TR2021021868A2 - DRUG FOR THE TREATMENT OF ADVANCED METASTATIC CANCER - Google Patents

Abstract

The present invention relates to an A3 adenosine receptor (A3AR) ligand for use in the treatment of an advanced solid tumor in a mammal, such as hepatocellular carcinoma (HCC).

Description

DESCRIPTION DRUG FOR THE TREATMENT OF ADVANCED METASTATIC CANCER TECHNICAL FIELD OF THE INVENTION The present invention relates to the treatment of advanced metastatic cancer, particularly advanced hepatocellular carcinoma, comprising the administration of an A3AR ligand. BACKGROUND OF THE INVENTION Primary liver cancer, especially hepatocellular carcinoma (HCC), is a major global health problem due to its incidence, associated mortality, and lack of effective treatment methods, especially for patients with moderate or advanced liver dysfunction. In patients with advanced HCC and Child-Pugh B (CPB) cirrhosis, liver function is borderline and therefore the benefit of any therapy may be offset by the decline in liver function. The only therapeutic option for these patients is successful downstaging and liver transplantation. However, this approach is only suitable for a minority of patients and is also limited by the limited number of livers available for transplantation [Granito common treatment is the multikinase inhibitor sorafenib, which is approved by the US Food and Drug Administration (FDA) for advanced HCC regardless of liver function. CPB patients are often excluded from clinical trials due to their poor prognosis and low expected response rates [Llovet J.M., et al. J. Natl. Cancer Inst. 2008; 100:698-711]. Clearly, treatments for HCC and CPB cirrhosis are still needed. The Gi protein-coupled A3 adenosine receptor (A3AR) is overexpressed in different types of solid tumors and HCC, including melanoma, breast, colon and prostate cancer, while low receptor expression is found in adjacent normal tissues [Bar-Yehuda S., Generic Cl-IB -Namodenoson, known as MECA, is a highly selective, orally bioavailable A3AR agonist that induces an apoptotic effect against HCC in syngeneic orthotopic and xenograft experimental animal models [Cohen S., and Safety of namodenosone in an open-label phase I/II study and its effectiveness was evaluated in patients with advanced unresectable HCC, 67% of whom had failed prior sorafenib therapy. The median overall survival (TS) time in the entire study population was 8.1 months. Namodenosone was assessed to be safe and well tolerated and was associated with baseline A3AR expression levels. BRIEF DESCRIPTION OF THE INVENTION In a primary aspect, the present invention provides an A3 adenosine receptor (A3AR) ligand for use in the treatment of an advanced solid tumor in a mammal. In another aspect, the present invention provides a pharmaceutical composition comprising an A3AR ligand and a pharmaceutically acceptable carrier or diluent, wherein said pharmaceutical composition is for treating an advanced solid tumor in a mammal. In one embodiment, the advanced solid tumor in question is advanced hepatocellular carcinoma. In one embodiment, the advanced solid tumor in question is metastatic hepatocellular carcinoma. In one embodiment, the subject is an advanced patient with Child-Pugh B (CPB) cirrhosis score 7 (CPB7), Child-Pugh B (CPB) cirrhosis score 8 (CPB8), or Child-Pugh B (CPB) cirrhosis score 9 (CPB9). has hepatocellular carcinoma. In one embodiment, the A3AR ligand is an AsAR agonist or an AsAR allosteric modulator. In some embodiments, the A3AR agonist of interest is N6-2-(4-aminophenyl)ethyladenosine (APNEA), N5-(4-amino-3-iodobenzyl)adenosine-5'-(N-methyluronamide) (AB-MECA), N6 - (3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA, namodenoson) is selected from the group consisting of: In some embodiments, said A3AR allosteric modulator is selected from the group consisting of: N-(3,4-Dichloro-phenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine; N-(3,4-Dichloro-phenyl)-2-cycloheptyl-1H-imidazo[4,5-c]quinoline-4-amine; N-(3,4-Dichloro-phenyl)-2-cyclobutyl-1H-imidazo[4,5-c]quinoline-4-amine; and N-(3,4-Dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinoline-4-amine. In one embodiment, the treatment further includes administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an anti-cancer drug, such as a monoclonal antibody and/or a multi-kinase inhibitor. In some embodiments, the A3AR ligand is administered once daily, twice daily, or three times daily. In some embodiments, the A3AR ligand is administered every 12 hours throughout the treatment period. In one embodiment, the A3AR ligand is applied continuously. In one embodiment, the treatment period is divided into cycles (e.g., 4-week cycles). In one embodiment, the mammal in question is a human. In some embodiments, said A3AR ligand is administered in an amount of 50ug/kg-10mg/kg body weight, preferably 100ug/kg-5 mg/kg body weight, or 200ug/kg-1mg/Kg body weight. In a specific embodiment, said A3AR ligand is CL-IB-MECA administered orally twice daily at a dose of 1-50 mg, preferably 5-30 mg. In a specific embodiment, the subject subject is A3AR as second-line therapy In a specific embodiment, said administration is for a treatment period of at least 9 months, at least 10 months, at least one year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years. In another aspect, the present invention is directed to increasing the overall survival of subjects with advanced HCC and a CPB7 score, comprising administering to the subject an A3AR ligand (e.g., Cl-IB-MECA), in a specific embodiment, said increase in overall survival at 9 months, 10 months. monthly, measured after a treatment period of 12 months or more, wherein said treatment comprises oral twice daily administration of A3AR ligand (e.g., Cl-IB-MECA) at a dose of 1-50 mg, preferably 5-30 mg In another aspect, the present invention provides a kit comprising: (a) a pharmaceutical formulation comprising an A3AR ligand as described above; (b) instructions for administering the pharmaceutical formulation for the treatment of a subject with an advanced solid tumor. BRIEF DESCRIPTION OF THE DRAWINGS In order to understand the invention and see how it can be put into practice, a preferred embodiment will now be described by way of non-limiting example only, with reference to the accompanying drawings, wherein: Figure 1, 12-month Overall Survival (TS) in Patients with a Child-Pugh Score of 7. A graph showing a comparison of the ratio (Namodenoson 25 mg BID compared to placebo). Figure 2 shows a formula from US 5,773,423. Figure 3 shows another formula from US 5,773,423. Figure 4 shows the general formula (I). Figure 5 shows the general formula (II). Figure 6 shows the general formula (III). Figure 7 shows a possible formula of the group R16. Figure 8 shows the general formula (IV). Figure 9 shows the general formula (V). Figure 10 shows the general formula (VI). Figure 11 shows the formula (Vla). Figure 12 shows the formula (Vlb). Figure 13 shows the formula VII). DETAILED DESCRIPTION OF EXAMPLE APPLICATIONS The present invention is based on the surprising finding that a patient with advanced HCC with CPB treated with namodenoson (CI-IB-MECA) showed unprecedented results and complete cancer regression after 5 years of treatment. The patient experienced advanced HCC CPB patients It was included in a randomized, placebo-controlled phase II study evaluating the efficacy/safety of namodenoson and placebo. Additionally, the phase II study demonstrated a surprising efficacy of namodenosone in increasing the 12-month overall survival rate of treated patients. This therapeutic method is specifically described in the specification for the treatment of CPB II HCC by administering an A3AR Iigand to a subject in need thereof. As used in the specification and claims, "a" and "the" refer to singular and plural unless the context clearly indicates otherwise. For example, the term "an A3AR Iigandi" includes one or more Iigandi. Additionally, as used herein, the term "comprising" is intended to mean that the method or formulation includes the specified elements but does not exclude others. Similarly, the phrase "consisting essentially of" is used to describe methods and formulations that contain the specified elements but exclude other elements that may have significant primary therapeutic activity against joint inflammation. For example, a formulation consisting primarily of an A3AR ligand will not contain, or will contain only negligible amounts of, other active ingredients that have such activity (amounts that would have a negligible effect on joint inflammation). Furthermore, a formulation consisting substantially of the A3AR ligand as defined herein shall not exclude trace contaminants from the isolation and purification method, pharmaceutically acceptable carriers such as phosphate buffered saline, excipients, preservatives, and the like. The expression "consisting of" should be interpreted in the sense of excluding the amounts of other elements that exceed the trace elements. Embodiments defined by each of these transitional expressions are within the scope of this invention. Moreover; All numerical values, such as concentrations, doses or ranges thereof, are approximate, varying up to (+) or (-) 20%, and in some cases up to 10%, of the stated values. All numerical representations use the term "approximate", even if not always expressly stated. It should also be understood that, although not always expressly stated, the reactants described herein are exemplary only and their equivalents are known in the art, providing a method for treating an advanced solid tumor. It comprises administering to a mammal in need of the A3 adenosine receptor (A3AR) ligand, or a pharmaceutical formulation comprising said A3AR ligand. In a specific embodiment, the advanced solid tumor is advanced hepatocellular carcinoma. In the context of the present invention, the term "treatment" means to achieve a desired therapeutic effect. treating an advanced solid tumor, such as advanced HCC, by administering a therapeutically effective amount of an A3AR ligand. The desired therapeutic effect may include, but is not limited to, complete or partial reversal of disease symptoms, clearance of cancer lesions, increased survival, restoration of ascites, normal liver function, and disappearance of peritoneal carcinomatosis. The term "advanced solid tumor" as used herein refers to a malignant solid neoplasm that has spread extensively to other anatomical sites or is no longer responsive to treatment. Non-limiting examples of malignant solid neoplasms include carcinomas (e.g., adenocarcinoma, breast carcinoma, ovarian carcinoma, non-small cell lung cancer, bladder cancer, prostate cancer, colon cancer, hepatocellular carcinoma, squamous cell carcinoma, or glioma) and sarcomas (e.g., bone, tendon , cartilage, muscle or fat sarcomas). The term "advanced hepatocellular carcinoma" as used herein refers to an advanced (metastatic) liver cancer that has spread to the lymph nodes or other organs. At this type of stage, the cancer has spread and usually cannot be removed by surgery. In one embodiment, the present invention relates to patients with hepatocellular carcinoma associated with cirrhosis. Cirrhotic status of the liver can be assessed using the Child-Pugh scoring system (also known as the Child-Pugh-Turcotte score), which is designed to predict mortality in patients with cirrhosis. This scoring system divides patients into three categories: A - good liver function, B - moderately impaired liver function, and C - advanced liver dysfunction. The scoring system uses five clinical and laboratory criteria to categorize patients: serum bilirubin, serum albumin, ascites, neurological disorder (encephalopathy), and prothrombin time; Each of these criteria is defined using a numerical value that describes the severity of cirrhosis: o Child-Pugh A: 5 to 6 points 0 Child-Pugh B: 7 to 9 points 0 Child-Pugh C: 10 to 15 points. In accordance with the invention, the subject has a Child-Pugh B cirrhosis score of 7 to 9 points, i.e. Child-Pugh B (CPB) cirrhosis score 7 (CPB7), Child-Pugh B (CPB) cirrhosis score 8 (CPB8) or Child-Pugh B (CPB) may have advanced hepatocellular carcinoma with cirrhosis score 9 (CPB9). In one embodiment of the invention, subjects are treated with the A3AR ligand as second-line therapy, meaning that the subjects have previously been treated with another anti-cancer drug and the therapy has failed. That is, in some embodiments, subjects according to the present invention are patients with advanced HCC with a CPS7-CPS9 score who have failed other treatment regimens. In one embodiment, the present invention provides a method for improving the overall survival of patients with advanced HCC having a CPB7 score. In a specific embodiment, the increase resulted in an increase in overall survival of 12 months or more. The term "an A3 adenosine receptor (A3AR) ligand" as used herein includes A3AR allosteric modulators as well as A3AR agonists. A3AR agonists are known in the art and are readily available. In general, an A3AR agonist is any compound that can specifically bind to the adenosine A3 receptor ("A3R"), thereby providing a therapeutic effect (e.g., an anti-arthritic effect) by fully or partially activating that receptor. Thus, the A3AR agonist is a molecule that provides its primary effect through the binding and activation of AgAR. That is, it essentially binds and activates only the A3R at the doses applied. In one embodiment, the A3AR agonist binds to and activates human A3AR at less than 1000 nM. preferably less than 500 nM, advantageously less than 200 nM and even less than 100 nM, typically less than 50 nM, preferably less than 20 nM, more preferably less than 10 nM and ideally less than 5 nM. The lower the Ki, the lower the dose of A3AR agonist that can be used to achieve a therapeutic effect by activating the AgR. Some A3AR agonists also have lower affinities (i.e. It should be noted that it may interact with and activate other receptors with a higher Ki. In the context of the invention; It has an affinity for A3R that is at least 3-fold higher than its affinity for other adenosine receptors (i.e., the Ki value for A3R is at least 3-fold lower), preferably 10-fold higher, preferably 20-fold higher, and most preferably at least 50-fold higher. A molecule that is will be considered an A3AR agonist (i.e., a molecule that exerts its primary effect through binding and activation of AgR) The affinity of A3AR agonists for human A3R and their relative affinity for other human adenosine receptors will be determined by various assays, e.g. a binding assay. It can be determined by . Binding assays, for example, by introducing membranes or cells with the receptor and measuring the ability of the A3AR agonist to displace a bound radioactive agonist; using cells expressing the relevant human adenosine receptor and measuring, in a functional assay, the ability of the A3AR agonist to activate or deactivate downstream signaling events such as the effect on adenylate cyclase measured by increasing or decreasing the level of cAMP, and the like. Clearly, if an applied level of an A3AR agonist is increased to such a level that the level of the AsAR agonist in the blood approaches the Ki of other adenosine receptors, these receptors may be activated as well as the activation of the AgR following this application. Therefore, an A3AR agonist would preferably be used based on the blood level to be achieved. The characteristics and preparation methods of some adenosine AAR agonists are described in detail in WO 01/19360: N6-(3-iodobenzyl)-9-methyladenine; iodobenzyl)-9-hydroxyethyladenine; R-N6-(3-iodobenzyl)-9-(2,3-dihydroxypropyl)adenine; -(3-iodobenzyladenin-9-yl)acetic acid; N6-(3-iodobenzyl)-9-(3-cyanopropyl)adenine; 2-chloro-N6-(3-iodobenzyl)-9-methyladenine; N6-(3-iodobenzyl)-9-methyladenine; 2-hydrazido-N5-(3-iodobenzyl)-9-methyladenine; 2-dimethylamino-N6-(3-iodobenzyl)-9-methyladenine; N6-(3-iodobenzyl)-9-methyl-2-propylaminoadenine; 2-hexylamino-No-(3-iodobenzyl)-9-methyladenine; N6-(3-iodobenzyl)-2-methoxy-9-methyladenine; N6-(3-iodobenzyl)-9-methyl-2-methylthioadenine; N6-(3-iodobenzyl)-9-methyl-2-(4-pyridylthio)adenine; (±)-9-[20(,30(-dihydroxy-4ß-(N-methylcarbamoyl)cyclopent-1ß-yl)]-N6-(3-iodobenzyl)-adenine; 2-chloro-9-(2'- amino-2',3'-dideoxy-ß-D-5'-methyl-arabino-furonamido)-N6-(3-iodobenzyl)adenine; 2-chloro-9-(2',3'-dideoxy-2'; -fluoro-ß-D-5'-methyl-arabino furonamido)-N6-(3-iodobenzyl)adenine; 9-(2-acetyl-3-deoxy-ß-D-S-methyl-ribofuronamido)-2-chloro-N6 (3-iodobenzyl)adenine; 2-chloro-9-(3-deoxy-2-methanesulfonyl-ß-D-5-methyl-ribofuronamido)-N6-(3-iodobenzyl)adenine; deoxy-ß-D-5-methyl-ribofuronamideO)-N6-(3-iodobenzyl)adenine; 2-chloro-9-(2',3'-O-thiocarbonyl-ß-D-5-methyl-ribofuronamido)-N6-(3-iodobenzyl)adenine; 9-(2-phenoxythiocarbonyl-3-deoxy-ß-D-S-methyl-ribofuronamido)-2-chloro-N6- (3-iodobenzyl) 1-(6-benzylamino-9H-purine-9-yl)-1-deoxy -N,4-dimethyl-ß-D-ribofuranosiduronamide; 2-chloro-9-(2,3-dideoxy-ß-D-S-methyl-ribofuronamido)-N6 benzyladenine; 2-chloro-9-(2'-azido-2',3'-dideoxy-ß-D-5'-methyl-arabino-furonamido)-N6-benzyladenine; 2-chloro-9-(ß-D-erythrofuranoside)-N6-(3-iodobenzyl)adenine; NG-(benzodioxanemethyl)adenosine; 1-(6-furfurylamino-9H-purine-9-yl)-1-deoxy-N-methyl-ß-D-ribofuranosiduronamide; NG-[3-(L-prolylamino)benzyl]adenosine-5'-N-methyluronamide; N6-[3-(ß-alanylamino)benzyl]adenosine-5'-N-methyluronamide; NG-[3-(N-T-Boc-ß-alanylamino)benzyl]adenosine-5'-N-methyluronamide 6-(N'-phenylhydrazinyl)purine-9-ß-ribofuranoside-S'-N-methyluronamide; 6-(O-phenylhydroxylamino)purine-9-ß-ribofuranoside-5'-N-methyluronamide; 9-(ß-D-2',3'-dideoxyerythrofuranosyl)-N5-[(3-ß-alanylamino)benzyl]adenosine; 9-(ß-D-erythrofuranoside)-2-methylamino-N6-(3-iodobenzyl)adenine; 2-chloro-N-(3-iodobenzyl)-9-(2-tetrahydrofuryl)-9H-purin-6-amine; 2-chloro-(2'-deoxy-6'-thio-L-arabinosyl)adenine; and 2-chloro-(6'-thio-L-arabinosyl)adenine. 7, line 14, where: R2 is selected from the group consisting of hydrogen, halo, C2-C10 alkyoxy, amino, C2-C10 alkenyl and R5 is unsubstituted; a benzyl group and a benzyl group substituted at one or more positions with a substituent selected from the group consisting of CL-C10 alkyl, amino, halo, CL-C10 haloalkyl, nitro, hydroxy, acetamido, CL-C10 alkoxy and sulpho. More specific compounds include compounds of the above formula in which Ra and Rb can be the same or different from each other and R2 is selected from the group consisting of hydrogen and R2, in particular where R5 is unsubstituted benzyl. are the compounds. More specific compounds are those where Rb is a CL-C10 alkyl or C3-C10 cycloalkyl, especially a CL-C10 alkyl and more particularly methyl. Particularly specific compounds are compounds where Ra is hydrogen, Rb is CL-C10 alkyl or C3-C10 cycloalkyl, and R5 is R- or S-1-phenylethyl or halo, amino, acetamido, CL-C10 haloalkyl and sulfodan. An example of a particularly preferred compound is IB-MECA disclosed in US 5,773,423. In addition, compounds conforming to the formula Rd- C=C- where Rz is a C2-C10 alkenylene and Rd is a CL-C8 alkyl are also specifically noted in this publication, especially compounds where R2 is other than hydrogen. Also specific are compounds where halo is CL-C10 alkylamino or CL-C10 alkylthio and preferably also where Ra is hydrogen, Rb is a CL-C10 alkyl and/or R5 is a substituted benzyl. Specifically disclosed such compounds are 2-chloro-N6-(3-iodobenzyl)-9-[5-(methylamido)-ß-D-ribofuranosyl]-adenine, N6-(3-iodobenzyl)-2-methylamino-9 -[5-(methylamido)-ß-D- ribofuranosyl]-adenine and N6-(3-iodobenzyl)-2-methylthio-9-[5-(methylamido)-ß-D- ribofuranosyl]-adenine. discloses A3AR agonists as modified xanthine-7-ribosides of the formula wherein Rs is RaRbNC(=O) wherein Ra and Rb may be the same or different from each other and hydrogen, CL-C10 alkyl, amino, CL-C10 haloalkyl is selected from the group consisting of CL-C10 aminoalkyl and C3-C10 cycloalkyl; R7 and R3 may be the same or different and include CL-C10 alkyl, R- and S-1-phenylethyl, an unsubstituted benzyl group, and CL-C10 alkyl, amino, halo, CL-C10 haloalkyl, nitro, hydroxy, acetamido. is selected from the group consisting of a benzyl group substituted at one or more positions with a substituent selected from the group consisting of CL-C11 alkoxy and sulfo; and R9 is selected from the group consisting of halo, benzyl, phenyl and C3-C10 cycloalkyl. disclosed: N6 4-biphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide; N6 2,4-dichlorobenzyl-carbonylamino)-adenosine-5'-N-ethyluronamide; N6 phenyl-carbonylamino)-adenosine-5'-N-ethyluronamide; 4-methoxyphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide; 4-chlorophenyl-carbonylamino)-adenosine-5'-N-ethyluronamide; N6 benzylcarbamoylamino)-adenosine-5'-N-ethyluronamide; N6 4-sulfonamido-phenylcarbamoyl)-adenosine-5'-N-ethyluronamide; N6 4-acetyl-phenylcarbamoyl)-adenosine-5'-N-ethyluronamide; (R)-oi-phenylethylcarbamoyl)-adenosine-5'-N-ethyluronamide; (8)- 0( -phenylethylcarbamoyl)-adenosine-5'-N-ethyluronamide; N6 5-methyl-isoxazol-3-yl-carbamoyl)-adenosine-5'-N-ethyluronamide; N6 1,3,4-thiadiazol-2-yl-carbamoyl)-adenosine-5'-N-ethyluronamide; NG-(4-n-propoxy-phenylcarbamoyl)-adenosine-5'-N-ethyluronamide; NG-bis-(4-nitrophenylcarbamoyl)-adenosine-5'-N-ethyluronamide; and N6-bis-(5-chloro-pyridin-2-yl-carbamoyl)-adenosine-5'-N-ethyluronamide. According to one embodiment of the invention, the A3AR agonist is a purine derivative compound falling within the general formula (I) shown in Figure 4, which exerts its primary effect through binding and activation of the adenosine A3AR, where: R11 is an alkyl, hydroxyalkyl, carboxyalkyl or cyanoalkyl or represents a group of the following general formula (II) shown in Figure 5, where: - Y is oxygen, sulfur or CH2; - is selected or combined to form a heterocyclic ring containing two to five carbon atoms; X14 is independently hydrogen, hydroxyl, amino, amido, azido, halo, alkyl, alkoxy, carboxy, nitrilo, nitro, trifluoro, aryl, alkaryl, thio, thioester, thioether, -OCOPh, -OC(=S)OPh" , or X13 and X14 are oxygens bonded to C=S to form a 5-membered ring, or represents alkyl group; R12 is hydrogen, halo, alkylether, amino, hydrazido, alkylamino, alkoxy, thioalkoxy, pyridylthio, alkenyl; alkynyl is selected from the group consisting of thio and alkylthio; and R13 is a group of the formula -NR15R16 where -R15 is a hydrogen atom or alkyl, substituted alkyl or aryl-NH-C(Z)-" wherein Z is 0, 8 or NRa and Re has the meanings defined above. is selected from the group consisting of -R15 where R15 is hydrogen; R- and S-1-phenylethyl, benzyl, phenylethyl; or anilide groups substituted or unsubstituted at one or more positions with a substituent selected from the group consisting of alkyl, amino, halo, haloalkyl, nitro, hydroxyl, acetoamido, alkoxy and sulfonic acid, or a salt thereof; selected from the group consisting of benzodioxanemethyl, fururyl, L-propylalanyl-aminobenzyl, ß-alanylamino-benzyl, T-BOC-ß-alanylaminobenzyl, phenylamino, carbamoyl, phenoxy or cycloalkyl; or R1s is a group of the formula shown in Figure 7: or where R15 is an alkyl or aryl-NH-C(Z)-; R1s, heteroaryl-NRa-C(Z)-, heteroaryl-C(Z)-, alkaryl-NRa-C(Z)-, alkaryl-C(Z)-, aryl-NR-C(Z)- and aryl- is selected from the group consisting of C(Z)-; Z represents an oxygen, sulfur or amine; or the physiologically acceptable salt of the above compound. In a preferred embodiment, the AsAR agonist is a nucleoside derivative of the general formula (IV) shown in Figure 8, wherein: X1, R2' and R5 are as defined above and are physiologically acceptable salts of the compound of interest. Non-cyclic carbohydrate groups (e.g. alkyl, alkenyl, alkynyl, alkoxy, aralkyl, alkaryl, alkylamine, etc.) forming part of the substituent of the compounds of the present invention may be branched or unbranched, preferably containing one or two to twelve carbon atoms. A specific group of A3AR agonists are N5-benzyladenosine-5'-uronamide derivatives. Some preferred N6-benzyladenosine-5'-uronamide derivatives are N6-2-(4-aminophenyl)ethyladenosine (APNEA), N5-(4-amino-3-iodobenzyl)adenosine-5'-(N-methyluronamide) (AB -MECA) and 1-deoxy-1-{6- [({3-iodophenyl} methyl)amino]- 9H- purin-9-yl}-N-methyl- ß-D-ribofuranuronamide (IB-MECA) and 2 -chloro-N5-(3-iodobenzyl)adenosine-5'-N-methyluronamide (CL-IB-MECA). According to another embodiment, the A3AR agonist may be an oxide derivative of adenosine such as No-benzyladenosine-5'-N-alkyluronamide-N1-oxide or No-benzyladenosine-5'-N-dialkyluronamide-N1-oxide, where the 2-purine position is a may be substituted with alkoxy, amino, alkenyl, alkynyl or halogen. Reference to an "A3AR allosteric modulator" or "A3ARM" should be understood as referring to the positive regulation, activation, or enhancement of receptor activity by binding of the allosteric modulator to the allosteric site of the receptor, which may differ from the binding site of the endogenous ligand or its agonist. "modulation" in one example; It indicates an effect of the A3AR ligand on the receptor; the effect is exhibited by at least a 15% increase in the activity of the A3 adenosine receptor through binding of the compound to the allosteric site of the receptor and/or a decrease in the rate of dissociation of adenosine or an A3AR agonist to the orthosteric binding site. In one example, the modulation is demonstrated by an imidazoquinoline derivative. In one example, A3ARAM or imidazoquinoline derivative is shown in Figure 9 with the following generics - R1, CL-C10 alkyl, halo, CL-C10 alkanol, hydroxyl, CL-C10 acyl, CL-C10 alkoxy. ; CL-C10-alkoxycarbonyl, CL-C10 alkoxylalkyl; CL-Cio thioalkoxy; CL-C10 alkylether, amino, hydrazido, CL-C10 alkylamino, pyridylthio, C2-C10 alkenyl; represents an aryl or alkaryl optionally substituted in the aromatic ring with one or more substituents selected from the group consisting of C2-C10 alkynyl, thio, C10 alkylthio, acetoamido, sulfonic acid; or said substituents may together form a cycloalkyl or cycloalkenyl conjugated to said aryl; cycloalkyl or cycloalkenyl optionally containing one or more heteroatoms if the aryl is not an unsubstituted phenyl group; C 0 cycloalkenyl, a five to seven membered heterocyclic aromatic ring, 0 5 - 0 15 fused cycloalkyl, bicyclic aromatic or heteroaromatic rings; CL-Cm alkylether, amino, hydrazido, CL-Cm alkylamino, CL-Cm alkoxy, CL-C10-alkoxycarbonyl, CL-Cm alkanol, CL-C10 acyl, CL-Cm thioalkoxy, pyridylthio, thio and CL-Cm alkylthio, acetoamido and sulfonic acid; and pharmaceutically acceptable salts thereof. In some embodiments, the substituent R1 in A3ARAM has the following general formula (VI) shown in Figure 10, where: - n is an integer selected from 0 or 1-5; preferably n is 0, 1 or 2; and - In case n is 0 and X1 and X2 are not hydrogen, X1 and X2 are selected from hydrogen, halogen, alkyl, alkanol or alkoxy, indanyl, pyrroline, which may be the same or different from each other. In some other examples, R1 in A3ARAM is selected from each other. is a substituent of formula (VI) above, where X1 or , wherein: - Y is selected from N or CH. In still other examples, R2 in A3ARAM is selected from H, CL-10 alkyl, 04-10 cycloalkyl, the alkyl chain may be straight or branched, or a four to seven membered cycloalkyl ring form. In one example, R2 in A3ARAM is selected to be a five- to seven-membered heterocyclic aromatic ring. In some examples, the substituents R2 in A3ARAM are selected from H, n-pentyl, or a five-membered heterocyclic aromatic ring of formula (VII) shown in Figure 13 where: -Z; It is selected from 0, 8 or NH, preferably 0. By way of example, R2 in A3ARAM contains one or more fused rings, particularly to form bicyclic substituents. Non-limiting examples of bicyclic compounds that can be used to form substituents within the context of A3ARAM include: bicyclo[3.1.0]hexane-3-carboxylic acid , bicyclo[4.1.0]heptane-2-carboxylic acid, bicyclo[3.1.0]hexane-2-carboxylic acid and bicyclo[2.2.1]heptane-2-carboxylic acid, according to some other examples, R2 in A3ARAM. is selected from 2-cyclohexene or 3-cyclohexene. Specific imidazoquinoline derivatives that can be used as allosteric modulators of A3AR are listed below: N-(4-Methyl-phenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine N-(4-Methoxy-phenyl )-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine N-(3,4-Dichloro-phenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4 -amine N-(4-chloro-phenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine N-(3-Methanol-phenyl)-2-cyclopentyl-1H-imidazo[4 ,5-c]quinoline-4-amine N-([3,4-c]ldan)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine N-(1H-indazole-6 -yl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine N-(4-Methoxy-benzyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4 -amine N-(1H-Indol-6-yl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine N-(benzyl)-2-cyclopentyl-1H-imidazo[4,5 -c]quinoline-4-amine N-(phenylethyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine N-(3,4-Dichloro-phenyl)-2-cycloheptyl-1H -imidazo[4,5-c]quinoline-4-amine N-(3,4-Dichloro-phenyl)-2-furyl-1H-imidazo[4,5-c]quinoline-4-amine N-(3, 4-Dichloro-phenyl)-2-cyclobutyl-1H-imidazo[4,5-c]quinoline-4-amine N-(3,4-Dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5- c]quinoline-4-amine N-(3,4-Dichloro-phenyl)-2--1H-imidazo[4,5-c]quinoline-4-amine N-(3,4-Dichloro-phenyl)-2 -pentyl-1H-imidazo[4,5-c]quinoline-4-amine. The above imidazoquinoline derivatives, A1 and Am, Am?, if present, are considered allosteric modulators as they have been shown to have reduced affinity for the orthosteric binding site of the adenosine receptors and low affinity for the orthosteric binding site of the A3 adenosine receptor and, on the other hand, high affinity for the allosteric site of the A3 adenosine receptor [ herein International Patent Application No. incorporated by reference to WOO7/089507]. A specifically preferred imidazoquinoline derivative according to the present disclosure is N-(3,4-dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-], which is an A3AR allosteric modulator (sometimes referred to by the abbreviation LUF6000 or CF602). c]quinoline-4-amine. In the context of the general formulas described herein, the following meanings for the various terms should be taken into consideration: The term "a/kir" herein includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-heptyl, octyl and the like are used to represent a linear or branched hydrocarbon chain having 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. Similarly, the terms "alkenyl" and "alkynyl" refer to a linear or branched hydrocarbon chain having 2 to 10 or 3 to 10 carbon atoms, respectively, and more preferably 2 to 6 or 3 to 6 carbon atoms, alkenyl or alkynyl being at least one The alkyl, alkenyl or alkynyl substituents may be substituted with a heteroatom containing group. Thus, although not explicitly stated, any of the alkyl modifications described above and below such as alkylthio, alkoxy, akanol, alkylamine, etc. Preferred aryls are phenyl, indanyl, benzimidazole. These types of alkaryl groups have 6 to 14 carbon atoms in the . exemplified by benzyl, phenethyl and the like. It refers to an aromatic moiety. As will be appreciated by those skilled in the art, various substituents are possible. However, some preferred substituents include, but are not limited to, halogen, (substituted) amino, nitro, cyano, alkyl, alkoxy, acyloxy or alkanol, sulfonyl, sulfinyl. or alkynylene chain. Used to mean -O-alkyl, including isopropoxy, n-butoxy and the like. Used to mean -S-alkyl, including isopropylthio, n-butylthio, and the like. Used to mean -alkyl-O-alkyl, including propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl, t-butoxymethyl, and the like. Used to refer to cyclic hydrocarbon radicals, including cyclohexyl, cycloheptyl, and the like. Used to mean -C(O)O-alkyl, including ethoxycarbonyl, propoxycarbonyl and the like. It is used to mean any compound or substituent containing at least two aliphatic rings bonded at two mutually bonded atoms or across a string of atoms (bridgehead). The fused rings may contain any bicyclic, tricyclic as well as polycyclic moieties. Bicyclic substituents are preferred according to some embodiments of the present disclosure. The present invention also relates to the use of physiologically acceptable salts of an A3AR selective ligand, such as the compounds disclosed above. A "physiologically acceptable salt" represents any non-toxic alkali metal, alkaline earth metal and ammonium salt commonly used in the pharmaceutical industry, prepared by methods known in the art, including sodium, potassium, lithium, calcium, magnesium, barium ammonium. and protamine zinc salts. The term also includes non-toxic acid addition salts, which are generally prepared by reacting the ligand with a suitable organic or inorganic acid. Acid addition salts are those that retain the biological activity and qualitative properties of the free bases and are nontoxic and are otherwise undesirable. Examples of this include, among others, acids derived from mineral acids, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, metaphosphoric and the like. Organic acids include, among others, tartaric, acetic, propionic, citric, malic, malonic, lactic, fumaric, benzoic, cinnamic, mandelic, glycolic, gluconic, pyruvic, succinic, salicylic, and arylsulfonic acids, such as p-toluenesulfonic. The A3AR ligand can be administered as a single dose (one-time drug) or as a continuous treatment. In one example, the A3AR ligand is used for long-term therapy. In the context of the present invention, long-term treatment should be understood to include a treatment window lasting at least days, weeks, months or even years until discontinuation, for example, due to intolerance, withdrawal of consent or death. Although continuous, the treatment period may be divided into cycles (e.g. 4-week cycles) for data recording purposes. In one embodiment, the A3AR ligand is administered every 12 hours until discontinuation. Additionally, in the context of some examples of the present disclosure, long-term treatment includes chronic treatment, e.g., prolonged daily administration (once, twice, or thrice daily) even when there is no anticipated end point for treatment. In some examples, long-term treatment includes daily administration of the A3AR ligand for at least one week, sometimes daily treatment for a month, sometimes daily administration of the ligand for at least 2, 3, 4, 5, 6, or even 12 months, sometimes daily administration of the ligand for at least It involves daily practice for 1, 2, 3, 4, 5, 6 or more years. In one embodiment, the treatment period is a long-term treatment lasting at least one year. A3AR Iigandi is administered in amounts sufficient to achieve a therapeutic anti-cancer effect. It will be appreciated that the amount of AsAR ligand will depend on the severity of the disease, the intended therapeutic regimen, and the desired therapeutic dose. For example, if the dose is 50 mg per day and the desired administration regimen is 2 days of administration, the amount of active agent in the pharmaceutical formulation will be 25 mg. An amount effective to achieve the desired effect is determined by matters known in the art. For purposes herein, an "effective amount" must be effective to achieve a therapeutic effect, wherein the therapeutic effect is as previously defined. It is appreciated that the effective amount depends on various factors, including various pharmacological parameters such as affinity of the selected AsAR agonist to A3AR, distribution profile in the body, half-life in the body, undesirable side effects if any, age and sex of the subject to be treated, etc. Effective The amount is typically tested in clinical studies aimed at finding the effective dose range, maximum tolerated dose, and optimal dose. The manner in which such clinical studies are conducted is well known to a person skilled in clinical research, in accordance with one embodiment of the invention, administration of the A3AR agonist preferably once or several times a day. daily administration, preferably once or twice daily, with the dose per administration ranging from about 1 to about 1000µg/kg body weight, preferably 50µg/kg body weight. In some embodiments, AsAR Iigandi is 1-50 mg per day. In a specific aspect, advanced solid tumor is advanced HCC, the AsAR agonist is Cl-IB-MECA (namodenoson) administered orally at a dose of 5-30 mg twice, and the dose is every 12 days. is 25 mg given orally every hour (i.e. twice a day). The A3AR agonist is formulated in a pharmaceutical formulation. In the context of the invention it is intended to mean a composable carrier and also a combination with other additives. The carrier is sometimes used to improve the delivery or penetration of the active ingredient into the target tissue, improve the stability of the drug, slow down clearance rates, provide slow release properties, reduce unwanted side effects, etc. may have an effect. The carrier may also be a substance that stabilizes the formulation (e.g., a preservative). For examples of carriers, stabilizers, and adjuvants, see E.W. Martin, REMINGTON'S PHARMACEUTICAL SCIENCES, MacK Pub Co (June 1990). In the context of the present invention, the term "pharmaceutically acceptable carrier" refers to any of the inert, non-toxic materials that do not react with the A3AR agonist and may be added to formulations as diluents, carriers, or to give form or consistency to the formulation. The formulation according to the present invention is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, the schedule of administration, the patient's age, sex, body weight and other factors known to medical practitioners. The choice of carrier will be determined in part by the specific active ingredient and also by the specific method used to administer the formulation. Accordingly, a wide variety of suitable pharmaceutical formulations of the present invention are available. As noted above, therapeutic use of an A3AR agonist is sometimes associated with monoclonal antibodies (e.g., the antibody atezolizumab alone or in combination with bevacizumab or the VEGFR2 inhibitor ramucirumab, the anti-PD1 receptor monoclonal antibodies pembrolizumab alone or in combination with the anti-CTLA-4 antibody ipilimumab, and nivolumab) and multi-kinase inhibitors (e.g. sorafenib, regorafenib, cabozantinib or lenvatinib). In this type of combination therapy, the other drug and the A3AR agonist may be given to patients simultaneously or at different times, depending on the dosing schedule for each drug. The invention has been described in an illustrative manner and it should be understood that the terminology used is intended to be an explanation rather than a limitation. In light of the above teaching, it is clear that many modifications and variations of the present invention are possible. It should therefore be understood that the invention within the scope of the appended claims may be implemented in a manner other than that specifically described below. EXEMPLARY EMBODIMENTS Study Participants The study population consisted of 218 patients with advanced/treatment-resistant HCC and CPB cirrhosis who were intolerant of sorafenib or whose disease had progressed despite prior sorafenib treatment. Diagnosis of HCC in subjects without underlying cirrhosis at diagnosis required cytology and/or histology; HCC diagnosis for subjects with underlying cirrhosis at diagnosis was based on the American Association for the Study of Liver Diseases practice guidelines algorithm [Marrero J.A., et al., 23 weeks of pretreatment was required, which was terminated 22 weeks earlier. Inclusion criteria included: ECOG PS ; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels being 5 times the upper limit of normal (ULN); total bilirubin, 53.0 mg/dL; serum albumin, 22.8 g/dL; prothrombin time (PT) <6 s longer than control; serum creatinine, 52.0 mg/dL; criteria included: presence of hepatic encephalopathy; and gastrointestinal bleeding requiring transfusion occurring within the last 4 weeks. Study Design and Treatment This was a multicenter, randomized, double-blind, placebo-controlled clinical trial (CIinicaITriaIs.gov identifier NCT02128958). The trial was conducted at 15 sites in Israel, Europe, and the United States. Subjects were enrolled by participating centers and randomly assigned 2:1 without any stratification prior to randomization using a central randomization schedule created by an independent biostatistician. Subjects were randomized to 25 mg namodenoson (CI-IB-MECA) or matching placebo administered orally every 12 hours until discontinuation due to intolerance, withdrawal of consent, or death. Although the treatment was administered continuously, the treatment period was divided into 4-week cycles for data recording purposes. Initially no crossover is allowed; However, with the protocol change, patients who continued blinded treatment were given namodenoson (25 mg twice daily) after unblinding of treatment assignments. The study was approved by all relevant national regulatory authorities and local Ethics Committees/Institutional Review Boards. The study was conducted in accordance with the Declaration of Helsinki and written informed consent was obtained from all patients. Assessments The primary endpoint of the study was overall survival (TS). Secondary endpoints; progression-free survival (IS), overall response rate (TRR), disease control rate (HCR) and safety. As with advanced HCC, IS has been found to be moderately associated with TS; IS is a reasonable secondary endpoint in this disease [Llovet J.M., et al., J. Hepatol. 2019, by using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [Eisenhauer E.A., et al. Euro. J. Cancer. evaluated by computed tomography scan or magnetic resonance imaging. Safety was monitored by assessment of AEs using the US National Cancer Institute's Common Terminology Criteria for Adverse Effects (CTCAE) v4.03. Vital signs, clinical laboratory parameters, electrocardiograms, physical examinations, and changes from baseline in ECOG PS were also evaluated. AFP levels were assessed at baseline and every 4 weeks thereafter, as were laboratory parameters associated with liver dysfunction and cirrhosis, such as serum ALT, AST, bilirubin and albumin levels, PT, and international normalized ratio. ALBI scores were calculated from albumin and bilirubin levels as previously described [Johnson P.J., et al. J. Clin. Oncol. Biomarker Studies Another secondary objective was to assess white blood cell (WBC) A3AR expression (which has been suggested to be expressed in HCC tumor cells [Bar-Yehuda S., et al.), as assessed at baseline and each cycle thereafter at selected study centers (n = 53 patients). has happened. A3AR mRNA expression in WBC was determined from blood collected into a PAXgene RNA tube (Qiagen, Venlo, Netherlands) using QuantiGene Plex 2.0® analysis (Thermo Fisher, Waltham, MA, USA). ß-actin was used as a reference control and oligonucleotide probe sets were designed by Thermo Fisher. Luminescence from each specific probe set was captured by GloMax Multi (Promega, Madison, WI, USA). A3AR is expressed in units, where 1 unit is defined as the average of A3AR expression in healthy subjects (n = 50). Healthy subjects were between 20 and 70 years old, had no underlying diseases, and had not received prior treatment. Statistical Analysis Power calculation determined that 75 deaths, assuming a hazard ratio of 0.5, would provide 80% power for the log-rank test at a significance level of 0.05. Primary efficacy analyzes were conducted on the ITT population. Descriptive statistics were used to summarize patient/tumor characteristics and safety. Kaplan-Meier curves were used to estimate TS/IS and comparisons were made using log-rank tests. Cox proportional hazards regression model was used to evaluate the effect of covariates. ORR/DCR was determined using normal approximation to the binomial distribution by treatment. The statistical analysis plan was modified to include subgroup analysis by CP score before unblinding. All statistical tests were 2-sided and p < 0.05 was considered statistically significant. Statistical analyzes were conducted using SAS. In a blinded, randomized, placebo-controlled phase II study, the namodenoson dose evaluated was 25 mg BID orally (twice daily) and the population consisted of 78 patients with advanced HCC and CPB cirrhosis who received namodenoson as second-line therapy. Patients were randomized 2:1 to receive namodenoson 25 mg BID (n = 50) or placebo (n = 28). No treatment-related deaths have been reported. Additionally, no patients withdrew from the study and there were no attributable dose reductions to namodenosone. Importantly, no hepatotoxicity was reported and liver function tests did not reveal any adverse effects due to namodenozone. Additionally, mean serum albumin levels and albumin-bilirubin (ALBI) scores did not change significantly in either arm throughout the study. Only one grade 3 treatment-related AE was reported (hyponatremia). Analysis of initial results Regarding anti-tumor efficacy, the primary trial endpoint of superiority of TS over placebo was not met; mean TS was 4.1 for namodenoson and placebo, respectively. Similarly, there was no superiority in terms of progression-free survival (IS). Of the CBP patients included in the study, patients with a Child-Pugh score of 7 (the least severe form of liver dysfunction in the CPB category) were the largest group (34 patients in the namodenoson arm and 22 patients in the placebo arm). Preplanned analysis evaluating patients by Child-Pugh subgroups showed nonsignificant differences in TS and IS for patients with a Child-Pugh score of 7. Mean TS in this subcategory was 6.9 months in the namodenoson group versus 4.3 months in the placebo group (HR, 0.81; 95% CI 6 months treated versus 6 treated with placebo), with TS and IS similar between the namodenoson and placebo arms and overall shorter than those reported for the subgroup of patients with a Child-Pugh score of 7 (TS: median TS and IS values for the 9 patients with a Child-Pugh score of 9 for the namodenoson and placebo arms, respectively, were 3.5 and 2.2, similar to those for patients with a Child-Pugh score of 8. Exploratory analysis comparing TS by treatment arm and classification by gender, alpha-fetoprotein levels, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), HPB and HPC status, locoregional therapy, extrahepatic extension status, and portal vein thrombosis status. did not find statistically significant differences between study arms in any of the subgroups, which may be partly attributable to the relatively small sample size of some groups. 18; p = 0.028) (Figure Analysis of response in all patients for whom at least 1 post-baseline assessment was available (55 patients; 34 treated with namodensone and 21 treated with placebo) showed that one patient in the namodensone group experienced CR and 3 patients in the namodensone group (9%) achieved PR versus none in the placebo group (Table 1). Duration of response in the 3 patients who experienced PR was 2, 6, and 26 months. Table 1: Best Observed Responses by Treatment Arm (RECIST 1.1) Response, n ( %) Namodenoson Placebo n = 34 n = 21 GR 1 (2.94%) 0 (0.0%) PR 3 (8.8%) 0 (0.0%) As shown in Table 1 above, one patient demonstrated a complete response. He was treated for 5 years under the Open Label Extension program of the Phase II study of Namodenosone in the treatment of hepatocellular carcinoma (HCC) and showed Complete Response (CR) to namodenosone, meaning that all cancer lesions were cleared under treatment with Namodenoson (25 mg administered orally twice daily). An inpatient Child Pugh B7 (CPB7) patient with advanced metastatic HCC with cirrhosis survived for five years. Clinical benefits of treatment, as demonstrated by a scan of the patient's chest, abdomen, and pelvis, included resolution of ascites, normal liver function, and disappearance of peritoneal carcinomatosis leading to complete clearance of all cancer lesions.TR TR

Claims (1)

STEMLER An A3 adenosine receptor (A3AR) ligand for use in the treatment of an advanced solid tumor in a mammalian subject. The A3AR ligand for use according to claim 1, wherein said advanced solid tumor is advanced hepatocellular carcinoma. A3AR ligand for use according to claim 2 for the treatment of metastatic hepatocellular carcinoma. AsAR ligand for use according to any one of claims 1 to 3; said A3AR ligand is an A3AR agonist or an A3AR allosteric modulator. A3AR ligand for use according to claim 4; The A3AR agonist in question is N adenosine-5'-(N-methyluronamide) (AB-MECA), N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and 2-chloro-N5- It is selected from the group consisting of (3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA). A3AR ligand for use according to claim 4; said A3AR allosteric modulator is selected from the group consisting of: N-(3,4-Dichloro-phenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine; N-(3,4-Dichloro-phenyl)-2-cycloheptyl-1H-imidazo[4,5-c]quinoline-4-amine; N-(3,4-Dichloro-phenyl)-2-cyclobutyl-1H-imidazo[4,5-c]quinoline-4-amine; and N-(3,4-Dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinoline-4-amine. AsAR ligand for use according to any one of claims 1 to 6; in combination with an additional therapeutic agent. It is an A3AR ligand for use according to claim 7; said additional therapeutic agent is an anti-cancer drug, such as a monoclonal antibody and/or a multi-kinase inhibitor. Claim 2 in a subject with advanced hepatocellular carcinoma with Child-Pugh B (CPB) cirrhosis score 7 (CPB7), Child-Pugh B (CPB) cirrhosis score 8 (CPB8), or Child-Pugh B (CPB) cirrhosis score 9 (CPB9) A3AR Iigandi for use in any of the to 8”. A3AR for use according to any one of claims 1 to 9 with said AsAR Iigandine administered once daily, twice daily or three times daily AsAR Iigandi for use according to. A3AR Iigand for use according to claim 11, with said A3AR Iigand being applied continuously. A3AR Iigandi for use according to any one of claims 11 or 12, dividing said treatment period into cycles, e.g. 4-week cycles. The A3AR ligand for use according to any one of claims 11 to 13; The mammalian subject in question is a human subject. A3AR for use according to any one of claims 11 to 14, with the AAR Iigandin in question administered in an amount of 50ug/kg-10mg/kg body weight, preferably 100ug/kg-5mg/Kg body weight or 200ug/kg-1mg/Kg body weight. According to any one of claims 11 to 15, wherein said A3AR Iigandin is Cl-IB-MECA and said Cl-IB-MECA is administered orally at a dose of 1-50 mg or 5-30 mg twice daily. A3AR Iigandi for use. An AsAR ligand such as Cl-IB-MECA for use in improving overall survival of subjects with advanced HCC and a CPB7 score. According to claim 17, wherein said increase in overall survival is measured after a treatment period of 12 months or more and said treatment comprises oral administration of Cl-IB-MECA at a dose of 1-50 mg, preferably 5-30 mg twice daily. A3AR ligand for use such as Cl-IB-MECA. A3AR Iigandi according to any one of claims 1 to 18; the subject has received A3AR Iigandi as a second-line therapy. Any of claims 1 to 19, provided that the application in question is for a treatment period of at least 9 months, at least 10 months, at least one year, at least 2 years, at least 3 years, at least 4 years or at least 5 years. AsAR Iigandi for use according to one. A pharmaceutical formulation comprising an A3AR Iigandi and a pharmaceutically acceptable carrier or diluent, said pharmaceutical formulation being for the treatment of an advanced solid tumor in a mammalian subject. The pharmaceutical formulation according to claim 21, wherein said advanced solid tumor is advanced hepatocellular carcinoma. Pharmaceutical formulation according to claim 22 for the treatment of metastatic hepatocellular carcinoma. Pharmaceutical formulation according to any one of claims 21 to 23; said A3AR ligand is an AsAR agonist or an A3AR allosteric modulator. It is a pharmaceutical formulation according to claim 24; the AsAR agonist in question is N6-2-(4-aminophenyl)ethyladenosine (APNEA), NG-(4-amino-3-iodobenzyl)adenosine-5'-(N-methyluronamide) (AB-MECA), Nö-(3 -iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and 2-chloro-NG-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA). It is a pharmaceutical formulation according to claim 24; wherein said A3AR allosteric modulator is selected from the group consisting of: N-(3,4-Dichloro-phenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine; N-(3,4-Dichloro-phenyl)-2-cycloheptyl-1H-imidazo[4,5-c]quinoline-4-amine; N-(3,4-Dichloro-phenyl)-2-cyclobutyl-1H-imidazo[4,5-c]quinoline-4-amine; and N-(3,4-dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinoline-4-amine. The pharmaceutical formulation according to any one of claims 21 to 26; It is combined with an additional therapeutic agent. It is a pharmaceutical formulation according to claim 27; wherein said additional therapeutic agent is an anti-cancer drug, such as a monoclonal antibody and/or a multi-kinase inhibitor. Pharmaceutical formulation according to any one of claims 22 to 28; the subject in question has advanced hepatocellular carcinoma with Child-Pugh B (CPB) cirrhosis score 7 (CPB7), Child-Pugh B (CPB) cirrhosis score 8 (CPB8), or Child-Pugh B (CPB) cirrhosis score 9 (CPB9) . Pharmaceutical formulation according to any one of claims 21 to 29; administering said pharmaceutical composition once a day, twice a day or three times a day. Pharmaceutical formulation according to any one of claims 21 to 30; said pharmaceutical formulation is administered every 12 hours throughout the treatment period. It is a pharmaceutical formulation according to claim 31; is the continuous administration of said pharmaceutical formulation. Pharmaceutical formulation according to any one of claims 31 or 32; The treatment period in question is divided into cycles, for example 4-week cycles. Pharmaceutical formulation according to any one of claims 21 to 33; The mammalian subject in question is a human subject. Pharmaceutical formulation according to any one of claims 21 to 34, wherein said A3AR ligand is administered in an amount of 50µg/kg-10mg/kg body weight, preferably 100µg/kg-5 mg/Kg body weight or 200µg/kg-1mg/Kg body weight. is its implementation. Pharmaceutical formulation according to any one of claims 21 to 35; said A3AR ligand being Cl-IB-MECA, said Cl-IB-MECA being administered twice daily It is administered orally at a dose of 1-50 mg, preferably 5-30 mg. A pharmaceutical formulation comprising an AsAR ligand such as Cl-IB-MECA and a pharmaceutically acceptable carrier or diluent; said pharmaceutical formulation is for improving the overall survival of subjects with advanced HCC and a CPB7 score. It is a pharmaceutical formulation according to claim 37; said increase in overall survival is measured after a treatment period of 12 months or longer and said treatment is administered at a dose of 1-50 mg twice daily, preferably 5-30 mg, of said A3AR ligand such as Cl-IB-MECA. It involves oral administration. Pharmaceutical formulation according to any one of claims 21 to 38; the subject receiving A3AR ligand as second-line therapy. Pharmaceutical formulation according to any one of claims 21 to 39; The application in question is for a treatment period of at least 9 months, at least 10 months, at least one year, at least 2 years, at least 3 years, at least 4 years or at least 5 years. A kit comprising: (a) a pharmaceutical formulation comprising an AsAR ligand according to any one of claims 21 to 40; (b) instructions for administering the pharmaceutical formulation to the treatment of a subject with an advanced solid tumor.