Azasetron for the prevention of hearing loss in subjects receiving cisplatin

Abstract

The present invention relates to azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of hearing loss in a subject suffering from a cancer who is scheduled to receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2.

Description

AZASETRON FOR THE PREVENTION OF HEARING LOSS IN SUBJECTSRECEIVING CISPLATINFIELD OF INVENTION

[0001] The present invention relates to the prevention of cisplatin-induced hearing loss in subjects suffering from a cancer treated with cisplatin at a cumulative dose equal to or higher than about 300 mg / m2.BACKGROUND OF INVENTION

[0002] Cisplatin (cis-diammine-dichloro-platinum II) is an organometallic platinum compound which was discovered to have potent anti -neoplastic effects on tumor cells in the 1970s. Cisplatin exerts tumoricidal effects by targeting the deoxyribonucleic acid (DNA) of proliferating cells. Cisplatin binds to DNA, forming intra- and inter-strand complexes that lead to the inhibition of DNA synthesis, the suppression of ribonucleic acid (RNA) transcription, cell cycle arrest, and apoptosis. The binding of cisplatin to DNA also activates the inflammatory cascade and generates oxidative stress in the proliferating cells.

[0003] Cisplatin is currently one of the most widely used chemotherapeutic agents for the treatment of cancer, either as a single agent or in a combination therapy. Cisplatin is notably indicated for the treatment of more than 30 different types of solid tumors in adults and children. Cisplatin is also indicated for the treatment of leukemia and lymphomas.

[0004] However, the toxic side effects of cisplatin remain major clinical limitations. Ototoxicity is the most common side effect and occurs in 40-60% of adults receiving cisplatin and in up to 60% of children receiving cisplatin (Tan WJT, Vlajkovic SM. Molecular Characteristics of Cisplatin-Induced Ototoxicity and Therapeutic Interventions. Int J Mol Sci. 2023 Nov 20;24(22): 16545). Cisplatin-induced ototoxicityis generally characterized by bilateral sensorineural hearing loss, with an estimated 18% of the affected adults suffering from severe to profound hearing loss. Cisplatin induces dose-dependent death of cochlear hair cells, in particular of outer hair cells, starting at the cochlear base and progressing apically with continued exposure to the drug. In cochlear hair cells, cisplatin alkylation in mitochondria results in the release of pro-apoptotic factors leading to caspase activation. Cytosolic reactive oxygen species (ROS) have also been implicated as a major mediator of cisplatin-induced hair cell death. Increased pools of ROS damage proteins and lipids and deplete the intrinsic antioxidant molecules (such as glutathione peroxidase, superoxide dismutase, catalase and glutathione reductase) resulting in lipid, protein and nucleic acid peroxidation with caspase system activation and apoptosis of auditory hair cells. In addition to the cochlear hair cells in the organ of Corti, cisplatin affects other major components of the cochlea, such as the spiral ganglion, the stria vascularis and the spiral ligament.

[0005] Owing to its potent anti -neoplastic activity, cisplatin is administered for the treatment of cancer despite the hearing loss it may induce and despite the current lack of means to treat, either preventively or therapeutically, cisplatin-induced hearing loss. There is thus an unmet clinical need for treatments effective in preventing cisplatin- induced hearing loss in subjects treated for cancer with cisplatin.

[0006] Azasetron is a small molecule which is currently being investigated as a therapeutic and preventive treatment for sensorineural hearing loss (WO2016 / 184900 and WO2017 / 178645). In particular, azasetron is thought to be able to protect and preserve inner ear tissue from damage responsible for hearing impairment. Azasetron may thus be able to prevent cisplatin-induced hearing loss.

[0007] The Inventors have now obtained data indicating that azasetron prevents hearing loss in subjects suffering from a cancer treated with cisplatin. In particular, the data indicate that subjects exposed to cisplatin at a cumulative dose equal to or higher than about 300 mg / m2are more likely to benefit from the administration of azasetron.

[0008] The present invention thus relates to azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of hearing loss in a subject sufferingfrom a cancer treated with cisplatin at a cumulative dose equal to or higher than about 300 mg / m2.SUMMARY

[0009] The present invention relates to azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of hearing loss in a subject suffering from a cancer, wherein the subject is scheduled to receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2.

[0010] In some embodiments, azasetron is (R)-azasetron, (S)-azasetron, a mixture thereof, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, azasetron is (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the pharmaceutically acceptable salt of azasetron is selected from a besylate salt, a malate salt, and a hydrochloride salt. In some embodiments, the pharmaceutically acceptable salt of azasetron is (R)-azasetron besylate.

[0011] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration from at least 1 week prior to the start of the cisplatin treatment. In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration until at least 4 weeks after the end of the cisplatin treatment. In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for daily administration from at least 1 week prior to the start of the cisplatin treatment and until at least 4 weeks after the end of the cisplatin treatment.

[0012] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration at a daily dose ranging from about 20 mg to about 200 mg. In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration at a daily free base equivalent dose of about 60 mg.

[0013] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for oral administration. In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration twice a day.DEFINITIONS

[0014] In the present disclosure, the following terms have the following meanings:

[0015] The terms “a” and “an” refer to one or to more than one (z.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0016] “About”, when preceding a figure, encompasses plus or minus 10%, or less, of the value of said figure. It is to be understood that the value to which the term “about” refers is itself also specifically, and preferably, disclosed.

[0017] “Baseline”, when qualifying a parameter observed in the subject, refers to the time preceding the start of administration of cisplatin to the subject. For example, for a given subject, the hearing threshold or pure-tone average (PTA) at baseline is the hearing threshold or PTA of the subject prior to the start of the first cycle of cisplatin chemotherapy.

[0018] A “chemotherapy cycle” corresponds to a defined period which includes days of actual administration of the chemotherapeutic agent and days of rest without any administration of the chemotherapeutic agent. For example, a chemotherapy cycle of 28 days may include administration of the chemotherapeutic agent on the first 3 days (z.e., day 1, day 2 and day 3) and rest (z.e., no administration) on the following 25 days (z.e., day 4 to day 28 ). Another example is a chemotherapy cycle of 21 days including administration of the chemotherapeutic agent on two separate days (e.g., day 1 and day 8) and rest (z.e., no administration) on the other 19 days (e.g., day 2 to day 7 then day 9 to day 21).

[0019] A “course of chemotherapy” corresponds to the administration of chemotherapy as a series of cycles over a set period. For example, a course of chemotherapy may include 3, 4, 5, 6, 7, 8 or more cycles of chemotherapy.

[0020] “Pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” refers to an excipient or carrier that does not produce an adverse, allergic or other untoward reaction when administered to a subject. It includes any and all solvents, such as, for example, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. A pharmaceutically acceptable excipient or carrier refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory offices such as the FDA (U.S. food and drug administration) or EMA (European medicines agency).

[0021] “Therapeutically effective amount” or “therapeutically effective dose” refers to the amount or dose of azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, that is aimed at, without causing significant negative or adverse side effects to the subject, (i) preserving hearing in the subject who is scheduled to receive cisplatin as described herein or (ii) preventing (completely or partially) or slowing down or minimizing or attenuating hearing loss (z.e., cisplatin-induced hearing loss) in the subject who is scheduled to receive cisplatin as described herein.

[0022] As used herein, “PTA” refers to pure-tone average and corresponds to the average of hearing thresholds determined at a set of fixed frequencies, preferably at a set of contiguous (or consecutive) frequencies. Ranges of consecutive frequencies may include for example 0.125, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12.5 kHz; or 0.125, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12.5 kHz; or 0.5, 0.75, 1, 2, 3, 4, 6, 8 kHz; or 0.5, 1, 2, 3, 4, 6, 8 kHz. For example, the pure-tone average may correspond to the average of the hearing thresholds determined with pure tone audiometry at 0.125, 0.5 and 0.75 kHz; 0.125, 0.25 and 0.5 kHz; 0.25, 0.5 and 0.75 kHz; 0.5, 0.75 and 1 kHz; 0.5, 1 and 2 kHz; 0.75, 1 and 2 kHz; 1, 2 and 3 kHz; 2, 3 and 4 kHz; 3, 4 and 6 kHz; 4, 6 and 8 kHz; 6, 8 and 10 kHz; 8, 10 and 12.5 kHz.DETAILED DESCRIPTION

[0023] The present invention relates to azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of hearing loss in a subject suffering from a cancer, wherein the subject is scheduled to receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2(milligram (mg) per body surface area expressed in square meter (m2)).

[0024] According to the present invention, the hearing loss to be prevented is cisplatin- induced hearing loss. Cisplatin-induced hearing loss is a sensorineural hearing loss resulting from damage to the cochlea.

[0025] Cisplatin-induced hearing loss usually manifests as bilateral hearing loss. Generally, cisplatin-induced hearing loss first affects high frequencies and then also affects low frequencies. In some embodiments, cisplatin-induced hearing loss is mild. In some embodiments, cisplatin-induced hearing loss is moderate. In some embodiments, cisplatin-induced hearing loss is moderately severe. In some embodiments, cisplatin- induced hearing loss is severe. In some embodiments, cisplatin-induced hearing loss is profound.

[0026] In particular, cisplatin-induced hearing loss may be a mild, moderate, moderately severe, severe or profound hearing loss according to the American Speech-Language- Hearing Association (ASHA) classification. The ASHA has proposed a classification of hearing loss, depending on the degree of hearing loss, which is commonly used in the field (Clark. ASHA. 1981 Jul;23(7):493-500). According to the ASHA classification, the degrees of hearing loss are as follows: hearing loss of -10 to 15 dB: normal, hearing loss of 16 to 25 dB: slight hearing loss, hearing loss of 26 to 40 dB: mild hearing loss, hearing loss of 41 to 55 dB: moderate hearing loss, hearing loss of 56 to 70 dB: moderately severe hearing loss, hearing loss of 71 to 90 dB: severe hearing loss, hearing loss equal to or greater than 91 dB: profound hearing loss.

[0027] Thus, in some embodiments, a mild cisplatin-induced hearing loss corresponds to a hearing loss ranging from 26 to 40 dB; a moderate cisplatin-induced hearing loss corresponds to a hearing loss ranging from 41 to 55 dB; a moderately severe cisplatin- induced hearing loss corresponds to a hearing loss ranging from 56 to 70 dB; a severe cisplatin-induced hearing loss corresponds to a hearing loss ranging from 71 to 90 dB; and a profound cisplatin-induced hearing loss corresponds to a hearing loss equal to or greater than 91 dB.

[0028] In particular, as described herein, cisplatin-induced hearing loss may be evaluated by assessing hearing prior to the start of cisplatin treatment (for example prior to the start of a course of cisplatin chemotherapy) and by assessing hearing after the completion of cisplatin treatment (for example after the completion of a course of cisplatin chemotherapy). Cisplatin-induced hearing loss may thus be evaluated by assessing hearing at baseline and after the end of a course of cisplatin chemotherapy.

[0029] Methods for assessing hearing (or hearing acuity) are well-known by the skilled artisan. Examples of such methods include audiometric testing, in particular pure tone audiometry corresponding to pure tone audiometric air conduction test and / or pure tone audiometric bone conduction test, speech audiometry, behavioral observation audiometry, visual reinforcement audiometry, conditioned play audiometry. Methods for assessing hearing (or hearing acuity) also include ABR (auditory brainstem responses) measurement, DPOAE (distortion product otoacoustic emissions) measurement, TEOAE (transiently evoked otoacoustic emissions) measurement, speech-in-noise test, speech-in- quiet test, word comprehension test, tympanometry, acoustic reflex tests, and tuning fork test.

[0030] In particular, hearing may be assessed using audiometry or audiometric testing, preferably pure tone audiometry. Pure tone audiometry is considered a gold standard test for assessing hearing acuity. Pure tone audiometry is a standardized subjective hearing test determining air-conduction and / or bone-conduction hearing thresholds (expressed in dB) at a given frequency or at a set of fixed frequencies, for example selected in the range from 0.125 kHz to 12.5 kHz. The hearing thresholds determined at a given frequency may be plotted on an audiogram for each ear independently. For example, thehearing threshold (at a given frequency or expressed as the average of hearing thresholds at a set of fixed frequencies) may be defined as the lowest audible level, measured twice out of three presentations to the subject.

[0031] A hearing threshold, in particular a hearing threshold determined with pure tone audiometry, may be referred to as pure-tone average (PTA), which corresponds to the average of hearing thresholds determined at a set of fixed frequencies. For example, a pure-tone average may correspond to the average of 2, 3, 4 or more hearing thresholds each determined at a different frequency. The frequencies may be selected from 0.125, 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12.5 kHz, preferably from 0.5, 0.75, 1, 2, 3, 4, 8, 10 and 12.5 kHz, more preferably from 0.5, 0.75, 1, 2, 3, 4 and 8 kHz. Alternatively, the frequencies may be selected from 0.125, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12.5 kHz; or preferably from 0.5, 1, 2, 3, 4, 8, 10 and 12.5 kHz, more preferably from 0.5, 1, 2, 3, 4 and 8 kHz. In particular, the frequencies may be consecutive frequencies (also sometimes referred to as contiguous frequencies). Example of consecutive frequencies selected from 0.5, 0.75, 1, 2, 3, 4, 6, 8, 10 and 12.5 kHz include 0.5, 0.75 and 1 kHz; 0.75, 1 and 2 kHz; 1, 2 and 3 kHz; 2, 3 and 4 kHz; 3, 4 and 6 kHz; 4, 6 and 8 kHz; 6, 8 and 10 kHz; and 8, 10 and 12.5 kHz. Example of consecutive frequencies selected from 0.5, 1, 2, 3, 4, 6, 8, 10 and 12.5 kHz include 0.5, 1 and 2 kHz; 1, 2 and 3 kHz; 2, 3 and 4 kHz; 3, 4 and 6 kHz; 4, 6 and 8 kHz; 6, 8 and 10 kHz; and 8, 10 and 12.5 kHz.

[0032] Cisplatin-induced hearing loss may thus be assessed with any of the standard methods known in the field, such as the methods mentioned herein. In particular, cisplatin-induced hearing loss may be assessed by determining the hearing threshold or audiometric threshold (e.g., pure-tone average or PTA) overtime, in particular before and after administration of cisplatin. For example, cisplatin-induced hearing loss may be assessed by determining the hearing threshold or audiometric threshold (e.g., pure-tone average or PTA) at 3 consecutive frequencies selected from 0.5, 1, 2, 3, 4, 6, 8, 10 and 12.5 kHz, preferably selected from 0.5, 1, 2, 3, 4, 6 and 8 kHz.

[0033] In some embodiments, cisplatin-induced hearing loss corresponds to the difference between the hearing threshold or audiometric threshold e.g., pure-tone average or PTA) after the end of the cisplatin treatment and the hearing threshold oraudiometric threshold (e.g., pure-tone average or PTA) before the start of the cisplatin treatment (z.e., at baseline). In some embodiments, cisplatin-induced hearing loss thus corresponds to the PTA change from baseline after the end of the cisplatin treatment. In some embodiments, the hearing threshold or audiometric threshold e.g., pure-tone average or PTA) is expressed as the average of the hearing threshold (in dB) of the 3 most affected consecutive frequencies. Thus, in some embodiments, cisplatin-induced hearing loss corresponds to the difference between the PTA at the 3 most affected contiguous frequencies after the end of the cisplatin treatment and the PTA at the same frequencies before the start of the cisplatin treatment (i.e., at baseline). In other words, in some embodiments, cisplatin-induced hearing loss corresponds to the PTA change from baseline after the end of the cisplatin treatment at the 3 most affected consecutive frequencies.

[0034] As used herein, “cisplatin treatment” may refer to a cycle of cisplatin chemotherapy or, preferably, to a course of cisplatin chemotherapy. Cisplatin-induced hearing loss may thus be assessed as described herein after the completion of a cycle of cisplatin chemotherapy and / or after the completion of a course of cisplatin chemotherapy. In particular, cisplatin-induced hearing loss may be assessed as described herein 4 weeks after the completion of a course of cisplatin chemotherapy. Cisplatin-induced hearing loss may also be assessed as described herein 12 weeks after the completion of a course of cisplatin chemotherapy. Cisplatin-induced hearing loss may thus be assessed as described herein 4 weeks and / or 12 weeks after the completion of a course of chemotherapy comprising a cumulative dose of cisplatin equal to or higher than about 300 mg / m2.

[0035] In some embodiments, the hearing threshold or audiometric threshold of the subject corresponds to the average of the hearing thresholds or audiometric thresholds for each ear. In some embodiments, the hearing threshold or audiometric threshold of the subject corresponds to the hearing threshold or audiometric threshold of the most affected ear.

[0036] As used herein, by “preventing hearing loss”, that is to say by “preventing cisplatin-induced hearing loss”, it is meant completely or partially preventing hearing loss induced by cisplatin, completely or partially preserving hearing from any loss induced bycisplatin, attenuating hearing loss induced by cisplatin, minimizing or reducing hearing loss induced by cisplatin, minimizing or reducing the degree of hearing loss induced by cisplatin, minimizing or reducing the severity of hearing loss induced by cisplatin, and / or slowing down hearing loss induced by cisplatin.

[0037] As used herein, “by completely preventing hearing loss induced by cisplatin” it is meant that the hearing acuity of the subject after the completion of the cisplatin treatment is comparable (z.e., not significantly different) to the hearing acuity of the subject before the start of the cisplatin treatment (ie., to the hearing acuity of the subject at baseline). Similarly, as used herein, by “completely preserving hearing from any loss induced by cisplatin”, it is meant that the hearing acuity of the subj ect after the completion of the cisplatin treatment is comparable to the hearing acuity of the subject before the start of the cisplatin treatment (ie., to the hearing acuity of the subject at baseline). In some embodiments, by “comparable” (ie., not significantly different), it is meant that after the completion of a course of cisplatin chemotherapy (preferably 4 weeks after the completion of a course of cisplatin chemotherapy), the hearing threshold or audiometric threshold of the subject does not increase by 10 dB or more, in particular as compared to the hearing threshold or audiometric threshold at baseline (z.e., the hearing threshold or audiometric threshold before the start of the course of cisplatin chemotherapy). As used herein, the expression “does not increase by 10 dB or more” encompasses any increase of less than 10 dB, any decrease and any absence of variation.

[0038] Therefore, in some embodiments, it is considered that cisplatin-induced hearing loss is completely prevented for a subject if, after the completion of a course of cisplatin chemotherapy (preferably 4 weeks after the completion of a course of cisplatin chemotherapy), the hearing threshold or audiometric threshold of said subject increases by less than 10 dB, in particular as compared to the hearing threshold or audiometric threshold at baseline (z.e., the hearing threshold or audiometric threshold before the start of the course of cisplatin chemotherapy).

[0039] As indicated above, “preventing hearing loss” as used herein also encompasses partially preventing hearing loss induced by cisplatin. In particular, “preventing hearingloss” as used herein also encompasses minimizing or reducing hearing loss induced by cisplatin and / or minimizing or reducing the degree of hearing loss induced by cisplatin.

[0040] For example, “partially preventing hearing loss” induced by cisplatin may be defined as a hearing loss exceeding 10 dB relative to baseline, coupled with a difference of 10 dB or more in favor of the treatment, compared to the projected loss without preventive treatment. In other words, “partially preventing hearing loss” induced by cisplatin may be defined as a hearing loss exceeding 10 dB relative to baseline, coupled with a difference of 10 dB or more in favor of azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, compared to the projected loss without azasetron, or a pharmaceutically acceptable salt and / or solvate thereof.

[0041] It may thus be considered that cisplatin-induced hearing loss is partially prevented for a subject if, after the completion of a course of cisplatin chemotherapy (preferably 4 weeks after the completion of a course of cisplatin chemotherapy), the hearing threshold or audiometric threshold of said subject increases by 10 dB or more, in particular as compared to the hearing threshold or audiometric threshold at baseline (z.e., the hearing threshold or audiometric threshold before the start of the course of cisplatin chemotherapy), said increase remaining lower than that expected for a subject not receiving any preventive treatment, preferably lower by 10 dB or more.

[0042] The subject as described herein is suffering from a cancer, which may a primary cancer or a cancer recurrence or relapse. A primary cancer may be defined as a first occurrence of the cancer in the subject. A cancer recurrence or relapse may be defined as a subsequent occurrence of the cancer in the subject after a period of remission. The cancer recurrence or relapse may be a local recurrence, wherein the cancer affects the same place as the original primary cancer; a regional recurrence, wherein the cancer affects lymph node(s) or tissue(s) near the original primary cancer; or a distant recurrence, wherein the cancer affects organ(s) or tissue(s) far from the original primary cancer.

[0043] In some embodiments, the subject is suffering from a solid cancer, a leukemia, or a lymphoma. In some embodiments, the subject is suffering from a solid cancer.

[0044] The cancer as described herein is a cancer treatable with cisplatin. By “treatable with cisplatin” it is meant that cisplatin (z.e., administration of cisplatin) is indicated for the treatment of the cancer, whatever the goal of the treatment may be. For example, the goal of the treatment may be curing the cancer, reducing or shrinking the cancer, stabilizing or controlling the cancer and / or preventing the spread of the cancer. In some embodiments, cisplatin (z.e., administration of cisplatin) is indicated as a first-line treatment, for example to a subject suffering from a primary cancer. In some embodiments, cisplatin (z.e., administration of cisplatin) is indicated as a second-line or subsequent treatment, for example to a subject suffering from a cancer recurrence.

[0045] The subject as described herein may also be defined as suffering from a cancer treated or to be treated with cisplatin. Thus, the subj ect as described herein may be defined as suffering from a cancer treated or to be treated with cisplatin at a cumulative dose equal to or higher than about 300 mg / m2. Alternatively, it may also be said that the subject as described herein is suffering from a cancer requiring cisplatin, in particular requiring a chemotherapy comprising a cumulative dose of cisplatin equal to or higher than about 300 mg / m2. Cisplatin is thus included in the treatment plan designed or elaborated for the subject. In particular, cisplatin is included in the chemotherapy plan designed or elaborated for the subject.

[0046] Upon diagnosis of a cancer in a subject and / or upon assessment or evaluation of a cancer in a subject, and before the actual administration of a course of chemotherapy, the generalized practice in cancerology is to first set up (or design or elaborate) a chemotherapy plan (or chemotherapy protocol). Taking into account a number of relevant parameters and based on the established guidelines in the field of cancerology, the chemotherapy plan defines at least the chemotherapeutic agent to be used, the way of administration, the dose to be administered per cycle expressed per body surface area (e.g., mg per m2of body surface area), the numbers of cycles, and the cumulative dose to be administered (which depends on the dose per cycle and number of cycles).

[0047] The chemotherapy plan may include other information, such as drug(s) that may be administered other than the chemotherapeutic agent. Relevant information taken into account to set up (or design or elaborate) a chemotherapy plan includes, for example,cancer type, cancer stage, goal of the treatment, clinical status of the subject, general health and fitness of the subject.

[0048] Therefore, the subject as described herein is a subject with a chemotherapy plan including cisplatin (z.e., the administration of cisplatin) at a cumulative dose equal to or higher than about 300 mg / m2. In other words, the subject as described herein is a subject whose chemotherapy plan includes cisplatin (z.e., the administration of cisplatin) at a cumulative dose equal to or higher than about 300 mg / m2.

[0049] Accordingly, by “cumulative dose of cisplatin”, it is meant the total dose of cisplatin to be administered in accordance with the chemotherapy plan. In some embodiments, the chemotherapy plan defines one course of chemotherapy. Therefore, in some embodiments, by “cumulative dose of cisplatin” it is meant the total dose of cisplatin to be administered over one course of chemotherapy. One course of chemotherapy may include several cycles of chemotherapy. For example, one course of chemotherapy resulting in a cumulative dose of cisplatin equal to or higher than about 300 mg / m2may include 3 cycles of chemotherapy, with a dose of cisplatin equal to or higher than about 100 mg / m2per cycle. Alternatively, one course of chemotherapy resulting in a cumulative dose of cisplatin equal to or higher than about 300 mg / m2may include 4 cycles of chemotherapy, with a dose of cisplatin equal to or higher than about 75 mg / m2per cycle; 5 cycles of chemotherapy, with a dose of cisplatin equal to or higher than about 60 mg / m2per cycle; or 6 cycles of chemotherapy, with a dose of cisplatin equal to or higher than about 50 mg / m2per cycle.

[0050] In some embodiments, the chemotherapy plan is the first chemotherapy plan of the subject, such as a chemotherapy plan elaborated upon diagnosis of a primary cancer. In some embodiments, the chemotherapy plan is the second or subsequent (z.e., not the first) chemotherapy plan of the subject, such as a chemotherapy plan elaborated upon diagnosis of a cancer recurrence in the subject or a chemotherapy plan elaborated upon evaluation of a cancer after administration of a course of treatment, for example after administration of a course of chemotherapy.

[0051] Although not frequent, deviations from a chemotherapy plan may occur. For example, deviations from a chemotherapy plan may be required if side effects are significant and / or if the chemotherapy is not tolerated. An example of deviation from a chemotherapy plan includes increasing the rest period between actual administrations. Such a deviation does not modify the cumulative dose of chemotherapeutic agent received over the course of chemotherapy.

[0052] As used herein, “a subject scheduled to receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2” includes a subject who is yet to receive cisplatin at a cumulative dose equal to or higher than about 300 mg / m2, a subject who is to receive cisplatin at a cumulative dose equal to or higher than about 300 mg / m2and a subject who is receiving cisplatin at a cumulative dose equal to or higher than about 300 mg / m2.

[0053] The subject as described herein is thus a subject suffering from cancer who will receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2as defined in their chemotherapy plan.

[0054] Cisplatin is usually administered by injection, preferably by intravenous infusion. Accordingly, in some embodiments, the cumulative dose of cisplatin as described herein is a cumulative dose of cisplatin by injection, preferably by intravenous infusion.

[0055] The subject is a human subject. The subject may be an adult. For example, the subject may be 18 year-old or older, 19 year-old or older, 20 year-old or older, or 21 year- old or older. The subject may be a pediatric subject. For example, the subject may be a newborn, an infant, a toddler, a child or a teenager. The pediatric subject may be 18 year- old or younger, 17 year-old or younger, 16 year-old or younger, 15 year-old or younger, 14 year-old or younger, 13 year-old or younger, 12 year-old or younger, 11 year-old or younger, or 10 year-old or younger. The pediatric subject may be 6 year-old or older, 7 year-old or older, 8 year-old or older, 9 year-old or older, 10 year-old or older, 11 year- old or older, or 12 year-old or older.

[0056] In some embodiments, the subject never received cisplatin prior to the scheduled cumulative dose of cisplatin equal to or higher than about 300 mg / m2. In some embodiments, the subject previously received cisplatin prior to the scheduled cumulativedose of cisplatin equal to or higher than about 300 mg / m2. In some embodiments, the subject previously received cisplatin over a prior chemotherapy course.

[0057] In some embodiments, before the start of the cisplatin treatment (for example before the start of the cisplatin chemotherapy course), the subject has a normal hearing (or normal hearing acuity or normal hearing range), preferably for both ears. Thus, in some embodiments, before the start of the cisplatin treatment (for example before the start of the cisplatin chemotherapy course), the subject is not affected by any hearing loss.

[0058] Azasetron is a compound of formula (I), wherein * stands for the (R)-enantiomer (or (+)-enantiomer), the (S)-enantiomer (or (-)-enantiomer), the racemate or a non- racemic mixture of (R)- and (S)-enanti omers (corresponding to mixtures of (+)-and (-)- enantiomers):

[0059] Azasetron thus corresponds to 6-chloro-3,4-dihydro-N-(8-methyl-8-azabicyclo- [3.2.1]-oct-3-yl)-2,4-dimethyl-3-oxo-2H-l,4-benzoxazine-8-carboxamide, which may also be referred to as N-(l-azabicyclo[2.2.2]octan-8-yl)-6-chloro-4-methyl-3-oxo-l,4- benzoxazine-8-carboxamide, as described in the U.S. patent 4,892,872.

[0060] As indicated above, azasetron has one chiral center that can give rise to two stereoisomers. In some embodiments, azasetron is racemic azasetron, or a pharmaceutically acceptable salt and / or solvate thereof.

[0061] In some embodiments, azasetron is the (R)-enantiomer of azasetron, or a pharmaceutically acceptable salt and / or solvate thereof. The (R)-enantiomer of azasetron is called (R)-azasetron or (+)-azasetron, corresponding to formula (R)-I:

[0062] Examples of processes that may be used to synthetize (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof are well-known in the art (see for example Chinese patent applications CN101786963 and CN104557906). In some embodiments, synthesis of (R)-azasetron or of a pharmaceutically acceptable salt and / or solvate thereof includes ab initio synthesis and / or chiral resolution. In some embodiments, when ab initio synthesis of (R)-azasetron or of a pharmaceutically acceptable salt and / or solvate thereof is implemented, at least one racemic starting compound and / or intermediate compound is substituted by a chiral compound.

[0063] In some embodiments, azasetron is the (S)-enantiomer of azasetron, or a pharmaceutically acceptable salt and / or solvate thereof. The (S)-enantiomer of azasetron is called (S)-azasetron or (-)-azasetron, corresponding to formula (S)-I:

[0064] In some embodiments, azasetron includes the compound of formula I, preferably of formula (R)-I, and all polymorphs, crystals and crystal habits thereof, and isotopically- labeled compounds of formula I, preferably of formula (R)-I.

[0065] Azasetron may be in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts of azasetron include the acid addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples of acid addition salts include besylate, hydrochloride / chloride, malate, benzoate, ethane- 1,2-di sulfonate, fumarate, tartrate, acetate, adipate, ascorbate, aspartate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, ethanesulfonate, formate, gluceptate, gluconate, glucuronate, glutamate, hexafluorophosphate, hibenzate, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, maleate, malonate, mesylate, methyl sulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, p-toluenesulfonate, tosylate, trifluoroacetate, and xinofoate salts.

[0066] Pharmaceutically acceptable salts of azasetron may be prepared by reacting azasetron with the desired acid, or by converting one salt of azasetron to another by reaction with an appropriate acid or by means of a suitable ion exchange column. All these reactions are typically carried out in solution. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may vary from completely ionized to not ionized resulting in a co-crystal.

[0067] In some embodiments, azasetron is in the form of a pharmaceutically acceptable salt selected from a besylate, hydrochloride, malate, benzoate, ethane-l,2-disulfonate, fumarate, and tartrate salt; more preferably from a besylate, hydrochloride, malate, and benzoate salt; even more preferably from a besylate, hydrochloride, and malate salt.

[0068] As used herein, “pharmaceutically acceptable solvate” in connection with azasetron refers to a molecular complex comprising azasetron and stoichiometric or sub stoichiometric amounts of one or more pharmaceutically acceptable solvent moleculessuch as ethanol or water. The term “hydrate” (as in “pharmaceutically acceptable hydrate”) may be specifically used when the solvent is water.

[0069] In some embodiments, azasetron is (R)-azasetron besylate, (R)-azasetron hydrochloride, (R)-azasetron malate, (R)-azasetron benzoate, (R)-azasetron ethane- 1,2-di sulfonate, (R)-azasetron fumarate, and / or (R)-azasetron tartrate. In some embodiments, azasetron is (R)-azasetron besylate, (R)-azasetron hydrochloride, (R)-azasetron malate, and / or (R)-azasetron benzoate; more preferably azasetron is (R)-azasetron besylate, (R)-azasetron hydrochloride, and / or (R)-azasetron malate.

[0070] In some embodiments, azasetron is (R)-azasetron besylate, also referred to as “SENS-401”.

[0071] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration at a therapeutically effective dose (or at a therapeutically effective amount).

[0072] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration at a daily dose ranging from about 20 mg to about 200 mg.

[0073] As used herein, a free base equivalent dose refers to the dose of active ingredient as such, z.e., azasetron, and not to its pharmaceutically acceptable salt and / or solvate form. Thus, compositional variations of a pharmaceutically acceptable salt and / or solvate of azasetron will not impact the free base equivalent dose to be administered.

[0074] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration at a free base equivalent dose ranging from about 0.5 to about 1 mg / kg / day (mg per kilo body weight per day). In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration at a free base equivalent dose of about 0.5, 0.6, 0.7, 0.8, 0.9 or 1 mg / kg / day.

[0075] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration at a daily free base equivalent dose of about 60 mg.

[0076] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration at least once a day, preferably twice a day.

[0077] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is to be administered systemically. Thus, in some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for systemic administration or is adapted for systemic administration.

[0078] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is to be administered orally. Thus, in some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for oral administration or is adapted for oral administration. Examples of formulations adapted for oral administration include solid forms and liquid forms. Examples of solid forms adapted for oral administration include tablets, pills, and capsules.

[0079] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is formulated for oral administration as a tablet.

[0080] In some embodiments, a tablet formulated for oral administration comprises or consists of about 10 mg free base equivalent of azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, preferably of (7?)-azasetron besylate.

[0081] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is to be first administered at least 1 week prior to the start of the cisplatin treatment. In other words, in some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration, preferably for daily administration, from at least 1 week prior to the start of the cisplatin treatment.

[0082] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is to be administered for at least 4 weeks after the end of the cisplatin treatment. In other words, in some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for administration, preferably for daily administration, until at least 4 weeks after the end of the cisplatin treatment.

[0083] In some embodiments, azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, is for daily administration from at least 1 week prior to the start of the cisplatin treatment and until at least 4 weeks after the end of the cisplatin treatment.

[0084] As indicated above, “cisplatin treatment” may refer to a cycle of cisplatin chemotherapy or, preferably, to a course of cisplatin chemotherapy.

[0085] Another object of the present invention is a method for preventing hearing loss in a subject suffering from a cancer as described herein, wherein the subject is scheduled to receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2, said method comprising administering to the subject azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, as described herein.

[0086] Another object of the present invention is a pharmaceutical composition for use in the prevention of hearing loss in a subject suffering from a cancer as described herein, wherein the subject is scheduled to receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2, said pharmaceutical composition comprising azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, and optionally at least one pharmaceutically acceptable excipient.

[0087] Another object of the present invention is the use of azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, for the manufacture of a medicament or a kit for the prevention of hearing loss in a subject suffering from a cancer requiring a chemotherapy comprising a cumulative dose of cisplatin equal to or higher than about 300 mg / m2.

[0088] Another object of the present invention is the use of azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, for the manufacture of a medicament or a kit for the prevention of hearing loss in a subject suffering from a cancer as described herein, wherein the subject is scheduled to receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2.BRIEF DESCRIPTION OF THE DRAWINGS

[0089] Figure 1 is a scheme depicting the phase Ila, open-label, randomized and controlled study to evaluate the efficacy of ( / / j-azasetron (SENS-401) to prevent hearing loss induced by cisplatin in subjects suffering from a cancer.

[0090] Figure 2 is a graph illustrating the change in PTA of the most affected ear for each participant, calculated relative to baseline at the three most affected consecutive frequencies, as a function of the cumulative cisplatin dose (mg / m2). The 13 participants in the control group (squares) received cisplatin only, without SENS-401. The 14 participants in the treatment group (circles) received cisplatin in combination with SENS-401, administered one week before the initiation of cisplatin therapy and continued for four weeks after the last cycle.EXAMPLES

[0091] The present invention is further illustrated by the following examples.Example 1 :

[0092] A phase Ila, multicenter, randomized, controlled, open-label study has been initiated to evaluate the efficacy of ( / / j-azasetron to prevent hearing loss induced by cisplatin in subjects suffering from a cancer (see scheme of Figure 1).

[0093] Hereinafter, the designation “SENS-401” corresponds to the investigational product ( / / j-azasetron (administered as ( / / j-azasetron besylate to the participants included in the study).Materials and MethodsParticipants included in the study

[0094] Participants are adults aged from 18 years and older, capable of giving signed informed consent, who are suffering from a cancer to be treated with a chemotherapy comprising a dose of cisplatin of at least 70 mg / m2per cycle and a cumulative dose ofcisplatin of at least 210 mg / m2.

[0095] In total, the study includes 48 participants, randomized to either arm A (control arm - participants receiving cisplatin-based chemotherapy without receiving SENS-401) or arm B (participants receiving cisplatin-based chemotherapy and SENS-401).

[0096] Cisplatin-induced hearing loss is assessed with pure tone audiometry (also referred to as pure tone audiometric testing), in particular with pure tone audiometric air conduction testing. Pure tone audiometry is a behavioral subjective test used to determine hearing thresholds (expressed in decibels or dB). Air conduction hearing thresholds are usually measured for tonal stimuli at set frequencies within the range from 0.500 kHz to 12.5 kHz, with the use of headphones. Then, bone conduction hearing thresholds are usually measured for tonal stimuli at set frequencies within the range from 0.25 to 4 kHz, with the use of a headband with oscillator. A hearing threshold, in particular a hearing threshold determined with pure tone audiometry, may be referred to as pure-tone average (PTA), which corresponds to the average of hearing thresholds determined at a set of fixed consecutive frequencies.

[0097] In the present study, pure tone air-conduction hearing thresholds are determined at 0.5, 1, 2, 3, 4, 6, 8, 10 and 12.5 kHz and bone-conduction hearing thresholds are determined at 0.5, 0.75, 1, 2, 3, and 4 kHz.

[0098] For all participants, pure tone audiometry is performed as described above at screening (which must occur within 28 days before randomization), 4 weeks after the cisplatin treatment (z.e., 4 weeks after the last cisplatin chemotherapy cycle and thus 4 weeks after the completion of the course of cisplatin chemotherapy) and 12 weeks after the cisplatin treatment (z.e., 12 weeks after the last cisplatin chemotherapy cycle and thus 12 weeks after the completion of the course of cisplatin chemotherapy).

[0099] Hearing thresholds determined at screening (z.e., prior to any cisplatin treatment) are defined as the hearing thresholds at baseline. Thus, a pure-tone average (PTA) determined at screening is defined as the PTA at baseline. The PTA at baseline is expressed as the average of the hearing thresholds (in dB) determined at three consecutive frequencies within the range spanning from 0.5 to 12.5 kHz.

[0100] Preferably, the pure-tone average (PTA) change from baseline corresponds to the difference between the PTA at the 3 most affected contiguous frequencies after the end of the cisplatin treatment (e.g., 4 weeks or 12 weeks after the completion of the course of cisplatin chemotherapy) and the PTA at the same frequencies at baseline. The PTA change from baseline according to said definition may also be referred as the maximum PTA change from baseline.

[0101] A higher pure-tone average (PTA) (and thus a positive PTA change from baseline) corresponds to a higher hearing threshold and thus to a poorer hearing. In a subject, an increase of the PTA over time may generally correspond to a decrease in hearing, z.e., to a hearing loss. Conversely, a lower PTA (and thus a negative PTA change from baseline) corresponds to a lower hearing threshold and thus to a better hearing. In a subject, a decrease of the PTA over time may generally correspond to an improvement of hearing.

[0102] For participants of the study, a decrease of the pure-tone average (PTA) overtime or an increase of the PTA over time of less than 10 dB is defined as a complete prevention of cisplatin-induced hearing loss. For participants of the study, a difference of 10 dB or more as compared to no SENS-401 treatment is regarded as a prevention of cisplatin- induced hearing loss.

[0103] Of note, exclusion criteria precluding recruitment in the study include in particular: a congenital or hereditary disease known to decrease hearing function; any medical history affecting the middle ear function such as chronic otitis, cholesteatoma, or tympanic membrane perforation; any inner ear disease that is likely to decrease hearing function according to the Investigator’ s judgment; having a history of sudden sensorineural hearing loss. having a fluctuating hearing loss; having a history of head trauma with hearing loss.Drug administration

[0104] After written informed consent is obtained and screening procedures completed, the eligible participants are randomized to either arm A (control arm) or arm B (SENS-401 arm) in a ratio 1 : 1 (up to 29 participants in arm A and up to 29 participants in arm B).

[0105] Arm A (control arm) participants receive cisplatin-based chemotherapy but do not receive SENS-401.

[0106] Arm B participants are administered SENS-401 twice daily for 1 week prior to the start of their cisplatin-based chemotherapy (z.e., prior to the start of their course of cisplatin-based chemotherapy). Arm B (SENS-401 arm) participants continue to take SENS-401 twice daily for 4 weeks after the last cycle of cisplatin chemotherapy (ie., after the completion of their course of cisplatin-based chemotherapy). SENS-401 is administered orally, twice a day at a dose of 43.5 mg-BID (bis in die), corresponding to a total daily dose of 87 mg (60 mg free base equivalent).Monitoring of subjects and objectives

[0107] Participants included in the study are monitored with a first visit during the screening period, followed by a visit 4 weeks after the course of the cisplatin chemotherapy (i.e., after the last of the cisplatin chemotherapy cycle), and a visit 12 weeks after the course of cisplatin chemotherapy i.e., after the last of the cisplatin chemotherapy cycle). Monitoring includes hearing test (pure tone audiometry at the frequencies ranging from 0.5 kHz to 12.5 kHz), otoscopy, immittance audiometry, speech-in-noise test, and speech-in-quiet test. Additionally, participants are closely monitored for adverse events throughout the study.

[0108] Otoscopy is part of standard of care, to examine structures of the ear, particularly the external auditory canal, tympanic membrane, and middle ear. Immitance audiometry evaluates middle ear function by three procedures: static immittance, tympanometry, and the measurement of acoustic reflex threshold sensitivity.

[0109] Speech-in-noise tests are useful for assessing “real -world” hearing ability tosimulate how an individual might hear in a restaurant or noisy grocery store. A speech- in-noise test typically is a sentence test. The participant is asked to repeat as many as possible of the words in the sentence they heard. They receive a point for each sentence correctly repeated as well as for each word correctly repeated. The noise signal (also known as “multi-talker babble”) depends on the number of people. The noise signal is commonly produced by 4 people talking at once (4-talker babble). As many as 20 people can be talking at once, although the number of people is not usually over 10.

[0110] Speech-in-quiet tests are monosyllabic word tests with a consonant-nucleus- consonant structure. The participant is presented with a single word and asked to repeat what they heard. Each word typically has three phonemes / sounds within the word and the middle / nucleus is a vowel.

[0111] The primary objective is to evaluate the efficacy of SENS-401 by assessing the PTA change from baseline, preferably at the 3 most affected contiguous frequencies, 4 weeks after the completion of the course of cisplatin chemotherapy (z.e., after the completion of the last of the cisplatin chemotherapy cycle).

[0112] Additional objectives include evaluating the efficacy of SENS-401 by assessing the PTA change from baseline, preferably at the 3 most affected contiguous frequencies, 12 weeks after the completion of the course of cisplatin chemotherapy (z.e., after the completion of the last of the cisplatin chemotherapy cycle).Results

[0113] A total of 48 subjects were enrolled in the study, of whom 27 had analyzable data at Visit 4 (z.e., visit 4 weeks after the course of the cisplatin chemotherapy). Hearing acuity was assessed at screening and again four weeks after the final cycle of cisplatin chemotherapy. Among the 27 evaluable participants, 13 were allocated to Arm A (cisplatin only, control group) and 14 to Arm B (cisplatin plus SENS-401). Hearing thresholds were measured across frequencies ranging from 0.5 to 12.5 kHz. For each participant, the pure-tone average (PTA) was calculated as the mean of the hearing thresholds at the three most affected contiguous frequencies within this range. The change in PTA from baseline was defined as the difference between the baseline PTA at thesefrequencies and the PTA obtained four weeks after the last cisplatin cycle (Visit 4). This value reflects the maximum PTA change from baseline for each individual subject.

[0114] Figure 2 illustrates the dose-response relationship between cumulative cisplatin exposure and the severity of hearing loss. The y-axis shows the change from baseline in the average pure tone thresholds (PTA) across the three most affected frequencies, measured four weeks after the last cisplatin cycle, while the x-axis represents the cumulative cisplatin dose (mg / m2). For each participant, the score corresponds to the ear with the greatest hearing loss. Control group subjects are represented by squares connected by a broken line, and SENS-401-treated subjects by circles connected by a solid line.

[0115] In the control group, a clear positive correlation is observed, with higher cumulative cisplatin doses associated with greater PTA deterioration. In contrast, this trend is absent in the SENS-401 group, where cisplatin exposure appears to have little or no effect on auditory threshold shifts. The two correlation lines intersect at approximately 300 mg / m2, indicating that beyond this cumulative dose, participants treated with SENS-401 experience less hearing loss compared with controls.

[0116] These results underscore a protective effect of SENS-401 against cisplatin- induced, dose-dependent ototoxicity, particularly in patients exposed to higher cumulative doses, such as a cumulative dose of cisplatin equal to or higher than 300 mg / m2.

Claims

CLAIMS1. Azasetron, or a pharmaceutically acceptable salt and / or solvate thereof, for use in the prevention of hearing loss in a subject suffering from a cancer, wherein the subject is scheduled to receive a cumulative dose of cisplatin equal to or higher than about 300 mg / m2.

2. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to claim 1, wherein azasetron is (R)-azasetron, (S)-azasetron, a mixture thereof, or a pharmaceutically acceptable salt and / or solvate thereof.

3. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to claim 1 or 2, wherein azasetron is (R)-azasetron or a pharmaceutically acceptable salt and / or solvate thereof.

4. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of azasetron is selected from a besylate salt, a malate salt, and a hydrochloride salt.

5. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of azasetron is (R)-azasetron besylate.

6. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 5, wherein azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, is for administration from at least 1 week prior to the start of the cisplatin treatment.

7. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 6, wherein azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, is for administration until at least 4 weeks after the end of the cisplatin treatment.

8. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 7, wherein azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, is for daily administration from at least 1 week prior to the start of the cisplatin treatment and until at least 4 weeks after the end of the cisplatin treatment.

9. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 8, wherein azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, is for administration at a daily dose ranging from about 20 mg to about 200 mg.

10. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 9, wherein azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, is for administration at a daily free base equivalent dose of about 60 mg.

11. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 10, wherein azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, is for oral administration.

12. Azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, for use according to any one of claims 1 to 11, wherein azasetron, or the pharmaceutically acceptable salt and / or solvate thereof, is for administration twice a day.

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