Therapeutic combination

Abstract

The present invention relates to a combination comprising a PSMA binding compound and a MEK inhibitor, wherein said PSMA binding compound and said MEK inhibitor are as defined herein, kits and medicaments comprising them, and their use in treating, preventing, ameliorating, controlling or reducing the risk of disorders associated with PSMA and / or MEK, including cancer, particularly prostate cancer.

Description

[0001] THERAPEUTIC COMBINATION

[0002] The present invention relates to a therapeutically useful combination of compounds, which may be useful in a variety of therapeutic areas associated with elevated expression of prostate-specific membrane antigen (PSMA), including the treatment and / or diagnosis of various cancers, such as prostate cancer. Suitably, the present invention relates to a therapeutically useful combination of compounds comprising: (i) a compound that binds to prostate-specific membrane antigen (hereinafter which may be referred to as a PSMA binding compound); and, (ii) a compound that inhibits the mitogen-activated protein kinase kinase enzyme MEK (hereinafter which may be referred to as a MEK inhibitor), for example a MEK- 1 inhibitor, MEK-2 inhibitor or a combination thereof. Suitably, the present invention further relates to therapeutic medicament(s) comprising the combination of (i) said PSMA binding compound and (ii) said MEK inhibitor; and, a kit of parts comprising (i) said PSMA binding compound and (ii) said MEK inhibitor. Suitably, the combination of compounds comprising (i) said PSMA binding compound and (ii) said MEK inhibitor, the therapeutic medicament(s) including said combination of compounds (i) and (ii), and the kit(s) including said combination of compounds (i) and (ii), may each be useful in treating (including prophylactic and curative treatment), preventing, ameliorating, controlling or reducing the risk of disorders associated with elevated expression of PSMA and / or MEK, including cancer, such as prostate cancer.

[0003] BACKGROUND OF THE INVENTION

[0004] Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is typically highly overexpressed on prostate cancer epithelial cells. Despite its name, PSMA is also expressed, to varying degrees, in the neovasculature of a wide variety of non-prostate cancers. Common non-prostate cancers to demonstrate PSMA expression include breast lung, colorectal and renal carcinoma.

[0005] Prostate Cancer (PCa) remains a common malignant disease in men with high incidence for poor survival rates. Due to its overexpression in prostate cancer (Silver et al., Clinical Cancer Research 3, 81-85 (1997)), PSMA represents an excellent target for the development of highly sensitive radiolabelled agents for endoradiotherapy and imaging of PCa (Afshar-Oromieh et al., European journal of nuclear medicine and molecular imaging 42, 197-209 (2015); Benesova et al., Journal of Nuclear Medicine 56, 914-920 (2015); Robu et al., Journal of Nuclear Medicine, 116.178939 (2016); Weineisen etal.; Journal of Nuclear Medicine 55, 1083- 1083 (2014); Rowe et al., Prostate cancer and prostatic diseases (2016); Maurer et al., Nature Reviews Urology (2016)). PSMA is an extracellular hydrolase whose catalytic centre comprises two zinc (II) ions with a bridging hydroxido ligand. It is highly upregulated in metastatic and hormone-refractory prostate carcinomas, but its physiologic expression has also been reported in kidneys, salivary glands, small intestine, brain and, to a low extent, also in healthy prostate tissue. In the intestine, PSMA facilitates absorption of folate by conversion of pteroylpoly-y-glutamate to pteroylglutamate (folate). In the brain, it hydrolyses N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and glutamate.

[0006] PSMA-targeted radioligand therapy (PSMA-RLT), has been demonstrated with177Lu-PSMA- 617, for example, which has typically been shown to extend progression-free and overall survival for men with metastatic castration-resistant prostate cancer (mCRPC) (Sartor O, et al. NEJM. 2021 ; 385: 1091-1103).177Lu-rhPSMA-10.1 is a PSMA-RLT agent which typically exhibits low kidney uptake, rapid blood clearance, and high accumulation in tumors (Wurzer A, et al. J Nucl Med. 2022; 63: 1489-1495).177Lu-rhPSMA-10.1 also typically demonstrates effective suppression of tumor growth in vivo (Foxton C, et al. J Nucl Med. 2022; 63(Suppl 2): abstract 2567), and promising efficacy in a patient with mCRPC (Bundschuh RA, et al. Clin Nucl Med. 2023; 48(4): 337-338). Other PSMA binding (PSMA radiohybrid (rh)) compounds are disclosed in WO2019 / 020831 , WO2020 / 157177, WO2020 / 157184, WO2022 / 144467, WO2022 / 144463 and W02022 / 171901. Whilst PSMA-RLT has typically been demonstrated to improve progression free survival of men with mCRPC, approaches that further improve the efficacy of such agents are desirable.

[0007] The RAS-RAF-MEK-ERK signalling pathway is activated in many human tumors, mediating tumor growth, progression, and metastasis, and is therefore an attractive therapeutic target (Solit DB, et al. Nature 2006; 439: 358-362; Sebolt-Leopold JS, et al. Nat Rev Cancer 2004; 4: 937-947). Although MEK itself is not an oncogene product, it is the focus of many of the signal transduction pathways activated by known oncogenes (including BRAF and KRAS mutations) and tyrosine kinase receptors (Ji H, et al. Cancer Res. 2007; 67: 4933-4939). Thus, inhibition of MEK has the potential to prevent the subsequent downstream phosphorylation and activation of MAP kinase (to pMAPK / pERK) and consequently induce tumor regression and / or stasis in some contexts. MEK inhibitors approved for clinical use include Binimetinib (used for treating melanoma), Cobimetinib (used for treating melanoma), Selumetinib (used for treating neurofibromatosis type 1) and Trametinib (used for treating melanoma). Other MEK inhibitors in clinical development include Refametinib (BAY86-9766), WX-554, mirdametinib (PD-0325901), FCN-159, Pimasertib, CS3006, ARRY-300, Tunlametinib (HL-085), TAK-733, and MSC2015103B. Suitably, a MEK inhibitor has not been used to treat cancer associated with an overexpression of PSMA, for example prostate cancer. It has been found that a combination of compounds comprising: (i) a PSMA binding compound, as defined herein, and (ii) a MEK inhibitor, as defined herein, may provide benefits for the treatment of cancer, suitably the treatment of prostate cancer. Suitably, it has been found that when (i) a PSMA binding compound, as defined herein, is used in combination with (ii) a MEK inhibitor, as defined herein, the combination of compounds may provide a synergistic beneficial effect (i.e. synergistic enhancement in therapeutic efficacy) for use in the treatment of cancer, suitably for the treatment of prostate cancer, as compared to the expected cumulative therapeutic efficacy which would be attributable from the combined use when considering the therapeutic efficacy for each compound (i) and (ii) alone.

[0008] SUMMARY OF THE INVENTION

[0009] According to a first aspect, the present invention provides a combination of compounds comprising (i) a compound that is capable of binding to prostate-specific membrane antigen (hereinafter which may be referred to as a PSMA binding compound), as defined herein; and, (ii) a compound that inhibits the mitogen-activated protein kinase kinase enzyme MEK (hereinafter which may be referred to as a MEK inhibitor) as defined herein, wherein the PSMA binding compound comprises:

[0010] (a) one or more ligand(s) which are capable of binding to PSMA; and

[0011] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation.

[0012] According to a second aspect, the present invention provides a combination of compounds (i) and (ii), as defined in the first aspect, for use in medicine. Suitably, the combination of compounds (i) and (ii), as defined in the first aspect, may be useful in the treatment of cancer, suitably in the treatment of prostate cancer, suitably in the treatment of hormone sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0013] According to a third aspect, the present invention provides a therapeutic medicament comprising the combination of compounds (i) and (ii), as defined in the first aspect, for use in medicine. Suitably, the therapeutic medicament may be useful in the treatment of cancer, suitably in the treatment of prostate cancer, suitably in the treatment of hormone sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC. According to a fourth aspect, the present invention provides a kit of parts comprising (i) a PSMA binding compound, as defined in the first aspect, and a separate (ii) MEK inhibitor, as defined in the first aspect. Suitably, the kit of parts may be useful in the treatment of cancer, suitably in the treatment of prostate cancer, suitably in the treatment of hormone sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0014] Suitably, the combination of compounds (i) and (ii) of the first aspect, the therapeutic medicament of the third aspect, and the kit of parts of the fourth aspect may each be useful in treating (including prophylactic and curative treatment), preventing, ameliorating, controlling or reducing the risk of disorders associated with an elevated expression of PSMA, MEK or a combination of an elevated expression of both PSMA and MEK.

[0015] Suitably, the combination of compounds (i) and (ii) of the first aspect, the therapeutic medicament of the third aspect, and the kit of parts of the fourth aspect may each be useful in the treatment of non-prostate cancer, such as salivary gland cancers, thyroid cancer, hepatocellular cancer, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma.

[0016] According to a fifth aspect, there is provided a method of treating cancer which comprises administering a therapeutically effective amount of either the combination of compounds (i) and (ii) of the first aspect, the therapeutic medicament of the third aspect, or the kit of parts of the fourth aspect to a patient in need thereof. Suitably, the cancer is prostate cancer. Suitably, the prostate cancer is hormone sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0017] According to a sixth aspect, there is provided a method of treating cancer which comprises administering a therapeutically effective amount of either the combination of compounds (i) and (ii) of the first aspect, the therapeutic medicament of the third aspect, or the kit of parts of the fourth aspect to a patient in need thereof, wherein the cancer is selected from salivary gland cancer, thyroid cancer, hepatocellular cancer, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma.

[0018] Suitably, the therapeutic administration of either the combination of compounds (i) and (ii) of the first aspect, the therapeutic medicament of the third aspect, or the kit of parts of the fourth aspect to a patient in need thereof typically provides a synergistic enhancement in therapeutic efficacy in the treatment of cancer, suitably the treatment of prostate cancer, as compared to the expected cumulative therapeutic efficacy which would be attributable from the combined use when considering the therapeutic efficacy for each compound (i) and (ii) alone.

[0019] Suitably, the therapeutic administration of either the combination of compounds (i) and (ii) of the first aspect, the therapeutic medicament of the third aspect, or the kit of parts of the fourth aspect to a patient in need thereof may increase potency of either (i) the PSMA binding compound or (ii) the MEK inhibitor or (iii) both the MEK inhibitor and PSMA binding compound for the treatment cancer.

[0020] Suitably, in each aspect of the invention, the (a) one or more ligand(s) of the PSMA binding compound (i) which is capable of binding to PSMA comprises the structure represented by formula (1):

[0021] Suitably, the PSMA binding compound (i), as defined in each aspect of the invention, further comprises (c) a silicon-fluoride acceptor (SI FA) moiety, as defined herein, which comprises a covalent bond between a silicon and fluorine atom.

[0022] Suitably, the silicon-fluoride acceptor (SI FA) moiety (c), when present, comprises the structure represented by formula (2):

[0023] Suitably, the fluorine atom of the silicon fluoride acceptor (SI FA) moiety, as defined herein, may be exchanged with18F. Suitably, the fluorine atom of the silicon fluoride acceptor (SI FA) moiety is19F for therapeutic applications disclosed herein.

[0024] Suitably, in each aspect of the invention, the one or more chelating group(s) of the PSMA binding compound (i), as defined herein, comprises a residue of a chelating agent selected from 1 ,4,7,10-tetracyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), a-(2-carboxyethyl)- 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTAGA) and 1 ,4,7- triazacyclononane-1 ,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP).

[0025] Suitably, in each aspect of the invention, the one or more chelating group(s), as defined herein, contains a chelated radioactive metal cation. Suitably, the chelated radioactive metal cation is selected from Sc3+, Cu3+, Ga3+, Y3+, ln3+, Tb3+, Ho3+, Lu3+, Re3+, Pb3+, Bi3+, Ac3+, Er3+and Th3+. Suitably, the radioactive metal cation is selected from64Cu3+,67Cu3+,149Tb3+,152Tb3+,155Tb3+,161Tb3+,225Ac3+,68Ga3+and177Lu3+. Suitably, the radioactive metal cation is177Lu3+or225Ac3+, preferably177Lu3+.

[0026] Suitably, in each aspect of the invention, the PSMA binding compound (i) is selected from: or a pharmaceutically acceptable salt thereof, wherein M3+is a chelated radioactive metal cation, as defined herein. Suitably, M3+is177Lu3+or225Ac3+, preferably177Lu3+.

[0027] Suitably, in each aspect of the invention, the PSMA binding compound (i) is selected from:

[0028] and pharmaceutically acceptable salts thereof, wherein M3+is a chelated radioactive metal cation, as defined herein. Suitably, M3+is177Lu3+or225Ac3+, preferably177Lu3+.

[0029] In an embodiment, in each aspect of the invention, the PSMA binding compound (i) is: or a pharmaceutically acceptable salt thereof. Suitably, in each aspect of the invention, the MEK inhibitor (ii) comprises a MEK-1 inhibitor, a MEK-2 inhibitor, or a combination of a MEK-1 and MEK-2 inhibitor.

[0030] Suitably, in each aspect of the invention, the MEK inhibitor (ii) is selected from: or a pharmaceutically acceptable salt thereof.

[0031] According to an embodiment, in each aspect of the invention, the MEK inhibitor (ii) is: or a pharmaceutically acceptable salt thereof.

[0032] According to a preferred embodiment, in each aspect of the invention, the PSMA binding compound (i) is: or a pharmaceutically acceptable salt thereof; and, the MEK inhibitor (ii) is: or a pharmaceutically acceptable salt thereof.

[0033] DETAILED DESCRIPTION OF THE INVENTION

[0034] It will be understood that the preferred features of each aspect of the invention are regarded as preferred features of every other aspect of the invention. Accordingly, preferred and more preferred features of one aspect of the invention may be independently combined with other preferred and / or more preferred features of the same aspect or different aspects of the invention.

[0035] Further, it will be understood that any upper and lower quantity, range, ratio limits set forth herein may be independently combined.

[0036] The present invention relates to novel combination of compounds, kits and medicaments comprising said combination of compounds. The invention also relates to the use of said novel combination of compounds, said kits and medicaments containing the same in medicine and in particular in the treatment of cancer. The invention further relates to said combinations of compounds, said kits and medicaments containing the same for use in treating, preventing, ameliorating, controlling or reducing the risk of diseases or disorders associated with PSMA, MEK or a combination of PSMA and MEK. The invention further relates to said combination of compounds, said medicaments and kits containing the same for use in the treatment of cancers in which PSMA is overexpressed. The invention further relates to said combination of compounds, said medicaments and kits containing the same for use in the treatment of prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular cancer, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma. The prostate cancer may be hormone sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0037] The present invention relates to a combination of compounds comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein the PSMA binding compound comprises:

[0038] (a) one or more ligand(s) which are capable of binding to PSMA; and

[0039] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation.

[0040] Also provided are medicaments and kits comprising a PSMA binding compound and a MEK inhibitor.

[0041] In the combinations, medicaments and kits herein, the PSMA binding compound may further comprise:

[0042] (c) a silicon-fluoride acceptor (SI FA) moiety which comprises a covalent bond between a silicon and a fluorine atom.

[0043] Accordingly, also provided is a combination of compounds comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein said PSMA binding compound is a compound comprising:

[0044] (a) one or more ligand(s) which are capable of binding to PSMA;

[0045] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation; and

[0046] (c) a silicon-fluoride acceptor (SI FA) moiety which comprises a covalent bond between a silicon and a fluorine atom.

[0047] Also provided is a kit of parts comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein the PSMA binding compound comprises:

[0048] (a) one or more ligand(s) which are capable of binding to PSMA; and

[0049] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation. Also provided is a kit of parts comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein the PSMA binding compound comprises:

[0050] (a) one or more ligand(s) which are capable of binding to PSMA;

[0051] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation; and

[0052] (c) a silicon-fluoride acceptor (SI FA) moiety which comprises a covalent bond between a silicon and a fluorine atom.

[0053] Suitably, the PSMA binding compound (i) is a separate physical entity to the MEK inhibitor (ii) in the kit of parts.

[0054] In the combinations, medicaments and kits herein, the PSMA binding compound may be a compound of formula (3):

[0055] PSMA— L— CG(3);or a pharmaceutically acceptable salt thereof, wherein;

[0056] PSMA represents a ligand which is capable of binding to PSMA;

[0057] L represents an optionally substituted linker group; and

[0058] CG represents a chelating group containing a chelated radioactive metal cation.

[0059] In the combinations, medicaments and kits herein, the PSMA binding compound may be a compound of formula (3’):

[0060] PSMA— L— CG(3>);or a pharmaceutically acceptable salt thereof, wherein;

[0061] PSMA represents a ligand which is capable of binding to PSMA;

[0062] L represents an optionally substituted linker group comprising a silicon-fluoride acceptor (SI FA) moiety which comprises a covalent bond between a silicon and a fluorine atom; and CG represents a chelating group containing a chelated radioactive metal cation.

[0063] In the combinations, medicaments and kits herein, the ligand which is capable of binding to PSMA may comprise any structure, moiety or functional group which is capable of binding to PSMA.

[0064] In the combinations, medicaments and kits herein, the ligand which is capable of binding to PSMA may comprise the structure represented by formula (1’): wherein p is 1 to 6.

[0065] Preferably, p in formula (1’) is 2. Suitably, the ligand which is capable of binding to PSMA is attached to the remainder of the PSMA binding compound via the bond marked by in formula (1’), and formula (1) hereinafter. Suitably, the ligand which is capable of binding to PSMA is attached to the linker group L of the compound of formula (3) and (3’).

[0066] In the combinations, medicaments and kits herein, the ligand which is capable of binding to PSMA may comprise the structure represented by formula (1):

[0067] In the combinations, medicaments and kits herein, the PSMA binding compound may be a compound of formula (1a): or a pharmaceutically acceptable salt thereof, wherein;

[0068] L represents an optionally substituted linker group, preferably L represents an optionally substituted linker group comprising a silicon-fluoride acceptor (SI FA) moiety which comprises a covalent bond between a silicon and a fluorine atom; and

[0069] CG represents a chelating group containing a chelated radioactive metal cation.

[0070] In the combinations, medicaments and kits herein, the chelating group may comprise at least one of the following (i), (ii) or (iii):

[0071] (i) A macrocyclic ring structure with 8 to 20 ring atoms of which 2 or more, more preferably 3 or more, are selected from oxygen atoms or nitrogen atoms. Preferably, 6 or less ring atoms are selected from oxygen atoms or nitrogen atoms. Especially preferred is that 3 or 4 ring atoms are nitrogen atoms or oxygen atoms. Among the oxygen and nitrogen atoms, preference is given to the nitrogen atoms. In combination with the macrocyclic ring structure, the preferred chelating group may comprise 2 or more, such as 2 to 6, preferably 2 to 4, carboxyl groups and / or hydroxyl groups. Among the carboxyl groups and the hydroxyl groups, preference is given to the carboxyl groups.

[0072] (ii) An acyclic, open chain chelating structure with 8 to 20 main chain (back bone) atoms of which 2 or more, more preferably 3 or more are heteroatoms selected from oxygen atoms or nitrogen atoms. Preferably, 6 or less back bone atoms are selected from oxygen atoms or nitrogen atoms. Among the oxygen and nitrogen atoms, preference is given to the nitrogen atoms. More preferably, the open chain chelating structure is a structure which comprises a combination of 2 or more, more preferably 3 or more heteroatoms selected from oxygen atoms or nitrogen atoms, and 2 or more, such as 2 to 6, preferably 2 to 4, carboxyl groups and / or hydroxyl groups. Among the carboxyl groups and the hydroxyl groups, preference is given to the carboxyl groups.

[0073] (iii) A branched chelating structure containing a quaternary carbon atom. Preferably the quaternary carbon atom is substituted with 3 identical chelating groups in addition to the SIFA / ligand moiety. The substituted chelating groups can comprise an amide. The substituted chelating groups can comprise an aromatic group. The substituted chelating groups can comprise a hydroxypyridinone.

[0074] In the combinations, medicaments and kits herein, the chelating group may comprise at least one of:

[0075] (i) a macrocyclic ring structure with 8 to 20 ring atoms of which 2 or more are heteroatoms selected from oxygen atoms and nitrogen atoms;

[0076] (ii) an acyclic, open chain chelating structure with 8 to 20 main chain atoms of which 2 or more are heteroatoms selected from oxygen atoms and nitrogen atoms; or

[0077] (iii) a branched chelating structure containing a quaternary carbon atom.

[0078] In the combinations, medicaments and kits herein, the chelating group may comprise a residue of a chelating agent selected from bis(carboxymethyl)-1 ,4,8,11- tetraazabicyclo[6.6.2]hexadecane (CBTE2a), cyclohexyl-1 ,2-diaminetetraacetic acid (CDTA), 4-(1 ,4,8,11 -tetraazacyclotetradec- 1-yl)-methylbenzoic acid (CPTA), N'-[5-

[0079] [acetyl(hydroxy)amino]pentyl]-N-[5-[[4-[5-aminopentyl-(hydroxy)amino]-4- oxobutanoyl]amino]pentyl]-N-hydroxybutandiamide (DFO), 4,11-bis(carboxymethyl)-1 , 4,8,11- tetraazabicyclo[6.6.2]hexadecan (DO2A) 1 ,4,7,10-tetracyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), a-(2-carboxyethyl)-1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTAGA), 1 ,4,7,10 tetraazacyclododecane N, N’, N”, N’” 1 ,4,7,10-tetra(methylene) phosphonic acid (DOTMP), N,N'-dipyridoxylethylendiamine-N,N'-diacetate-5,5'-bis(phosphat) (DPDP), diethylene triamine N,N’,N” penta(methylene) phosphonic acid (DTMP), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-N,N'-tetraacetic acid (EDTA), ethyleneglycol-O,O-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N- bis(hydroxybenzyl)-ethylenediamine-N,N'-diacetic acid (HBED), hydroxyethyldiaminetriacetic acid (HEDTA), 1-(p-nitrobenzyl)-1 ,4,7,10-tetraazacyclodecan-4,7,10-triacetate (HP-DOA3), 6- hydrazinyl-N-methylpyridine-3-carboxamide (HYNIC), tetra 3-hydroxy-N-methyl-2-pyridinone chelators (4-((4-(3-(bis(2-(3-hydroxy-1-methyl-2-oxo-1 ,2-dihydropyridine-4- carboxamido)ethyl)amino)-2-((bis(2-(3-hydroxy-1-methyl-2-oxo-1 ,2-dihydropyridine-4- carboxamido)ethyl)amino)methyl)propyl)phenyl)amino)-4-oxobutanoic acid), abbreviated as Me-3,2-HOPO, 1 , 4, 7-triazacyclononan-1 -succinic acid-4, 7-diacetic acid (NODASA), 1-(1- carboxy-3-carboxypropyl)-4,7-(carbooxy)-1 ,4,7-triazacyclononane (NODAGA), 1 ,4,7- triazacyclononanetriacetic acid (NOTA), 4,11-bis(carboxymethyl)-1 , 4,8,11- tetraazabicyclo[6.6.2]hexadecane (TE2A), 1 ,4,8,11 -tetraazacyclododecane- 1 ,4,8,11- tetraacetic acid (TETA), tris(hydroxypyridinone) (THP), terpyridin- bis(methyleneamintetraacetic acid (TMT), 1 ,4,7-triazacyclononane-1 ,4,7-tris[methylene(2- carboxyethyl)phosphinic acid] (TRAP), 1 ,4,7,10-tetraazacyclotridecan-N,N',N",N"'-tetraacetic acid (TRITA), 3-[[4,7-bis[[2-carboxyethyl(hydroxy)phosphoryl]methyl]-1 ,4,7-triazonan-1- yl]methyl-hydroxy-phosphoryl]propanoic acid, and triethylenetetraaminehexaacetic acid (TTHA).

[0080] In the combinations, medicaments and kits herein, the chelating group may comprise a residue of a chelating agent selected from 1 ,4,7,10-tetracyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), a-(2-carboxyethyl)-1 ,4,7,10- tetraazacyclododecane- 1 ,4,7, 10-tetraacetic acid (DOTAGA) and 1 ,4,7-triazacyclononane-1 ,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP).

[0081] In the combinations, medicaments and kits herein, the chelating group may comprise a residue of a chelating agent selected from: Especially preferred is that the chelating group comprises a chelating agent selected from DOTA and DOTAGA bound with one of its carboxylic groups via an amide bond to the remainder of the conjugate.

[0082] In the combinations, medicaments and kits herein, the optional silicon-fluoride acceptor (SIFA) moiety (c) may comprise the structure represented by formula (2’): wherein R1Sand R2Sare independently a linear or branched C3-10 alkyl group;

[0083] R3Sis a C1-20 hydrocarbon group comprising one or more aromatic and / or aliphatic units; q is 0 to 3; and, wherein the SI FA moiety is attached to L via the bond marked by

[0084] Suitably, R1Sand R2Sare each independently selected from isopropyl and tert-butyl. Preferably, R1Sand R2Sare identical. Suitably, both R1Sand R2Sare tert-butyl. Suitably, R3Sis a Ce-io hydrocarbon group which comprises an aromatic ring; preferably R3Scomprises a phenyl ring; more preferably, R3Sis a phenyl ring wherein the Si-containing substituent and the amide group are in a para-position with respect to one another. Suitably, q may be 0, 1 , 2 or 3. Preferably, q is 1. The SI FA moiety is attached to the remainder of the PSMA binding compound via the bond marked by *vwvw in formula (2), (2’), (2”) and (2”’).

[0085] In the combinations, medicaments and kits herein, the silicon-fluoride acceptor (SIFA) moiety may comprise the structure represented by formula (2”): wherein q is 0 to 3. In the combinations, medicaments and kits herein, the silicon-fluoride acceptor (SIFA) moiety may comprise the structure represented by formula (2”’):

[0086] In the combinations, medicaments and kits herein, F is to be understood to encompass both19F and18F. The fluorine atom of the silicon-fluoride acceptor (SI FA) moiety may be19F. The fluorine atom of the silicon-fluoride acceptor (SI FA) moiety may be18F.18F may be useful for diagnostic applications, for example in positron emission tomography (PET) imaging. Whereas19F may be present in instances where18F imaging is not required. Preferably, the fluorine atom of the silicon-fluoride acceptor (SI FA) moiety is19F.

[0087] In the combinations, medicaments and kits herein, the silicon-fluoride acceptor (SIFA) moiety may comprise the structure represented by formula (2):

[0088] Suitably, a silicon-fluoride acceptor (SIFA) moiety which comprises the structure represented by formula (2) may be obtainable by use of a silicon-fluoride acceptor (SIFA) moiety which comprises the structure represented by formula (2”) or (2”’).

[0089] Suitably, there is provided a combination of compounds comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein the PSMA binding compound comprises:

[0090] (a) one or more ligand(s) which are capable of binding to PSMA comprising the structure represented by formula (1):

[0091] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation, and wherein the chelating group is selected from 1 ,4,7,10-tetracyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), a-(2-carboxyethyl)-1 ,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA) and 1,4,7-triazacyclononane- 1 ,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP); and

[0092] (c) a silicon-fluoride acceptor (SI FA) moiety comprising the structure represented by formula (2):

[0093] Suitably, there is provided a combination of compounds comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein the PSMA binding compound comprises:

[0094] (a) a ligand which is capable of binding to PSMA comprising the structure represented by formula (1):

[0095] (b) a 1,4,7,10-tetracyclododecan-N,N',N",N"'-tetraacetic acid (DOTA) chelating containing a chelated radioactive metal cation; and

[0096] (c) a silicon-fluoride acceptor (SI FA) moiety comprising the structure represented by formula (2): Suitably, there is provided a kit of parts comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein the PSMA binding compound comprises:

[0097] (a) one or more ligand(s) which are capable of binding to PSMA comprising the structure represented by formula (1):

[0098] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation, wherein the chelating group is selected from 1 ,4,7,10-tetracyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), a-(2-carboxyethyl)-1 ,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA) and 1 ,4,7-triazacyclononane- 1 ,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP); and

[0099] (c) a silicon-fluoride acceptor (SI FA) moiety comprising the structure represented by formula (2):

[0100] Suitably, there is provided a kit of parts comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein the PSMA binding compound comprises:

[0101] (a) a ligand which is capable of binding to PSMA comprising the structure represented by formula (1):

[0102] (b) a 1,4,7,10-tetracyclododecan-N,N',N",N"'-tetraacetic acid (DOTA) chelating group containing a chelated radioactive metal cation; and

[0103] (c) a silicon-fluoride acceptor (SI FA) moiety comprising the structure represented by formula (2):

[0104] In the compounds of formula (1a), (3) and (3’) described herein, the group L may be an optionally substituted linker comprising one or more amide bonds, oligoamide bonds or oligo(ester-amide) bonds. Suitable linker groups L include those groups which are described and exemplified in WO2019 / 020831 , WO2020 / 157177 and WO2020 / 157184. Suitably, the linker group L may be an optionally substituted linker comprising one or more amide bonds and comprise the optional silicon-fluoride acceptor (SI FA) moiety, when present, which comprises a covalent bond between a silicon and a fluorine atom. Suitably, the linker group L may be an optionally substituted oligoamide or oligo(ester-amide) and comprise the optional silicon-fluoride acceptor (SI FA) moiety, when present, which comprises a covalent bond between a silicon and a fluorine atom.

[0105] In the compounds of formula (1a), (3) and (3’) described herein, the group L-CG may be selected from:

[0106] In the compounds of formula (1a), (3) and (3’) described herein, the group CG may be selected from:

[0107] Suitably, the chelated radioactive metal cation of the chelating group may be chelated to one or more O atoms. Suitably, the chelated radioactive metal cation of the chelating group may be chelated to one or more N atoms. Suitably, the chelated radioactive metal cation of the chelating group may be chelated to one or more N atoms and / or one or more O atoms. Where the chelated radioactive metal cation is shown, functional groups of the molecule are merely representatively shown as negatively charged in order to balance overall charge (i.e. it will be understood that a negative charge may reside at any feasible location in the molecule).

[0108] In the PSMA binding compounds herein, the chelated radioactive metal cation, which may be referred to herein as M3+, may be selected from the cations of Sc, Cu, Ga, Y, In, Tb, Ho, Lu, Re, Pb, Bi, Ac, Er and Th. Suitably, M3+can be selected from Sc3+, Cu3+, Ga3+, Y3+, I n3+, Tb3+, Ho3+, Lu3+, Re3+, Pb3+, Bi3+, Ac3+, Er3+and Th3+.

[0109] Suitably, the chelating group may contain a chelated radioactive metal cation selected from Cu3+, Tb3+, Ac3+, Ga3+and Lu3+. Suitably, the chelating group may contain a chelated Ac3+cation, such as225Ac3+. Suitably, the chelating group may contain a chelated Ga3+cation, such as68Ga3+. Suitably, the chelating group may contain a chelated Lu3+cation, such as177Lu3+. Suitably, the radioactive Lu3+cation, especially177Lu3+, is preferred. Suitably, the chelating group may contain a chelated radioactive metal cation selected from62Cu,64Cu,67Cu,68Ga,90Y,111ln,149Tb,152Tb,155Tb,161Tb,166Ho,177Lu,186Re188Re,212Pb,212Bi,213Bi,225Ac, and227Th. Suitably, the chelated radioactive metal cation is selected from the cations of62Cu,64Cu,67Cu,149Tb,152Tb,155Tb,161Tb,68Ga,177Lu and225Ac. Suitably, the radioactive metal cation is selected from68Ga,177Lu and225Ac. The chelating group may contain chelated177Lu cation. The chelating group may contain a chelated225Ac cation. The chelating group may contain a chelated68Ga cation. In a preferred embodiment of each aspect of the invention, the chelating group contains a chelated177Lu cation.

[0110] Suitably, the chelating group may contain a chelated radioactive metal cation selected from62Cu3+ 64Cu3+ 67Cu3+ 68Ga3+ 90Y3+ 111ln3+ 149Tb3+ 152Tb3+ 155Tb3+ 161Tb3+ 166Ho3+ 177Lu3+186Re3+,188Re3+,212Pb3+,212Bi3+,213Bi3+,225Ac3+, and227Th3+. The chelating group may contain a chelated radioactive metal cation selected from62Cu3+,64Cu3+,67Cu3+,149Tb3+,152Tb3+,155Tb3+,161Tb3+,225Ac3+,68Ga3+and177Lu3+. Suitably, the radioactive metal cation is selected from225AC3+,68Ga3+and177Lu3+. The chelating group may contain a chelated177Lu3+cation. The chelating group may contain a chelated225Ac3+cation. The chelating group may contain a chelated68Ga3+cation. In a preferred embodiment of each aspect of the invention, the chelating group contains a chelated177Lu3+cation.

[0111] In the combinations, medicaments and kits herein, the PSMA binding compound may be selected from: and pharmaceutically acceptable salts thereof, wherein M is a chelated radioactive metal cation, as defined herein, for example177Lu3+or225Ac3+, preferably177Lu3+.

[0112] In the combinations, medicaments and kits herein, the PSMA binding compound may be selected from:

[0113]

[0114] and pharmaceutically acceptable salts thereof, wherein M is a chelated radioactive metal cation, as defined herein, for example177Lu3+or225Ac3+, preferably177Lu3+. In the combinations, medicaments and kits herein, the PSMA binding compound may be selected from: and pharmaceutically acceptable salts thereof, wherein M is a chelated radioactive metal cation, as defined herein, for example177Lu3+or225Ac3+, preferably177Lu3+.

[0115] In the combinations, medicaments and kits herein, the PSMA binding compound may be selected from: and pharmaceutically acceptable salts thereof, wherein M is a chelated radioactive metal cation, as defined herein, for example177Lu3+or225Ac3+, preferably177Lu3+.

[0116] In the combinations, medicaments and kits herein, the PSMA binding compound may be: or a pharmaceutically acceptable salt thereof. Alternatively, in the combinations, medicaments and kits herein, the PSMA binding compound may be selected from: and pharmaceutically acceptable salts thereof, wherein M is a chelated radioactive metal cation, as defined herein, for example177Lu3+or225Ac3+, preferably177Lu3+. In the combinations, medicaments and kits herein, the MEK inhibitor may be any compound which is capable of inhibiting the mitogen-activated protein kinase (MAPK) kinase enzymes MEK1 and / or MEK2.

[0117] In the combinations, medicaments and kits herein, the MEK inhibitor may be selected from: Binimetinib, Cobimetinib, Selumetinib, Trametinib, Refametinib (BAY86-9766), WX-554, mirdametinib (PD-0325901), FCN-159, Pimasertib, CS3006, ARRY-300, Tunlametinib (HL- 085), TAK-733, MSC2015103B and pharmaceutically acceptable salts thereof.

[0118] In the combinations, medicaments and kits herein, the MEK inhibitor may be selected from: Binimetinib, Cobimetinib, Selumetinib, Trametinib, and pharmaceutically acceptable salts thereof.

[0119] In the combinations, medicaments and kits herein, the MEK inhibitor may be selected from:

[0120] or a pharmaceutically acceptable salt thereof. In the combinations, medicaments and kits herein, the MEK inhibitor may be selected from: or a pharmaceutically acceptable salt thereof. In the combinations, medicaments and kits herein, the MEK inhibitor may be: or a pharmaceutically acceptable salt thereof.

[0121] In the combinations, medicaments and kits herein, the MEK inhibitor may be Cobimetinib or a pharmaceutically acceptable salt thereof.

[0122] In the combinations, medicaments and kits herein, the PSMA binding compound may be: or a pharmaceutically acceptable salt thereof; and the MEK inhibitor may be: or a pharmaceutically acceptable salt thereof.

[0123] Suitably, there is provided a combination of compounds comprising:

[0124] or a pharmaceutically acceptable salt thereof; and or a pharmaceutically acceptable salt thereof.

[0125] Suitably, there is provided a kit of parts comprising: or a pharmaceutically acceptable salt thereof; and or a pharmaceutically acceptable salt thereof.

[0126] The combinations, kits and medicaments described herein may useful in the treatment of cancer. The combinations, kits and medicaments described herein may useful in the treatment of a cancer in which PSMA is overexpressed. Also provided is a method of treatment of cancer comprising administering to a patient in need thereof, a combination or medicament as described herein.

[0127] The combinations, kits and medicaments described herein may be for use in the treatment of prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular cancer, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma. Also provided is a method of treatment of prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular cancer, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma comprising administering to a patient in need thereof, a combination, kit or medicament as described herein.

[0128] The combinations, kits and medicaments described herein may be for use in the treatment of cancer. The combinations, kits and medicaments described herein may be for use in the treatment of prostate cancer. The cancer may be in a metastatic or non-metastatic state. The combinations, kits and medicaments described herein may be for use in the treatment of prostate cancer, wherein the prostate cancer is hormone sensitive prostate cancer, castrationresistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0129] Also provided is a method of treatment of prostate cancer comprising administering to a patient in need thereof, a combination, kit or medicament as described herein. Also provided is a method of treatment of prostate cancer, wherein the prostate cancer is hormone sensitive prostate cancer, castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC, comprising administering to a patient in need thereof, a combination, kit or medicament as described herein. Also provided is a PSMA binding compound, as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein the PSMA binding compound comprises:

[0130] (a) one or more ligand(s) which are capable of binding to PSMA; and (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation; wherein said treatment comprises administration of said PSMA binding compound and simultaneous, separate or sequential administration of an MEK inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof.

[0131] Also provided is the PSMA binding compound: or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein said treatment comprises administration of said PSMA binding compound and simultaneous, separate or sequential administration of an MEK inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof.

[0132] Also provided is the PSMA binding compound:

[0133] or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, wherein said treatment comprises administration of said PSMA binding compound and simultaneous, separate or sequential administration of the MEK inhibitor compound: or a pharmaceutically acceptable salt thereof.

[0134] Also provided is a PSMA binding compound, as defined herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer, wherein the PSMA binding compound comprises:

[0135] (a) one or more ligand(s) which are capable of binding to PSMA; and

[0136] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation; and wherein said treatment comprises administration of said PSMA binding compound and simultaneous, separate or sequential administration of an MEK inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof.

[0137] Also provided is the PSMA binding compound: or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer, wherein said treatment comprises administration of said PSMA binding compound and simultaneous, separate or sequential administration of an MEK inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof.

[0138] Also provided is the PSMA binding compound: or a pharmaceutically acceptable salt thereof, for use in the treatment of prostate cancer, wherein said treatment comprises administration of said PSMA binding compound and simultaneous, separate or sequential administration of the MEK inhibitor compound: or a pharmaceutically acceptable salt thereof. Also provided is a method of treatment of cancer comprising administering to a patient in need thereof, a PSMA binding compound, as defined herein, or a pharmaceutically acceptable salt thereof, wherein the PSMA binding compound comprises: (a) one or more ligand(s) which are capable of binding to PSMA; and

[0139] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation; and wherein said treatment comprises simultaneous, separate or sequential administration of a MEK inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof.

[0140] Also provided is a method of treatment of cancer comprising administering to a patient in need thereof, the compound: or a pharmaceutically acceptable salt thereof, wherein said treatment comprises simultaneous, separate or sequential administration of a MEK inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof.

[0141] Also provided is a method of treatment of cancer comprising administering to a patient in need thereof, the compound:

[0142] or a pharmaceutically acceptable salt thereof, wherein said treatment comprises simultaneous, separate or sequential administration of the MEK inhibitor compound: or a pharmaceutically acceptable salt thereof.

[0143] Also provided is a method of treatment of prostate cancer comprising administering to a patient in need thereof, a PSMA binding compound, as defined herein, or a pharmaceutically acceptable salt thereof, wherein the PSMA binding compound comprises: (a) one or more ligand(s) which are capable of binding to PSMA; and

[0144] (b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation; and wherein said treatment comprises simultaneous, separate or sequential administration of an MEK inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof.

[0145] Also provided is a method of treatment of prostate cancer comprising administering to a patient in need thereof, the compound: or a pharmaceutically acceptable salt thereof, wherein said treatment comprises simultaneous, separate or sequential administration of an MEK inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof.

[0146] Also provided is a method of treatment of prostate cancer comprising administering to a patient in need thereof, the compound: or a pharmaceutically acceptable salt thereof, wherein said treatment comprises simultaneous, separate or sequential administration of the MEK inhibitor compound: or a pharmaceutically acceptable salt thereof. The cancer may be prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular cancer, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma. Preferably, the cancer is prostate cancer. The prostate cancer may be hormone sensitive prostate cancer or castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0147] The prostate cancer may be hormone sensitive prostate cancer or castration-resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC.

[0148] In the combinations, kits, medicaments and associated medical uses and methods described herein a synergistic enhancement in therapeutic efficacy in the treatment of cancer, suitably in the treatment of prostate cancer, may be observed, as compared to the expected cumulative therapeutic efficacy which would be attributable from the combined use when considering the therapeutic efficacy for each compound (i) and (ii) alone.

[0149] In the combinations, kits, medicaments and associated medical uses and methods described herein an increase in potency of either (i) the PSMA binding compound or (ii) the MEK inhibitor or (iii) both the MEK inhibitor and PSMA binding compound may be observed.

[0150] Suitably, there is provided a combination, medicament or kit of parts, as described herein, for use in the treatment of cancer, suitably prostate cancer, wherein the therapeutic administration of said combination of compounds comprising (i) the PSMA binding compound, as defined herein, and (ii) the MEK inhibitor, as defined herein, provides a synergistic enhancement in therapeutic efficacy in the treatment of cancer, suitably the treatment of prostate cancer, as compared to the expected cumulative therapeutic efficacy which would be attributable from the combined use when considering the therapeutic efficacy for each compound (i) and (ii) alone.

[0151] Suitably, there is provided a combination, medicament or kit of parts as described herein, for use in the treatment of cancer wherein the therapeutic administration of the combination of compounds comprising (i) the PSMA binding compound, as defined herein, and (ii) the MEK inhibitor, as defined herein, provides an increase in potency of either (i) the PSMA binding compound or (ii) the MEK inhibitor or (iii) both the MEK inhibitor and PSMA binding compound.

[0152] In the combinations, kits, medicaments and associated medical uses and methods described herein the PSMA binding compound and MEK inhibitor may be as defined anywhere herein. In the combinations, kits, medicaments, medical uses and methods described herein the PSMA binding compound and MEK inhibitor may be administered by any feasible route of administration. In some embodiments the MEK inhibitor may be administered orally and the PSMA binding compound may be administered intravenously. The PSMA inhibitor and the MEK inhibitor may be administered simultaneously, separately or sequentially. The combinations, kits, medicaments, medical uses and methods described herein are not limited to a single PSMA binding compound and a single MEK inhibitor. As such, the combinations, kits and medicaments may comprise one or more different PSMA binding compounds and one or more different MEK inhibitors. The medical uses and methods may also comprise the use of one or more different PSMA binding compounds and one or more different MEK inhibitors.

[0153] Dosage of the PSMA binding compound and MEK inhibitor may be in any amount or regimen sufficient to achieve the desired therapeutic effect. Dosage of the PSMA binding compound and MEK inhibitor may be sequential, separate or simultaneous. Dosage may comprise administration of a single dose of the PSMA binding compound and once daily doses of the MEK inhibitor, with administration of the PSMA binding compound and first dose of MEK inhibitor occurring on the same day. Dosage of the MEK inhibitor may continue until the desired therapeutic effect has been realised. The first dose of MEK inhibitor may be administered shortly before the PSMA binding compound.

[0154] DEFINITIONS

[0155] In this application, the following definitions apply, unless indicated otherwise.

[0156] The term “PSMA binding compound” refers to a compound capable of binding to prostatespecific membrane antigen (PSMA) expressed in mammalian, especially human, tissue. Exemplary PSMA binding compounds are identified herein and / or disclosed in WO20 19 / 020831 , WO2020 / 157177 and WO2020 / 157184.

[0157] The term “MEK inhibitor” refers to a compound capable of binding to and modulating the activity of mitogen-activated protein kinase (MAPK) kinase enzymes MEK1 and / or MEK2.

[0158] Where the term “combination” or “combination of compounds” is used it will be understood that this may refer to simultaneous, separate or sequential administration of the components of the combination. For the avoidance of doubt it will be appreciated that the components of the combination, for example (i) the PSMA binding compound and (ii) the MEK inhibitor, are separate distinct compounds. “SI FA moiety” means a silicon-fluoride acceptor moiety which comprises a covalent bond between a silicon and a fluorine atom and which is optionally labelled with18F.

[0159] “Chelating group” includes, amongst other things: (i) a macrocyclic ring structure with 8 to 20 ring atoms of which 2 or more are heteroatoms selected from oxygen atoms and nitrogen atoms; (ii) an acyclic, open chain chelating structure with 8 to 20 main chain atoms of which 2 or more are heteroatoms selected from oxygen atoms and nitrogen atoms; (iii) a branched chelating structure containing a quaternary carbon atom.

[0160] The term “treatment”, in relation to the uses of the combinations, kits and medicaments described herein is used to describe any form of intervention where a product is administered to a subject suffering from, or at risk of suffering from, or potentially at risk of suffering from the disease or disorder in question. Thus, the term “treatment” covers both preventative (prophylactic) treatment and curative treatment where measurable or detectable symptoms of the disease or disorder are being displayed.

[0161] The term “effective therapeutic amount” (for example in relation to methods of treatment of a disease or condition) refers to an amount of each component selected from PSMA binding compound and MEK inhibitor which is effective to produce a desired therapeutic effect. For example, if the condition is pain, then the effective therapeutic amount is an amount sufficient to provide a desired level of pain relief. The desired level of pain relief may be, for example, complete removal of the pain or a reduction in the severity of the pain.

[0162] Chemical terms such as “alkyl”, “hydrocarbon”, “aromatic”, “phenyl”, “chelated” (chelate, chelation) and “cation” are all used in their conventional sense (e.g. as defined in the IIIPAC Gold Book), unless indicated otherwise. “Optionally substituted” as applied to any group means that the said group may if desired be substituted with one or more substituents, which may be the same or different.

[0163] To the extent that any of the compounds described have chiral centres, the present invention extends to all optical isomers of such compounds, whether in the form of racemates or resolved enantiomers. The invention described herein relates to all crystal forms, solvates and hydrates of any of the disclosed compounds however so prepared. To the extent that any of the compounds disclosed herein have acid or basic centres such as carboxylates or amino groups, then all salt forms of said compounds are included herein. In the case of pharmaceutical uses, the salt should be seen as being a pharmaceutically acceptable salt. Salts or pharmaceutically acceptable salts that may be mentioned include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

[0164] Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals such as sodium, magnesium, potassium and calcium. Examples of acid addition salts include acid addition salts formed with acetic, 2,2-dichloroacetic, adipic, alginic, aryl sulfonic acids (e.g. benzenesulfonic, naphthalene-2-sulfonic, naphthalene-1 ,5-disulfonic and p-toluenesulfonic), ascorbic (e.g. L- ascorbic), L-aspartic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphorsulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, gluconic (e.g. D-gluconic), glucuronic (e.g. D- glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, lactic (e.g. (+)-L-lactic and (±)-DL-lactic), lactobionic, maleic, malic (e.g. (-)-L-malic), malonic, (±)-DL-mandelic, metaphosphoric, methanesulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, tartaric (e.g.(+)-L-tartaric), thiocyanic, undecylenic and valeric acids.

[0165] Also encompassed are any solvates of the compounds and their salts. Preferred solvates are solvates formed by the incorporation into the solid state structure (e.g. crystal structure) of the compounds of the invention of molecules of a non-toxic pharmaceutically acceptable solvent (referred to below as the solvating solvent). Examples of such solvents include water, alcohols (such as ethanol, isopropanol and butanol) and dimethylsulfoxide. Solvates can be prepared by recrystallising the compounds of the invention with a solvent or mixture of solvents containing the solvating solvent. Whether or not a solvate has been formed in any given instance can be determined by subjecting crystals of the compound to analysis using well known and standard techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and X-ray crystallography. The solvates can be stoichiometric or non-stoichiometric solvates. Particular solvates may be hydrates, and examples of hydrates include hemihydrates, monohydrates and dihydrates. For a more detailed discussion of solvates and the methods used to make and characterise them, see Bryn et al, Solid-State Chemistry of Drugs, Second Edition, published by SSCI, Inc of West Lafayette, IN, USA, 1999, ISBN 0-967-06710-3.

[0166] The term “pharmaceutical composition” in the context of this invention means a composition comprising an active agent and comprising additionally one or more pharmaceutically acceptable carriers. The composition may further contain ingredients selected from, for example, diluents, adjuvants, excipients, vehicles, preserving agents, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavouring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. The compositions may take the form, for example, of tablets, dragees, powders, elixirs, syrups, liquid preparations including suspensions, sprays, inhalants, tablets, lozenges, emulsions, solutions, cachets, granules, capsules and suppositories, as well as liquid preparations for injections, including liposome preparations.

[0167] The compounds of the invention may contain one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope1H,2H (D), and3H (T). Similarly, references to carbon and oxygen include within their scope respectively12C,13C and14C and16O and18O. Similarly, unless specified, references to lutetium include within their scope all known isotopes of lutetium, including, for example,173Lu,174Lu,175Lu,176Lu and177Lu. In an analogous manner, a reference to a particular functional group also includes within its scope isotopic variations, unless the context indicates otherwise. For example, a reference to an alkyl group such as an ethyl group or an alkoxy group such as a methoxy group also covers variations in which one or more of the hydrogen atoms in the group is in the form of a deuterium or tritium isotope, e.g. as in an ethyl group in which all five hydrogen atoms are in the deuterium isotopic form (a perdeuteroethyl group) or a methoxy group in which all three hydrogen atoms are in the deuterium isotopic form (a trideuteromethoxy group). The isotopes may be radioactive or non-radioactive.

[0168] Therapeutic dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compounds being employed. Determination of the proper dosage for a particular situation is within the skill of the art. The magnitude of an effective dose of a compound will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound and its route of administration. The selection of appropriate dosages is within the ability of one of ordinary skill in this art, without undue burden. In general, the daily dose range may be from about 10 pg to about 30 mg per kg body weight of a human and non-human animal, preferably from about 50 pg to about 30 mg per kg of body weight of a human and non-human animal, for example from about 50 pg to about 10 mg per kg of body weight of a human and non-human animal, for example from about 100 pg to about 30 mg per kg of body weight of a human and non-human animal, for example from about 100 pg to about 10 mg per kg of body weight of a human and non-human animal and most preferably from about 100 pg to about 1 mg per kg of body weight of a human and non-human animal.

[0169] PHARMACEUTICAL FORMULATIONS

[0170] While it is possible for the active compounds of the combinations, kits and medicaments described herein to be administered alone, it is preferable to present each as a pharmaceutical composition (e.g. formulation).

[0171] Accordingly, in another embodiment of the invention, there is provided a combination wherein at least one PSMA binding compound and MEK inhibitor compound are presented as pharmaceutical compositions, each comprising at least one pharmaceutically acceptable excipient.

[0172] Administration of the pharmaceutical compositions may be by any means suitable to achieve the desired therapeutic effect. Administration may be effected in different ways, e.g., by enteral, parenteral, oral, intravenous, intraperitoneal, subcutaneous, intramuscular, topical, intradermal, intranasal or intrabronchial administration.

[0173] The PSMA binding compound may be presented as a parenteral formulation. The PSMA binding compound may be presented as an intravenous formulation. The PSMA binding compound may be administered by intravenous (IV) injection. Administration may be carried out by injection and / or delivery, e.g., to a specific site in the patient. The compositions may also be administered directly to a target site, e.g., by biolistic delivery to an external or internal target site, like the pancreas or brain.

[0174] The MEK inhibitor compound may be presented as an enteral formulation. The MEK inhibitor compound may be presented as a tablet composition. The MEK inhibitor compound may be presented as a capsule composition. Administration of the MEK inhibitor may be peroral (PO). The pharmaceutically acceptable excipient(s) can be selected from, for example, carriers (e.g. a solid, liquid or semi-solid carrier), adjuvants, diluents (e.g solid diluents such as fillers or bulking agents; and liquid diluents such as solvents and co-solvents), granulating agents, binders, flow aids, coating agents, release-controlling agents (e.g. release retarding or delaying polymers or waxes), binding agents, disintegrants, buffering agents, lubricants, preservatives, anti-fungal and antibacterial agents, antioxidants, buffering agents, tonicityadjusting agents, thickening agents, flavouring agents, sweeteners, pigments, plasticizers, taste masking agents, stabilisers or any other excipients conventionally used in pharmaceutical compositions.

[0175] The term “pharmaceutically acceptable” as used herein means compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. a human subject) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio. Each excipient must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

[0176] Pharmaceutical compositions containing compounds of the combinations, kits and medicaments described herein may be formulated in accordance with known techniques, see for example, Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.

[0177] Pharmaceutical dosage forms suitable for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches such as buccal patches.

[0178] Tablet compositions may contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and / or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as microcrystalline cellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate / bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.

[0179] Tablets may be designed to release the drug either upon contact with stomach fluids (immediate release tablets) or to release in a controlled manner (controlled release tablets) over a prolonged period of time or with a specific region of the Gl tract.

[0180] The pharmaceutical compositions typically comprise from approximately 1% (w / w) to approximately 95%, preferably % (w / w) active ingredient and from 99% (w / w) to 5% (w / w) of a pharmaceutically acceptable excipient (for example as defined above) or combination of such excipients. Preferably, the compositions comprise from approximately 20% (w / w) to approximately 90% (w / w) active ingredient and from 80% (w / w) to 10% of a pharmaceutically excipient or combination of excipients. The pharmaceutical compositions comprise from approximately 1 % to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, pre-filled syringes, dragees, powders, tablets or capsules.

[0181] Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5% lubricants, 0-5% flow aids and / or 0-99% (w / w) fillers / or bulking agents (depending on drug dose). They may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, 0-5% (w / w) pigments. Slow release tablets would in addition typically contain 0-99% (w / w) release-controlling (e.g. delaying) polymers (depending on dose). The film coats of the tablet or capsule typically contain 0-10% (w / w) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0182] Parenteral formulations typically contain 0-20% (w / w) buffers, 0-50% (w / w) cosolvents, and / or 0-99% (w / w) Water for Injection (WFI) (depending on dose and if freeze dried). Formulations for intramuscular depots may also contain 0-99% (w / w) oils.

[0183] The pharmaceutical formulations may be presented to a patient in “patient packs” containing an entire course of treatment in a single package, usually a blister pack.

[0184] These pharmaceutical compositions can be administered to the subject at a suitable dose. The active compounds will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect (effective amount). The precise amounts of each compound administered may be determined by a supervising physician in accordance with standard procedures. As is well known in the medical arts, dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Pharmaceutically active matter may be present in an effective therapeutic amount, which may be between 0.1 ng and 10 mg / kg body weight per dose; however, doses below or above this exemplary range are envisioned, especially considering the aforementioned factors.

[0185] EXAMPLES

[0186] The invention will now be illustrated, but not limited, by reference to the following examples.

[0187] PREPARATION OF COMPOUNDS OF THE INVENTION

[0188] PSMA binding compounds may be prepared according to methods known in the art, including those described in WO2019 / 020831 , WO2020 / 157177, WO2020 / 157184, WO2022 / 144467, WO2022 / 144463 and W02022 / 171901.

[0189] General Information

[0190] Analytical and preparative high-performance liquid chromatography (HPLC) was performed using Shimadzu gradient systems (Neufahrn, Germany) equipped with a SPD-20A UV / Vis detector. The columns for analytical (MultoKrom 100C18, 150x4.6mm, 5 pm), radio-analytical (Multospher 100RP18, 125x4.6mm, 5pm) and preparative (MultoKrom 100C18, 250x20mm, 5pm) HPLC were purchased from CS Chromatographie Service (Langerwehe, Germany). Eluents for all HPLC operations were water (solvent A) and acetonitrile with 2 vol.-% water (solvent B), both containing 0.1 vol.% trifluoroacetic acid (TFA). Radioactivity was detected via a HERM LB 500 Nal detector (Berthold Technologies, Bad Wildbad, Germany). Radio-thin layer chromatography (TLC) was carried out with a Scan-RAM detector (LabLogic Systems, Sheffield, United Kingdom). Electrospray ionization-mass spectra were acquired on an expression1- CMS (Advion, Harlow, UK).

[0191] rhPSMA-10.1 rhPSMA-10.1 in its free chelator form was synthesized according to the methods described in WO2020 / 157184 and WO2020 / 157177. Briefly, the fert-butyl protected chelator, DOTA(tBu)3was conjugated to the free / V-terminus with a mixture of HOAt (2.0 eq.), TBTLI (2.0 eq.) and 2,4,6-trimethylpyridine (6.7 eq.) for 2 h in DMF. Cleavage from the resin and deprotection of acid labile protecting groups was performed in TFA for 6 h. After RP-HPLC-based purification, rhPSMA-10.1 (18%) was obtained as a colorless solid. RP-HPLC (10 to 70% B in 15 min): tR= 9.9 min, K’ = 3.95. Calculated monoisotopic mass (CeoHgsFN-^ChsSi): 1398.6; found: m / z = 1399.6 [M+H]+, 700.6 [M+2H]2+.natLu-rhPSMA-10.1 was prepared from a 2 mM solution of rhPSMA-10.1 (1.0 eq.) in DMSO with a 20 mM aqueous solution of LuCh (2.5 eq.), heated to 95 °C for 30 min. After cooling, thenatLu-chelate formation was confirmed using RP-HPLC and MS.natLu-rhPSMA-10.1 : RP-HPLC (10 to 70% B in 15 min): tR= 9.9 min, K’ = 3.95. Calculated monoisotopic mass (CeoH92FLuNi2023Si): 1570.6; found: m / z = 1572.2 [M+H]+, 786.6 [M+2H]2+.

[0192] 177Lu-rhPSMA-10.1 Radiolabelling was carried out at a molar activity (MA) of ~25 MBq / nmol in ~40 pL 0.045 sodium acetate (NaOAc) buffer (Sigma Aldrich) at a scale of 2 nmol rhPSMA per reaction. The precursor (natLu-rhPSMA-10.1) was added from frozen aliquoted 1 mM stocks of DMSO and heated in buffer and177Lu at 50°C for 30 min. Instant thin-layer chromatography (iTLC) was performed on glass microfiber chromatography paper (Agilent Technologies) using citrate (0.1 M, pH 5) as a running buffer and strips were analysed with a Bioscan AR-2000 radio-TLC scanner (Eckert & Ziegler). Radiochemical yield (RCY) and radiochemical purity (RCP) were calculated based upon the activity of the radiolabelled compound retained on the baseline compared to the unbound177Lu activity in the solvent front, and was > 98% for all radiolabellings.

[0193] MEK Inhibitor

[0194] Cobimetinib was obtained commercially (MedChemExpress), but may also be prepared according to methods known in the art.

[0195] BIOLOGICAL ACTIVITY

[0196] EXAMPLE A - In Vitro Studies

[0197] The therapeutic effect of the combination of Cobimetinib and177Lu-rhPSMA-10.1 was determined across different concentrations of Cobimetinib and different doses of177Lu- rhPSMA-10.1. Cobimetinib IC50 was assessed across a spectrum of177Lu-rhPSMA-10.1 concentrations. Zero interaction potency (ZIP) analysis and multi-dimensional synergy of combinations (MuSyc) analysis were undertaken.

[0198] The 22Rv1 human prostate adenocarcinoma cell line was used (ATCC; CRL-2505). Cells were maintained in complete Roswell Park Memorial Institute (RPMI) media (10% fetal bovine serum [FBS], L-Glutamine, Penicillin / Streptomycin) and used at passages between 10-20 for the experiments.

[0199] 177Lu-rhPSMA-10.1 was radiolabelled according to the conditions outlined above. The 22Rv1 cells were prepared in suspension (1.67 x 106cells / mL) and were incubated with177Lu- rhPSMA-10.1 for 2 hours at 37°C with gentle agitation in a final volume of 3.2 mL. Controls were prepared using cell solution only (3.2 mL, 1.67 x 106cells / mL) from the same cell suspension batch.

[0200] Serial dilutions of Cobimetinib with a starting concentration of 8 pM were prepared using a 3- fold dilution in complete RPMI medium in a volume of 180 pL. These dilution series were plated in quadruplicate for each concentration (20 pL / well) in 96-well plates (Corning® 96-well Clear Flat Bottom Polystyrene TC-treated Microplates) for Cobimetinib only and for the combined177Lu-rhPSMA-10.1 treatments. Multiple doses of 177Lu-rhPSMA-10.1 were assessed (0, 5, 10, 15, 20, 25 MBq / mL).

[0201] The cell suspensions were diluted in media and dispensed onto wells pre-treated with Cobimetinib solutions for a final well volume of 200 pL. This represented 1600 cells / well for177Lu-rhPSMA-10.1 -treated cells, and 800 cells / well for Cobimetinib only plates to compensate for the estimated reduction in clonogenic survival caused by 15 MBq / mL treatment of177Lu- rhPSMA-10.1 alone. These plates were left to incubate for 10 days at 37°C and 5% CO2 and subsequently washed with hard phosphate-buffered saline (PBS; Ca2+and Mg2+added) and stained with 0.05 w / w% Crystal Violet in 1 :4 methanokethanol solution for at least 1 hour. Stained plates were washed with distilled water and air dried. Colony counts were scanned and analysed using a Celigo Imaging Cytometer.

[0202] Survival fractions were calculated as the number of colonies formed per number of cells seeded and normalised to controls (DMSO 0.5% (v / v)). Survival fractions were further adjusted by normalising to the drug-alone treatment (without177Lu-rhPSMA-10.1). Data representing survival fraction at different Cobimetinib concentrations and different doses of177Lu-rhPSMA- 10.1 are shown in Fig. 1.

[0203] The data presented in Fig. 1 demonstrate synergistic therapeutic efficacy for the combination comprising Cobimetinib and177Lu-rhPSMA-10.1 in vitro (22Rv1 prostate cancer cell line).

[0204] For comparative purposes, the above experimental procedure was followed to evaluate the therapeutic effect of a combination of each of AZD0156, Berzosertib, and Everolimus with177Lu-rhPSMA-10.1. Different optimised starting concentrations were used: Cobimetinib (8 pM), AZD0156 (3 pM), Berzosertib (750nM), Everolimus (100 nM).

[0205] Synergy Analysis

[0206] Two synergy analysis platforms, known to those in the art, were used to analyse the in vitro data: SynergyFinder (https: / / synerqyfinder.fimm.fi / ) and multi-dimensional synergy of combinations (MuSyC; https: / / musyc. lolab.xyz / about) .

[0207] SynergyFinder is a stand-alone web-application for interactive analysis and visualization of multi-drug (2 or more drugs) multi-dose combination response data (lanevski A, Giri AK, Aittokallio T. Nucleic Acids Res. 2022 Jul 5;50(W1):W739-W743). SynergyFinder quantifies the degree of combination synergy, or antagonism, by comparing observed drug combination responses against the expected response, calculated using a reference model (selected from Zero interaction potency (ZIP), Bliss independence, Loewe additivity or Highest Single Agent (HSA)) that assumes no interaction between drugs.

[0208] The ZIP reference model captures drug interaction relationships by comparing the change in potency (effect at certain dose level) of the dose-response curves between individual drugs and their combinations (Yadav B, Wennerberg K, Aittokallio T, Tang J. Comput Struct Biotechnol J. 2015 Sep 25;13:504-13. doi: 10.1016 / j.csbj.2015.09.001). The ZIP model takes the advantages of both the Loewe additivity and the Bliss independence models, aiming at a systematic assessment of various types of drug interactions patterns that may arise in a high- throughput drug combination screening. ZIP assumes that two non-interacting drugs are expected to incur minimal changes in their dose-response curves. Deviations between observed and expected responses with positive and negative values denote synergy and antagonism, respectively.

[0209] ZIP synergy scores can be interpreted as the average excess response due to drug interactions, for example, a synergy score of 10 corresponds to 10% of response beyond expectation e.g. 10% more cell inhibition (Yadav B, Wennerberg K, Aittokallio T, Tang J. Comput Struct Biotechnol J. 2015 Sep 25; 13:504-13. doi: 10.1016 / j.csbj.2O15.09.001). A high ZIP synergy score is considered to be >5%. To perform a ZIP score analysis, the survival fractions and corresponding Cobimetinib (or where appropriate other comparative active agent) and177Lu-rhPSMA-10.1 doses are uploaded onto SynergyFinder and the ZIP score calculated.

[0210] The second synergy platform, MuSyC, may be used to determine whether the observed synergy is due to enhanced potency or enhanced efficacy of the single agents (Meyer CT et al. Cell Syst. 2019 Feb 27;8(2):97-108). MuSyC is based on a two-dimensional (2D) extension of the Hill equation derived from mass action kinetics. The parameter alpha (a) quantifies how the effective dose of one drug is altered by the presence of another drug, and vice versa. In the case of synergistic potency (indicated by Log a > 0, where a may correspond to either drug, e.g.177Lu-rhPSMA-10.1 or Cobimetinib), the ECso decreases because of the addition of the other second drug, corresponding to an increase in potency.

[0211] To perform a MuSyC analysis, mean survival fractions, corresponding Cobimetinib (or where appropriate other comparative active agent) and177Lu-rhPSMA-10.1 doses, and 95% confidence interval values (Cl=95%) (calculated using GraphPad Prism), are uploaded onto MuSyC and the Log alpha (a) score for synergistic potency calculated. Based on the ZIP analyses, the combination of Cobimetinib and177Lu-rhPSMA-10.1 demonstrated an overall synergistic interaction (e.g. synergistic enhancement of therapeutic efficacy) across a range of different activity concentrations (Table 1 , Fig. 2). Based on MuSyc analysis, the synergy observed appears to be due to an enhanced potency of both Cobimetinib and177Lu-rhPSMA-10.1 in the combination.

[0212] Table 1 - ZIP Synergy Scores and MuSyc Synergistic Potency Scores

[0213] EXAMPLE B - In Vivo Studies

[0214] Prostate cancer xenograft model

[0215] Efficacy of177Lu-rhPSMA-10.1 in combination with Cobimetinib was assessed based on tumor volume and survival in the 22Rv1 tumor-cell derived prostate cancer model (Sigma Aldrich) established in 6-week old male NMRI nude mice (Janvier, France). Prior to inoculation, 22Rv1 cells were maintained in complete RPMI media (10% fetal bovine serum [FBS], L-Glutamine, Penicillin / Streptomycin).

[0216] Procedures

[0217] Animals were anesthetized and placed in a prone position on a sterile barrier. 3x106cells in 100 pL 1 :1 PBS / Matrigel were inoculated subcutaneously at the right flank. Individual animal identification was ensured by a microchip. Animals with tumour volumes of 100-200mm3were included in the study. Intravenous injections (IV) and oral dosing (PO) were performed in nonanesthetized animals. The injection site used was the lateral tail vein.

[0218] As detailed in Table 2, frequency of Cobimetinib dosing was once daily for 21 days (QDx21).177Lu-rhPSMA-10.1 was administered in a single dose. For groups receiving Cobimetinib and177Lu-rhPSMA-10.1 ,177Lu-rhPSMA-10.1 was administered on the first day just before the first dose of Cobimetinib. Groups included in this study are listed in Table 2.

[0219] Tumor growth was monitored starting 5 days after inoculation. Tumor size was measured by caliper twice every week and on the day of randomization. T umor volume was estimated with the following formula: 0.52 (length x width2). Animal body weight was also monitored. If body weight loss was more than 20% relative to body weight at study day -1 (where day 0 is treatment initiation day), the animals were euthanized due to humane endpoints. Data presentation and statistical analysis were performed in GraphPad Prism. The effect of therapy on tumor volume was evaluated from study day -1 to study termination day, which was pre-defined, or until 3 or more animals remained alive within each group. Tumor volumes were carried forward until 3 animals remained per group. Survival analysis was performed to study termination day or to when animals reached endpoint (tumor volume of >1500mm2). The analyses performed are summarised in Table 3.

[0220] Table 2: Group Overview Table 3: Statistical analysis for in vivo efficacy study

[0221] Tumor volume, survival and relative body weight data are presented in Figures 3 to 5. Compared to the untreated control group (Group A), the strongest effect on mean tumor volume was observed for the combination treatment group (177Lu-rhPSMA-10.1+ Cobimetinib - Group D), showing significant tumor growth repression (p<0.01 , two-way ANOVA, Tukey’s multiple comparison test) from study day 13 to 30. Compared to177Lu-rhPSMA-10.1 alone (Group C), the combination treatment group (177Lu-rhPSMA-10.1+ Cobimetinib - Group D) significantly suppressed mean tumor volume (p<0.001 , two-way ANOVA, Tukey’s multiple comparison test) from study day 17 to 30.

[0222] Median survival was 23 days for untreated control (Group A), 39 days for Cobimetinib (Group B), 36 days for177Lu-rhPSMA-10.1 (Group C) and 49 days for177Lu-rhPSMA-10.1 in combination with Cobimetinib (Group D). Log-rank Mantel-Cox survival test showed a significant improvement in survival for the combination treatment group (Group D), as compared to the untreated control group (p=0.001) and the177Lu-rhPSMA-10.1 group (p=0.002).

[0223] Some temporary body weight loss was observed in the two groups treated with Cobimetinib (Groups B and D). However, mean relative body weight loss did not exceed 10%, suggesting no major compound-related toxicity.

[0224] The data demonstrate that the drug combination of177Lu-rhPSMA-10.1 plus Cobimetinib (MEK inhibitor) enhances therapeutic efficacy in vivo compared to either drug alone (22Rv1 prostate cancer xenograft model).

[0225] Together EXAMPLE A and EXAMPLE B demonstrate that the drug combination of177Lu- rhPSMA-10.1 plus Cobimetinib (MEK inhibitor) provides a significant enhancement in therapeutic efficacy in both in vitro and in vivo prostate cancer models, compared to what would be expected when considering the efficacy of each drug alone.

[0226] BRIEF DESCRIPTION OF THE FIGURES

[0227] Fig. 1 : Combination screening data of EXAMPLE A (survival fraction at different Cobimetinib concentrations and different doses of177Lu-rhPSMA-10.1). Data represent mean ± SD with N=4 / group.

[0228] Fig. 2: ZIP synergy analysis of data from EXAMPLE A (median percentage inhibition ± SD and ZIP synergy scores at different Cobimetinib concentrations and different doses of177Lu- rhPSMA-10.1).

[0229] Fig. 3: Tumor volume data of EXAMPLE B (following administration of177Lu-rhPSMA-10.1 (30MBq, single dose), Cobimetinib (0.25mg, QDx21), or177Lu-rhPSMA-10.1 (30MBq, single dose) plus Cobimetinib (0.25mg, QDx21)). Data represent mean ± SEM with N=7-8 / group.

[0230] Fig. 4: Percent survival data of EXAMPLE B (following administration of177Lu-rhPSMA-10.1 (30MBq, single dose), Cobimetinib (0.25mg, QDx21), or177Lu-rhPSMA-10.1 (30MBq, single dose) plus Cobimetinib (0.25mg, QDx21)). Data represent mean ± SEM with N=7-8 / group.

[0231] Fig. 5 : Relative body weight data of EXAMPLE B (following administration of177Lu-rhPSMA- 10.1 (30MBq, single dose), Cobimetinib (0.25mg, QDx21), or177Lu-rhPSMA-10.1 (30MBq, single dose) plus Cobimetinib (0.25mg, QDx21)), normalised to treatment day -1. Data represent mean ± SEM with N=7-8 / group.

Claims

CLAIMS1. A combination of compounds comprising (i) a PSMA binding compound and (ii) a MEK inhibitor, wherein the PSMA binding compound comprises:(a) one or more ligand(s) which are capable of binding to PSMA; and(b) one or more chelating group(s), wherein said one or more chelating group(s) contain a chelated radioactive metal cation.

2. The combination according to claim 1 , wherein the PSMA binding compound (i) further comprises:(c) a silicon-fluoride acceptor (SI FA) moiety which comprises a covalent bond between a silicon and a fluorine atom.

3. The combination according to any one of claims 1 or 2, wherein (a) said one or more ligand(s), of the PSMA binding compound (i), which is capable of binding to PSMA comprises the structure represented by formula (1):

4. The combination according to any one of claims 1 to 3, wherein (b) the one or more chelating group(s), of the PSMA binding compound (i), comprises a residue of a chelating agent selected from 1 ,4,7,10-tetracyclododecan-N,N',N",N"'-tetraacetic acid (DOTA), a-(2- carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA) and 1 ,4,7-triazacyclononane-1 ,4,7-tris[methylene(2-carboxyethyl)phosphinic acid] (TRAP).

5. The combination according to any one of claims 2 to 4, wherein (c) the silicon-fluoride acceptor (SI FA) moiety, of the PSMA binding compound (i), comprises the structure represented by formula (2):

6. The combination according to claim 1, wherein the PSMA binding compound (i) is selected from:or a pharmaceutically acceptable salt thereof, wherein M3+is a chelated radioactive metal cation.

7. The combination according to claim 1, wherein the PSMA binding compound (i) is selected from:and pharmaceutically acceptable salts thereof, wherein M3+is a chelated radioactive metal cation.

8. The combination according to any one of claims 1 to 7, wherein the chelated radioactive metal cation is selected from Sc3+, Cu3+, Ga3+, Y3+, ln3+, Tb3+, Ho3+, Lu3+, Re3+, Pb3+, Bi3+, Ac3+, Er3* and Th3+.

9. The combination according to claim 8, wherein the chelated radioactive metal cation is selected from64Cu3+,67Cu3+,149Tb3+,152Tb3+,155Tb3+,161Tb3+,225Ac3+,68Ga3+and177Lu3+.

10. The combination according to claim 9, wherein the chelated radioactive metal cation is177Lu3+.

11. The combination according to claim 9, wherein the chelated radioactive metal cation is225Ac3+.

12. The combination according to claim 1 , wherein the PSMA binding compound (i) is:or a pharmaceutically acceptable salt thereof.

13. The combination according to any one of claims 1 to 12, wherein the MEK inhibitor is selected from:or a pharmaceutically acceptable salt thereof.

14. The combination according to claim 13, wherein the MEK inhibitor is:or a pharmaceutically acceptable salt thereof.

15. The combination according to claim 1, wherein the PSMA binding compound (i) is:or a pharmaceutically acceptable salt thereof; and the MEK inhibitor is:or a pharmaceutically acceptable salt thereof.

16. A medicament comprising a combination according to any one of claims 1 to 15.

17. A kit of parts comprising (i) a PSMA binding compound as defined in any one of claims1 to 15 and a separate MEK inhibitor (ii) as defined in any one of claims 1 to 15.

18. The combination, medicament or kit of parts according to any one of claims 1 to 17 for use in the treatment of cancer.

19. The combination, medicament or kit of parts according to claim 18 for use in the treatment of cancer, wherein the cancer is prostate cancer, salivary gland cancer, thyroid cancer, hepatocellular cancer, glioblastoma, glioma, testicular cancer, breast cancer, lung cancer, colorectal cancer or renal cell carcinoma.

20. The combination, medicament or kit of parts according to claim 19 for use in the treatment of prostate cancer.

21. The combination, medicament or kit of parts as claimed in any one of claims 18 to 20, wherein the therapeutic administration of the combination of compounds comprising (i) the PSMA binding compound, as defined in any one of claims 1 to 15, and (ii) the MEK inhibitor, as defined in any one of claims 1 to 15, provides a synergistic enhancement in therapeutic efficacy in the treatment of cancer, suitably the treatment of prostate cancer, as compared to the expected cumulative therapeutic efficacy which would be attributable from the combined use when considering the therapeutic efficacy for each compound (i) and (ii) alone.

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