Drug combinations for treatment of diseases associated with tyrosine kinase receptor activation

Abstract

A tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite, or a derivative thereof for use in a method of treatment of a disease associated with tyrosine kinase receptor activation in a subject, wherein the tyrosine kinase receptor inhibitor is administered in combination with a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II): wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and AΘ is a pharmaceutically acceptable anion.

Description

DRUG COMBINATIONS FOR TREATMENT OF DISEASES ASSOCIATED WITH TYROSINE KINASE RECEPTOR ACTIVATIONTECHNICAL FIELD

[0001] The present invention relates to a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite, or a derivative thereof for use in a method of treatment of a disease associated with tyrosine kinase receptor activation in a subject, wherein the tyrosine kinase receptor inhibitor is administered in combination with a compound of formula (I), and / or a compound of formula (II), as described herein. The present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I), and / or a compound of formula (II). The present invention also relates to the pharmaceutical composition for use as a medicament. Also, the present invention relates to a kit of parts comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I), and / or a compound of formula (II).BACKGROUND

[0002] Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Tyrosine kinases, by way of substrate phosphorylation, play critical roles in signal transduction for a number of cell functions. Activated tyrosine kinase receptors have been shown to be important factors in cell proliferation, carcinogenesis and cell differentiation, and thus play a role in the genesis and mediation of various diseases. About twenty different subfamilies of tyrosine kinase receptors have been identified, including, for example, the EGF receptor family, the insulin receptor family, the PDGF receptor family, the VEGF receptors family, the FGF receptor family, the CCK receptor family, the NGF receptor family, the HGF receptor family, the Eph receptor family, the AXL receptor family, the TIE receptor family, the RYK receptor family, the DDR receptor family, the RET receptor family, the ROS receptor family, the LTK receptor family, the ROR receptor family, the MuSK receptor family and the LMR receptor family.

[0003] In order to provide therapies for the treatment of diseases associated with tyrosine kinase receptor activation, tyrosine kinase receptor inhibitors have been developed. However, severaldrawbacks remain, in particular severe side effects of the inhibitors and / or development of resistance.

[0004] Medullary Thyroid Carcinoma (MTC) is an example for a disease associated with activation of a tyrosine kinase receptor, more exactly activation of the tyrosine kinase receptor RET. MTC is a rare tumor of the calcitonin-producing parafollicular cells of the thyroid gland. At the time of diagnosis about half of the patients show local invasion and distant metastases. While surgical resection can be curative at the early stages of the disease, patients with advanced / progressive disease often die from tumor progression. For the past 15 years, targeted therapy with the multikinase inhibitors vandetanib (Van) and cabozantinib (Cab), which besides RET also inhibit other tyrosine kinase receptor(s), has demonstrated clinical benefits for patients with progressive or metastatic MTC. However, these drugs associate with severe side effects, and patients almost invariably develop resistance over time. A similar situation occurs for the newly FDA-approved RET inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) that also quickly elicit tumor resistance.

[0005] MTC originates from the calcitonin-producing parafollicular C-cells of the thyroid gland. MTC represents only 5-7% of all thyroid carcinomas but it accounts for a substantial fraction of thyroid cancer mortality due to its aggressive behavior (Woyach & Shah, 2009). MTC often metastasizes to lymph nodes early in the course of the disease, and spread to distant organs is common (Rendl et al. 2008). At the time of diagnosis, 35-50% of patients have regional metastases, whereas approximately 15% have distant metastases and a 10-year survival of 20% (Roman et al. 2006). Total thyroidectomy is the elective treatment for MTC with high curative rates for early stage tumors. However, complete remission is rare and tumors often recur. For patients with locally advanced or metastatic MTC, systemic treatment is the only option. Conventional chemotherapy has been used with only marginal benefits due to limited responsiveness of the tumors (Cabanillas et al. 2016). Targeted therapies have provided clinical benefits, but have significant adverse effects and resistance often develops within a few years. The most important factors associated with poor prognosis in MTC are advanced stage of tumor progression at diagnosis and the presence of lymph node metastases (Wells et al. 2015). The 10-year overall survival rate of patients with localized disease is around 95% while that of patients with regional involvement is about 75% (Wells et al. 2015). Although MTC is mostly sporadic, about 25% of the cases occurs in the context of the hereditary multiple endocrine neoplasia type 2 syndrome and is associated with germline activating mutations of the REarranged during Transfection (RET) gene encoding a tyrosine kinase transmembrane receptor (Romei et al. 2016). In the past 15 years, molecular therapies using multi-tyrosine kinase inhibitors (TKIs) targeting RET, the vascular endothelial growth factor receptors (VEGFR) and other receptor tyrosine kinases have beendeveloped and tested in patients with advanced MTC, large tumour burden and documented disease progression (Woyach & Shah, 2009). Between 2011 and 2012, two RET inhibitors, Van and Cab, were FDA-approved for the treatment of late-stage MTC patients who are ineligible for surgery and show disease progression. Although treatment of patients with progressive metastatic MTC with Van and Cab led to an improvement in progression-free survival (PFS) in clinical trials (Durante et al. 2013; Kurzrock et al. 2011), no significant improvement in overall survival (OS) was observed (Wells et al. 2017; Elisei et al. 2013). These drugs were found to cause severe secondary toxicities, and are therefore recommended only for selected patients, and administered under strict surveillance by a multidisciplinary team in specialized centers. Clinical studies highlighted an intrinsic resistance of MTCs to these TKIs: even the tumors that initially respond to these therapies almost always acquire resistance (secondary resistance) which results in disease progression. Secondary resistance may be an on target, e.g. change in the structure or activity of the target protein, or to off-target effects, i.e. due to activation of alternate routes to tumor cell growth. In the case of MTC, it seems that both molecular mechanisms could be involved. In human cancers, the primary escape mechanism for targeted small-molecule TKIs are the so-called gatekeeper mutations, which modulate the accessibility of the kinase ATP binding pocket to the drugs. In RET, it has been shown that the mutations V804M and V804L cause steric hindrance that interferes with the binding of TKIs, and are therefore referred to as gatekeeper mutations. In vitro studies have shown that these two mutations confer intrinsic resistance to Van (Carlomagno et al. 2004). Also the I788N RET mutation was reported to confer resistance to both Van and Cab (Plenker et al. 2017). During the year 2020, two highly potent and selective RET-targeting TKIs, LOXO-292 (selpercatinib) and BLU-667 (pralsetinib), were approved by the FDA for the treatment of thyroid cancers (and non small cell lung cancers - NSCLC) with RET mutations or fusions. Both selpercatinib and pralsetinib are orally bioavailable selective drugs that are effective also on tumors carrying the gatekeeper RET V804M / L mutations (Subbiah V et al. 2018; Subbiah V et al. 2020). Initial clinical trials using these drugs on patients with MTC showed good tolerability, improved ORR, and the responses were more durable than with first-generation multikinase inhibitors. Despite these promising results, however, incomplete response has been documented in about one-third of RET-altered cancers. Additionally, acquired resistance to selpercatinib and pralsetinib through secondary on-target mutations and / or through the activation of other oncogenes has been documented in both MTC and NSCLC (Subbiah V et al. 2020). The multikinase inhibitor Cab has recently been found effective in various solid tumors in addition to MTC. One year ago, the FDA approved the combination of nivolumab (PD-1 inhibitor) and Cab as first-line treatment for patients with advanced renal cell carcinoma (RCC). This decision was based on the results of the CheckMate 9ER study [ClinicalTrials.gov Identifier: NCT03141177], a randomized, open-label clinical trial of patients with previously untreated advanced RCC. This trial demonstrated a statistically significant improvement in PFS, OS and confirmed overall response rate (ORR) inpatients treated with nivolumab plus Cab versus those who received sunitinib (Choueiri TK et al. 2021). Additionally, Cab has been evaluated in patients with radioiodine (RAI)-refractory differentiated thyroid cancer. Following promising results of Phase l / ll clinical trials studies (Cabanillas 2017; Brose 2018), a Phase III trial was initiated where the efficacy and safety of Cab versus placebo was assessed in patients with RAI -refractory differentiated thyroid cancer who had progressed during / after prior VEGFR-targeted therapy. Importantly, for these patients there is no standard of care. Cab treatment elicited a clinically and statistically significant improvement in PFS over placebo in those patients with no unexpected toxicities. Cab may therefore represent a new treatment option for patients with RAI-refractory differentiated thyroid cancer, currently orphan of available standard of care (Brose et al. 2021). Another tumor type where Cab has shown clinical benefits is hepatocellular carcinoma (HCC). The phase III CELESTIAL trial demonstrated improved PFS and OS with Cab compared to placebo, thereby establishing this drug as a potential treatment option for patients with advanced HCC previously treated with sorafenib (reviewed in Braun DA et al. 2021). It is important to consider that Cab at the doses currently used causes severe secondary toxicities, and consequently these therapy regimens are recommended only for selected patients, and conducted under strict surveillance by a multidisciplinary team in specialized centers.

[0006] Accordingly, there is a need for further compounds and compositions for use in a method of treatment of a disease associated with tyrosine kinase receptor activation.SUMMARY

[0007] The technical problem is solved by the subject-matter as defined in the claims.

[0008] The present invention relates to a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite, or a derivative thereof for use in a method of treatment of a disease associated with tyrosine kinase receptor activation in a subject, wherein the tyrosine kinase receptor inhibitor is administered in combination with a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

[0009] The present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / ora compound of formula (II):(II), wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

[0010] The present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion for use as a medicament.

[0011] The present invention also relates to a kit of parts comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The invention will be better understood with reference to the detailed description when considered in conjunction with the non-limiting examples and the accompanying drawings, respectively. The Figures show:

[0013] Figure 1 shows the efficacy of Clofilium Tosylate (Ct) and Cabozantinib (Cab) combination on the viability of TT (human medullary thyroid carcinoma - MTC) cells grown as 2D monolayer cultures. Concentrations used were: 1.4µM Ct and 2.5µM Cab. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. ****, P<0.0001.

[0014] Figure 2 shows the efficacy of Monensin (Mon) and Cabozantinib (Cab) / Vandetanib (Van) combinations on the viability of TT (A) and MZ-CRC-1 (B) (human MTC) cells grown as 2D monolayer cultures. Concentrations used were: 0.12 / 0.37µM Mon (TT); 0.66µM Mon (MZ-CRC-1); 1µM Van and 2.5µM Cab. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001.

[0015] Figure 3 shows the efficacy of Monensin (Mon) and Cabozantinib (Cab) / Vandetanib (Van) combinations on the viability of other tumour models grown as 2D monolayer cultures. PC12 cells were derived from a rat pheochromocytoma (A, neuroendocrine tumor of the adrenal gland); BON- 1 are human pancreatic neuroendocrine tumor cells (B); NCI-H69 are human small cell lung cancer cells (C, also neuroendocrine origin); GH3 are derived from a rat pituitary neuroendocrine tumor (D); RCC4 are clear cell renal cell carcinoma cells (E, non-neuroendocrine tumor cells). Concentrations used were: 0.12 / 0.37µM Mon; 1µM Van and 2.5µM Cab. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed bytwo-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001; ns, not significant.

[0016] Figure 4 shows the efficacy of Clofilium Tosylate (Ct) and / or Monensin (Mon) in combination with the RET-specific inhibitors Selpercatinib (Sel) or Pralsetinib (Pra) on the viability of TT (A and B) and MZ-CRC-1 (C) cells grown as 2D monolayer cultures. Concentrations used were: 1.4µM Ct; 0.12µM Mon (TT); 0.66µM Mon (MZ-CRC-1) ; 0.02µM Sel; 0.02µM Pra. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001; ns, not significant.

[0017] Figure 5 shows the efficacy of Clofilium Tosylate (Ct) and / or Monensin (Mon) in combination with multikinase inhibitors, Alectinib (Ale), Sunitinib (Sun) and Regorafenib (Reg) on the viability of TT (A and B) and MZ-CRC-1 (C) cells grown as 2D monolayer cultures. Concentrations used were: 1.4µM Ct; 0.04µM Ale; 0.12µM Mon (TT); 0.66µM Mon (MZ-CRC-1); 0.16µM Sun and 0.0µM Reg. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001; ns, not significant.

[0018] Figure 6 shows the efficacy of Clofilium Tosylate (Ct) and / or Monensin (Mon) in combination with non-RET multikinase inhibitors, Axitinib (Axi) and Nintedanib (Nin) on the viability of TT and MZ-CRC-1 (human MTC) cells grown as 2D monolayer cultures. Concentrations used were: 1.4 µM Ct; 0.16 µM Axi; 0.12 µM Mon (TT); 0.66 µM Mon (MZ-CRC-1) and 0.08 µM Nin. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *, P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001; ns, not significant.

[0019] Figure 7 shows the effect of Clofilium Tosylate (Ct) or Monensin (Mon) in combination with Cabozantinib (Cab) / Vandetanib (Van) on the viability of TT (A and B) and MZ-CRC-1 (C) cells grown as 3D organotypic cultures. Concentrations used were: 1.25µM Ct, 0.156 / 0.078µM Cab, 0.08 µM Van, 2 µM Mon (TT) and 7 µM Mon (MZ-CRC-1). DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ****, P<0.0001.

[0020] Figure 8 shows the efficacy of Monensin (Mon) and Cabozantinib (Cab) alone or in combination on TT cells-derived xenografts.1x107 TT cells were injected subcutaneously into the right flank of each mouse (6 mice per treatment group). Five weeks after injection, treatmentsstarted. Mice were treated with vehicle only (control group), Cab (5mg / kg), Mon (15mg / Kg) or both drugs: Cab (5mg / kg) + Mon (15mg / Kg). Drugs were administered daily by oral gavage for 28 days. Tumor volume was monitored 3x / week by external caliper measurements performed always by the same operator. Data represent the mean and all replicates of each group and were analysed by two-way ANOVA with Tukey post hoc test for each individual time points. *,P<0.05; **, P<0.01; ****, P<0.0001. DETAILED DESCRIPTION

[0021] The present invention is described in detail in the following and is also illustrated by the appended examples and figures.

[0022] The present invention relates to a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite, or a derivative thereof for use in a method of treatment of a disease associated with tyrosine kinase receptor activation in a subject, wherein the tyrosine kinase receptor inhibitor is administered in combination with a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):(II),wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

[0023] As an advantage, the inventors have surprisingly found that a combination of a tyrosine kinase inhibitor with a compound of formula (I) and / or a compound of formula (II) results in an unexpected synergistic effect in the treatment of diseases associated with tyrosine kinase receptor activation (Examples 2, 3 and 4, and Figures 1, 2, 3, 4, 5, 6, 7 and 8). In particular, the inventors have found an unexpected synergistic effect of a tyrosine kinase receptor inhibitor in combination with a compound of formula (I) and / or a compound of formula (II) to decrease the viability of various cell lines of cancers associated with tyrosine kinase receptor activation in vitro, both on cells grown as 2D monolayers (Example 2, and Figures 1, 2, 3, 45 and 6) and 3D organotypic cultures (Example 3, and Figure 7). An advantageous, unexpected synergistic effect was also observed in vivo (Example 4, and Figure 8). The synergistic effect allows to lower the doses of the tyrosine kinase receptor inhibitors when administering the tyrosine kinase receptor inhibitor in combination with a compound of formula (I) and / or formula (II), compared to treatment with the tyrosine kinase receptor inhibitors alone. Accordingly, by lowering the dose of the tyrosine kinase receptor inhibitor, it should be possible to decrease undesired side effects of the tyrosine kinase receptor inhibitors and resistance development under therapy.

[0024] In some embodiments, the present invention relates to a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite, or a derivative thereof for use in a method of treatment of a disease associated with tyrosine kinase receptor activation in a subject, wherein the tyrosine kinase receptor inhibitor is administered in combination with a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl.

[0025] In some embodiments, the present invention also relates to a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite, or a derivative thereof for use in a method of treatment of a disease associated with tyrosine kinase receptor activation in a subject, wherein the tyrosine kinase receptor inhibitor is administered in combination with a compound of formula (II):(II), wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

[0026] The term “tyrosine kinase” refers to a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. For example, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.

[0027] Tyrosine kinases can be categorized as receptor type or non-receptor type. A “tyrosine kinase receptor”, or also known as “receptor type tyrosine kinase” or “receptor tyrosine kinase”, as used herein and known in the art, have an extracellular, a transmembrane and an intracellular portion. A “non-receptor type tyrosine kinase”, or also known as “non-receptor tyrosine kinase”, is wholly intracellular.

[0028] The tyrosine kinase receptors are comprised of a large number of transmembrane receptors with various biological activities. About twenty different subfamilies of tyrosine kinase receptors have been identified, including, for example, the EGF receptor family, the insulin receptor family, the PDGF receptor family, the VEGF receptors family, the FGF receptor family, the CCK receptor family, the NGF receptor family, the HGF receptor family, the Eph receptor family, the AXL receptor family, the TIE receptor family, the RYK receptor family, the DDR receptor family, the RET receptor family, the ROS receptor family, the LTK receptor family, the ROR receptor family, the MuSK receptor family and the LMR receptor family.

[0029] A “tyrosine kinase receptor inhibitor” (TKI) is an agent that inhibits tyrosine kinase receptors. Tyrosine kinase receptors are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosphate group to the protein (phosphorylation), a step that TKIs inhibit.

[0030] The term “disease associated with tyrosine kinase receptor activation” refers to any disease or disorder which arises directly or indirectly from activation of a tyrosine kinase receptor in a subject.

[0031] The term “treating” or “treatment” includes administration of a tyrosine kinase inhibitor in combination with a compound of formula (I) and / or a compound of formula (II) preferably in the form of a medicament, to a subject suffering from a disease associated with tyrosine kinase receptor activation for the purpose of ameliorating or improving symptoms accompanying said disease.

[0032] The “subject”, which is treated with by the tyrosine kinase receptor inhibitor in combination with a compound of formula (I) and / or a compound of formula (II), is preferably a vertebrate. In the context of the present invention, the term “subject” includes any individual in need of a treatment of a disease associated with tyrosine kinase receptor activation. Preferably, the subject is a patient suffering from a disease associated with tyrosine kinase receptor activation. Preferably, the patient is a vertebrate, more preferably a mammal. Mammals include, but are not limited to, farm animals,sport animals, pets, primates, mice and rats. Preferably, a mammal is a human, horse, dog, cat, cow, pig, mouse, rat, etc., particularly preferred, it is a human.

[0033] The present disclosure also relates to a “pharmaceutically acceptable salt”. Any pharmaceutically acceptable salt can be used. In particular, the term “pharmaceutically acceptable salt” refers to a salt of an inhibitor or compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts have low toxicity and may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane- disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]- oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, purely by way of example, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of nontoxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. A counterion or anionic counterion can be used in a quaternary amine to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F“, Cl-, Br“, l“), NO3“, CIO4“, OH“, H2PO4“, HSO4“, sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p- toluenesulfonate, benzenesulfonate, 10-camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0034] As used herein, the term “solvate” may refer to an aggregate that comprises one or more molecules of an inhibitor or compound described herein with one or more molecules of solvent. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the conjugates or compounds of the present disclosure may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate,tetrahydrate and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, while in other cases, the compounds of the invention may merely retain adventitious water or be a mixture of water plus some adventitious solvent.

[0035] The term “metabolite” refers to any naturally occurring metabolic product which may arise.

[0036] The term “derivative”, as generally known in the art, refers to any compound which is derived from the core compound by any reaction, such as a chemical or a biological reaction. In accordance with the present invention, a derivate may encompass any functional active derivate. A person skilled in the art is able to identify such a functional active derivate for example by testing any candidate derivate in a suitable assay.

[0037] Unless otherwise indicated, the term "alkyl" by itself or as part of another term in general refers to a substituted or unsubstituted straight chain or branched, saturated hydrocarbon having the indicated number of carbon atoms; e.g., "-(Ci-C8)alkyl" or "-(Ci-C6)alkyl” refer to an alkyl group having from 1 to 8 or 1 to 6 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkyl group may have from 1 to 8 carbon atoms. Representative straight chain -(CrC8)alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n- hexyl, -n-heptyl and -n-octyl; branched -(Ci-C8)alkyl groups include, but are not limited to, - isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2-methylbutyl.

[0038] Unless otherwise indicated, the term "alkylene" by itself or as part of another term, in general refers to a substituted or unsubstituted branched or straight chain, saturated hydrocarbon radical of the stated number of carbon atoms, preferably 1-8 carbon atoms (-(Ci-C8)alkylene-) or preferably 1 to 6 carbon atoms (-(Ci-C6)alkylene-), and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. When the number of carbon atoms is not indicated, the alkylene group may have from 1 to 8 carbon atoms. Typical alkylene radicals include, but are not limited to: methylene (- CH2-), 1 ,2-ethylene (-CH2CH2-), 1,3-n-propylene (-CH2CH2CH2-), and 1 ,4-n-butylene (- CH2CH2CH2CH2-).

[0039] The term “halogen”, as known in the art, refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0040] The present disclosure also refers to the term “pharmaceutically acceptable anion”. Any pharmaceutically acceptable anion can be used. In particular, the term “pharmaceutically acceptable anion” refers to an anion which is capable to form a salt of an inhibitor or compound ofthe invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts have low toxicity. Exemplary pharmaceutically acceptable anions include halide ions (e.g., F– , Cl– , Br– , I–), NO – – – 3 , ClO4 , OH , H2PO – 4 , HSO – 4 , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0041] Preferably, the tyrosine kinase receptor inhibitor is a RET inhibitor and the disease associated with tyrosine kinase receptor activation is a disease associated with RET activation. RET, as known in the art, is a tyrosine kinase receptor. The abbreviation RET stands for “rearranged during transfection”. Gain of function mutations of the RET proto-oncogene, in other words RET activation, are associated with the development of various types of human cancer, including medullary thyroid carcinoma.

[0042] The tyrosine kinase receptor inhibitor, in particular the RET inhibitor, may be a multikinase inhibitor. The term “multikinase inhibitor”, as generally used in the art and herein, refers to a compound (i.e., a RET inhibitor) that targets RET and, in addition, one or more other tyrosine kinase receptor(s). Accordingly, multikinase inhibitors are not designed to bind RET specifically, but also have other targets such as, for example, VEGFR, c-MET and / or c-KIT.

[0043] In some embodiments, the tyrosine kinase receptor inhibitor is a compound of formula (III):or a pharmaceutically acceptable salt or solvate thereof; wherein:RIII6, preferably (C1-C6)alkyl or; more rO O RIII2 is -O-(C1-C8)alkyl or; preferably -O-(C1-C6)alkyl; more preferably -RIII3 is H or halogen; preferably H or F or Cl; more preferably H or F; RIII4 is H or halogen; preferably H or F or Cl or Br; more pferably H or Cl; IIR I5 is selected from the group consisting of halogen, H H andRIII6 is (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl; RIII7 is halogen; preferably F or Cl; more preferably F; A is CH or N; and Z is O or NH.

[0044] In some embodiments,RIII1 is (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl; RIII2 is -O-(C1-C8)alkyl; preferably -O-(C1-C6)alkyl; more preferably -O-(C1-C4)alkyl; still more preferably -O-(C1-C2)alkyl;RIII7 is halogen; preferably F or Cl; more preferably F; A is CH; and Z is O.

[0045] In some preferred embodiments, the tyrosine kinase receptor inhibitor is cabozantinib. Cabozantinib has formula (IIIa):RIII2 is -O-(C1-C8)alkyl; preferably -O-(C1-C6)alkyl; more preferably -O-(C1-C4)alkyl; still more preferably -O-(C1-C2)alkyl; RIII3 is halogen; preferably F or Cl; more preferably F; RIII4 is H; RIII5 is halogen; preferably Cl or Br; preferably Br; RIII6 is (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl; A is N; and Z is NH.

[0047] In some preferred embodiments, the tyrosine kinase receptor inhibitor is vandetanib. Vandetanib has formula (IIIb):(IIIb).

[0048] In some embodiments, RIII1 is (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl;A is CH; and Z is O.

[0049] In some preferred embodiments, the tyrosine kinase receptor inhibitor is lenvatinib. Lenvatinib has formula (IIIc):

[0050] In some embodiments, the tyrosine kinase receptor inhibitor is a compound of formula (IV):or a pharmaceutically acceptable salt or solvate thereof; wherein: RIV1 is halogen; preferably F, Cl or Br; more preferably Cl; RIV2 is H or halogen; preferably H or F or Cl; more preferably H or F; and RIV3 is (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl.

[0051] In some embodiments, RIV1 is halogen; preferably F, Cl or Br; more preferably Cl; RIV2 is H; and RIV3 is (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl.

[0052] In some preferred embodiments, the tyrosine kinase receptor inhibitor is sorafenib. Sorafenib has formula (IVa):(IVa).

[0053] In some embodiments, RIV1 is halogen; preferably F, Cl or Br; more preferably Cl; RIV2 is halogen; preferably F or Cl; more preferably F; and RIV3 is (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl.

[0054] In some preferred embodiments, the tyrosine kinase receptor inhibitor is regorafenib. Regorafenib has formula (IVb):(IVb).

[0055] In some embodiments, the tyrosine kinase receptor inhibitor is a compound of formula (V):(V), or a pharmaceutically acceptable salt or solvate thereof; wherein: RV1 is halogen; preferably F or Cl; more preferably F; RV2 , RV3, RV4 and RV5 are, each independently, (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl.

[0056] In some preferred embodiments, the tyrosine kinase receptor inhibitor is sunitinib. Sunitinib has formula (Va):

[0057] In some embodiments, the tyrosine kinase receptor inhibitor is a compound of formula (VI):(VI), or a pharmaceutically acceptable salt or solvate thereof; wherein: RVI1 and RVI2 are, each independently, (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1- C4)alkyl; still more preferably (C1-C2)alkyl.

[0058] In some preferred embodiments, the tyrosine kinase receptor inhibitor is motesanib. Motesanib has formula (VIa):

[0059] In some embodiments, the tyrosine kinase receptor inhibitor is a compound of formula (VII):, or a pharmaceutically acceptable salt or solvate thereof; wherein:RVII1 and RVII2 are, each independently, (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1- C4)alkyl; still more preferably (C1-C2)alkyl.

[0060] In some preferred embodiments, the tyrosine kinase receptor inhibitor is imatinib. Imatinib has formula (VIIa):(VIIa).

[0061] In some embodiments, the tyrosine kinase receptor inhibitor is a compound of formula (VIII):(VIII), or a pharmaceutically acceptable salt or solvate thereof; wherein: RVIII1 , RVIII2 and RVIII3 are, each independently, (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl.

[0062] In some preferred embodiments, the tyrosine kinase receptor inhibitor is alectinib. Alectinib has formula (VIIIa):

[0063] Preferably, the tyrosine kinase receptor inhibitor is selected from the group consisting of of axitinib, nintedanib, cabozantinib, vandetanib, lenvatinib, sorafenib, sunitinib, motesanib, imatinib, alectinib and regorafenib, preferably selected from the group consisting of cabozantinib, vandetanib, lenvatinib, sorafenib, sunitinib, motesanib, imatinib, alectinib and regorafenib, more preferably selected from the group consisting of cabozantinib, vandetanib, sunitinib, imatinib, alectinib and regorafenib. These tyrosine kinase receptor inhibitors are multikinase inhibitors (RET inhibitors which target RET and one or more other tyrosine kinase(s)). More preferably, the tyrosine kinase receptor inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sunitinib and regorafenib. Still more preferably, the tyrosine kinase receptor inhibitor is cabozantinib or vandetanib. Even more preferably, the tyrosine kinase receptor inhibitor is cabozantinib.

[0064] In some preferred embodiments, the tyrosine kinase receptor inhibitor is selected from the group consisting of cabozantinib, vandetanib, alectinib, sunitinib and regorafenib, in combination with a compound of formula (I). In some more preferred embodiments, the tyrosine kinase receptor inhibitor is cabozantinib or vandetanib, in combination with a compound of formula (I). In some still more preferred embodiments, the tyrosine kinase receptor inhihibitor is cabozantinib, in combination with a compound of formula (I).

[0065] In some preferred embodiments, the tyrosine kinase receptor inhibitor is selected from the group consisting of cabozantinib, alectinib, sunitinib and regorafenib, in combination with a compound of formula (II), preferably wherein the compound of formula (II) is clofilium tosylate. In some more preferred embodiments, the tyrosine kinase receptor inhihibitor is cabozantinib, in combination with a compound of formula (II), preferably wherein the compound of formula (II) is clofilium tosylate.

[0066] Also, the tyrosine kinase receptor inhibitor may be a selective RET inhibitor. The term “selective RET inhibitor”, as generally used in the art and herein, refers to a compound (i.e. , a RET inhibitor) that targets RET with high potency, while having only low affinity for other tyrosine kinase receptors such as, for example, VEGFR-family kinases.

[0067] In some embodiments, the tyrosine kinase receptor inhibitor is a compound of formula (IX):(IX), or a pharmaceutically acceptable salt or solvate thereof; wherein: RIX1 , RIX2 , RIX3 and RIX4 are, each independently, (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl; and RIX5 is halogen; preferably F or Cl; more preferably F.

[0068] In some preferred embodiments, the tyrosine kinase receptor inhibitor is pralsetinib (also known as BLU-667). Pralsetinib has formula (IXa):(IXa).

[0069] In some embodiments, the tyrosine kinase receptor inhibitor is a compound of formula (X):or a pharmaceutically acceptable salt or solvate thereof; wherein: RX1 , RX2 and RX3 are, each independently, (C1-C8)alkyl; preferably (C1-C6)alkyl; more preferably (C1-C4)alkyl; still more preferably (C1-C2)alkyl.

[0070] In some preferred embodiments, the tyrosine kinase receptor inhibitor is selpercatinib (also known as LOXO-292). Selpercatinib has formula (Xa):

[0071] Preferably, the tyrosine kinase receptor inhibitor is pralsetinib (also known as BLU-667) or selpercatinib (also known as LOXO-292). These tyrosine kinase receptor inhibitors are selective RET inhibitors.

[0072] In some preferred embodiments, the tyrosine kinase receptor inhibitor is pralsetinib or selpercatinib, in combination with a compound of formula (I).

[0073] In some preferred embodiments, the tyrosine kinase receptor inhibitor is pralsetinib or selpercatinib, in combination with a compound of formula (II), preferably wherein the compound of formula (II) is clofilium tosylate.

[0074] In accordance with the present invention, in the compound of formula (I) R1 is selected from the group consisting of H and (C1-C8)alkyl, and R2 is selected from the group consisting of H and (C1-C8)alkyl. Preferably, in the compound of formula (I) R1 is selected from the group consisting of H and (C1-C6)alkyl, and R2 is selected from the group consisting of H and (C1-C6)alkyl. More preferably, in the compound of formula (I) R1 is selected from the group consisting of H and (C1- C4)alkyl, and R2 is selected from the group consisting of H and (C1-C4)alkyl. Still more preferably, in the compound of formula (I) R1 is selected from the group consisting of H and (C 2 1-C2)alkyl, and R is selected from the group consisting of H and (C1-C2)alkyl. Even more preferably, in the compound of formula (I) R1 is selected from the group consisting of H and methyl (CH 2 3), and R is selected from the group consisting of H and (CH)3.

[0075] The compound of formula (I) may be monensin. In the present invention, monensin can be used as a mixture comprising monensin A (in monensin A, R1 is CH 2 3 and R is H), monensin B (in monensin B, R1 is H and R2 is H) and monensin C (in monensin C, R1 is CH , and 2 3 R is CH3). In naturally occurring and / or commercially available monensin, monensin A may be the main component, along with monensin B and monensin C as concomitant substances.

[0076] Preferably, the compound of formula (I) has the following structure:, wherein R1 and R2 are as defined herein. More preferably, the compound of formula (I) is monensin A, which has the following structure:. * * *

[0077] In accordance with the present invention, in the compound of formula (II) R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion. Preferably, Y is Cl or Br; more preferably Y is para-Cl or para-Br; still more preferably, Y is para-Cl. Preferably, in the compound of formula (II) R3 is (C 4 5 4-C8)alkyl; R and R are, each independently, (C1-C3)alkyl; X is (C2-C6)alkylene; Y is para-Cl; and A is tosylate. More preferably, in the compound of formula (II) R3 is (C 4 5 6-C8)alkyl; R and R are, each independently, (C1-C3)alkyl; X is (C3-C5)alkylene; Y is para-Cl; and A is tosylate.

[0078] In preferred embodiments, the compound of formula II has the following structure:This compound is clofilium tosylate.

[0079] In some embodiments, the disease associated with tyrosine kinase receptor activation is a cancer associated with tyrosine kinase receptor activation. Preferably, the tyrosine kinase receptor inhibitor is a RET inhibitor and the cancer associated with tyrosine kinase receptor activation is a cancer associated with RET activation.

[0080] In alternative embodiments, the tyrosine kinase receptor inhibitor is not a RET inhibitor and the disease associated with tyrosine kinase receptor activation is not a disease associated with RET activation. Examples of non-RET multikinase inhibtors according to the disclosure are axitinib (Axi) and nintedanib (Nin).

[0081] In some preferred embodiments, the disease associated with tyrosine kinase receptor activation is selected from the group consisting of thyroid cancer, a pituitary tumor, an adrenal tumor, a pancreatic neuroendocrine tumor, small lung cell cancer (neuroendocrine) and renal cell carcinoma (non-neuroendocrine). These diseases are cancers associated with tyrosine kinase receptor activation. More preferably, the disease associated with tyrosine kinase receptor activation is thyroid cancer, still more preferably medullary thyroid carcinoma. Medullary thyroid carcinoma is a cancer associated with RET activation.

[0082] The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a metabolite, a derivative or a solvate thereof may be administered contemporaneously, previously or subsequently to the compound of formula (I) and / or the compound of formula (II). The tyrosine kinase inhibitor or inhibitors in combination with the compound of formula (I) and / or the compound of formula (II) are preferably administered in a therapeutically effective amount. The “therapeutically effective amount” for the tyrosine kinase inhibitor and the compound of formula (I) and / or the compound of formula (II), or each active compound / inhibitor envisaged according to the present invention, can vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient’s body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the compound by the body, the age and sensitivity of thepatient to be treated, adverse events, and the like, as will be apparent to a skilled artisan. The amount of administration can be adjusted as the various factors change over time. A skilled artisan is able to determine suitable dose amounts and dose regimens.

[0083] The present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

[0084] In some embodiments, the present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl.

[0085] In some embodiments, the present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (II):(II), wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

[0086] The present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):(II), wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion for use as a medicament.

[0087] In some embodiments, the present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl for use as a medicament.

[0088] In some embodiments, the present invention also relates to a pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (II):(II), wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion for use as a medicament.

[0089] In the pharmaceutical composition, the tyrosine kinase receptor inhibitor, the compound of formula (I) and / or the compound of formula (II) may be as defined herein.

[0090] The pharmaceutical composition may be for use in a method of treatment of a disease associated with tyrosine kinase receptor activation. The disease associated with tyrosine receptor activation may be as defined herein.

[0091] The pharmaceutical composition may further comprise a carrier, preferably a pharmaceutically acceptable carrier. The composition can be in any suitable form for administration, for example in the form of orally administrable suspensions or tablets, or sterile injectable preparations - intravenously, intrapleurally, intramuscularly-, for example, as sterile injectable aqueous or oleaginous suspensions, or suppositories.

[0092] The present invention also relates to a kit of parts comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):wherein:R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

[0093] In some embodiments, the present invention relates to a kit of parts comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl.

[0094] In some embodiments, the present invention relates to a kit of parts comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (II):wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; andis a pharmaceutically acceptable anion.

[0095] In the kit of parts, the tyrosine kinase receptor inhibitor, the compound of formula (I) and / or the compound of formula (II) may be as defined herein.

[0096] The invention further relates to the following items: 1. A tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite, or a derivative thereof for use in a method of treatment of a disease associated with tyrosine kinase receptor activation in a subject, wherein the tyrosine kinase receptor inhibitor is administered in combination with a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene;Y is halogen; and A is a pharmaceutically acceptable anion. 2. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of item 1, wherein the tyrosine kinase receptor inhibitor is a RET inhibitor and the disease associated with tyrosine kinase receptor activation is a disease associated with RET activation. 3. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of item 1 or 2, wherein the tyrosine kinase receptor inhibitor is a multikinase inhibitor. 4. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of items 1 to 3, wherein the tyrosine kinase receptor inhibitor is selected from the group consisting of axitinib, nintedanib, cabozantinib, vandetanib, lenvatinib, sorafenib, sunitinib, motesanib, imatinib, alectinib and regorafenib, preferably selected from the group consisting of cabozantinib, vandetanib, lenvatinib, sorafenib, sunitinib, motesanib, imatinib, alectinib and regorafenib, more preferably selected from the group consisting of cabozantinib, vandetanib, sunitinib, imatinib, alectinib and regorafenib. 5. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of item 1 or 2, wherein the tyrosine kinase receptor inhibitor is a selective RET inhibitor. 6. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of claims 1, 2 or 5, wherein the tyrosine kinase receptor inhibitor is pralsetinib (BLU-667) or selpercatinib (LOXO-292). 7. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding items, wherein the compound of formula (I) has the following structure:or a pharmaceutically acceptable salt or solvate thereof; wherein R1and R2are as defined in any one of the preceding items; preferably wherein the compound of formula (I) has the following structure:or a pharmaceutically acceptable salt or solvate thereof.8. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding items, wherein the compound of formula (II) has the following structure:9. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding items, wherein the disease associated with tyrosine kinase receptor activation is a cancer associated with tyrosine kinase receptor activation.10. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of item 9, wherein the tyrosine kinase receptor inhibitor is a RET inhibitor and the cancer associated with tyrosine kinase receptor activation is a cancer associated with RET activation.11. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding items, wherein the disease associated with tyrosine kinase receptor activation is selected from the group consisting of thyroid cancer, a pituitary tumor, an adrenal tumor, a pancreatic neuroendocrine tumor, small lung cell cancer (neuroendocrine) and renal cell carcinoma (non-neuroendocrine).12. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of item 11 , wherein the disease associated with tyrosine kinase receptor activation is thyroid cancer, preferably medullary thyroid carcinoma.13. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding items, wherein the tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a metabolite, a derivative or a solvate thereof is administered contemporaneously, previously or subsequently to the compound of formula (I) and / or the compound of formula (II).14. A pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):(II), wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion. 15. A pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):(II), wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion for use as a medicament. 16. The pharmaceutical composition of item 14 or the pharmaceutical composition for use of claim 15, wherein the tyrosine kinase receptor inhibitor, the compound of formula (I) and / or the compound of formula (II) are as defined in any one of the preceding items. 17. The pharmaceutical composition of any one of items 14 to 16 for use in a method of treatment of a disease associated with tyrosine kinase receptor activation.18. The pharmaceutical composition for use of item 17, wherein the disease associated with tyrosine kinase receptor activation is as defined in any one of the preceding claims. 19. A kit of parts comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):, or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):(II), wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion. 20. The kit of parts of item 19, wherein the tyrosine kinase receptor inhibitor, the compound of formula (I) and / or the compound of formula (II) are as defined in any one of the preceding items.

[0097] The term "and / or" wherever used herein includes the meaning of "and", "or" and "all or any other combination of the elements connected by said term".

[0098] The term “less than” or in turn “more than” does not include the concrete number. For example, less than 20 means less than the number indicated. Similarly, more than or greater than means more than or greater than the indicated number, e.g. more than 80 % means more than or greater than the indicated number of 80 %.

[0099] Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”. When used herein “consisting of" excludes any element, step, or ingredient not specified.

[0100] The term “including” means “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.

[0101] As used herein the terms "about", "approximately" or “essentially” mean within 20%, preferably within 15%, preferably within 10%, and more preferably within 5% of a given value or range. It also includes the concrete number, i.e. “about 20” includes the number of 20.

[0102] It should be understood that this invention is not limited to the particular methodology, protocols, material, reagents, and substances, etc., described herein and as such can vary. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims.

[0103] All publications cited throughout the text of this specification (including all patents, patent application, scientific publications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. To the extent the material incorporated by reference contradicts or is inconsistent with this specification, the specification will supersede any such material.

[0104] The content of all documents and patent documents cited herein is incorporated by reference in their entirety.EXAMPLES

[0105] An even better understanding of the present invention and of its advantages will be evident from the following examples, offered for illustrative purposes only. The examples are not intended to limit the scope of the present invention in any way.Example 1 : Material and MethodsCell culture

[0106] TT and MZ-CRC-1 (human medullary thyroid carcinoma), PC12 (rat pheochromocytoma), BON1 (human pancreatic neuroendocrine tumor), NCI-H69 (human small cell lung carcinoma), GH3 (rat pituitary gland tumor) and RCC4 (human clear cell renal carcinoma) were used in this study. TT cells were maintained in Ham’s F-12K medium (F12K) supplemented with 15% fetal bovine serum (FBS), MZ-CRC-1 in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 15% of FBS, PC12 in Roswell Park Memorial Institute Medium (RPMI) supplemented with 5% of FBS and 10% horse serum (HS), BON1 DMEM / F12K supplemented with 10% of FBS, NCI-H69 in RPMI supplemented with 10% of FBS, GH3 in F12K supplemented with 15% of HS and 2.5% of FBS, and RCC4 in DMEM supplemented with 10% of FBS. All cells were cultured at 37°C in a 5% CO2incubator.Drugs

[0107] Monensin (CAS Registry Number 17090-79-8) and clofilium tosylate (CAS Registry Number 92953-10-1), were obtained from GreenPharma (Orleans, France). Pralsetinib (CAS Registry Number 2097132-94-8), selpercatinib (CAS Registry Number 2152628-33-4), alectinib (CAS Registry Number 1256580-46-7), sunitinib (CAS Registry Number 557795-19-4) and regorafenib (CAS Registry Number 755037-03-7) vandetanib (CAS Registry Number 443913-73- 3), axitinib (CAS Registry Number 319460-85-0), nintedanib (CAS Registry Number 656247-18-6) and cabozantinib (CAS Registry Number 849217-68-1) were obtained from MedChemExpress (Monmouth Junction, NJ, USA).Cell viability analysis (2D)

[0108] In order to assess the cell viability 10000 cells were seeded into flat bottom white wells 96-well plates (Greiner CELLSTAR). After 24h, cells were treated with the drugs or vehicle controls as indicated in the figures. After 48h of the treatment cell viability of 2D monolayer cultureswas measured using the CellTiter-Glo® Cell Viability Assay kit (Promega), following the manufacturer’s instructions.Cell viability analysis (3D)

[0109] Prior to experiment performance, cell lines were tested for the formation of 3D spheroids, and the optimal seeding density for each cell line was determined. To this end, 500- 2000 cells per cell line were seeded into 96-well round bottom black ULA plate (Corning). The formation of spheroids was examined after five days. The optimal seeding densities for the two cell lines are 1000 cells. Three-dimensional cell viability was measured 72 h (3 days) post-treatment using the 3D RealTime-Glo™ MT Cell Viability Assay (Promega), following the manufacturer’s instructions.In vivo xenografts studies

[0110] Six-week old female CD-1 immunocompromised mice (Charles River) were maintained in agreement with general husbandry rules approved by Helmholtz Munich and as approved by the government of Upper Bavaria, Germany (Az. 55.2-2532.Vet_02-21-133).All animal experiments were conducted in accordance to animal protocols approved by the government of Upper Bavaria, Germany (Az. 55.2-2532. Vet_02-21 -50).

[0111] A total of 1x107TT cells were diluted in 50 pl of PBS and 50 pl of Matrigel (BD Biosciences) and were injected subcutaneously into the right flank of each mouse (6 mice per treatment). Tumors were monitored until they reached an average size of 50-80mm3(approximately 5 weeks), at which point treatments were begun. Vehicle (PEG), cabozantinib (5mg / kg), monensin (15mg / Kg) or the combination of both drugs (cabozantinib 5mg / kg +monensin 15mg / Kg) were administered daily by oral gavage. Cabozantinib was dissolved in NMP / PEG and Monensin in ethanol / PEG. Tumor volume was monitored 3X / week by external caliper measurements performed always by the same operator to avoid variability. Mice were also weighted 3X weekly to check for weight loss. No toxic effect of the treatments was observed. At the end of the treatment, all mice were euthanized using CO2inhalation followed by cervical dislocation following the institutional guidelines approved at Helmholtz Munich.Statistical analysis

[0112] Study endpoints from in vitro cell viability experiments are displayed by bar graphs with means mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Sidak's post hoc test. All statistical analyses were executed using GRAPHPAD (GraphPad Software Inc), with the level of statistical significance set at 0.05.Example 2: Cell Viability Measurements Performed Using Cells Grown as 2D Monolayer Cultures

[0113] In order to discover drugs able to synergize with low dose Vandetanib (Van) and Cabozantinib (Cab), therapies highly associated with severe side effects, the inventors have performed a drug screening and we have discovered two promising hits able to synergize with low dose of the multikinase inhibitors (MKI) Cab and / or Van - the antibacterial Monensin (Mon) and the antiarrythmic agent Clofilium Tosylate (Ct). The results showed that the combination of Ct and Cab was able to decrease the cell viability of TT cells in a more effective manner than Ct or Cab alone (Figure 1). TT cells are cells of human medullary thyroid carcinoma – MTC, which is a cancer associated with RET activation.

[0114] Figure 1 shows the efficacy of Clofilium Tosylate (Ct) and Cabozantinib (Cab) combination on the viability of TT (human medullary thyroid carcinoma - MTC) cells grown as 2D monolayer cultures. Concentrations used were: 1.4µM Ct and 2.5µM Cab. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. ****, P<0.0001.

[0115] Moreover, the combinations of Mon with Cab / Van showed higher efficacy at decreasing the cell viability of TT and MZ-CRC-1 cells when compared to the single drug treatments (Figures 2A and B). TT and MZ-CRC-1 cells are cells of medullary thyroid carcinoma, which is a cancer associated with RET activation.

[0116] Figure 2 shows the efficacy of Monensin (Mon) and Cabozantinib (Cab) / Vandetanib (Van) combinations on the viability of TT (A) and MZ-CRC-1 (B) (human MTC) cells grown as 2D monolayer cultures. Concentrations used were: 0.12 / 0.37µM Mon (TT); 0.66µM Mon (MZ-CRC-1); 1µM Van and 2.5µM Cab. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001.

[0117] In addition, the inventors have tested the efficacy of the same combinations in other tumor models, where at least Cab is already used as monotherapy for patients or is being evaluated in clinical trials, and is known to be associated with severe side effects. Interestingly, Mon in combinations with Cab / Van showed to be more effective decreasing the cell viability of PC12 (pheochromocytoma, a cancer associated with RET activation), BON-1 (pancreatic neuroendocrine tumor, a cancer associated with tyrosine kinase receptor activation), NCI-H69(lung neuroendocrine tumor, a cancer associated with tyrosine kinase activation) and RCC4 (renal cancer, a cancer associated with tyrosine kinase activation) tumor cells (Figures 3A-E).

[0118] Figure 3 shows the efficacy of Monensin (Mon) and Cabozantinib (Cab) / Vandetanib (Van) combinations on the viability of other tumour models grown as 2D monolayer cultures. PC12 cells were derived from a rat pheochromocytoma (A, neuroendocrine tumor of the adrenal gland); BON-1 are human pancreatic neuroendocrine tumor cells (B); NCI-H69 are human small cell lung cancer cells (C, also neuroendocrine origin); GH3 are derived from a rat pituitary neuroendocrine tumor (D); RCC4 are clear cell renal cell carcinoma cells (E, non-neuroendocrine tumor cells). Concentrations used were: 0.12 / 0.37µM Mon; 1µM Van and 2.5µM Cab. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001; ns, not significant.

[0119] Moreover, the results showed that Mon and Ct could also synergize with RET- specific inhibitors, Selpercatinib (Sel) or Pralsetinib (Pra), inhibiting the proliferation of TT and MZ- CRC-1 cells in more effective manner than the drugs alone (Figures 4A-C).

[0120] Figure 4 shows the efficacy of Clofilium Tosylate (Ct) and / or Monensin (Mon) in combination with the RET-specific inhibitors Selpercatinib (Sel) or Pralsetinib (Pra) on the viability of TT (A and B) and MZ-CRC-1 (C) cells grown as 2D monolayer cultures. Concentrations used were: 1.4µM Ct; 0.12µM Mon (TT); 0.66µM Mon (MZ-CRC-1) ; 0.02µM Sel; 0.02µM Pra. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001; ns, not significant.

[0121] The synergism of Ct and Mon with other multikinase inhibitors (MKIs) was also validated in TT and MZ-CRC-1 cells. In general, the results showed that Ct and Mon were able to synergyze with Alectinib (Ale), Sunitinib (Sun) and / or Regorafenib (Reg), being more effective at decreasing the cell viability than the single drug treatments (Figures 5A-C).

[0122] Figure 5 shows the efficacy of Clofilium Tosylate (Ct) and / or Monensin (Mon) in combination with multikinase inhibitors, Alectinib (Ale), Sunitinib (Sun) and Regorafenib (Reg) on the viability of TT (A and B) and MZ-CRC-1 (C) cells grown as 2D monolayer cultures. Concentrations used were: 1.4µM Ct; 0.04µM Ale; 0.12µM Mon (TT); 0.66µM Mon (MZ-CRC-1); 0.16µM Sun and 0.0µM Reg. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's posthoc test. *,P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001; ns, not significant.

[0123] Figure 6 shows the efficacy of Clofilium Tosylate (Ct) and / or Monensin (Mon) in combination with non-RET multikinase inhibitors, Axitinib (Axi) and Nintedanib (Nin) on the viability of TT and MZ-CRC-1 (human MTC) cells grown as 2D monolayer cultures. Concentrations used were: 1.4µM Ct; 0.16µM Axi; 0.12µM Mon (TT); 0.66µM Mon (MZ-CRC-1) and 0.08µM Nin. DMSO was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *, P<0.05; **, P<0.01; ***,P<0.001; ****, P<0.0001; ns, not significant. Example 3: Cell Viability Measurements Performed Using Cells Grown As 3D Organotypic Cultures

[0124] Moreover, the inventors have validated the combinations efficacy in TT and MZ- CRC-13D organotypic cultures. The anti-proliferative effect of the combinations was stronger than the single drug treatments (Figures 6A-C).

[0125] Figure 7 shows the effect of Clofilium Tosylate (Ct) or Monensin (Mon) in combination with Cabozantinib (Cab) / Vandetanib (Van) on the viability of TT (A and B) and MZ- CRC-1 (C) cells grown as 3D organotypic cultures. Concentrations used were: 1.25µM Ct, 0.156 / 0.078µM Cab, 0.08 µM Van, 2 µM Mon (TT) and 7 µM Mon (MZ-CRC-1). Dmso was used as control. Data represent the mean ±SD from three independent experiments and were analysed by two-way ANOVA with Holm-Šídák's post hoc test. *,P<0.05; **, P<0.01; ****, P<0.0001. Example 4: Efficacy of the Combination Mon + Cab In TT Cell-Derived Xenografts In Vivo

[0126] Furthermore, the inventors have evaluated the efficacy of Mon in combination with Cab in MTC xenograft models in vivo.

[0127] The results showed, after 11 days of treatment, the combination of Mon with Cab was more effective inhibiting tumor growth in vivo, than Cab or Mon alone.

[0128] Figure 8 of Monensin (Mon) and Cabozantinib (Cab) alone or in combination on TT cells-derived xenografts. 1x107 TT cells were injected subcutaneously into the right flank of each mouse (6 mice per treatment group). Five weeks after injection, treatments started. Mice were treated with vehicle only (control group), Cab (5mg / kg), Mon (15mg / Kg) or both drugs: Cab (5mg / kg) + Mon (15mg / Kg). Drugs were administered daily by oral gavage for 28 days. Tumorvolume was monitored 3x / week by external caliper measurements performed always by the same operator. Data represent the mean and all replicates of each group and were analysed by two-way ANOVA with Tukey post hoc test for each individual time points. *,P<0.05; **, P<0.01; ****, P<0.0001. REFERENCES 1. Braun DA, Bakouny Z, Hirsch L, Flippot R, Van Allen EM, Wu CJ, Choueiri TK. Beyond conventional immune-checkpoint inhibition - novel immunotherapies for renal cell carcinoma. 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Plenker D, Riedel M, Brägelmann J, Dammert MA, Chauhan R, Knowles PP, Lorenz C, KeulM, Bührmann M, Pagel O, et al.Drugging the catalytically inactive state of RET kinase in RET-rearranged tumors. Sci Transl Med 2017;9(394). 11. Rendl G, Manzl, M, Hitzl W, Sungler P, Pirich C. Long-Term Prognosis of Medullary Thyroid Carcinoma. Clin Endocrinol 2008; 69:497–505. 12. Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 2006; 107:2134-2142. 13. Romei C, Ciampi R, Elisei R. A comprehensive overview of the role of the RET proto- oncogene in thyroid carcinoma. Nat Rev Endocrinol 2016; 12:192-202. 14. Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, et al. 2012. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2017; 30:134-41. 15. 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Claims

CLAIMS 1. A tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite, or a derivative thereof for use in a method of treatment of a disease associated with tyrosine kinase receptor activation in a subject, wherein the tyrosine kinase receptor inhibitor is administered in combination with a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

2. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of claim 1, wherein the tyrosine kinase receptor inhibitor is a RET inhibitor and the disease associated with tyrosine kinase receptor activation is a disease associated with RET activation or wherein the tyrosine kinase receptor inhibitor is not a RET inhibitor and the disease associated with tyrosine kinase receptor activation is not a disease associated with RET activation.

3. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of claim 1 or 2, wherein the tyrosine kinase receptor inhibitor is a multikinase inhibitor.

4. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of claims 1 to 3, wherein the tyrosine kinase receptor inhibitor is selected from the group consisting of axitinib, nintedanib, cabozantinib, vandetanib, lenvatinib, sorafenib, sunitinib, motesanib, imatinib, alectinib and regorafenib, preferably is selected from the group consisting of cabozantinib, vandetanib, lenvatinib, sorafenib, sunitinib, motesanib, imatinib, alectinib and regorafenib, more preferably selected from the group consisting of cabozantinib, vandetanib, sunitinib, imatinib, alectinib and regorafenib.

5. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of claim 1 or 2, wherein the tyrosine kinase receptor inhibitor is a selective RET inhibitor.

6. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of claims 1 , 2 or 5, wherein the tyrosine kinase receptor inhibitor is pralsetinib (BLU-667) or selpercatinib (LOXO-292).

7. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding claims, wherein the compound of formula (I) has the following structure:or a pharmaceutically acceptable salt or solvate thereof; wherein R1and R2are as defined in any one of the preceding claims; preferably wherein the compound of formula (I) has the following structure:or a pharmaceutically acceptable salt or solvate thereof.

8. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding claims, wherein the compound of formula (II) has the following structure:

9. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding claims, wherein the disease associated with tyrosine kinase receptor activation is a cancer associated with tyrosine kinase receptor activation; preferably wherein the tyrosine kinase receptor inhibitor is a RET inhibitor and the cancer associated with tyrosine kinase receptor activation is a cancer associated with RET activation.

10. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding claims, wherein the disease associated with tyrosine kinase receptor activation is selected from the group consisting of thyroid cancer, a pituitary tumor, an adrenal tumor, a pancreatic neuroendocrine tumor, small lung cell cancer (neuroendocrine) and renal cell carcinoma (non- neuroendocrine); preferably wherein the disease associated with tyrosine kinase receptor activation is thyroid cancer, more preferably medullary thyroid carcinoma.

11. The tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof for use of any one of the preceding claims, wherein the tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a metabolite, a derivative or a solvate thereof is administered contemporaneously, previously or subsequently to the compound of formula (I) and / or the compound of formula (II).

12. A pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):, wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion.

13. A pharmaceutical composition comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof; wherein:R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion for use as a medicament.

14. The pharmaceutical composition of claim 12 or the pharmaceutical composition for use of claim 13, wherein the tyrosine kinase receptor inhibitor, the compound of formula (I) and / or the compound of formula (II) are as defined in any one of the preceding claims; and / or wherein the pharmaceutical composition is for use in a method of treatment of a disease associated with tyrosine kinase receptor activation, preferably wherein the disease associated with tyrosine kinase receptor activation is as defined in any one of the preceding claims.

15. A kit of parts comprising a tyrosine kinase receptor inhibitor or a pharmaceutically acceptable salt, a solvate, a metabolite or a derivative thereof, and a compound of formula (I):or a pharmaceutically acceptable salt or solvate thereof; wherein: R1 is selected from the group consisting of H and (C1-C8)alkyl; and R2 is selected from the group consisting of H and (C1-C8)alkyl; and / or a compound of formula (II):, wherein: R3, R4 and R5 is, each independently, (C1-C8)alkyl; X is (C1-C8)alkylene; Y is halogen; and A is a pharmaceutically acceptable anion; preferably wherein the tyrosine kinase receptor inhibitor, the compound of formula (I) and / or the compound of formula (II) are as defined in any one of the preceding claims.

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