assigned to the trolamine experimental group, the patient undergoes additional safety evaluations including the collection of adverse events, dose change profiles, hematology, serum chemistry panels, and coagulation profiles on a bi-weekly basis. These additional safety evaluations, called Enhanced Safety Management (ESM), are carried out in approximately the first 30 patients assigned to the trolamine experimental group (20 newly diagnosed patients (NDU and NDM), and 10 recurrent patients).

[0066] The treatment group with tolarizole as part of GBM AGILE consists of two stages. The first stage is the Bayesian adaptively randomized screening stage (Stage 1) to identify the effectiveness of tolarizole in improving survival. In Stage 1, up to 200 patients are randomized to tolarizole across all applicable disease subtypes. The second stage (Stage 2) uses fixed randomization to confirm the effectiveness signal identified in Stage 1 and support drug approval. The target maximum sample size for Stage 2 is 50 patients in the experimental group. The initial screening stage (Stage 1) uses a Bayesian adaptively randomized algorithm to assign patients to the experimental group or the control group based on disease subtypes (defined below).

[0067] Dose setting phase Tolarizole has been studied in various disease and oncology fields and has good tolerability. However, GBM AGILE is the first trial in which tolarizole is being studied in combination with temozolomide and radiation in newly diagnosed patients and with romidepsin in patients with recurrent disease. To confirm the recommended doses of tolarizole in combination with radiotherapy and temozolomide, and with romidepsin, and to ensure patient safety, tolarizole undergoes a dose setting phase. This phase of the study is conducted only at selected trial sites in the United States and is completed before starting treatment groups in additional regions.

[0068] Newly diagnosed patients. The first 6 patients of the newly diagnosed subtype are administered tolarizole 100 mg BID for the first 2 weeks in combination with temozolomide and radiotherapy, and then 200 mg BID for the next 2 weeks. If no DLTs are observed or 1 DLT is observed (1 / 6) in these 6 patients, these patients continue the trial and continue to receive enhanced safety monitoring (ESM) (described in detail below), and this dose is determined as dose level 0 or the starting dose.

[0069] In the case of two DLTs in the first six patients (2 / 6), the dose is tapered to 100 mg once daily in the morning (qAM) and 200 mg once daily in the evening (qPM) for four weeks. Thereafter, the six patients are administered 100 mg qAM for four weeks, followed by 200 mg qPM, and are observed for DLT. If no DLT is observed or one DLT is observed in these six patients (1 / 6), these patients continue the trial, continue to receive ESM (described in detail below), and this dose of 100 mg qAM and 200 mg qPM is confirmed as dose level 0 or the starting dose.

[0070] In the case of two DLTs in these six patients (2 / 6), the dose is tapered to 100 mg BID. Subsequently, the six patients are administered 100 mg BID for four weeks and are observed for DLT. If no DLT is observed or one DLT is observed in the six patients (1 / 6), these patients continue the trial, continue to receive ESM (described in detail below), and this dose of 100 mg BID is confirmed as dose level 0 or the starting dose.

[0071] Patients with recurrent disease. Similarly, the first six patients with the recurrent disease subtype are administered torilizole in combination with romustatin at 100 mg BID for the first two weeks and then 200 mg BID for the next two weeks. These patients are monitored for DLT for four weeks. If no DLT is observed or one DLT is observed in the six patients (1 / 6), these patients continue the trial, continue to receive ESM (described in detail below), and the 200 mg BID dose of torilizole is determined as dose level 0 or the starting dose.

[0072] If there are more than 2 / 6 DLTs in the initial six patients, the dose is tapered to 100 mg once daily in the morning (qAM) and 200 mg once daily in the evening (qPM) for four weeks. Thereafter, the six patients are administered 100 mg qAM for four weeks, followed by 200 mg qPM, and are observed for DLTs. If no DLTs are observed or one DLT is observed (1 / 6) in the six patients, these patients continue the trial, continue to receive ESM (described in detail below), and this dose of 100 mg qAM and 200 mg qPM is confirmed as dose level 0 or the starting dose.

[0073] If there are two DLTs (2 / 6) in these six patients, the dose is tapered to 100 mg BID. Subsequently, the six patients are administered 100 mg BID for four weeks and are observed for DLTs. If no DLTs are observed or one DLT is observed (1 / 6) in the six patients, these patients continue the trial, continue to receive ESM (described in detail below), and this dose of 100 mg BID is confirmed as dose level 0 or the starting dose.

[0074] If dose tapering is carried out, patients who were administered a higher dose during the dose-setting phase and had no DLTs can continue the trial and be administered the confirmed starting dose. However, these patients are not included in the final analysis.

[0075] DLTs must be reversible and monitorable within four weeks. An evaluable DLT is considered when the patient has received 75% or more of the investigational drug within the dose-setting phase. If a patient has a DLT before receiving 75% of the investigational drug during this phase, a new patient is added to the rolling six design to complete the evaluation in place of this patient. During the dose-setting phase, patients are evaluated for AEs every other week. Additionally, patients receive an ESM evaluation at this stage.

[0076] After the sixth patient is enrolled in the dose - setting phase, enrollment into the trolertuzumab treatment group is paused for four weeks to enable DLT assessment in this patient according to the rolling 6 - design. Once the DLT assessment is completed, the starting dose is confirmed and enrollment into the trolertuzumab treatment group is resumed for both newly diagnosed and recurrent subtypes.

[0077] Enhanced Safety Management (ESM) Enhanced Safety Management is a seamless process for new treatment groups using different classes of combination agents where there is limited safety data to capture and support their inclusion in the GBM AGILE trial. The decision to adopt ESM for these treatment groups to enter GBM AGILE is based on the recommendation of the treatment group selection committee. ESM provides the opportunity to test agents with a favorable safety profile in all subgroups of GBM AGILE (patients newly diagnosed with methylation, patients newly diagnosed without methylation, and recurrent patients). ESM is conducted only at selected US trial sites and is completed before starting treatment groups in additional regions.

[0078] Once a patient is assigned to the trolertuzumab experimental group, the patient receives additional safety evaluations including collection of adverse events, dose - change profile, hematology, serum chemistry panel, and coagulation profile on a bi - weekly basis. These additional safety evaluations are conducted in the first approximately 30 patients assigned to the trolertuzumab experimental group. There is no minimum or maximum number of patients, but it is estimated to be approximately 20 newly diagnosed patients and 10 recurrent patients.

[0079] These additional evaluations are entered into monthly reports, reviewed by the Global Principal Investigator (PI) and Medical Monitor (MM), and presented to one or two clinical members of the Data Safety Monitoring Board (DSMB).

[0080] ESM is monitored by clinical leadership and the DSMB in the following ways. · Real-time: Dose changes or temporary interruption of drug administration based on AE evaluation are monitored in real time by the global PI and MM. · Monthly report: The global PI and MM review the monthly data and recommend to one or two clinical members of the DSMB to continue, temporarily stop, or terminate the ESM data collection or the trial treatment group. · Quarterly report: The comprehensive ESM data to date are presented at quarterly DSMB meetings. All members of the DSMB reconsider the decisions made in the monthly reports. If a decision to temporarily stop ESM data collection is made during a quarterly DSM meeting, a special review by all DSMB members may be required.

[0081] If the DSMB decides to discontinue the ESM, the researchers are notified and additional safety measurements are no longer required.

[0082] If there are two grade 5 or grade 4 events considered to be at least related to trolipazole by the DSMB during the ESM period, the increase of patients is temporarily stopped until a thorough safety review is conducted by the DSMB before restarting the enrollment according to the advice of the DSMB members.

[0083] Treatment procedures Required tests or evaluations. Unless otherwise specified below, the following procedures are performed for newly diagnosed and relapsed patients at each visit before the administration of trolipazole (± 3 days). · Neurological examination and clinical evaluation of neurological function were performed according to local practice. Note: For relapsed patients, within 14 days of randomization and If performed on cycle (C) day 1 (D) 1, the patient does not require additional evaluation at C1D1. · Vital signs (including BP, body temperature, heart rate) were performed according to local practice. · The ECG to be collected was performed as follows during the screening period. · For newly diagnosed patients: on day 1 and day 29 of the treatment period, and on day 1 of each cycle during the maintenance period · For relapsed patients: on day 1 of each cycle · For all participants in the torilizole treatment group, additional ECG monitoring should be performed as clinically indicated. · Karnofsky Performance Status was performed according to local practice (see Table 2 below). · Adverse event assessment. · Concomitant medications. · Use of corticosteroids. · QOL assessments (EORTC QLQ-C-30, EORTC QLQ-BN20, and EQ-5D-5L) should be performed before the test treatment at C1D1 and then (if feasible) before the patient receives daily results and should be performed simultaneously with the imaging response assessment as follows: · For newly diagnosed patients: every 8 weeks (± 4 weeks). · For relapsed patients: every 6 weeks (± 1 week). · Clinical blood or urine tests (collected and evaluated locally): · Hematology: Complete blood count (absolute) with differential, including but not limited to: · Red blood cell count. · Hemoglobin. · Hematocrit. · White blood cell count. · Absolute neutrophil count. · Absolute lymphocyte count. · Platelet count. · Serum Chemistry: Chemical panel, including but not limited to: · Sodium. · Potassium. · Calcium. · Chloride. · Blood urea nitrogen. · Creatinine. · Fasting blood glucose. · Total bilirubin (if total bilirubin exceeds the normal upper limit, direct and indirect bilirubin should be performed). · Aspartate aminotransferase / Serum glutamate oxaloacetate transaminase (AST / SGOT). · Alanine aminotransferase (ALT / SGPT). · Lipase. · Amylase. · Urine tests, following local practice. · Administration or dispensing of test treatment. · MRI is performed for response assessment / tumor assessment: · For newly diagnosed patients: Every 8 weeks (± 4 weeks). · For recurrent patients: Every 6 weeks (± 1 week). Note: For recurrent patients, within 14 days of randomization and If an MRI scan is performed on C1D1, the patient does not require an additional MRI on C1D1. MRI scans should be performed according to the above frequencies for newly diagnosed patients and recurrent patients, regardless of treatment delays. If the criteria for "preliminary" progressive disease are met, a confirmatory MRI scan should be performed within 4 weeks according to section 14.2.3 of the master protocol. · For consenting patients, research blood samples are collected on Day 1 of each cycle.

Table 2

[0084] Schedule of events for the trolipazole treatment group. In the trolipazole treatment group, the evaluations defined above need to be carried out according to the trial calendar.

[0085] Throughout this protocol, for all treatment visits (defined to include mandatory tests or evaluations), an administrative window of ±3 days (or more if otherwise specified) is allowed. Delays in treatment or visits due to holidays, weather conditions, or force majeure do not constitute a protocol violation, but every effort should be made to adhere to the specified evaluation schedule.

[0086] Evaluation at the end of treatment. All procedures described must be completed within 14 days before or at the completion of the discontinuation of trolipazole, or repeated at the treatment end visit within 14 days of the discontinuation or completion of trolipazole.

[0087] All patients are followed for safety evaluation 28 days after the last dose of trolipazole.

[0088] Follow-up evaluation after treatment. The follow-up evaluation after treatment must be completed as described below.

[0089] Treatment of patients Instructions for administration to patients. Subjects randomized to the trolipazole experimental group are administered the trolipazole dose confirmed in the dose-setting phase of each cohort.

[0090] All subjects are recommended to take the study drug twice a day, once in the morning and once at night (at the same time every day, at approximately 12-hour intervals), regardless of diet.

[0091] Newly diagnosed patients are administered 75 mg / m 2 of TMZ orally (7 days a week) during the treatment period, and during the maintenance period, the first cycle of TMZ is 150 mg / m 2 on days 1 - 5 of a 28-day cycle. The second and subsequent maintenance therapy cycles are 200 mg / m 2 on days 1 - 5 of a 28-day cycle if there is no toxicity. TMZ is administered in combination with trolipazole for a maximum of 6 cycles during the maintenance phase. After 6 cycles, patients continue with trolipazole only.

[0092] Relapsed patients are administered romustatin at 110 mg / m2 on D1 of a 42-day cycle for a maximum of 6 cycles. After 6 cycles, patients continue treatment with tolryzole only.

[0093] Concomitant medications. The pre-use and co-administration of riluzole are prohibited. Tolryzole should be used with caution when accompanied by drugs that are inhibitors or inducers of the CYP1A2 enzyme system due to the potential for drug interactions, and should be avoided with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin). If a patient is taking a CYP1A2 inhibitor or inducer, the subject should be appropriately monitored. At least 5 half-lives before randomization and during the study period, the following drugs are prohibited: 1. Potent to moderate CYP1A2 inhibitors that may increase the risk of riluzole-related AEs, including SSRI fluvoxamine. Potent inhibitors are prohibited. 2. Potent to moderate CYP1A2 inducers that may cause a decrease in efficacy. 3. Hepatotoxic drugs that may increase the risk of hepatotoxicity (e.g., allopurinol, methyldopa, sulfasalazine).

[0094] Oral contraceptives containing ethinyl estradiol (a moderate CYP1A2 inhibitor) are acceptable.

[0095] Growth factors. For growth factors acceptable in supportive therapy, see below.

[0096] Anticoagulants. There are no additional guidelines regarding anticoagulants specific to the tolryzole group.

[0097] Herbal preparations / drugs. The use of medical or recreational marijuana and cannabidiol (CBD) oil is strongly discouraged starting 30 days before randomization.

[0098] Other anticancer therapies or experimental therapies. There are no additional guidelines regarding other anticancer therapies or experimental therapies specific to the torinlazole treatment group.

[0099] Supportive therapy. There are no additional guidelines regarding supportive therapy specific to the torinlazole treatment group.

[0100] Antiemetics. Premedication with antiemetics is permitted if clinically necessary.

[0101] Anticonvulsants. There are no additional guidelines regarding anticonvulsants specific to the torinlazole treatment group.

[0102] Dose modification and toxicity management. The following Tables 3 - 5 outline dose modifications for torinlazole. Dose modifications are the same in the newly diagnosed cohort and the recurrence cohort and are based on the starting dose confirmed from the dose - setting phase. Toxicity is graded according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5).

Table 3

[0103] If a clinically significant AE occurs while the participant is receiving torinlazole 200 mg BID and it is determined to be related to torinlazole, the investigator may consider changing the dosing regimen. Taper to 100 mg BID (dose level - 1) is possible after the second week.

[0104] Torinlazole may also be withheld at the discretion of the investigator. Consultation with the medical monitor is recommended. When the problem is resolved, the dose can be titrated up to a maximum of 200 mg BID at the discretion of the investigator.

Table 4

Table 5

[0105] If DLT is ≧ grade 3, trolipazole needs to be withheld. When DLT resolves to ≦ grade 1 at dose level -1, trolipazole can be restarted. For trolipazole to be restarted, DLT needs to resolve within 28 days. If another DLT ≧ grade 3 occurs, the drug is permanently discontinued.

[0106] Patients who experience toxicity described based on the definition of DLT after dose reduction discontinue the trial. CTCAE defines dose-limiting toxicity (DLT) as toxicity that prevents further administration of the drug at that dose level.

[0107] An AE is considered DLT if it is a clinically significant AE (based on CTCAE v5.0) evaluated to be unrelated to tumor progression, comorbidities, temozolomide, radiation, or other concomitant medications.

[0108] DLT should be defined as the following events that are clearly not due to underlying diseases or exogenous causes: · Any death · Non-hematologic toxicity · Grade 3 or higher · Hy’s law case · Hematologic toxicity · Grade 4 neutropenia > 7 days · Grade 3 or higher thrombocytopenia with clinically significant bleeding · Neutropenic fever

[0109] In the DLT definition, the following may be excluded. · Grade 3 nausea / vomiting or diarrhea < 72 hours with appropriate antiemetics and other supportive therapies · Grade 3 fatigue > 1 week · Grade 3 or higher electrolyte abnormalities that last up to 72 hours, are not clinically complex, and resolve spontaneously or respond to conventional medical interventions · Grade 3 or higher amylase or lipase not related to the symptoms or clinical manifestations of pancreatitis

[0110] Seizures of grade 3 or higher (without further reason based on grade or baseline frequency), deep vein thrombosis, and pulmonary embolism considered to be caused by the investigational drug are not excluded as DLTs.

[0111] The dose modification and discontinuation of TMZ need to be as described in the guidelines provided in the prescribing information of the regulatory authorities approved locally. The guidelines specific to hematotoxicity (neutropenia and thrombocytopenia) need to be followed as outlined in Table 6 below.

Table 6

[0112] The dose modification and discontinuation of romustatin need to be as described in the guidelines provided in the prescribing information of the regulatory authorities approved locally. For details, please refer to Table 7 below.

Table 7

[0113] Mild increases in liver enzymes are the adverse events most frequently observed with torilizole. The dose modification guidelines for liver enzymes are listed in Table 8 below. Generally, mild elevations of liver enzymes due to torilizole are caused by enzyme induction and are likely to resolve spontaneously within 12 weeks without a change in the dose of torilizole. However, the investigator needs to evaluate the subject as needed.

[0114] If the AST / ALT increase exceeds 3×ULN, consultation with a medical monitor is required within 72 hours. In these cases, the clinical evaluation should include repeated clinical laboratory evaluations (ALT, AST, total bilirubin and direct bilirubin, alkaline phosphatase, PT, aPTT, INR) that are performed within 1 week and followed until resolved. Additional tests for the cause of the liver enzyme increase may be performed as needed (e.g., viral serology). If TMZ and troleandomycin are withheld, no special management is indicated other than supportive therapy.

[0115] The guidelines for dose modification for liver enzyme and bilirubin changes are listed in Table 8 below.

Table 8

[0116] Throughout this application, various publications are referenced by author name and date, or patent number or patent publication number. The disclosures of these publications are hereby incorporated by reference in their entirety to more fully describe the state of the art known to those of ordinary skill in the art as of the date of the invention described and claimed herein. However, the citation of a reference herein should not be construed as an admission that such reference is prior art to the present invention.

[0117] Those of ordinary skill in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and examples herein can be used. Further, specific items within a list of items, or subsets of items within a larger group of items, are intended to be combinable with other specific items, subsets of items, or larger groups of items whether or not there is a specific disclosure herein identifying such combinations.

Claims

1. A first pharmaceutical agent for treating glioblastoma in a patient requiring treatment for glioblastoma, comprising troriruzole or a pharmaceutically acceptable salt thereof.

2. The first pharmaceutical product according to claim 1, comprising 100 mg or 200 mg of troriruzole or a pharmaceutically acceptable salt thereof in a corresponding amount.

3. The first pharmaceutical product according to claim 1, wherein the first pharmaceutical product is administered once or twice a day.

4. The first pharmacopoeia according to claim 1, wherein the treatment period is four weeks, and troriruzole or a pharmaceutically acceptable salt thereof is administered at a dose of 100 mg twice daily for the first two weeks, and at a dose of 200 mg twice daily for the remaining two weeks.

5. The first pharmaceutical product according to claim 1, wherein the total amount of troriruzole or a pharmaceutically acceptable salt thereof administered to the patient during one day is 200 mg, 300 mg, or 400 mg.

6. The first pharmaceutical product according to any one of claims 1 to 5, used in combination with a second pharmaceutical product comprising temozolomide or a pharmaceutically acceptable salt thereof for the treatment of glioblastoma.

7. The first pharmaceutical product according to claim 6, wherein the second pharmaceutical product comprises a corresponding amount of 10 mg to 200 mg of temozolomide or a pharmaceutically acceptable salt thereof.

8. The first pharmaceutical product according to claim 6, wherein the second pharmaceutical product is administered once or twice a day.

9. The first pharmaceutical product according to claim 6, wherein the total amount of temozolomide or a pharmaceutically acceptable salt thereof administered to the patient during one day is 75 mg / m² or 150 mg / m².

10. The aforementioned glioblastoma was newly diagnosed in O ６ The first pharmaceutical product according to claim 1, which is a methylguanine-DNA-methyltransferase (MGMT)-methylated glioblastoma.

11. The aforementioned glioblastoma was newly diagnosed in O ６ The first pharmaceutical product according to claim 1, wherein the patient is a non-methylated glioblastoma of methylguanine-DNA-methyltransferase (MGMT).

12. The first pharmacopoeia according to any one of claims 1 to 5, used in combination with a third pharmacopoeia comprising lomustine or a corresponding amount of a pharmaceutically acceptable salt thereof for the treatment of glioblastoma.

13. The first pharmaceutical product according to claim 12, wherein the third pharmaceutical product comprises 50 mg or 100 mg of lomustine or a pharmaceutically acceptable salt thereof in corresponding amounts.

14. The first pharmaceutical product according to claim 12, wherein the third pharmaceutical product is administered once or twice a day.

15. The first pharmaceutical product according to claim 12, wherein the total amount of lomustine or a pharmaceutically acceptable salt thereof administered to the patient during one day is 50 mg to 200 mg.

16. The first pharmaceutical product according to claim 12, wherein the glioblastoma is a recurrent glioblastoma.

17. The first pharmaceutical product according to any one of claims 1 to 5, used in combination therapy with ionizing radiation for the treatment of glioblastoma, wherein the combination therapy includes irradiating glioblastoma cells with ionizing radiation.

18. A kit for treating glioblastoma, wherein the kit is (a) Troriluzole or a pharmaceutically acceptable salt thereof, (b) Temozolomide or a pharmaceutically acceptable salt thereof, (c) A kit comprising instructions for using (a) and (b) in combination to treat glioblastoma.

19. A kit for treating glioblastoma, wherein the kit is (a) Troriluzole or a pharmaceutically acceptable salt thereof, (b) Lomustine or a pharmaceutically acceptable salt thereof, (c) A kit comprising instructions for using (a) and (b) in combination to treat glioblastoma.

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