JP2024028923A - Treatment of advanced metastatic cancer - Google Patents

Abstract

To provide a method for treatment of advanced metastatic cancer, in particular, advanced hepatoma.SOLUTION: A pharmaceutical composition comprises an A3AR ligand and a pharmaceutically acceptable carrier or a diluent. The pharmaceutical composition is for treating an advanced solid tumor in a mammal subject.SELECTED DRAWING: None

Description

Application for application of Article 30, Paragraph 2 of the Patent Act filed on January 7, 2021 at https://doi. org/10.3390/cancers13020187, the content of the clinical trial related to the present invention was published. On December 20, 2021, the content of the clinical trial related to the present invention was made public in a publication.

The present invention relates to the treatment of advanced metastatic cancer, particularly advanced hepatocellular carcinoma, comprising administering A3AR ligands.

Primary liver cancer, particularly hepatocellular carcinoma (HCC), is a major disease due to its incidence, associated mortality, and lack of effective treatments, especially for patients with moderate or advanced liver dysfunction. It is a global health problem.

Patients with advanced HCC and Child-Pugh B (CPB) cirrhosis have borderline liver function, so the effects of any treatment may be offset by the decline in liver function. The only curative options for these patients include successful downstaging and liver transplantation. However, this approach is appropriate only for a small number of patients and is further limited by the limited number of livers available for transplantation [Granito A. , and Bolondi L. Lancet Oncol. 2017;18:e101-e112]. The most common treatment for HCC and CPB 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 generally excluded from clinical trials due to poor prognosis and low expected response rates [Llovet J. M. , et al. J. Natl. Cancer Inst. 2008;100:698-711]. It is clear that there remains a need for treatments for HCC and CPB cirrhosis.

Gi protein-coupled A3 adenosine receptor (A3AR) is overexpressed in various types of solid cancers such as melanoma, breast cancer, colon cancer, prostate cancer, and HCC, but receptor expression in adjacent normal tissues is It is recognized that it is low [Bar-Yehuda S. , et al. Int. J. Oncol. 2008;33:287-295].

Namodenoson, commonly known as Cl-IB-MECA, has been used in syngeneic orthotopic and xenograft experimental animal models [Cohen S. , et al. , J. Cell Physiol. 2011;226:2438-2447] is a highly selective orally bioavailable A3AR agonist that induces apoptotic effects on HCC.

An open-label Phase I/II study evaluated the safety and efficacy of namodenoson in patients with advanced, unresectable hepatocellular carcinoma (HCC), 67% of whom had failed prior sorafenib treatment. did. Median overall survival (OS) was 7.8 months for the entire study population and 8.1 months for CPB patients (28%). Namodenoson was safe and well-tolerated, with a direct correlation between baseline A3AR expression levels and tumor response to namodenoson [Stemmer S. M. , et al. Oncologist. 2013;18:25-26].

In a first embodiment thereof, the present invention provides a pharmaceutical composition comprising an A ₃ AR ligand and a pharmaceutically acceptable carrier or diluent, said pharmaceutical composition comprising an advanced solid state in a mammalian subject. It is for treating tumors.

In one embodiment, the advanced solid tumor is advanced hepatocellular carcinoma.

In one embodiment, the advanced solid tumor is metastatic hepatocellular carcinoma.

In one embodiment, the subject has a Child-Pugh B (CPB) Cirrhosis Score of 7 (CPB7), a Child-Pugh B (CPB) Cirrhosis Score of 8 (CPB8), or a Child-Pugh B (CPB) Cirrhosis Score of 9 (CPB9). ) has advanced hepatocellular carcinoma.

In one embodiment, the _A3AR ligand is an _A3AR agonist or an _A3AR allosteric modulator.

In some embodiments, the A ₃ AR agonist is N ⁶ -2-(4-aminophenyl)ethyladenosine (APNEA), N ⁶ -(4-amino-3-iodobenzyl)adenosine-5′-( N-methyluronamide) (AB-MECA), N ⁶ -(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and 2-chloro-N ⁶ -(3-iodobenzyl)-adenosine- 5'-N-methyluronamide (Cl-IB-MECA, namodenoson).

In some embodiments, the A _AR allosteric modulator is:
N-(3,4-dichlorophenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinolin-4-amine;
N-(3,4-dichlorophenyl)-2-cycloheptyl-1H-imidazo[4,5-c]quinolin-4-amine;
N-(3,4-dichlorophenyl)-2-cyclobutyl-1H-imidazo[4,5-c]quinolin-4-amine; and N-(3,4-dichlorophenyl)-2-cyclohexyl-1H-imidazo[4 , 5-c] quinolin-4-amine.

In one embodiment, the treatment further comprises administration of an additional therapeutic agent.

In some embodiments, the additional therapeutic agent is an anti-cancer drug, such as a monoclonal antibody and/or a multikinase inhibitor.

In some embodiments, the A ₃ AR ligand is administered once a day, twice a day, or three times a day.

In one embodiment, the A ₃ AR ligand is administered every 12 hours during the treatment period.

In one embodiment, the A ₃ AR ligand is administered continuously.

In one embodiment, the treatment period is divided into cycles (eg, 4 week cycles).

In one embodiment, the mammalian subject is a human subject.

In some embodiments, the A ₃ AR ligand is administered in an amount of 50 μg/kg to 10 mg/kg body weight, preferably 100 μg/kg to 5 mg/kg body weight, or 200 μg/Kg to 1 mg/Kg body weight.

In a particular embodiment, said A ₃ AR ligand is Cl-IB-MECA, administered orally twice a day at a dose of 1-50 mg, preferably 5-30 mg.

In certain embodiments, the subject received an A ₃ AR ligand as a second line treatment.

In certain embodiments, the administration is for a treatment period of at least 9 months, at least 10 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years, or at least 5 years.

In another aspect, the invention provides a pharmaceutical composition comprising an A ₃ AR ligand (e.g., Cl-IB-MECA) and a pharmaceutically acceptable carrier or diluent, wherein the pharmaceutical composition The purpose of this study is to prolong overall survival in subjects with HCC and CPB7 scores.

In certain embodiments, said prolongation of overall survival is measured after a treatment period of 9 months, 10 months, 12 months or more, and said treatment comprises A ₃ AR at a dose of 1 to 50 mg, preferably 5 to 30 mg. This involves administering the ligand (eg, Cl-IB-MECA) orally twice daily.

In another aspect, the invention provides:
Provided is a kit comprising: (a) a pharmaceutical composition comprising an _A3AR ligand as described above; and (b) instructions for administering the pharmaceutical composition for the treatment of a subject having an advanced solid tumor. do.

In order to understand the invention and how it may be implemented in practice, preferred embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which: FIG.

Figure 2 is a comparative graph of 12-month overall survival (OS) in patients with a Child-Pugh score of 7 (namodenoson 25 mg BID vs. placebo).

The present invention is based on the surprising discovery that a patient with advanced HCC with CPB treated with namodenoson (Cl-IB-MECA) showed unprecedented results and complete remission of cancer after 5 years of treatment. based on. This patient was included in a randomized, placebo-controlled Phase II trial evaluating the efficacy/safety of namodenoson versus placebo in patients with advanced HCC CPB. Additionally, this Phase II trial demonstrated the surprising efficacy of namodenoson in increasing 12-month overall survival in treated patients.

The present invention is described in the detailed description below with respect to a therapeutic method for the treatment of advanced solid tumors, particularly HCC with CPB, comprising the administration of an A3AR ligand to a subject in need thereof.

As used in the specification and claims, the forms "a,""an," and "the" refer to the singular and plural unless the context clearly dictates otherwise. include. For example, the term "A ₃ AR ligand" encompasses one or more ligands.

Additionally, as used herein, the term "comprising" is intended to mean that the method or composition includes the recited element but does not exclude others. Similarly, "consisting essentially of" refers to methods and compositions that include the listed elements but exclude other elements that may have essentially significant therapeutic activity against joint inflammation. used to define. For example, a composition consisting essentially of A3AR ligand may or may not contain only insignificant amounts (amounts that have a negligible effect on joint inflammation) of other active ingredients with such activity. Dew. Compositions consisting essentially of A3AR ligands as defined herein may also contain trace contaminants from isolation and purification methods, pharmaceutically acceptable carriers such as phosphate buffered saline, excipients, etc. Do not exclude excipients, preservatives, etc. "Consisting of" shall mean excluding trace elements or more of other elements. Embodiments defined by each of these transition phrases are within the scope of the invention.

Furthermore, all numerical values, eg concentrations or doses or ranges thereof, are approximations that vary (+) or (-) by up to 20%, sometimes up to 10%, of the stated values. It is to be understood that all numerical designations are preceded by the term "about" even if not always explicitly stated. Although not always explicitly stated, it should also be understood that the reagents described herein are merely exemplary and that such equivalents are known in the art.

The present invention provides a method of treating an advanced solid tumor, comprising administering to a mammalian subject in need thereof an A3 adenosine receptor (A ₃ AR) ligand or a pharmaceutical composition comprising said A3AR ligand. including administering.

In certain embodiments, the advanced solid tumor is advanced hepatocellular carcinoma (HCC).

In the context of the present invention, the term "treatment" includes treating an advanced solid tumor, e.g., advanced HCC, by administering a therapeutically effective amount of A3AR ligand to achieve the desired therapeutic effect. . Said desired therapeutic effects include complete or partial reversal of disease symptoms, elimination of cancerous lesions, improved survival rates, achieving disappearance of ascites, normal liver function, and disappearance of peritoneal carcinomatosis. However, it is not limited to these.

As used herein, the term "advanced solid tumor" refers to a malignant solid neoplasm that has spread extensively to other anatomical locations or is no longer responsive to treatment. Non-limiting examples of malignant solid neoplasms include carcinomas (e.g., adenocarcinoma, breast cancer, ovarian cancer, non-small cell lung cancer, bladder cancer, prostate cancer, colorectal cancer, hepatocellular carcinoma , squamous cell carcinoma, or glioma) and sarcomas (eg, bone, tendon, cartilage, muscle, or liposarcoma).

As used herein, the term "advanced hepatocellular carcinoma" refers to advanced (metastatic) liver cancer that has spread to either the lymph nodes or other organs. At this stage, the cancer has spread and generally cannot be removed by surgery.

In one embodiment, the invention relates to a patient with hepatocellular carcinoma associated with liver cirrhosis. The 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 cirrhotic patients. This scoring system classifies patients into three categories. A-Good liver function, B-Moderate liver dysfunction, C-Advanced liver dysfunction. The scoring system uses five clinical and laboratory criteria to classify patients: serum bilirubin, serum albumin, ascites, neuropathy (encephalopathy), and prothrombin time. Each of these criteria is defined using a numerical value that together defines the severity of cirrhosis.
・Child-Pugh A: 5-6 points ・Child-Pugh B: 7-9 points ・Child-Pugh C: 10-15 points

In accordance with the present invention, the subject has a Child-Pugh B cirrhosis score of 7 to 9, i.e., a Child-Pugh B (CPB) cirrhosis score of 7 (CPB7), a Child-Pugh B (CPB) cirrhosis score of 8 (CPB8), or a Child-Pugh B (CPB) cirrhosis score of 8 (CPB8) or a Child-Pugh It may be advanced hepatocellular carcinoma with a Pugh B (CPB) cirrhosis score of 9 (CPB9).

According to one embodiment of the invention, the subject is treated with an A3AR ligand as a second-line treatment, ie, the subject was previously treated with another anti-cancer drug and treatment failed. In other words, in some embodiments, a subject according to the invention is a patient with advanced HCC with a CPS7-CPS9 score who has failed other treatment regimens.

In one embodiment, the invention provides a method of prolonging overall survival of advanced HCC patients with a CPB7 score.

In certain embodiments, the prolongation is an prolongation of overall survival by 12 months or more.

As used herein, the term "A ₃ adenosine receptor (A ₃ AR) ligand" includes A ₃ AR agonists as well as A ₃ AR allosteric modulators.

A ₃ AR agonists are known in the art and readily available. In general, A ₃ AR agonists are capable of specifically binding to adenosine A ₃ receptors (“A ₃ R”), thereby fully or partially activating said receptor and producing therapeutic effects (e.g. any compound that provides an anti-arthritic effect). Therefore, A ₃ AR agonists are molecules that exert their primary effects through binding and activation of A ₃ AR. This means that at the dose being administered, _{it essentially binds and activates only A 3 R.}

In certain embodiments, the _A3AR agonist is less than 1000 nM, desirably less than 500 nM, advantageously less than 200 nM and less than 100 nM, typically less than 50 nM, preferably less than 20 nM, more preferably less than 10 nM and ideally It has a binding affinity (K _i ) for human A ₃ AR of less than 5 nM. The lower the K _i , the lower the dose of A ₃ AR agonist (which may be used) is effective to activate A ₃ R and achieve a therapeutic effect.

It should be noted that some A3AR agonists can also interact with and activate other receptors with lower affinity (ie, higher Ki). The molecule has an affinity for A ₃ R that is at least 3 times greater than its affinity for any other adenosine receptor (i.e. at least a 3 times lower Ki for A ₃ R), preferably 10 times, desirably 20 times lower. , most preferably at least 50 times greater, would be considered an A3AR agonist (ie, a molecule that exerts its primary effect via binding and activating A3R) in the context of the present invention.

The affinity of an A ₃ AR agonist for human A ₃ R, and its relative affinity for other human adenosine receptors, can be determined by a variety of assays, such as binding assays. Examples of binding assays include providing membranes or cells with receptors and measuring the ability of the A _AR agonist to displace bound radioactive agonist; utilizing cells displaying the respective human adenosine receptor; In functional assays, the ability of A _AR agonists to activate or inactivate downstream signaling events, such as effects on adenylate cyclase, as measured through increases or decreases in cAMP levels; Apparently, increasing the dose of an _A3AR agonist so that the blood concentration approaches the Ki of other adenosine receptors increases the activation of these receptors in addition to the activation of _A3Rs . It may occur after its administration. Accordingly, A ₃ AR agonists are preferably administered at doses such that the blood concentrations achieved result essentially only in activation of A ₃ R.

Characteristics of some adenosine _A3AR agonists and methods of their preparation are described, inter alia, in U.S. Patent No. 5,688,774; U.S. Patent No. 5,773,423; Patent No. 5,443,836; US Patent No. 6,048,865; International Publication No. 95/02604; International Publication No. 99/20284; International Publication No. 99/06053; International Publication No. 97/27173 , and WO 01/19360, all of which are incorporated herein by reference.

The following examples are from column 4, line 67 to column 6, line 16, column 5, lines 40-45, and column 6, lines 21-42 of U.S. Patent No. It is clearly stated in column 7, lines 1 to 11, column 7, lines 34 to 36, and column 7, lines 60 to 61:
N ⁶ -(3-iodobenzyl)-9-methyladenine;
N ⁶ -(3-iodobenzyl)-9-hydroxyethyladenine;
RN ⁶ -(3-iodobenzyl)-9-(2,3-dihydroxypropyl)adenine;
SN ⁶ -(3-iodobenzyl)-9-(2,3-dihydroxypropyl)adenine;
N ⁶ -(3-iodobenzyladenin-9-yl)acetic acid;
N ⁶ -(3-iodobenzyl)-9-(3-cyanopropyl)adenine;
2-chloro-N ⁶ -(3-iodobenzyl)-9-methyladenine;
2-amino-N ⁶ -(3-iodobenzyl)-9-methyladenine;
2-hydrazide-N ⁶ -(3-iodobenzyl)-9-methyladenine;
N ⁶ -(3-iodobenzyl)-2-methylamino-9-methyladenine;
2-dimethylamino-N ⁶ -(3-iodobenzyl)-9-methyladenine;
N ⁶ -(3-iodobenzyl)-9-methyl-2-propylaminoadenine;
2-hexylamino-N ⁶ -(3-iodobenzyl)-9-methyladenine;
N ⁶ -(3-iodobenzyl)-2-methoxy-9-methyladenine;
N ⁶ -(3-iodobenzyl)-9-methyl-2-methylthioadenine;
N ⁶ -(3-iodobenzyl)-9-methyl-2-(4-pyridylthio)adenine;
(1S,2R,3S,4R)-4-(6-amino-2-phenylethylamino-9H-purin-9-yl)cyclopentane-1,2,3-triol;
(1S,2R,3S,4R)-4-(6-amino-2-chloro-9H-purin-9-yl)cyclopentane-1,2,3-triol;
(±)-9-[2α,3α-dihydroxy-4β-(N-methylcarbamoyl)cyclopenten-1β-yl)]-N ⁶ -(3-iodobenzyl)-adenine;
2-chloro-9-(2'-amino-2',3'-dideoxy-β-D-5'-methyl-arabino-furonamide)-N ⁶ -(3-iodobenzyl)adenine;
2-chloro-9-(2',3'-dideoxy-2'-fluoro-β-D-5'-methyl-arabinofuronamide)-N ⁶ -(3-iodobenzyl)adenine;
9-(2-acetyl-3-deoxy-β-D-5-methyl-ribofuronamide)-2-chloro-N ⁶ (3-iodobenzyl)adenine;
2-chloro-9-(3-deoxy-2-methanesulfonyl-β-D-5-methyl-ribofuronamide)-N ⁶ -(3-iodobenzyl)adenine;
2-chloro-9-(3-deoxy-β-D-5-methyl-ribofuronamide)-N ⁶ -(3-iodobenzyl)adenine;
2-chloro-9-(3,5-1,1,3,3-tetraisopropyldisiloxyl-β-D-5-ribofuranosyl)-N ⁶ -(3-iodobenzyl)adenine;
2-chloro-9-(2',3'-O-thiocarbonyl-β-D-5-methyl-ribofuronamide)-N ⁶ -(3-iodobenzyl)adenine;
9-(2-phenoxythiocarbonyl-3-deoxy-β-D-5-methyl-ribofuronamide)-2-chloro-N ⁶ -(3-iodobenzyl)adenine;
1-(6-benzylamino-9H-purin-9-yl)-1-deoxy-N,4-dimethyl-β-D-ribofuranosiduronamide;
2-chloro-9-(2,3-dideoxy-β-D-5-methyl-ribofuronamide)-N ⁶ benzyladenine;
2-chloro-9-(2'-azido-2',3'-dideoxy-β-D-5'-methyl-arabino-furonamide)-N ⁶ -benzyladenine;
2-chloro-9-(β-D-erythrofuranoside)-N ⁶ -(3-iodobenzyl)adenine;
N ⁶ -(benzodioxanemethyl)adenosine;
1-(6-furfurylamino-9H-purin-9-yl)-1-deoxy-N-methyl-β-D-ribofuranosiduronamide;
N ⁶ -[3-(L-prolylamino)benzyl]adenosine-5'-N-methyluronamide;
N ⁶ -[3-(β-alanylamino)benzyl]adenosine-5′-N-methyluronamide;
N ⁶ -[3-(NT-Boc-β-alanylamino)benzyl]adenosine-5'-N-methyluronamide 6-(N'-phenylhydrazinyl)purine-9-β-ribofuranoside-5'-N-methyluronamide;
6-(O-phenylhydroxylamino)purine-9-β-ribofuranoside-5'-N-methyluronamide;
9-(β-D-2',3'-dideoxyerythrofuranosyl)-N ⁶ -[(3-β-alanylamino)benzyl]adenosine;
9-(β-D-erythrofuranoside)-2-methylamino-N ⁶ -(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.

The compounds specifically disclosed in column 6, line 39 to column 7, line 14 of US Patent No. 5,773,423 are compounds containing the following formula.

here,
X ₁ is R ^a R ^b NC(=O), where R ^a and R ^b may be the same or different, hydrogen, C ₁ -C ₁₀ alkyl, amino, C ₁ -C ₁₀ selected from the group consisting of haloalkyl, C ₁ -C ₁₀ aminoalkyl and C ₃ -C ₁₀ cycloalkyl;
R ₂ is selected from the group consisting of hydrogen, halo, C ₁ -C ₁₀ alkoxy, amino, C ₂ -C ₁₀ alkenyl, and C ₂ -C ₁₀ alkynyl; and
R ₅ is R- and S-1-phenylethyl, unsubstituted benzyl group, and C ₁ -C ₁₀ alkyl, amino, halo, C ₁ -C ₁₀ haloalkyl, nitro, hydroxy, acetamido, C ₁ -C ₁₀ alkoxy , and a benzyl group substituted at one or more positions with a substituent selected from the group consisting of , and sulfo.

As a more specific example of a compound, R ^a and R ^b may be the same or different, especially when R2 is hydrogen or halo, especially hydrogen, selected from the group consisting of hydrogen and C ₁ -C ₁₀ alkyl. The above formula is included.

More specific compounds and examples are those where R ^a is hydrogen and R ₂ is hydrogen, especially when R ₅ is unsubstituted benzyl.

More particular compounds are those where Rb is C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl, especially C ₁ -C ₁₀ alkyl, more particularly methyl.

Particularly specifically, R ^a is hydrogen, R ^b is C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl, and R ₅ is R- or S-1-phenylethyl or halo, amino, A compound which is benzyl substituted in one or more positions with a substituent selected from the group consisting of acetamido, C ₁ -C ₁₀ haloalkyl, and sulfo, and the sulfo derivative is a salt such as a triethylammonium salt.

An example of a particularly preferred compound disclosed in US Pat. No. 5,773,423 is IB-MECA. Furthermore, compounds in which R ₂ is C ₂ -C ₁₀ alkenylene of the formula R d -C=C-, where R ^d is C ₁ -C ₈ alkyl, are specifically described therein. More specific examples of compounds include compounds in which R ₂ is other than hydrogen, particularly R ₂ is halo, C ₁ -C ₁₀ alkylamino, or C ₁ -C ₁₀ alkylthio, and more preferably R 2 is hydrogen. In some cases, compounds are included where R ^b is C ₁ -C ₁₀ alkyl and/or R ₅ is substituted benzyl.

Examples of such specifically disclosed compounds include 2-chloro-N ⁶ -(3-iodobenzyl)-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine, N ⁶ -( 3-iodobenzyl)-2-methylamino-9-[5-(methylamide)-β-D-ribofuranosyl]-adenine, and N ⁶ -(3-iodobenzyl)-2-methylthio-9-[5-( methylamide)-β-D-ribofuranosyl]-adenine.

Further, in U.S. Pat. No. 5,773,423, column 7, line 60 and column 8, line 6, the A ₃ AR agonist is described as a modified xanthine-7-riboside having the formula: Disclosed.

here,
X is O;
R ₆ is R ^a R ^b NC(=O), where R ^a and R ^b may be the same or different, hydrogen, C ₁ -C ₁₀ alkyl, amino, C ₁ - selected from the group consisting of C ₁₀ haloalkyl, C ₁ -C ₁₀ aminoalkyl, and C ₃ -C ₁₀ cycloalkyl;
R ₇ and R ₈ may be the same or different and include C ₁ -C ₁₀ alkyl, R- and S-1-phenylethyl, unsubstituted benzyl group, and C ₁ -C ₁₀ alkyl, amino, halo , C ₁ -C ₁₀ haloalkyl, nitro, hydroxy, acetamido, C ₁ -C ₁₀ alkoxy, and sulfo. and R ₉ is selected from the group consisting of halo, benzyl, phenyl and C ₃ -C ₁₀ cycloalkyl.

WO 99/06053 discloses in Examples 19-33 compounds selected from:
N ⁶ -(4-biphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide;
N ⁶ -(2,4-dichlorobenzyl-carbonylamino)-adenosine-5'-N-ethyluronamide;
N ⁶ -(4-methoxyphenyl-carbonylamino)-adenosine-5'-N-ethyluronamide;
N ⁶ -(4-chlorophenyl-carbonylamino)-adenosine-5'-N-ethyluronamide;
N ⁶ -(phenyl-carbonylamino)-adenosine-5'-N-ethyluronamide;
N ⁶ -(benzylcarbamoylamino)-adenosine-5'-N-ethyluronamide;
N ⁶ -(4-sulfonamido-phenylcarbamoyl)-adenosine-5'-N-ethyluronamide;
N ⁶ -(4-acetyl-phenylcarbamoyl)-adenosine-5'-N-ethyluronamide;
N ⁶ -((R)-α-phenylethylcarbamoyl)-adenosine-5'-N-ethyluronamide;
N ⁶ -((S)-α-phenylethylcarbamoyl)-adenosine-5′-N-ethyluronamide;
N ⁶ -(5-methyl-isoxazol-3-yl-carbamoyl)-adenosine-5'-N-ethyluronamide;
N ⁶ -(1,3,4-thiadiazol-2-yl-carbamoyl)-adenosine-5'-N-ethyluronamide;
N ⁶ -(4-n-propoxy-phenylcarbamoyl)-adenosine-5'-N-ethyluronamide;
N ⁶ -bis-(4-nitrophenylcarbamoyl)-adenosine-5'-N-ethyluronamide; and N ⁶ -bis-(5-chloro-pyridin-2-yl-carbamoyl)-adenosine-5'-N -Ethyluronamide.

According to one embodiment of the invention, the _A3AR agonist is a compound that exerts its primary effect through the binding and activation of the adenosine _A3AR , and is a purine derivative within the scope of general formula (I). can be:

here,
-R ₁₁ represents alkyl, hydroxyalkyl, carboxyalkyl, cyanoalkyl, or a group of the following general formula (II):

here:
-Y represents oxygen, sulfur or _CH2 :
-X ₁₁ represents H, alkyl, R ^e R ^f NC(=O)- or HOR ^g -, where
-R ^e and R ^f may be the same or different and are selected from the group consisting of hydrogen, alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl, and cycloalkyl, or are bonded together to form 2 forming a heterocycle containing ~5 carbon atoms;
-Rg is selected from the group consisting of alkyl, amino, haloalkyl, aminoalkyl, BOC-aminoalkyl, and cycloalkyl;
-X ₁₂ is H, hydroxyl, alkylamino, alkylamido, or hydroxyalkyl;
-X ₁₃ and X ₁₄ are independently hydrogen, hydroxyl, amino, amide, azide, halo, alkyl, alkoxy, carboxy, nitrile, nitro, trifluoro, aryl, alkaryl, thio, thioester, thioether, -OCOPh, -OC (=S) represents OPh, or both X ₁₃ and X ₁₄ are oxygen connected to >C=S to form a 5-membered ring, or X ₁₂ and X ₁₃ form a ring of formula (III) death:

Here, R' and R'' independently represent an alkyl group;
-R ₁₂ is selected from the group consisting of hydrogen, halo, alkyl ether, amino, hydrazide, alkylamino, alkoxy, thioalkoxy, pyridylthio, alkenyl; alkynyl, thio, and alkylthio;
-R ₁₃ is a group of formula -NR ₁₅ R ₁₆ , where
-R ₁₅ is a hydrogen atom or a group selected from alkyl, substituted alkyl or aryl -NH-C(Z)-, Z is O, S or NR ^a , R ^e has the above meaning , where R ₁₅ is hydrogen,
R ₁₆ is an R- and S-1-phenylethyl group, benzyl group, phenylethyl group or anilide group, which in one or more positions is alkyl, amino, halo, haloalkyl, nitro, hydroxyl, acetamido, alkoxy, unsubstituted or substituted with a substituent selected from the group consisting of -BOC-β-alanylaminobenzyl, phenylamino, carbamoyl, phenoxy or cycloalkyl; or R ₁₆ is a group of the formula:

or when R ₁₅ is alkyl or aryl-NH-C(Z)-, R ₁₆ is heteroaryl-NRa-C(Z)-, heteroaryl-C(Z)-, alkaryl-NRa-C(Z) -, alkaryl-C(Z)-, aryl-NR-C(Z)- and aryl-C(Z)-; Z represents oxygen, sulfur or amine; or the physiological It is an acceptable salt.

According to one preferred embodiment, the A ₃ AR agonist is a nucleoside derivative of general formula (IV):

X ₁ , R ₂ ' and R ₅ are as defined above and are physiologically acceptable salts of said compound.

Acyclic carbohydrate groups (e.g. alkyl, alkenyl, alkynyl, alkoxy, aralkyl, alkaryl, alkylamines, etc.) forming part of the substituents of compounds of the invention are either branched or unbranched, preferably , containing 1 or 2 to 12 carbon atoms.

A particular group of A ₃ AR agonists are N ⁶ -benzyladenosine-5'-uronamide derivatives. Some preferred N ⁶ -benzyladenosine-5'-uronamide derivatives are N ⁶ -2-(4-aminophenyl)ethyladenosine (APNEA), N6-(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-β-D -ribofuranuronamide (IB-MECA) and 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA).

According to another embodiment, the A ₃ AR agonist is N ⁶ -benzyladenosine-5'-N-alkyluronamide-N1-oxide or N ⁶ -benzyladenosine-5'-N-dialkyluronamide-N1- It may be an oxide derivative of adenosine, such as an oxide, where the 2-purine position may be substituted with alkoxy, amino, alkenyl, alkynyl or halogen.

When referring to an " _A3AR allosteric modulator" or " _A3ARM ", we refer to positive receptor activity due to binding of the allosteric modulator at an allosteric site on the receptor that may be different from the endogenous ligand or agonist binding site. is understood to refer to the regulation, activation or increase of

In one example, "modulation" refers to an increase in the potency of an _A3 adenosine receptor by at least 15% by binding of a compound to an allosteric site of the receptor, and/or dissociation of adenosine or an _A3 AR agonist to an orthosteric binding site. Figure 3 shows the effect of A ₃ AR ligand on the receptor as indicated by a decrease in velocity.

In one example, the modulation is by the imidazoquinoline derivative A ₃ AR allosteric modulator (A ₃ ARAM).

In one example, A ₃ ARAM, an imidazoquinoline derivative, has the following general formula (V):

here:
-R ₁ is C ₁ -C ₁₀ alkyl, halo, C ₁ -C ₁₀ alkanol, hydroxyl, C ₁ -C ₁₀ acyl, C ₁ -C ₁₀ alkoxyl; C ₁ -C ₁₀ -alkoxycarbonyl, C ₁ -C ₁₀ alkoxyalkyl; C ₁ -C ₁₀ thioalkoxy; C ₁ -C ₁₀ alkyl ether, amino, hydrazide, C ₁ -C ₁₀ alkylamino, pyridylthio, C ₂ -C ₁₀ alkenyl; C ₂ -C ₁₀ alkynyl , thio, C ₁ -C ₁₀ alkylthio, acetamido, sulfonic acid; together may form a fused cycloalkyl or cycloalkenyl, the cycloalkyl or cycloalkenyl optionally containing one or more heteroatoms; provided that the aryl is not an unsubstituted phenyl group;
-R ₂ is hydrogen or C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl; C ₂ -C ₁₀ alkynyl, C ₄ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, 5-7 membered heterocycle Formula aromatic ring, C ₅ -C ₁₅ fused cycloalkyl, bicyclic aromatic ring or heterocycle; C ₁ -C ₁₀ alkyl ether, amino, hydrazide, C ₁ -C ₁₀ alkylamino, C ₁ -C ₁₀ alkoxy, C selected from the group consisting of ₁ -C ₁₀ alkoxycarbonyl, C ₁ -C ₁₀ alkanol, C ₁ -C ₁₀ acyl, C ₁ -C ₁₀ thioalkoxy, pyridylthio, thio, and C ₁ -C ₁₀ alkylthio, acetamido and sulfonic acid represents a substituent;
and its pharmaceutically acceptable salts.

According to some embodiments, the R ₁ substituent in A ₃ ARAM has the following general formula (VI).

where n is 0 or an integer selected from 1 to 5; preferably n is 0, 1 or 2; and - X ₁ and X ₂ which may be the same or different, Hydrogen is selected from halogen, alkyl, alkanol or alkoxy, indanyl, pyrroline, provided that when n is 0, X ₁ and X ₂ are not hydrogen.

In further examples, R ₁ of A ₃ ARAM is a substituent having formula (VI) above, where X ₁ or X ₂ may be the same or different, and hydrogen , chloro, methoxy, methanol, or a substituent having formula (VIa) or (VIb):

Here, Y is selected from N or CH.

In some further examples, R ₂ in A ₃ ARAM is selected from H, C _1-10 alkyl, C _4-10 cycloalkyl, and the alkyl chain may be straight or branched. Alternatively, a 4- to 7-membered cycloalkyl ring may be formed.

In one example, R ₂ of A ₃ ARAM is selected from a 5-7 membered heteroaromatic ring.

In some examples, the R ₂ substituent of A ₃ ARAM is selected from H, n-pentyl, or a 5-membered heteroaromatic ring having the following formula (VII):

Here, Z is selected from O, S or NH, preferably O.

According to one example, R ₂ of A ₃ ARAM comprises one or more fused rings, in particular to form a bicyclic substituent.

Non-limiting examples of bicyclic compounds that can be used to form substituents in the context of _A3 ARAM include bicyclo[2.2.1]heptane, bicyclo[4.1.0]heptane, bicyclo[4 .1.0] heptane-3-carboxylic acid, bicyclo[3.1.0]hexane-3-carboxylic acid, bicyclo[4.1.0]heptane-2-carboxylic acid, bicyclo[3.1.0] Examples include hexane-2-carboxylic acid and bicyclo[2.2.1]heptane-2-carboxylic acid.

According to some further examples, R ₂ of A ₃ ARAM is selected from two cyclohexene and 3-cyclohexene.

Specific imidazoquinoline derivatives that can be used as allosteric modulators of _A3AR are listed below:
N-(4-Methoxy-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]quinolin-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]indan)-2-cyclopentyl-1H-imidazo[4,5-c]quinoline-4-amine N-(1H-indazol-6-yl)-2-cyclopentyl-1H-imidazo[4 ,5-c]quinoline-4-amine N-(4-methoxy-benzyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinolin-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 have a reduced affinity, if any, for the orthosteric binding site of the A ₁ and A _2A , A _2B adenosine receptors, and a reduced affinity for the orthosteric binding site of the A3 adenosine receptor. , on the other hand, was shown to have a high affinity for the allosteric site of the A3 adenosine receptor [International Patent Application No. WO 07/089507, incorporated herein by reference] and is therefore considered an allosteric modulator.

A particularly preferred imidazoquinoline derivative according to the present disclosure is N-(3,4-dichloro-phenyl)-2-cyclohexyl-1H-imidazo[4,5-c]quinoline-4-amine (also referred to by the abbreviation LUF6000 or CF602). , A3AR allosteric modulator.

In the context of the general formulas disclosed herein, the following meanings for various terms should be considered.

The term "alkyl" is used herein to refer to a straight or branched hydrocarbon chain having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms; Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-heptyl, octyl, and the like.

Similarly, the terms "alkenyl" and "alkynyl" refer to linear or branched carbon atoms having 2 to 10 or 3 to 10 carbon atoms, more preferably 2 to 6 or 3 to 6 carbon atoms, respectively. Indicates a hydrogen chain, alkenyl or alkynyl having at least one unsaturated bond.

Alkyl, alkenyl or alkynyl substituents may be substituted with heteroatom-containing groups. Thus, although not explicitly stated, any of the alkyl modifications defined above and below, such as alkylthio, alkoxy, akanol, alkylamine, etc., may be replaced by akenylthio, akenyloxy, alkenol, alkenylamine, or, respectively, aquinylthio, It is to be understood that corresponding alkenyl or alkynyl modifications are also included, such as alkynyloxy, alkynol, alkynylamine.

The term "aryl" means an unsaturated aromatic carbocyclic group of 5 to 14 carbon atoms having a single ring (eg, phenyl) or multiple fused rings (eg, naphthyl or anthryl). Examples of preferred aryls include phenyl, indanyl, benzimidazole.

The term "alkaryl" preferably refers to an -alkylene-aryl group having 1 to 10 carbon atoms in the alkylene portion and 6 to 14 carbon atoms in the aryl portion. Such alkaryl groups are exemplified by benzyl, phenethyl, and the like.

The term "substituted aryl" means an aromatic moiety substituted with 1 to 3 substituents as defined above. A variety of substituents are possible, as will be understood by those skilled in the art. Nevertheless, examples of some preferred substituents include, but are not limited to, halogen, (substituted) amino, nitro, cyano, alkyl, alkoxy, acyloxy or alkanol, sulfonyl, sulfinyl.

The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo, preferably chloro.

The term "acyl" refers to the group H-C(O)- as well as alkyl-C(O)-.

The term "alkanol" refers to the groups -COH and alk-OH, where "alk" means an alkylene, alkenylene, or alkynylene chain.

The term "alkoxy" as used herein means -O-alkyl and includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, and the like.

The term "alkylthio" as used herein means -S-alkyl and includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and the like.

The term "alkoxyalkyl" as used herein means -alkyl-O-alkyl, including methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl, t-butoxymethyl Examples include, but are not limited to, methyl and the like.

The term "cycloalkyl" as used herein refers to a cyclic hydrocarbon radical and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

The term "alkoxycarbonyl" as used herein means -C(O)O-alkyl, and includes, but is not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and the like.

As used herein, the term "fused cycloalkyl" refers to cycloalkyls connected by a single atom (to form a spirocyclic moiety), by two interconnected atoms, or by a series of atoms (bridgehead). used to mean any compound or substituent containing at least two aliphatic rings. Fused rings can include bicyclic, tricyclic, and polycyclic moieties. According to some embodiments of the present disclosure, bicyclic substituents are preferred.

The present disclosure also utilizes physiologically acceptable salts of A ₃ AR selective ligands, such as the compounds described above. "Physiologically acceptable salts" means any non-toxic salt commonly used in the pharmaceutical industry, including sodium, potassium, lithium, calcium, magnesium, barium ammonium and protamine zinc salts. alkali metal, alkaline earth metal, and ammonium salts, which can be prepared by methods known in the art. 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 retain the biological effectiveness and qualitative properties of the free base and are not toxic or otherwise undesirable. Examples include acids derived from mineral acids, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc., among others. Organic acids include, in particular, tartaric acid, acetic acid, propionic acid, citric acid, malic acid, malonic acid, lactic acid, fumaric acid, benzoic acid, cinnamic acid, mandelic acid, glycolic acid, gluconic acid, pyruvic acid, salicylic acid succinate and Mention may be made of arylsulfonic acids such as p-toluenesulfonic acid.

The A ₃ AR ligand may be administered in a single dose (one dose) or continuously. In one example, A ₃ AR ligands are used for long-term therapy.

In the context of this disclosure, long-term treatment is to be understood to include a treatment period lasting at least a period of days, weeks, months, or years, until discontinuation due to intolerance, withdrawal of consent, or death, for example. . Although the treatment period is continuous, it may be divided into cycles (eg, 4 week cycles) for data recording. In one embodiment, A ₃ AR ligand is administered every 12 hours until discontinuation.

Additionally, in the context of some examples of this disclosure, long-term treatment refers to chronic treatment, e.g., long-term daily administration (once, twice a day) even when there is no envisioned endpoint of treatment. , or 3 times). In some examples, long-term treatment includes daily administration of A _AR ligand for at least one week, sometimes daily treatment for one month, sometimes at least 2, 3, 4, 5, 6, or 12 months. , sometimes comprising daily administration of the ligand for at least 1, 2, 3, 4, 5, 6 or more years.

In one embodiment, the treatment period is long-term treatment lasting at least one year.

The A ₃ AR ligand is administered in an amount sufficient to achieve a therapeutic anti-cancer effect. As will be appreciated, the amount of _A3AR ligand will depend on the severity of the disease, the intended treatment regimen, and the desired therapeutic dose. By way of example, if the dose is 50 mg per day and the desired dosing regimen is twice daily administration, the amount of active agent in the pharmaceutical composition is 25 mg.

The amount effective to achieve the desired effect is determined by considerations known in the art. An "effective amount" for purposes herein must be effective to achieve a therapeutic effect, as defined above.

The effective amount depends on various pharmacological parameters such as the selected _A3AR agonist's affinity for the _A3AR , biodistribution profile, half-life in the body, undesirable side effects, if any, and the age of the subject being treated. It is understood that it depends on various factors such as sex and sex. Effective amounts are typically tested in clinical trials aimed at finding an effective dose range, maximum tolerated dose, and optimal amount. Methods for conducting such clinical trials are well known to those skilled in the art of clinical development.

According to one embodiment of the invention, the administration of the A ₃ AR agonist is preferably daily administration once to several times a day, preferably once to twice a day, the dose in each administration being: It ranges from about 1 to about 1000 μg/kg body weight, preferably from 50 μg/kg to 10 mg/kg body weight, preferably from 100 μg/kg to 5 mg/kg body weight, or from 200 μg/kg to 1 mg/kg body weight.

In some embodiments, the A ₃ AR ligand is Cl-IB-MECA administered orally at a dose of 1-50 mg, preferably 5-30 mg twice daily.

In a specific embodiment, the advanced solid tumor is advanced HCC and the A ₃ AR agonist is Cl-IB-MECA (twice daily) at a dose of 25 mg administered orally every 12 hours.

The A ₃ AR agonist is formulated into a pharmaceutical composition. "Composition" in the context of the present invention is intended to mean a combination of the active agent, together or separately, with a pharmaceutically acceptable carrier and other excipients. The carrier may have effects such as improving the delivery or penetration of the active ingredient into the target tissue, improving the stability of the drug, slowing the clearance rate, imparting sustained release properties, and reducing undesirable side effects. There is. The carrier may also be a substance that stabilizes the formulation (eg, a preservative). For examples of carriers, stabilizers, and adjuvants, see E. W. See Martin, REMINGTON'S PHARMACEUTICAL SCIENCES, MacK Pub Co (June 1990).

The term "pharmaceutically acceptable carrier" in the context of the present invention means a carrier that does not react with the _A3AR agonist and can be added to the formulation as a diluent, carrier, or imparts form or consistency to the formulation. Refers to any one of the inert, non-toxic materials that can be used.

The compositions of the present invention are formulated according to 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, weight, and other factors known to health care professionals. Administered and medicated accordingly. The choice of carrier will be determined in part by the particular active ingredient, which will also be determined by the particular method used to administer the composition. Accordingly, suitable pharmaceutical compositions of the invention are diverse.

As mentioned above, therapeutic use of _A3AR agonists is sometimes combined with monoclonal antibodies (e.g., the antibodies atezolizumab alone or in combination with bevacizumab, or the VEGFR2 inhibitor ramucirumab, the anti-PD1 receptor monoclonal antibodies pembrolizumab and nivolumab alone or in combination with bevacizumab). It may be used in combination with other anticancer drugs, such as the CTLA-4 antibody ipilimumab), as well as multikinase inhibitors (eg, sorafenib, regorafenib, cabozantinib, lenvatinib). In such combination therapy, the other drug and the A ₃ AR agonist may be administered to the patient at the same time or at different times, depending on the administration schedule of each drug.

The invention has been described in an illustrative manner and the terminology used is to be understood to be intended to be descriptive rather than limiting. Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described below.

Study Participants The study population consisted of patients 18 years of age or older with advanced/refractory HCC and CPB cirrhosis who did not tolerate sorafenib or whose disease progressed on previous sorafenib treatment. HCC diagnosis in subjects without underlying cirrhosis at the time of diagnosis required cytology and/or histology. For subjects with an underlying disease of cirrhosis at the time of diagnosis, the clinical practice guideline algorithm of the American College of Hepatology [Marrero J. A. , et al. , Hepatology. 2018;68:723-750], the HCC diagnosis was confirmed. Subjects who tolerated sorafenib required at least 3 weeks of prior treatment, which was completed at least 2 weeks before study initiation. Inclusion criteria: ECOG PS≦2; CPB cirrhosis (i.e., CP score 7-9); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values ≤5 times the upper limit of normal (ULN). Total bilirubin 3.0 mg/dL or less; Serum albumin 2.8 g/dL or more; Prothrombin time (PT) less than 6 seconds longer than control; Serum creatinine 2.0 mg/dL or less; Absolute neutrophil count 1500 x 109/ L or more; platelet count 75,000 x 109/L or more. Exclusion criteria: presence or absence of hepatic encephalopathy; gastrointestinal bleeding requiring blood transfusion within 4 weeks.

Study Design and Treatment This study was a multicenter, randomized, double-blind, placebo-controlled clinical trial (ClinicalTrials.gov ID: NCT02128958). The study was conducted at 15 sites in Israel, Europe, and the United States.

Subjects were enrolled by participating sites and randomized in a 2:1 ratio using a central randomization schedule developed by an independent biostatistician, with no pre-randomization stratification. . Patients were randomly assigned to namodenoson (Cl-IB-MECA) 25 mg or matching placebo orally every 12 hours until discontinuation due to intolerance, withdrawal of consent, or death. Treatment was continuous, but the treatment period was divided into 4-week cycles for data recording. Initially, no crossover was observed, but due to a protocol amendment, patients who continued blinded treatment were offered namodenoson (25 mg twice daily) after being unassigned to treatment. Study site staff were blinded to patient treatment during the study period.

This study has been approved by the relevant national regulatory authorities and local ethics committees/institutional review boards. This study was conducted in accordance with the Declaration of Helsinki, and written informed consent was obtained from all patients.

Endpoint The primary endpoint of this study was overall survival (OS). Secondary endpoints were progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety. Similar to advanced HCC, PFS has been found to be moderately correlated with OS, making it a valid secondary endpoint in this disease [Llovet J. M. , et al. , J. Hepatol. 2019, 70:1262-1277]. Disease response evaluation was performed using RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1 [Eisenhauer E. A. , et al. Eur. J. Cancer. 2009;45:228-247] locally by two independent blinded radiologists. Tumor status was assessed by computed tomography or magnetic resonance imaging at baseline and every 8 weeks thereafter. Safety was monitored through evaluation of AEs using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Changes from baseline in vital signs, laboratory parameters, electrocardiogram, physical examination, and ECOG PS were also evaluated. AFP levels were assessed at baseline and every 4 weeks thereafter, as were laboratory parameters related to liver dysfunction and cirrhosis, including serum ALT, AST, bilirubin, albumin levels, PT, and international sensitivity ratio. ALBI scores were calculated from albumin and bilirubin levels as previously described [Johnson P. J. , et al. J. Clin. Oncol. 2015;33:550-558].

Biomarker Testing Another secondary objective was to measure white blood cell (WBC) _A3AR expression (which represents HCC tumor cell [Bar-Yehuda S., et al. Int. J. Oncol. 2008; 33:287-295]) and clinical response. . _A3AR mRNA expression in WBC was measured from blood collected into PAX gene RNA tubes (Qiagen, Venlo, The Netherlands) using the QuantiGene Plex 2.0® assay (Thermo Fisher, Waltham, MA, USA). . Oligonucleotide probe sets were designed by Thermo Fisher using β-actin as a control. Luminescence from each specific probe set was captured on a GloMax Multi (Promega, Madison, Wis., USA). A ₃ AR was expressed in units, with 1 unit defined as the average A ₃ AR expression in healthy subjects (n=50). The healthy subjects were between 20 and 70 years old and had no known disease or treatment history.

Statistical Analysis In calculating the power, it was determined that the log-rank test would have 80% power at a significance level of 0.05 for 75 deaths assuming a hazard ratio of 0.5. The primary efficacy analysis was performed in the ITT population. Descriptive statistics were used to summarize patient/tumor characteristics and safety. A Kaplan-Meier curve was used to estimate OS/PFS, and a log-rank test was used for comparison. Cox proportional hazards regression model was used to assess the influence of covariates. ORR/DCR was determined by treatment using the normal approximation of the binomial distribution. The statistical analysis plan was modified before unblinding to include subgroup analysis by CP score. All statistical tests were two-tailed, and p<0.05 was considered statistically significant. Statistical analyzes were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

Example 1
In a phase II blinded, randomized, placebo-controlled trial, the dose of namodenoson evaluated was 25 mg BID orally (twice daily) in patients with advanced hepatocellular carcinoma (HCC) who received namodenoson as second-line treatment. and 78 patients with CPB liver cirrhosis. Patients were randomized 2:1 to namodenoson 25 mg BID (n=50) or placebo (n=28).

No treatment-related deaths were reported. Additionally, no patients dropped out of the study and no dose reductions were observed with namodenoson. Importantly, no hepatotoxicity was reported, and liver function tests showed no adverse events associated with namodenoson. Mean serum albumin levels and albumin-bilirubin (ALBI) scores also did not change significantly in both groups during the study period. Only one grade 3 treatment-related AE was reported (hyponatremia).

Analysis of initial results Regarding antitumor efficacy, the primary endpoint of OS superiority over placebo was not met. Median OS was 4.1 months with namodenoson and 4.3 months with placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI] 0.49-1.38; p=0. 46). Similarly, no superiority was observed in terms of progression-free survival (PFS). Among the CBP patients included in this study, patients with a Child-Pugh score of 7 (the least severe liver dysfunction in the CPB classification) were the most common group (34 patients in the namodenoson group, 22 patients in the placebo group). given name). A pre-planned analysis evaluating patients by Child-Pugh score found no significant difference in OS and PFS for patients with a Child-Pugh score of 7. In this subcategory, median OS was 6.9 months in the namodenoson group and 4.3 months in the placebo group (HR, 0.81; 95% CI 0.45-1.43; p=0. 46). Median PFS was 3.5 months vs. 1.9 months (HR, 0.89; 95% CI 0.51-1.55; p=0.67). In patients with a Child-Pugh score of 8 (13 patients, 7 in the namodenoson group and 6 in the placebo group), OS and PFS were similar between the namodenoson and placebo groups, and the reported subgroup of Child-Pugh scores of 7 (OS: 3.3 months vs. 3.4 months, HR 0.88, 95% CI 0.28-2.77, p=0.83 for namodenoson and placebo groups, respectively. PFS : 2.1 months vs. 1.9 months, respectively, HR: 0.71, 95% CI: 0.23-2.17, p = 0.53). Median OS and PFS for the nine patients with a Child-Pugh score of 9 (all in the namodenoson group) were 3.5 months and 2.2 months, respectively, similar to those with a Child-Pugh score of 8. OS by treatment group and stratification by gender, alpha-fetoprotein level, Eastern Cooperative Oncology Group (ECOG) performance status (PS), HPB, HPC status, local therapy, extrahepatic spread status, and portal vein thrombosis status. An exploratory analysis comparing the results showed no statistically significant differences between study arms in any subgroup, which may be due to relatively small sample sizes in some groups. There is sex.

Analysis of long-term treatment. However, in contrast to the initial results, the difference in OS rates at 12 months was statistically significant (44% and 18% in the namodenoson and placebo groups, respectively, p=0.028) (Figure 1).

As a result of analyzing the responses of all patients who were able to undergo at least one post-baseline evaluation (55 patients, 34 receiving namodenoson, 21 receiving placebo), there was one CR in the namodenoson group, and a PR in the namodenoson group. There were 3 patients (9%) and none in the placebo group (see Table 1). The duration of response for the three patients who achieved PR was 2 months, 6 months, and 26 months.

As shown in Table 1 above, one patient showed a complete response. This patient received five years of treatment in an open-label extension program of a Phase II trial of namodenoson in hepatocellular carcinoma (HCC) and achieved a complete response, meaning all cancer lesions had disappeared, on namodenoson. I experienced (CR).

A patient with advanced metastatic HCC with underlying Child Pugh B7 (CPB7) cirrhosis has now survived for 5 years with treatment with namodenoson (25 mg orally twice daily). Scans of the patient's chest, abdomen, and pelvis showed clinical treatment effects, including disappearance of ascites, normal liver function, disappearance of peritoneal carcinomatosis, and complete disappearance of cancer lesions. It is shown that there is.

Claims (21)

A pharmaceutical composition comprising an _A3AR ligand and a pharmaceutically acceptable carrier or diluent, said pharmaceutical composition for treating an advanced solid tumor in a mammalian subject. thing. The pharmaceutical composition according to claim 1, wherein the advanced solid tumor is advanced hepatocellular carcinoma. The pharmaceutical composition according to claim 2, for treating metastatic hepatocellular carcinoma. Pharmaceutical composition according to any one of claims 1 to 3, wherein the A ₃ AR ligand is an A ₃ AR agonist or an A ₃ AR allosteric modulator. The A ₃ AR agonists include N ⁶ -2-(4-aminophenyl)ethyladenosine (APNEA), N ⁶ -(4-amino-3-iodobenzyl)adenosine-5'-(N-methyluronamide) (AB- MECA), N ⁶ -(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and 2-chloro-N ⁶ -(3-iodobenzyl)-adenosine-5'-N-methyluronamide ( 5. The pharmaceutical composition according to claim 4, selected from the group consisting of Cl-IB-MECA). The A ₃ AR allosteric modulator is:
N-(3,4-dichlorophenyl)-2-cyclopentyl-1H-imidazo[4,5-c]quinolin-4-amine;
N-(3,4-dichlorophenyl)-2-cycloheptyl-1H-imidazo[4,5-c]quinolin-4-amine;
N-(3,4-dichlorophenyl)-2-cyclobutyl-1H-imidazo[4,5-c]quinolin-4-amine; and N-(3,4-dichlorophenyl)-2-cyclohexyl-1H-imidazo[4 , 5-c] quinolin-4-amine. A pharmaceutical composition according to any one of claims 1 to 6, in combination with an additional therapeutic agent. 8. A pharmaceutical composition according to claim 7, wherein the additional therapeutic agent is an anticancer drug, such as a monoclonal antibody and/or a multikinase inhibitor. The subject has advanced liver disease 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). The pharmaceutical composition according to any one of claims 2 to 8, which is a cell cancer. A pharmaceutical composition according to any one of claims 1 to 9, wherein the A ₃ AR ligand is administered once a day, twice a day, or three times a day. A pharmaceutical composition according to any one of claims 1 to 10, wherein the A ₃ AR ligand is administered every 12 hours throughout the treatment period. 12. The pharmaceutical composition of claim 11, wherein the _A3AR ligand is administered continuously. 13. A pharmaceutical composition according to any one of claims 11 or 12, wherein the treatment period is divided into cycles (eg 4 week cycles). 14. A pharmaceutical composition according to any one of claims 1 to 13, wherein the mammalian subject is a human subject. Any one of claims 1 to 14, wherein the A3AR ligand is administered in an amount of 50 μg/kg to 10 mg/kg body weight, preferably 100 μg/kg to 5 mg/Kg body weight, or 200 μg/kg to 1 mg/Kg body weight. The pharmaceutical composition described in section. 16. Any one of claims 1 to 15, wherein the A ₃ AR ligand is Cl-IB-MECA, and the Cl-IB-MECA is orally administered twice a day at a dose of 1 to 50 mg, preferably 5 to 30 mg. The pharmaceutical composition described in section. A pharmaceutical composition comprising an A ₃ AR ligand (e.g., Cl-IB-MECA) and a pharmaceutically acceptable carrier or diluent, wherein the pharmaceutical composition is used to treat a subject with advanced HCC and a CPB7 score. A pharmaceutical composition for increasing overall survival. Said increase in overall survival is measured after a treatment period of 12 months or more, said treatment comprising a dose of said A ₃ AR ligand (eg Cl-IB-MECA) of 1 to 50 mg, preferably 5 to 30 mg. 18. A pharmaceutical composition according to claim 17, comprising oral administration twice a day. A pharmaceutical composition according to any one of claims 1 to 18, wherein the subject received an A ₃ AR ligand as a second line therapy. 20. According to any one of claims 1 to 19, the administration is for a treatment period of at least 9 months, at least 10 months, at least 1 year, at least 2 years, at least 3 years, at least 4 years or at least 5 years. Pharmaceutical composition. (a) a pharmaceutical composition comprising an A ₃ AR ligand according to any one of claims 1 to 20; and (b) for the administration of a pharmaceutical composition for the treatment of a subject having an advanced solid tumor. Kit containing instructions.

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