Combination therapy for treating cancer such as lymphoma

Abstract

The present disclosure relates to a combination therapy for treating cancer comprising belinostat or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and at least one glucose transporters (GLUT) inhibitor. Belinostat and the GLUT inhibitor can either be administered separately or in the form of a single composition. Thus, the disclosure relates to a kit comprising Belinostat and at least one GLUT inhibitor, wherein Belinostat and the GLUT inhibitor are in separate formulations and, alternatively, to a composition comprising belinostat and at least one GLUT inhibitor, such as a pharmaceutical composition. It also relates to such kit or such composition for use in the treatment of cancer, preferably for the treatment of lymphoma(s).

Description

[0001] Combination therapy for treating cancer such as lymphoma

[0002] FIELD OF THE INVENTION

[0003] The present disclosure relates to a combination therapy for treating cancer comprising belinostat or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and at least one glucose transporters (GLUT) inhibitor. Belinostat and the GLUT inhibitor can either be administered separately or in the form of a single composition. Thus, the disclosure relates to a kit comprising Belinostat and at least one GLUT inhibitor, wherein Belinostat and the GLUT inhibitor are in separate formulations and, alternatively, to a composition comprising belinostat and at least one GLUT inhibitor, such as a pharmaceutical composition. It also relates to such kit or such composition for use in the treatment of cancer, preferably for the treatment of lymphoma(s).

[0004] BACKGROUND OF THE INVENTION

[0005] Histone deacetylase (HD AC) inhibitors exhibit clinical efficacy in lymphomas, particularly T-cell lymphomas (TCL), as described in J Clin Oncol. 2015 Aug 10;33(23):2492-9.

[0006] Belinostat is a pan-HDAC inhibitor, targeting enzymes of all three classes (I, II, IV) of the zinc-dependent HDACs. During the 10 years since its FDA approval for treatment of relapsed / refractory peripheral T-cell lymphoma (R / R PTCL), several studies have supported its efficacy in up to one-fourth of R / R PTCL. See for example the following studies:

[0007] O’Connor OA, Horwitz S, Masszi T, Van Hoof A, Brown P, Doorduijn J, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492-9. PMID: 26101246 PMCID: PMC5087312 DOI: 10.1200 / JC0.2014.59.2782;

[0008] - Wolska-Washer A, Smolewski P, Robak T. Advances in the pharmacotherapeutic options for primary nodal peripheral T-cell lymphoma. Expert Opin Pharmacother. 2021;22(9): 1203-15. PMID: 33524268 DOI: 10.1080 / 14656566.2021.1882997; and

[0009] Foss F, Advani R, Duvic M, Hymes KB, Intragumtornchai T, Lekhakula A, et al. A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T- cell lymphoma. Br J Haematol. 2015; 168(6):811-9. PMID: 25404094 DOI: 10.1111 / bjh.13222.

[0010] The activity of belinostat as an anti-cancer agent has namely been described in US6888027B2 and in US8835501B2.

[0011] However, most PTCL are not cured by single agent belinostat, there is therefore a need to find therapeutic options having improved efficacy and to enhance the therapeutic index of this HD AC inhibitor.

[0012] SUMMARY OF THE INVENTION

[0013] The present disclosure provides a combination therapy wherein the combined belinostat and GLUT inhibitor act synergistically. The synergistic active principles can be administered separately in the form of different formulations, such as separate pharmaceutical compositions or can be administered together in the form of a single composition such as a single pharmaceutical composition.

[0014] The present disclosure provides a kit comprising

[0015] - belinostat, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, in a suitable packaging; and at least one glucose transporters (GLUT) inhibitor in a suitable packaging.

[0016] In a preferred aspect, the present disclosure provides a kit comprising a pharmaceutical composition comprising belinostat, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, together with a pharmaceutically acceptable carrier in a suitable packaging; and a pharmaceutical composition comprising at least one GLUT inhibitor together with a pharmaceutically acceptable carrier in a suitable packaging.

[0017] Preferably, the kit further comprises a label and / or instructions for use of the kit in the treatment of the indications, including the diseases or conditions, described herein.

[0018] When belinostat and the GLUT inhibitor are administered as separate formulations forming a kit, belinostat and the GLUT inhibitor are administered either simultaneously or sequentially. The present disclosure further provides a composition comprising belinostat or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and at least one GLUT inhibitor.

[0019] Further provided is a pharmaceutical composition comprising belinostat or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and at least one GLUT inhibitor, together with a pharmaceutically acceptable carrier.

[0020] Further provided is a kit, a composition or a pharmaceutical composition according to the invention for use in the treatment of cancer, preferably of lymphoma(s).

[0021] Further provided is a method of treatment of cancer, preferably of lymphoma(s), said method comprising administering belinostat and at least one GLUT inhibitor to a subject in need thereof. In other terms, further provided is a method of treatment of cancer, preferably of lymphoma(s), said method comprising administering the substances, compositions or pharmaceutical compositions that are part of the kit of the invention, the composition of the invention or the pharmaceutical composition of the invention to a subject in need thereof.

[0022] Further provided is the use of belinostat and of at least one GLUT inhibitor for treating cancer, preferably lymphoma(s), wherein belinostat and the at least one GLUT inhibitor are administered to a subject in need thereof. In other words, the invention provides for the use of a kit of the invention, of a composition of the invention or of a pharmaceutical composition of the invention for treating cancer, preferably lymphoma(s), wherein belinostat and the at least one GLUT inhibitor are administered to a subject in need thereof.

[0023] Further provided is the use of belinostat and of at least one GLUT inhibitor for the manufacture of a medicament, preferably of a medicament for the treatment of cancer, more preferably of lymphoma(s). In a particular aspect, belinostat and the at least one GLUT inhibitor are used in the form of a composition of the invention or of a pharmaceutical composition of the invention.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS

[0025] [Fig. 1] is a graph representing the activity of belinostat alone in the T-cell lymphoma cell lines H9, HH, MAC1, and FE-PD. [Fig.2] to [Fig. 5] Combination treatment with belinostat plus STF-31 enhances antiproliferative activity in T-cell lymphoma cell lines. Combination MTTs were performed in four T-cell lymphoma cell lines using increasing concentrations of belinostat plus STF-31 as described in Example 1. For each combination MTT experiment, cells were treated with three technical replicates of a concentration matrix comprising 49 combinations of the two drugs. Cells were also treated with increasing concentrations of STF-31 alone. The charts show the average cell viability percentage at each compound(s) concentration. Error bars denote the standard deviation. Average absorbance values from combination MTTs were used to calculate the Chou-Talalay combination index (CI), allowing the quantitative definition for additive effect (CI 0.9-1.1), synergism (CI 0.3-0.9), and antagonism (CI > 1.1).

[0026] DESCRIPTION OF THE INVENTION

[0027] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0028] In the case of conflict, the present specification, including definitions, will control. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

[0029] Reference throughout this specification to "one aspect", "an aspect", "another aspect", "a particular aspect", "combinations thereof' means that a particular feature, structure or characteristic described in connection with the invention aspect is included in at least one aspect of the present invention. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same aspect. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more aspects. The term "comprise(s)", or "comprising" is generally used in the sense of include(s) / including, that is to say, permitting the presence of one or more features or components. The terms "comprise(s)" and "comprising" also encompass the more restricted ones "consist(s)" and "consisting", respectively.

[0030] As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.

[0031] The term “about,” particularly in reference to a given quantity, is meant to encompass deviations of plus or minus ten (10) percent.

[0032] While it is possible for belinostat and the GLUT inhibitor to be administered as such, for example in the form of a kit of active principles or as a composition of active principles, it may be preferable to present it as a kit of pharmaceutical compositions or as a pharmaceutical composition according to the invention. The kits, compositions, pharmaceutical compositions of the invention, which can be both for veterinary and for human use, comprise a therapeutically effective amount of belinostat, or of a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and a therapeutically effective amount of at least one GLUT inhibitor. The pharmaceutical composition further comprises one or more acceptable carriers thereof and optionally other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the composition and physiologically innocuous to the recipient thereof.

[0033] The glucose transporters (GLUT) inhibitor is preferably a glucose transporter 1 (GLUT1) and / or a glucose transporter 3 (GLUT3) inhibitor. In a particular aspect the GLUT inhibitor, is selected from the group consisting of STF-31 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, WZB1 17 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, BAY-876 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and combinations thereof.

[0034] STF-31 (CAS No. : 724741-75-7) has the IUPAC name 4-[[(4-tert- butylphenyl)sulfonylamino]methyl]-N-pyridin-3-ylbenzamide (source PubChem) and is of formula (IV)

[0035] WZB1 17 (CAS No. : 1223397-11-2) has the IUPAC name [3-fluoro-2-(3- hydroxybenzoyl)oxyphenyl] 3 -hydroxybenzoate and is of formula (IX)

[0036] (ix).

[0037] BAY-876 (CAS No. : 1799753-84-6) has the IUPAC name 4-N-[l-[(4-cyanophenyl)methyl]- 5-methyl-3-(trifluoromethyl)pyrazol-4-yl]-7-fluoroquinoline-2,4-dicarboxamide and is of Formula (X)

[0038] Belinostat (CAS No. : 866323-14-0), also known as PXD101, has the IUPAC name (E)-N- hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide (source Pubchem) and is of formula (XI)

[0039] Belinostat, and the GLUT inhibitor are preferably present in a therapeutically effective amount. The term "therapeutically effective amount" as used herein means an amount of the active principle, a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof (the active ingredient), as defined herein, high enough to significantly positively modify the symptoms and / or condition to be treated, but low enough to avoid serious side effects (at a reasonable risk / benefit ratio), within the scope of sound medical judgment.

[0040] The therapeutically effective amount of the active ingredient as defined herein is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient. A physician of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the cancer.

[0041] The substances, compositions or pharmaceutical compositions forming the kit of the invention, the composition of the invention or the pharmaceutical composition of the invention can be administered by a number of routes including, but not limited to, oral, intravenous, intraperitoneal, intramuscular, transdermal, subcutaneous, topical, sublingual, or rectal means.

[0042] The pharmaceutical compositions include those suitable for the foregoing administration routes. The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and compositions generally are found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association belinostat or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and the GLUT inhibitor, with inactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.) which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0043] In certain aspects, compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.

[0044] The administration of the pharmaceutical compositions may be designed or formulated so as to result in sequential exposures to belinostat and the at least one GLUT inhibitor, preferably by means of the kits, compositions or pharmaceutical compositionsof the invention, over a certain time period, for example, hours, days, weeks, months or years. This may be accomplished, for example, by repeated administrations of the kit or composition or by a sustained or controlled release delivery system in which belinostat and the GLUT inhibitor are delivered over a prolonged period without repeated administrations. Administration of the compositions or compounds using such a delivery system may be, for example, by oral dosage forms, bolus injections, transdermal patches or subcutaneous implants. Maintaining a substantially constant concentration of the composition may be preferred in some cases.

[0045] Other delivery systems suitable include, but are not limited to, time-release, delayed release, sustained release, or controlled release delivery systems. Such systems may avoid repeated administrations in many cases, increasing convenience to the subject and the physician. Many types of release delivery systems are available and known to those of ordinary skill in the art. They include, for example, polymer-based systems such as polylactic and / or polyglycolic acids, polyanhydrides, polycaprolactones, copolyoxalates, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and / or combinations of these. Microcapsules of the foregoing polymers containing nucleic acids are described in, for example, U.S. Patent No. 5,075,109. Other examples include nonpolymer systems that are lipid-based including sterols such as cholesterol, cholesterol esters, and fatty acids or neutral fats such as mono-, di- and triglycerides; hydrogel release systems; liposome-based systems; phospholipid based- systems; silastic systems; peptide-based systems; wax coatings; compressed tablets using conventional binders and excipients; or partially fused implants. Specific examples include, but are not limited to, diffusional systems in which an active component controls the release rate (for example, as described in U.S. Patent Nos. 3,832,253, 3,854,480, 5,133,974 and 5,407,686). The composition may be formulated as, for example, microspheres, hydrogels, polymeric reservoirs, cholesterol matrices, or polymeric systems. The system may allow sustained or controlled release of the composition to occur, for example, through control of the diffusion or erosion / degradation rate of the active principles. In addition, a pump-based hardware delivery system may be used for delivery.

[0046] In certain aspects, the pharmaceutical compositions include one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agent(s). Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing belinostat and the GLUT inhibitor in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0047] The amount of belinostat and of the GLUT inhibitor (together designated herein below as the "active material") that is combined with the inactive ingredients to produce a dosage form will vary depending upon the host treated and the particular mode of administration. For example, in some aspects, a dosage form for oral administration to humans contains approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material varies from about 5 to about 95% of the total compositions (weightweight). In some aspects, the pharmaceutical compositions described herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1 to 200 mg, 1 to 100 mg or 1 to 50 mg of the active material, or stereoisomer, mixture of stereoisomers, solvate, or tautomer thereof. In some aspects, the pharmaceutical compositions described herein contain not more than about 400 mg of the active material. In some embodiments, the pharmaceutical compositions described herein contain about 100 mg of the active material, or a pharmaceutically acceptable salt thereof.

[0048] It should be understood that in addition to the ingredients particularly mentioned above the compositions disclosed herein may include other agents conventional in the art having regard to the type of composition in question, for example those suitable for oral administration may include flavoring agents.

[0049] In a particular aspect, the kit, the composition or the pharmaceutical composition according to the invention further comprises one or more additional active principle, preferably an anticancer active principle. In a particular aspect, the additional active principle is selected from a Bcl-2 family protein inhibitor and / or a NAMPT inhibitor.

[0050] The Bcl-2 family protein inhibitor is preferably selected from a Bcl-2 / Bcl-2 family protein inhibitor (or Bcl-2 inhibitor), a Bcl-XL / Bcl-2 family protein inhibitor (or Bcl-XL inhibitor), a Mcl-l / Bcl-2 family protein inhibitor (or Mcl-1 inhibitor), a CED-9 / Bcl-2 family protein inhibitor (or CED-9 inhibitor), a Al / Bcl-2 family protein inhibitor (or Al inhibitor) and a Bfl-l / Bcl-2 family protein inhibitor (or Bfl-1 inhibitor). Preferably the Bcl-2 family protein inhibitor is selected from a Bcl-2 / Bcl-2 family protein inhibitor (or Bcl-2 inhibitor), a Bcl- XL / Bcl-2 inhibitor (or Bcl-XL inhibitor) or a Mcl-l / Bcl-2 family protein inhibitor (or Mcl-1 inhibitor). The Bcl-2 family protein inhibitor is preferably selected from the group consisting of Venetoclax, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, MIK665 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, Navitoclax, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and combinations thereof. Preferably the Bcl-2 family protein inhibitor is selected from the group consisting of Navitoclax or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, MIK665 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and combinations thereof.

[0051] Navitoclax (CAS No. : 923564-51-6), also known as ABT-263 has the IUPAC name 4-[4- [[2-(4-chlorophenyl)-5,5-dimethylcyclohexen-l-yl]methyl]piperazin-l-yl]-N-[4-[[(2R)-4- morpholin-4-yl-l-phenylsulfanylbutan-2-yl]amino]-3- (trifluoromethylsulfonyl)phenyl]sulfonylbenzamide (source PubChem) and is of formula (I)

[0052] Venetoclax (CAS No. : 1257044-40-8), also named GDC-0199, ABT-199, RG-7601 has the IUPAC name 4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-l-yl]methyl]piperazin-l- yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(lH-pyrrolo[2,3-b]pyridin-5- yloxy)benzamide (source PubChem) and is of formula (II)

[0053] MIK665 (CAS No. : 1799631-75-6), also known as S-64315 has the IUPAC name (2R)-2-[5- [3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4- fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2-(hydroxymethyl)phenyl]pyrimidin- 4-yl]methoxy]phenyl]propanoic acid (source PubChem) and is of formula (III)

[0054] The nicotinamide phosphoribosyltransferase (NAMPT) inhibitor is preferably selected from the group consisting of

[0055] GMX1778 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof,

[0056] OT-82 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof,

[0057] ATG-019 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and

[0058] - FK866 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, a compound of formula salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, a compound of formula or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and combinations thereof.

[0059] GMX1778 (CAS No. : 200484-11-3) has the IUPAC name 2-[6-(4-chlorophenoxy)hexyl]-l- cyano-3-pyridin-4-ylguanidine and is of formula (V)

[0060] OT-82 (CAS No. : 1800487-55-1) has the IUPAC name 3-[2-(4-fluorophenyl)ethynyl]-N-[3- (lH-pyrazol-4-yl)propyl]-4-pyridin-4-ylbenzamide and is of Formula (VI)

[0061] ATG-019 (CAS No. : 1643913-93-2), also named KPT-9274 or Padnarsertib, has the IUPAC name (E)-3-(6-aminopyridin-3-yl)-N-[[5-[4-(4,4-difluoropiperidine-l-carbonyl)phenyl]-7-(4- fluorophenyl)- l-benzofuran-2-yl]methyl]prop-2-enamide and is of formula (VII)

[0062] FK866 (CAS No. : 658084-64-1), also named (E)-Daporinad or APO866 has the IUPAC name (E)-N-[4-(l-benzoylpiperidin-4-yl)butyl]-3-pyridin-3-ylprop-2-enamide and is of Formula (VIII) Preferably the NAMPT inhibitor is OT-82 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.

[0063] Preferably, the kits, the compositions or the pharmaceutical compositions of the invention are for use in the treatment of cancer, preferably lymphoma(s), i.e. a disease in which malignant (cancer) cells form from lymphocytes. Lymphomas are largely represented by B-cell or T- cell lymphomas. Examples of lymphoma comprise indolent lymphomas, for example follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma (such as nodal marginal zone lymphoma, extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT), mediterranean abdominal lymphoma or splenic marginal zone lymphoma), primary cutaneous anaplastic large cell lymphoma or cutaneous T-cell and NK-cell lymphomas such as Mycosis fungoides (MF) and MF variants and subtypes, and aggressive lymphomas, for example diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma / high-grade B-cell lymphoma with MYC and BCL2 rearrangements, follicular lymphoma grade 3b, anaplastic large cell lymphoma (such as cutaneous anaplastic large cell lymphoma or systemic anaplastic large cell lymphoma), extranodal NK - / T-cell lymphoma, lymphomatoid granulomatosis, angioimmunoblastic T-cell lymphoma, peripheral T- cell lymphoma (such as hepatosplenic T-cell lymphoma, Subcutaneous panniculitislike T-cell lymphoma or enteropathy -type intestinal T-cell lymphoma), intravascular large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, adult T-cell leukemia / lymphoma, mantle cell lymphoma, posttransplantation lymphoproliferative disorder, true histiocytic lymphoma, primary effusion lymphoma or plasmablastic lymphoma, Sezary syndrome or classic Hodgkin lymphoma.

[0064] In a particular aspect, the lymphoma is an aggressive lymphoma such as described herein.

[0065] In some aspects, the pharmaceutical compositions of the invention further comprise other therapeutic agents (e.g. chemotherapeutic agent and / or immunotherapeutic agents) and / or are administered in association with a treatment selected from the group comprising surgery, chemotherapy, immunotherapy, irradiation and combinations thereof.

[0066] Also provided is a method of treatment and / or prevention of cancer, preferably lymphoma(s), said method comprising administering substances, compositions or pharmaceutical compositions forming the kit of the invention, a composition of the invention or a pharmaceutical composition of the invention as therapeutic agent to a subject.

[0067] As used herein, the term “treatment” or “treating” means any administration of substances, compositions or pharmaceutical compositions forming the kit of the invention, a composition of the invention or a pharmaceutical composition of the invention to a subject for the purpose of:

[0068] (i) inhibiting the disease, that is, arresting the development of clinical symptoms; and / or

[0069] (ii) relieving the disease, that is, causing the regression of clinical symptoms.

[0070] In the context of the present invention, the disease is cancer, preferably non-Hodgkin lymphoma, as defined herein.

[0071] The administration routes are, preferably, chosen among those described herein.

[0072] The terms “inhibit”, “inhibiting”, “inhibitor”, and “inhibition” refer to the slowing, halting, or reversing the growth, activity or progression of a disease, infection, condition, protein or group of cells. The inhibition can be greater than about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, compared to the growth, activity or progression that occurs in the absence of the treatment or contacting.

[0073] Alternatively, the method of treatment can be associated with a treatment selected from the group comprising surgery, chemotherapy, immunotherapy, irradiation and combinations thereof.

[0074] "Administering", as it applies in the present invention, refers to contact of a therapeutically effective amount of the substances, compositions or pharmaceutical compositions forming the kits of the invention, the compositions of the invention or the pharmaceutical compositions of the inventions to the subject, preferably a subject in need thereof.

[0075] As used herein the terms " subject", or " patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some aspects, the subject is a subject in need of treatment or a subject suffering from cancer, preferably lymphoma, such as defined herein, or a subject that might be at risk of suffering from cancer, preferably lymphoma, such as defined herein. However, in other aspects, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.

[0076] Provided herein are also articles of manufacture that include a composition, preferably a pharmaceutical composition described herein in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.

[0077] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and active principles referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

[0078] EXAMPLES

[0079] Example 1

[0080] GLUT inhibitors, either alone or in combination with belinostat were screened in four T-cell lymphoma cell lines (HH, H9, FE-PD, MAC1) for their anti-proliferative activities.

[0081] Beneficial combinations identified from the screen were validated with combination MTT experiments and in HSA, LOEWE, BLISS and ZIP models.

[0082] 1. Materials and methods

[0083] Belinostat was provided by Acrotech (East Windsor, NJ, USA). For MTT [3-(4,5- Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] experiments, belinostat was solubilized in DMSO to obtain a 100 mM stock, diluted as necessary to get working concentrations. Solubilised belinostat was stored in aliquots at -80°C.

[0084] STF-31 was purchased from Selleckchem (Houston, TX, USA), cat. # S7931. Cell lines and cell culture

[0085] The T-cell lymphoma cell lines used were H9, HH, MAC1, and FE-PD. Cells were maintained in RPMI medium containing 10% FBS and supplemented with 1 X penicillin / streptomycin (complete RPMI). Cells were kept in a humidified incubator at 37°C with 5% CO2.

[0086] MTT proliferation assay for belinostat

[0087] Anti-proliferative activity was assessed as previously described in Oncotarget. 2015 Mar 10;6(7):5059-71 (MTT assay). 10,000 cells were seeded per well in 96-well plates and exposed to belinostat, serially diluted in complete RPMI without phenol red (1 :3 dilutions, 7 concentrations) for 72 hours. Serially diluted belinostat spanned a dose range of 10,000 nM - 13.7 nM. Vehicle (DMSO) controls corresponded to the highest drug concentration used. Wells containing only medium (complete RPMI without phenol red) served as background controls. Cells were incubated (37°C with 5% CO2) with 20 pL of MTT reagent per well for 3 - 4 hours. SDS lysis buffer (50 pL) was added to each well to solubilize the MTT reagent. Absorbances were read in a Cytation 3 multimode plate reader (Biotek) at 560 nm. Background- subtracted absorbance values were used to calculate drug response.

[0088] Inhibitory activities

[0089] STF-31 was diluted in 2 mL of complete RPMI without phenol red to obtain 10 pM working concentrations. Compounds at 10 pM were diluted 1 : 10 or 1 :5 to get 2x and 4x compounds for single agent and combination treatments, respectively. Cells seeded in 96-well plates (10,000 / well) were treated as follows: 0.5 pM chemical library compound alone, belinostat alone (half the IC50 concentration), 0.5 pM chemical STF-31 + belinostat at half the IC50 concentration for the specific cell line, DMSO alone. Wells containing only complete RPMI without phenol red served as background controls. After three days of compound exposure, MTT reagent (20 pL) was added, followed by 50 pL SDS lysis buffer. Absorbances were read in a Cytation 3 plate reader at 560 nm. Background-subtracted absorbance values were used to calculate drug response.

[0090] To ensure robustness of findings, the benefit of combinations was also determined using highest single agent (HSA) (Berenbaum MC. What is synergy? Pharmacol Rev 1989;41 : 93- 141), Loewe additivity (LOEWE) (Loewe S. The problem of synergism and antagonism of combined drugs. Arzneimittelforschung 1953;3:285-90) models, Bliss independence (BLISS) (Bliss CI. The toxicity of poisons applied jointly. Ann App Biol 1939;26:585-615), and zero interaction potency (ZIP) (Yadav B, Wennerberg K, Aittokallio T, Tang J.

[0091] Searching for drug synergy in complex dose-response landscapes using an interaction potency model. Comput Struct Bi otechnol J 2015;13 : 504-13) models.

[0092] Drug combination studies

[0093] Further validation by combination MTT experiments was then performed. Cells were exposed for 72 hours to increasing doses of belinostat alone or in combination with increasing doses of STF-31, followed by the MTT assay. The Chou-Talalay combination index (CI), as disclosed in Leuk Lymphoma. 2008 Nov;49(l l):2059-80, was estimated using the Synergy R package 3, allowing the quantitative definition for additive effect (CI 0.9-1.1), synergism (CI 0.3 -0.9), and antagonism (CI > 1.1) 2.

[0094] 2. Results

[0095] Assessment of the antiproliferative activity of single agent belinostat in T-cell lymphomas

[0096] Belinostat showed robust anti-proliferative activity in the four T-cell lymphoma cell lines ([Fig. 1]), with a median IC50 value of 110. Belinostat IC50 values are provided in Table 1 below.

[0097] Table 1. Belinostat IC50 values

[0098] * Mean of > 2 biological replicates

[0099] Assessment of the antiproliferative activity of single agent STF-31 in T-cell lymphomas

[0100] The antiproliferative activity of the single agent STF-31 in T-cell lymphoma cells is shown in [Fig. 2] to [Fig. 5] (first block of bars, wherein the belinostat concentration is of 0 nM).

[0101] Validation

[0102] STF-31 synergized in all four T-cell lymphoma cell lines tested (HH, H9, MAC1, FE-PD). Absorbance values obtained from combination MTTs with belinostat and each indicated compound were used to calculate Chou Talalay combination indexes (<0.9, synergistic; 0.9 - 1.1, additive; >1.1, no benefit / antagonistic). The results are provided in [Fig. 2] to [Fig. 5] and Table 3.

[0103] Table 3. Chou Talalay combination indexes.

[0104] The results of the HSA, LOEWE, BLISS and ZIP models in T cell lymphoma cell lines are provided for STF-31 in combination with belinostat in Table 4 below. Positive scores and p- value s£0.05.

[0105] Table 4: results of the HSA, LOEWE, BLISS and ZIP models for STF-31 in combination with belinostat in T cell lymphoma cell lines

[0106] 3. Conclusions

[0107] The pan HD AC inhibitor belinostat, approved by the FDA for treating relap sed / refractory peripheral T-cell lymphoma in 2014, was tested in combination with STF-31. The synergism of the combination of belinostat with STF-31 was mathematically and statistically determined using multiple synergy models that are widely recognized and reported as reliable models of synergism, indicating that belinostat enhances the anti-proliferative activity of STF-31.

Claims

CLAIMS1. A kit comprising:- belinostat or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof in a suitable packaging, preferably a pharmaceutical composition comprising belinostat or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof together with a pharmaceutically acceptable carrier in a suitable packaging; and at least one GLUT inhibitor in a suitable packaging, preferably a pharmaceutical composition comprising at least one GLUT inhibitor together with a pharmaceutically acceptable carrier in a suitable packaging.

2. The kit of claim 1 further comprising a Bcl-2 family protein inhibitor and / or a NAMPT inhibitor.

3. A composition comprising belinostat or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and at least one GLUT inhibitor.

4. The composition according to claim 3, further comprising a Bcl-2 family protein inhibitor and / or a NAMPT inhibitor.

5. A composition according to claim 3 or 4, wherein said composition is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

6. A kit according to claim 1 or 2 or a composition according to any one of claims 3 to 5 for use in the treatment of cancer, preferably wherein the cancer is at least one lymphoma.

7. The kit according to claim 1 or 2, the composition according to any one of claim 3 to 5 or the kit or composition for use according to claim 6, wherein the GLUT inhibitor is selected from the group consisting of STF-31 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, GMX1778 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, OT-82 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, ATG-019 or apharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and FK866 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and combinations thereof.

8. The kit, the composition, or the kit or composition for use according to claim 7, wherein the GLUT inhibitor is STF-31.

9. The kit or composition for use according to any one of claims 6 to 8, wherein the at least one lymphoma is selected from indolent lymphomas and aggressive lymphomas, preferably it is an aggressive lymphoma.

10. The kit or composition for use according to claim 9, wherein the indolent lymphoma, is selected from the group consisting of follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma (such as nodal marginal zone lymphoma, extranodal marginal zone lymphomas of the mucosa-associated lymphoid tissue (MALT), mediterranean abdominal lymphoma or splenic marginal zone lymphoma), primary cutaneous anaplastic large cell lymphoma and cutaneous T-cell and NK-cell lymphomas such as Mycosis fungoides (MF) and MF variants and subtypes.

11. The kit or composition for use according to claim 9, wherein the aggressive lymphoma is selected from the group consisting of diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma / high-grade B-cell lymphoma with MYC and BCL2 rearrangements, follicular lymphoma grade 3b, anaplastic large cell lymphoma (such as cutaneous anaplastic large cell lymphoma or systemic anaplastic large cell lymphoma), extranodal NK - / T-cell lymphoma, lymphomatoid granulomatosis, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (such as hepatosplenic T-cell lymphoma, Subcutaneous panniculitis-like T-cell lymphoma or enteropathy-type intestinal T-cell lymphoma), intravascular large B-cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, adult T-cell leukemia / lymphoma, mantle cell lymphoma, posttransplantation lymphoproliferative disorder, true histiocytic lymphoma, primary effusion lymphoma or plasmablastic lymphoma, Sezary syndrome and classic Hodgkin lymphoma.

12. The kit for use according to any one of claims 6 to 11, wherein belinostat, the at least one GLUT inhibitor, and optionally the additional active principle are administered simultaneously.

13. The kit for use according to any one of claims 6 to 11, wherein belinostat and the at least one GLUT inhibitor, and optionally the additional active principle are administered sequentially.

14. The kit according to any one of claims 1, 2, 7 or 8, the composition according to any one of claims 3 to 5, 7 or 8, the kit for use according to any one of claims 6 to 13 or the composition for use according to any one of claims 6 to 11, wherein the Bcl-2 family protein inhibitor is selected from the group consisting of Venetoclax, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, MIK665 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, Navitoclax, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, and combinations thereof and / or wherein the NAMPT inhibitor is selected from the group consisting ofGMX1778 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof,OT-82 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof,ATG-019 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and- FK866 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, a compound of formulasalt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof; a compound of formulaor a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof; and combinations thereof.

15. The kit, composition, or kit or composition for use according to claim 14, whereinthe Bcl-2 protein family inhibitor is selected from the group consisting of MIK665 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, Navitoclax, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and combinations thereof; and / or the NAMPT inhibitor is OT-82 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof.

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