WO2020239948A1

WO2020239948A1 - A CENTRALLY ACTING µ-OPIOID RECEPTOR AGONIST IN COMBINATION WITH A CURCUMINOID FOR USE IN THE TREATMENT OF A TUMOUR OF THE CENTRAL NERVOUS SYSTEM

Info

Publication number: WO2020239948A1
Application number: PCT/EP2020/064910
Authority: WO
Inventors: Titus Kretzschmar; Christa ZWICKY
Original assignee: Isanas Ag
Priority date: 2019-05-28
Filing date: 2020-05-28
Publication date: 2020-12-03

Abstract

The present invention is inter alia concerned with a combination of a centrally acting µ-opioid receptor agonist or a pharmaceutically acceptable salt thereof and a 5 curcuminoid or a pharmaceutically acceptable salt thereof, optionally further in combination with one or more curcuminoid bioavailability enhancers, for use in the treatment of a tumour of the central nervous system.

Description

A centrally acting m-opioid receptor agonist in combination with a curcuminoid for use in the treatment of a tumour of the central nervous system

FIELD OF THE INVENTION

The present invention relates to a combination of a centrally acting m-opioid receptor agonist and a curcuminoid for use in the treatment of cancer, wherein said cancer is a tumour of the central nervous system. The present invention further relates to a kit of dosage forms comprising a) a dosage form comprising a centrally acting m-opioid receptor agonist and b) a dosage form comprising a curcuminoid. The present invention is also concerned with a dosage form comprising a centrally acting m- opioid receptor agonist and a curcuminoid.

BACKGROUND OF THE INVENTION

Many currently applied cancer therapies suffer from being effective only in a minority of cancer patients, leading to cancer cells being resistant to further treatments, and/or provoking serious side effects undermining the original therapy benefits and, thus, only provide marginal, if at all, survival benefits and/or increased quality of life. Inefficient treatment of various types of cancer may be caused by cancer cells developing a resistance against chemotherapy or radiotherapy as the two most commonly applied cancer therapies. Cancer cells may also develop a resistance against the more recent cancer therapies using antibodies, cytokines, engineered T cells and the like (referred to herein as“biotherapies”), which are based on biological systems or defined biological structures to fight cancer via various pathways. Thus, resistance to chemotherapy can be a result of overexpression of oncogenes or inactivation of tumour suppressor genes, whereas resistance to radiotherapy can be induced by the epithelia-mesenchymal transition caused thereby. Finally, resistance to biotherapies is often the result of intrinsic (e.g. insensibility of T cells) and/or extrinsic (e.g. induction of immunosuppressive regulatory T cells) tumour cell mechanisms.

In addition to the development of resistance, the afore-mentioned therapies are accompanied by adverse events that significantly impair the quality of life. Examples are chemotherapy-induced nausea and vomiting, radiation-induced skin injury and adverse events associated with biotherapies such as e.g. hypertension, proteinuria, perforations of the gastrointestinal tract, dermatological toxicities and cardiotoxicity. As a result, quite a few cancer drugs have entered the market without clear evidence of benefit, be it on survival or on quality of life, as exemplarily shown for cancer drugs approved between 2009 and 2013: in 49% (33 out of 68) of approved cancer drug indications, no improvement (be it on survival or on quality of life) could be shown after a median follow-up of 5.4 years. Of the 23 (= 34%) cancer indications for which a survival benefit was claimed, only 11 were assessed to offer a clinically meaningful benefit (Davis C et al. (2017)“Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13”. BMJ 359, doi:

10.1136/bmj.j4530). To give a more specific example, only 9.8% of patients with newly diagnosed glioblastoma, the most common type of primary intracranial tumours, survived after 5 years despite the combined application of radiotherapy and concomitant chemotherapy with temozolomide followed by up to six cycles of adjuvant temozolomide. The median overall survival was calculated to be 14.6 months (Stupp R et al. (2009)“Effects of radiotherapy with concomitant and adjuvant

temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial”. Lancet Oncol 10(5), 459-66).

EP 2 149 372 Al describes that methadone induces in vitro the apoptosis in the human glioblastoma cell line A172. Said cell line was derived from a human glioblastoma patient. The cell line is not tumorigenic in immunosuppressed mice.

The lack of tumorigenicity does not allow to reasonably extrapolate the results to the treatment of human glioblastoma in vivo.

DE 100 29 770 Al describes that a solution of curcumin in ethanol at low doses was effective in vitro in inhibiting proliferation and killing of highly malignant human glioblastoma cells after an incubation for seven days. Said document does not describe how the human glioblastoma cells were obtained. The in vitro results cannot reasonably be extrapolated to the treatment of human glioblastoma in vivo.

WO 2011/068894 A2 describes that CD68 antibody-curcumin conjugates show a higher potency to kill GL261 tumor cells implanted in C57BL6 mice than solubilized curcumin. GL261 tumor cells were originally induced via intracranial injection of methylcholanthrene followed by serial intracranial and subcutaneous transplantations into syngeneic C57BL6 mice. GL261 tumors resemble ependymoblastomas on histology. GL261 tumors differ from glioblastomas in cancer patients in that the GL261 tumors show a moderate immunogenicity which is not observed for glioblastomas. Further, GL261 tumors show a different growth pattern compared to glioblastomas.

Due to these differences the results from murine GL261 tumors cannot reasonably be extrapolated to the treatment of human glioblastomas. EP 3 144 006 A1 relates to the use of curcuminoid and a chemotherapeutic agent for the treatment of glioblastoma. Said document does not provide any experimental data supporting the suitability of the combination.

Hence, there is strong need to provide more effective therapies for patients suffering from a cancer, wherein said cancer is a tumour of the central nervous system, in particular for patients suffering from a glioblastoma. Further, there is the need for an effective dosage regime for the treatment of human cancer patients, in particular human glioblastoma patients. OBJECTS AND SUMMARY OF THE INVENTION

The inventors of the present invention have surprisingly found that a combination of a centrally acting m-opioid receptor agonist, in particular methadone, and a curcuminoid, in particular curcumin, can be used to treat a tumour of the central nervous system, in particular a glioblastoma, without inducing major adverse events. The present invention further provides an effective dosage regime for the treatment of human cancer patients, in particular human glioblastoma patients.

The first aspect of the present invention

In a first aspect, the present invention relates to a combination of a centrally acting m- opioid receptor agonist or a pharmaceutically acceptable salt thereof and a curcuminoid or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein said cancer is a tumour of the central nervous system.

Cancer types

In an embodiment of the first aspect, said cancer, namely a tumour of the central nervous system (CNS), is selected from the group consisting of a diffuse astrocytic and oligodendroglial tumour, an astrocytic tumour, an ependymal tumour, a glioma, a choroid plexus tumour, a neuronal and mixed neuronal-glial tumour, a tumour of the pineal region, an embryonal tumour, a tumour of the cranial and paraspinal nerves, a meningioma, a mesenchymal non-meningothelial tumour, a melanocytic tumour, a lymphoma, a histiocytic tumour, a germ cell tumour, a tumour of the sellar region, and a metastatic tumour (see, e.g., Louis DN et al. (2016)“The 2016 World Health Organization classification of tumours of the central nervous system: a summary”. Acta Neuropathol 131, 803-820).

More preferably, said tumour of the CNS is selected from the group consisting of a diffuse astrocytic and oligodendroglial tumour, a glioma, and a neuronal and mixed neuronal-glial tumour.

Even more preferably, said tumour of the CNS is selected from the group consisting of a glioma and a glioblastoma.

In the most preferred embodiment of the first aspect when it comes to the medical use, said cancer is a glioblastoma.

In one preferred embodiment the patient to be treated is a human patient, more preferably a human glioblastoma patient. Particularly preferred the human glioblastoma patient is chemotherapy-resistant. The chemotherapeutic agent may preferably be temozolomide.

In one further preferred embodiment, the patient to be treated is a child suffering from glioblastoma and being from 1 to 15 years, preferably 4 to 10 years.

In a further preferred embodiment, the treatment results in a reduction of tumor size and/or increased survival time of the human patient. Preferably, the tumor size is reduced by at least 25% compared to the tumor size before start of the treatment. The tumor size may be determined by magnetic resonance imaging often enhanced with contrast agents (e.g. gadolinium-based agents).

Also preferred the survival time is increased by at least three months, preferably the survival time is increase by at least nine months. The actual survival time is compared with a theoretical prediction of survival time before start of the treatment.

Adjunct therapy

In another embodiment of the first aspect, the combination for use as mentioned above is used as adjunct cancer therapy to cancer therapy selected from the group consisting of surgery, chemotherapy, radiotherapy, biotherapy and combinations thereof.

In this embodiment, the combination for use as described herein may be administered in between surgeries, radiotherapies, chemotherapies and/or biotherapies.

Alternatively, the combination for use as described herein may be administered in parallel to ongoing cancer therapy, in particular cancer therapy selected from the group consisting of surgery, chemotherapy, radiotherapy, biotherapy and

combinations thereof.

When it comes to glioblastoma, the combination for use in the treatment of glioblastoma of the present invention may be administered in particular i) after a surgery followed by radiotherapy in combination with chemotherapy (using e.g. temozolomide) or ii) after a radiotherapy in combination with chemotherapy (using e.g. temozolomide), e.g. for a time period of several months, in order to inhibit regrowth of the tumour or to at least substantially slow down the regrowth of the tumour.

The centrally acting u-opioid receptor agonist In yet another embodiment of the first aspect, said centrally acting m-opioid receptor agonist or pharmaceutically acceptable salt thereof is selected from the group consisting of the opium alkaloids (in particular codeine and morphine); morphines (in particular dihydromorphine); esters of morphines (in particular heroin); codeine- dionines; morphinones/morphols (in particular oxycodone); morphides;

dihydrocodeines; nitrogen morphine derivatives; halogenated morphine derivatives; hydrazones; morphinans; benzomorphans; phenylpiperidines (in particular pethidine); open chain opioids (in particular methadone); anilidopiperidines (in particular fentanyl); oripavine derivatives (in particular buprenorphine),

phenazepanes (in particular meptazinol); piritramides (in particular piritramide); benzimidazoles; indoles (in particular mitragynine); beta-amino-ketones;

diphenylmethylpiperazines; opioid peptides (in particular b-endorphin,

endomorphin-1 and -2) or others with central m-opioid receptor activity (in particular tramadol and tapentadol), pharmaceutically acceptable salts thereof and

combinations thereof.

In the most preferred embodiment of the first aspect when it comes to the centrally acting m-opioid receptor agonist, said centrally acting m-opioid receptor agonist or pharmaceutically acceptable salt thereof is methadone or a pharmaceutically acceptable salt thereof, preferably methadone hydrochloride.

Loperamide is not an opioid receptor agonist according to the present invention since loperamide mainly is a peripherally acting m-opioid receptor agonist. The curcuminoid

In yet another embodiment of the first aspect, said curcuminoid or pharmaceutically acceptable salt thereof is a linear diarylheptanoid of the following general structure:

It is noted that the keto-enol-tautomerism leads to an equilibrium between an enol- group, if present, in the heptanoid part of the molecule and the corresponding keto- group. Both, the enol- and the keto-form of the linear diarylheptanoids, if applicable, are members of the group of curcuminoids as well as stereoisomers thereof (in particular all-trans or cis,trans). Said linear diarylheptanoid is preferably selected from the group consisting of curcumin (R1 = R4 = OH; R2 = R3 = OMe), demethoxycurcumin (R1 = R4 = OH; R2 = OMe; R3 = H), bisdem ethoxy curcumin (R1 = R4 = OH; R2 = R3 = H), dimethoxycurcumin (R1 = R2 = R3 = R4 = OMe), and tetrahydrocurcumin (R1 = R4 = OH; R2 = R3 = OMe), in which both double bonds (labelled 1 and 2 in the above structure) are reduced by H to single bonds, pharmaceutically acceptable salts thereof and combinations thereof.

In the most preferred embodiment of the first aspect when it comes to the curcuminoid, said curcuminoid or pharmaceutically acceptable salt thereof is curcumin or a pharmaceutically acceptable salt thereof, preferably curcumin.

The additional curcuminoid bioavailabilitv enhancer

In a preferred embodiment of the first aspect, said curcuminoid or pharmaceutically acceptable salt thereof is used together with a curcuminoid bioavailability enhancer.

Said curcuminoid bioavailability enhancer may be selected from the group consisting of a liposome, an organic solvent, a cyclodextrin, a polymeric micelle, a surfactant, an alkaloid and combinations thereof. Any technique for mechanical reduction of the drug particle size to increase the surface area is also suitable to enhance the bioavailability.

Said organic solvent may be dimethylsulfoxide, ethyl acetate, or ethanol.

Said polymeric micelle may be PEG-Z>-PLA micelles (poly(ethylene glycol )-block- poly(D,L-lactic acid).

Said surfactant may be polysorbate 80.

Said alkaloid is preferably an alkaloid found in the genus Piper. The alkaloid found in genus Piper can be selected from the group consisting of piperine and its stereoisomers such as chavicine. In the most preferred embodiment of the first aspect when it comes to the curcuminoid bioavailability enhancer, said curcuminoid bioavailability enhancer is piperine. Accordingly, it is most preferred that said curcuminoid or pharmaceutically acceptable salt thereof is used together with piperine as curcuminoid bioavailability enhancer. This particularly applies if the curcuminoid is curcumin or a

pharmaceutically acceptable salt thereof.

The piperine may be used together with a second curcuminoid bioavailability enhancer, in particular a cyclodextrin, even more particularly with a gamma- cyclodextrin. Accordingly, it is also preferred that said curcuminoid or

pharmaceutically acceptable salt thereof is used together with piperine and a cyclodextrin, preferably gamma-cyclodextrin, which act in combination as curcuminoid bioavailability enhancer. This particularly applies if the curcuminoid is curcumin or a pharmaceutically acceptable salt thereof. It should be noted that curcuminoids usually have a rather low bioavailability, if administered orally. This means that active curcuminoids are present at a rather low concentration in the systemic circulation and the CNS, if administered orally.

Accordingly, the additional administration of a curcuminoid bioavailability enhancer is clearly preferred for a medical indication as claimed herein, namely when treating a tumour of the central nervous system.

The administration of the combination In yet another embodiment of the first aspect, said centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and said curcuminoid or a pharmaceutically acceptable salt thereof and said curcuminoid bioavailability enhancer, if present, for the use as described herein are administered in the form of separate dosage forms. In this case, the curcuminoid or pharmaceutically acceptable salt thereof and the curcuminoid bioavailability enhancer are preferably administered together (but as separate dosage forms), if not all three dosage forms are

administered together.

An alternative embodiment thereof, said centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and said curcuminoid or a

pharmaceutically acceptable salt thereof and said curcuminoid bioavailability enhancer, if present, for the use as described herein are administered in the form of a single dosage form. Independent of whether the combination of the present invention is administered in the form of separate dosage forms or as single dosage form, it can be preferred that the administration takes place once a day (e.g. in the morning or in the evening) or twice a day (e.g. in the morning and in the evening). The second aspect of the present invention In a second aspect, the present invention relates to a kit of dosage forms comprising a. a dosage form comprising a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof; and

b. a dosage form comprising a curcuminoid or a pharmaceutically

acceptable salt thereof.

In an embodiment of the second aspect, said centrally acting m-opioid receptor agonist or pharmaceutically acceptable salt thereof comprised in a dosage form is selected from the group consisting of the opium alkaloids (in particular codeine and morphine); morphines (in particular dihydromorphine); esters of morphines (in particular heroin); codeine-dionines; morphinones/morphols (in particular oxycodone); morphides; dihydrocodeines; nitrogen morphine derivatives;

halogenated morphine derivatives; hydrazones; morphinans; benzomorphans;

phenylpiperidines (in particular pethidine); open chain opioids (in particular methadone); anilidopiperidines (in particular fentanyl); oripavine derivatives (in particular buprenorphine), phenazepanes (in particular meptazinol); piritramides (in particular piritramide); benzimidazoles; indoles (in particular mitragynine); beta- amino-ketones; diphenylmethylpiperazines; opioid peptides (in particular b- endorphin, endomorphin-1 and -2) or others with central m-opioid receptor activity (in particular tramadol and tapentadol), pharmaceutically acceptable salts thereof and combinations thereof. In the most preferred embodiment of the second aspect when it comes to the centrally acting m-opioid receptor agonist comprised in a dosage form, said centrally acting m-opioid receptor agonist is methadone or a pharmaceutically acceptable salt thereof, preferably methadone hydrochloride.

In yet another embodiment of the second aspect, said curcuminoid or

pharmaceutically acceptable salt thereof comprised in a dosage form is a linear diarylheptanoid (with the general formula as depicted above), which is preferably selected from the group consisting of curcumin, demethoxycurcumin,

bisdemethoxycurcumin, dimethoxycurcumin, tetrahydrocurcumin, pharmaceutically acceptable salts and combinations thereof. In the most preferred embodiment of the second aspect when it comes to the curcuminoid comprised in a dosage form, said curcuminoid is curcumin or a pharmaceutically acceptable salt thereof, preferably curcumin.

In a preferred embodiment of the second aspect, said kit further comprises a dosage form comprising a curcuminoid bioavailability enhancer. Preferably, said curcuminoid bioavailability enhancer comprised in a dosage form is selected from the group consisting of a liposome, an organic solvent, a cyclodextrin, a polymeric micelle, a surfactant, an alkaloid and combinations thereof. Any technique for mechanical reduction of the drug particle size to increase the surface area is also suitable to enhance the bioavailability.

Said organic solvent may be dimethylsulfoxide, ethyl acetate, or ethanol.

Said polymeric micelle may be PEG-Z>-PLA micelles (poly(ethylene glycol )-block- poly(D,L-lactic acid). Said surfactant may be polysorbate 80. Said alkaloid is preferably an alkaloid found in the genus Piper. The alkaloid found in genus Piper can be selected from the group consisting of pipeline and its stereoisomers such as chavicine.

In the most preferred embodiment of the second aspect when it comes to the curcuminoid bioavailability enhancer being comprised in a further dosage form of the kit, said curcuminoid bioavailability enhancer is piperine. Piperine may be used in combination with a cyclodextrin, preferably gamma-cyclodextrin.

The third aspect of the present invention In a third aspect, the present invention relates to a dosage form comprising a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and a curcuminoid or a pharmaceutically acceptable salt thereof. In an embodiment of the third aspect, said centrally acting m-opioid receptor agonist or pharmaceutically acceptable salt thereof comprised in the dosage form is selected from the group consisting of the opium alkaloids (in particular codeine and morphine); morphines (in particular dihydromorphine); esters of morphines (in particular heroin); codeine-dionines; morphinones/morphols (in particular oxycodone); morphides; dihydrocodeines; nitrogen morphine derivatives;

halogenated morphine derivatives; hydrazones; morphinans; benzomorphans;

phenylpiperidines (in particular pethidine); open chain opioids (in particular methadone); anilidopiperidines (in particular fentanyl); oripavine derivatives (in particular buprenorphine), phenazepanes (in particular meptazinol); piritramides (in particular piritramide); benzimidazoles; indoles (in particular mitragynine); beta- amino-ketones; diphenylmethylpiperazines; opioid peptides (in particular b- endorphin, endomorphin-1 and -2) or others with central m-opioid receptor activity (in particular tramadol and tapentadol), pharmaceutically acceptable salts thereof and combinations thereof. In the most preferred embodiment of the third aspect when it comes to the centrally acting m-opioid receptor agonist comprised in the dosage form, said centrally acting m-opioid receptor agonist is methadone or a

pharmaceutically acceptable salt thereof, preferably methadone hydrochloride.

In yet another embodiment of the third aspect, said curcuminoid or pharmaceutically acceptable salt thereof comprised in a dosage form is a linear diarylheptanoid (with the general formula as depicted above), which is preferably selected from the group consisting of curcumin, dem ethoxy curcumin, bisdem ethoxy curcumin,

dimethoxycurcumin, tetrahydrocurcumin, pharmaceutically acceptable salts and combinations thereof. In the most preferred embodiment of the third aspect when it comes to the curcuminoid comprised in a dosage form, said curcuminoid is curcumin or a pharmaceutically acceptable salt thereof, preferably curcumin.

In a preferred embodiment of the third aspect, said dosage form further comprises a curcuminoid bioavailability enhancer. Preferably, said curcuminoid bioavailability enhancer is selected from the group consisting of a liposome, an organic solvent, a cyclodextrin, a polymeric micelle, a surfactant, an alkaloid and combinations thereof. Any technique for mechanical reduction of the drug particle size to increase the surface area is also suitable to enhance the bioavailability.

Said organic solvent may be dimethylsulfoxide, ethyl acetate, or ethanol. Said polymeric micelle may be PEG-Z>-PLA micelles (poly(ethylene glycol )-block- poly(D,L-lactic acid). Said surfactant may be polysorbate 80. Said alkaloid is preferably an alkaloid found in the genus Piper. The alkaloid found in genus Piper can be selected from the group consisting of pipeline and its stereoisomers such as chavicine.

In the most preferred embodiment of the third aspect when it comes to the curcuminoid bioavailability enhancer being further comprised in the dosage form, said curcuminoid bioavailability enhancer is piperine. Pipeline may be used in combination with a cyclodextrin, preferably gamma-cyclodextrin.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the surprising finding that the combination of a centrally acting m-opioid receptor agonist, in particular methadone, and a

curcuminoid, in particular curcumin, is capable of treating cancer, wherein said cancer is a tumour of the central nervous system, preferably a glioblastoma. It was particularly surprising that by use of the dosage regimen according to the invention the tumor size could be reduced and the survival time of the patients could be significantly extended. This was also found in cases where the patient was resistant to treatment with conventional chemotherapy. The treatment of the invention was also effective in young glioblastoma patients, in particular of a 5year old child. In addition, when the inventive treatment was applied as adjunct therapy to

chemotherapy, it was observed that the side-effect profile was improved.

Before the present invention is described in more detail, the following definitions are introduced.

1. Definitions

As used in the specification and the claims, the singular forms of“a” and“an” also include the corresponding plurals unless the context clearly dictates otherwise.

The term“about” in the context of the present invention denotes an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±10% and preferably ±5%.

It needs to be understood that the term“comprising” is not limiting. For the purposes of the present invention, the term“consisting of’ is considered to be a preferred embodiment of the term“comprising”. If hereinafter a group is defined to comprise at least a certain number of embodiments, this is also meant to encompass a group which preferably consists of these embodiments only.

Unless defined otherwise, all technical and scientific terms used herein have the meanings as commonly understood by a skilled person. The term“centrally acting m-opioid receptor agonist” as used herein includes one centrally acting m-opioid receptor agonist or a combination of more than one centrally acting m-opioid receptor agonist; a partial centrally acting m-opioid receptor agonist; stereoisomers thereof; or a mixture of any of the foregoing. Even if not explicitly stated, pharmaceutically acceptable salts of the centrally acting m-opioid receptor agonists are also meant to be encompassed unless reference is made to a specific salt (e.g. the hydrochloride salt) or the free base.

“Centrally acting” means that the main biological effect(s) of the receptor agonist are mediated by receptors of the central nervous system, however, such agonist might to some extent also act at peripheral receptors, which are mainly located at peripheral sensory neurons and in the intestinal tract. This distinguishes the opioid receptor agonist of the present invention from those opioid receptor agonists of which the main biological effect(s) are mediated by opioid receptors located outside the CNS. Furthermore, an opioid receptor agonist not acting at the m-opioid receptor is also not an opioid receptor agonist of the present invention.

“m-opioid receptor agonists” useful in the present invention include, but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, buprenorphine, codeine, dextromoramide, dextropropoxyphene, dezocine, dihydrocodeine, dihydroetorphine, dihydromorphine, dimethylthiambutene, ethylmethylthiambutene, ethylmorphine, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levacetylmethadol, levorphanol, meptazinol, metazocine, methadone, metopon, mitragynine, morphine, myrophine, nicomorphine, norlevorphanol, normethadone, , oxycodone,

oxymorphone, , pethidine, phenomorphan, piritramide, remifentanil, sufentanil, tapentadol, tilidine, tramadol, pharmaceutically acceptable salts, hydrates and solvates thereof, mixtures of any of the foregoing, and the like. “Opioid peptides” useful in the present invention means the group of endorphins, endomorphins, enkephalins, and dynorphin A_I.8, whereby the group of endorphins encompasses a-endorphin, b-endorphin, g-endorphin and d-endorphin, the group of endomorphins encompasses endomorphin-1 and -2, and the group of enkephalins encompasses met-enkephalin, lleu-enkephalin, metorphamide and peptide E.

The term“curcuminoid” as used herein describes an organic compound having a linear diarylheptanoid structure with the following formula:

Curcumin (R1 = R4 = OH; R2 = R3 = OMe), also called diferuloylmethane, is one of the most commonly used and highly researched natural curcuminoids and the principal curcuminoid of turmeric ( Curcuma longa ), a member of the ginger family (. Zingiberaceae ). If reference is made herein to curcumin, demethoxycurcumin (R1 = R4 = OH; R2 = OMe; R3 = H), bisdem ethoxy curcumin (R1 = R4 = OH; R2 = R3 = H), dimethoxycurcumin (R1 = R2 = R3 = R4 = OMe) or tetrahydrocurcumin (R1 = R4 = OH; R2 = R3 = OMe), in which both double bonds (labelled 1 and 2) are reduced by H to single bonds, this is meant to include a tautomer thereof (in particular the keto or enol form) and a stereoisomer thereof (in particular all-trans or cis,trans). If reference is made herein to curcumin without explicit reference to a pharmaceutically acceptable salt thereof, this means that curcumin as such is used. The term“pharmaceutically acceptable salt” as used herein in particular refers to those containing counterions present in drug products listed in the US FDA Orange Book database. Such salts can be formed in a customary manner, e.g., by reacting the compound with an acid of the anion in question if the compound has a basic functionality or by reacting an acidic compound with a suitable base. Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH ⁺) and substituted ammonium. Suitable acidic counterions are in particular chloride, bromide, hydrogensulfate, sulfate,

dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C _r C₄-alkanoic acids, preferably formate, acetate, propionate and butyrate, furthermore lactate, gluconate, and poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate.

The term“curcuminoid bioavailability enhancer” as used herein refers to agents or delivery systems capable of improving a curcuminoid’ s bioavailability, in particular if the curcuminoid is orally administered. Generally, curcuminoids exhibit a rather low bioavailability such that they are usually either used at a higher concentration, e.g. when applied orally, or administered together with a“curcuminoid

bioavailability enhancer” in order to improve their systemic availability. In particular a“liposome” as curcuminoid bioavailability enhancer forms a carrier system, by which the curcuminoid’ s uptake into the systemic circulation is greatly increased. The present application does not describe new systems for increasing the uptake and thus the bioavailability of a curcuminoid but rests on presently applied systems, such as e.g. the liposome-system described in Wang Y et al. (2017)“The functional curcumin liposomes induce apoptosis in C6 glioblastoma cells and C6 glioblastoma stem cells in vitro and in animals”. Int J Nanomedicine 12, 1369-84. The term“genus Piper” may also be referred to as the“pepper” plant of the family of Piperaceae.

The term“chemotherapy” is used herein in its common meaning and e.g. refers to the administration of DNA-alkylating agents to kill proliferating cancer cells.

Temozolomide is an example of a chemotherapeutic agent used in the treatment of glioblastoma.

The term“radiotherapy” is used herein in its common meaning when it comes to cancer treatment, namely the local induction of DNA damage (as selective as possible) in cancer cells by DNA ionization and stimulation of the production of reactive oxygen species to kill proliferating cancer cells.

The term“biotherapy” as used herein refers to cancer treatments, which are based on biological systems or defined biological structures to fight cancer via various pathways. Examples are the administration of therapeutic antibodies, engineered T- cells and cytokines.

2. A dosage form of the present invention

The term“for use in the treatment of cancer” is used herein in the meaning of a second medical indication in line with the wording required by the EPO. Alternative wordings are“use of a combination of a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and a curcuminoid or a

pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer” (so-called“Swiss-type” format) or“method of treating cancer, comprising administering to a subject in need thereof an effective amount of a combination of a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and a curcuminoid or a pharmaceutically acceptable salt thereof’ (so-called“method of treatment” format). Such alternative wordings are meant to be encompassed by the present“for use” wording and may be used in jurisdictions, where such wordings are mandatory for second medical use claims. Corresponding reformulations in accordance with the above wordings (but also different wordings, if applicable) may be carried out using the present“for use” language as basis.

The centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and the curcuminoid or a pharmaceutically acceptable salt thereof as disclosed herein in combination are the“pharmaceutically active agents”, which may be present in separate dosage forms (but administered in combination) or in a single dosage form.

“Pharmaceutically active agent” as used herein means that a given agent is capable of modulating a response in a human or animal being in vivo. The term

“pharmaceutically acceptable excipient” as used herein refers to a component commonly comprised in a dosage form, which are known to the skilled person. Such components are exemplary listed below. In view of the definition“pharmaceutically active agent” as given above, a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive.

A dosage form according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal, intrathecal, intracranial or parenteral application.

A dosage form may be formulated to provide an immediate or a sustained release of the pharmaceutically active agents.

Oral application is particularly preferred for the combination of the present invention in view of the patient compliance. Prior to the invention it was known that upon oral administration curcumin is only available to a limited extent in the blood stream. It was considered that due to the low systemic availability this prevents the use of curcumin as a chemopreventive agent for target organs distant from the intestinal tract (Garcea et al., Cancer Epidemiol Biomarkers & Prevention 14 (2005), 120-125).

In general, a dosage form can comprise various pharmaceutically acceptable excipients, which will be selected depending on which functionality is to be achieved for the dosage form. A“pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, release-modifying materials, carrier materials, diluents, binding agents and other adjuvants. Typical pharmaceutically acceptable excipients include substances such as sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants and buffering agents.

The term“carrier material” denotes pharmaceutically acceptable organic or inorganic carrier substances, with which the active agents may be combined to facilitate the application. Suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohols, oils, preferably vegetable oils, polyethylene glycols, gelatine, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides and diglycerides, hydroxymethyl-cellulose, polyvinylpyrrolidone and the like. A dosage form can be sterilized and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colourings, flavouring and/or aromatic substances and the like, which do not deleteriously react with the pharmaceutically active agents. If liquid dosage forms are considered for the present invention, these can include pharmaceutically acceptable emulsions, solutions, suspensions and syrups containing inert diluents commonly used in the art such as water. Such dosage forms may contain e.g. microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavouring agents.

For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Dosage forms for parenteral administration can include aqueous solutions in water- soluble form. Additionally, suspensions may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.

Suppositories for rectal administration can be prepared by e.g. mixing the pharmaceutically active agents of the present invention with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the pharmaceutically active agents from said suppositories. Oral dosage forms are particularly preferred and may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, effervescent formulations, dragees and granules. Dosage forms for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatine, gum tragacanth, methyl cellulose,

hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or

polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Oral dosage forms may be formulated to ensure an immediate or a sustained release of the pharmaceutically active agents.

Tablets and liquid dosage forms comprising the specific opioid receptor agonist methadone hydrochloride are inter alia known from substitution therapy. Such tablets or liquids may suitably be used in the present invention for the treatment of cancer, particularly glioblastoma or pancreatic adenocarcinoma, when it comes to the specific opioid receptor agonist to be administered in combination with the curcuminoid. A particularly suitable curcuminoid is curcumin, in combination with methadone hydrochloride.

Tablets or capsules comprising curcumin are inter alia known from an anti inflammatory use. Such tablets or capsules may suitably be used in the present invention for use in the treatment of cancer, particularly glioblastoma or pancreatic adenocarcinoma, when it comes to the specific curcuminoid to be administered in combination with the opioid receptor agonist. A particularly suitable opioid receptor agonist is methadone hydrochloride, in combination with curcumin.

Dosage regimen

As regards human patients, the pharmaceutically active agents may be administered as follows, preferably orally: 1 mg to 100 mg methadone HC1 (or an equipotent amount of a different centrally acting m-opioid receptor agonist) per day; 1 g to 10 g curcumin (or an equipotent amount of a different curcuminoid) per day, if no curcuminoid bioavailability enhancer is concurrently administered; 10 mg to 1000 mg curcumin (or an equipotent amount of a different curcuminoid) per day in combination with 0.5 mg to 15 mg piperine as curcuminoid bioavailability enhancer (or an equal-enhancing amount of a different curcuminoid bioavailability enhancer) per day, optionally further in combination with a gamma-cyclodextrin in an amount of 20-5000 mg per day (or an equal-enhancing amount of a different curcuminoid bioavailability enhancer) per day.

In one preferred embodiment a human glioblastoma patient is administered a daily dosage of 2 to 20 mg centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof, 50 to 150 mg curcuminoid or a pharmaceutically acceptable salt thereof and 2 to 500 mg of at least one curcumin bioavailability enhancer.

Preferably the centrally acting m-opioid receptor agonist is methadone or a salt thereof, the curcuminoid is curcumin and the curcumin bioavailability enhancer is piperine and/or gamma-cyclodextrin. Preferably, the daily dosage is administered orally once, twice or three times daily.

More preferably, a human glioblastoma patient is administered a daily dosage of 8 to 12 mg methadone or a salt thereof, 70 to 110 mg curcumin, 3 to 5 mg piperine, and gamma-cyclodextrin (1 : 1 molar ratio of curcumimgamma-cyclodextrin). Particularly preferred the daily dosage consists of 10 mg methadone hydrochloride, 90 mg curcumin, 4.5 mg piperine, and gamma-cyclodextrin (1 : 1 molar ratio of

curcumimgamma-cyclodextrin). It is preferred that the daily dosage is administered once daily, twice daily or three times daily.

Particularly preferred, the centrally acting m-opioid receptor agonist or a

pharmaceutically acceptable salt thereof is administered twice daily, while the curcuminoid or the pharmaceutically acceptable salt thereof and the curcumin bioavailability enhancer are administered three times daily.

In a further preferred embodiment a human glioblastoma patient who is a child from 1 to 15 years, preferably 4 to 10 years is administered a daily dosage of 1 to 10 mg of a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof, 10 to 100 mg of a curcuminoid or a pharmaceutically acceptable salt thereof, and 0.5 to 500 mg of a curcumin bioavailability enhancer. Preferably the centrally acting m-opioid receptor agonist is methadone or a salt thereof, the curcuminoid is curcumin and the curcumin bioavailability enhancer is pipeline and/or gamma- cyclodextrin. Preferably, the daily dosage is administered orally once, twice or three times daily. More preferably, the young human patient is administered a daily dosage from 1 to 6 mg of methadone or a salt thereof, 20 to 50 mg of a curcumin and 0.5 to 3 mg of pipeline, and gamma-cyclodextrin (1 : 1 molar ratio of curcumimgamma- cyclodextrin).

Particularly preferred, the centrally acting m-opioid receptor agonist or a

pharmaceutically acceptable salt thereof is administered once daily, and the curcuminoid or the pharmaceutically acceptable salt thereof and the curcumin bioavailability enhancer are also administered once daily.

In a further aspect the present invention relates to a method for the prevention and/or treatment of a cancer of the central nervous system, preferably a human glioblastoma comprising administering a centrally acting m-opioid receptor agonist or a

pharmaceutically acceptable salt thereof as defined above and a curcuminoid or a pharmaceutically acceptable salt thereof as defined above to a patient in need thereof. The dosage regimen to be used for the above method are the same as described in detail in the preceding paragraph“dosage regimen”.

A kit as described in the second aspect of the present invention or a dosage form as described in the third aspect of the present invention may comprise the two pharmaceutically active agents of the present invention, namely the centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and the curcuminoid or a pharmaceutically acceptable salt thereof, as the only

pharmaceutically active agents. Alternatively, said kit or dosage form may comprise at least one further pharmaceutically active agent in addition to said two agents. Said kit or said dosage form is used in the treatment of cancer, wherein said cancer is a tumour of the central nervous system, most preferably in the treatment of a glioblastoma, such that the at least one further pharmaceutically active agent is also directed to the treatment of the above cancer types (such as in particular a chemotherapeutic agent). 3. The present invention

Centrally acting m-opioid receptor agonists and in particular methadone have been discussed and claimed as agents capable of treating cancer patients, see e.g. EP 2 149 372 Bl. However, recently the use of methadone in cancer therapy has very controversially been discussed in the media (see e.g. Hiibner J et al. (2017)

“Methadon in der Onkologie:“Strohhalmfunktion” ohne Evidenz”. Dtsch Arztebl 114(33-34): A-1530 / B-1298 / C-1269), and a recent article by Onken J et al. (2017) (“Safety and tolerance of D,L-methadone in combination with chemotherapy in patients with glioma”. Anticancer Res 37(3), 1227-36) summarises the findings of a study in 27 patients as follows:“ Despite the promising results from laboratory data and the safe and well-tolerated application of D,L-methadone in glioma patients found in this study, reliable clinical data are lacking, providing evidence that D,L- methadone has substantial antitumor effects in patients with glioma” Furthermore, and as another example, Zagon IS and McLaughin PJ (2003) (“Opioids and the apoptotic pathway in human cancer cells”. Neuropeptides 37(2), 79-88) reported that the application of methadone could not be shown to inhibit the growth of three human cancer cell lines including the MIA PaCa-2 pancreatic

adenocarcinoma cell line.

Thus, there is no reliable clinical evidence that methadone (or a centrally acting m- opioid receptor agonist) is indeed capable of treating cancer, if methadone (or a centrally acting m-opioid receptor agonist) is administered as the sole

pharmaceutically active agent or as sole adjunct therapy to conventionally used cancer therapies, such as e.g. chemotherapy or radiotherapy. The effect of curcumin as the most frequently studied member of the curcuminoids was inter alia determined on brain tumours of glioblastoma patients, see Diitzmann S et al. (2016)“ Intratumor al concentrations and effects of orally administered micellar curcuminoids in glioblastoma patients" . Nutr Cancer 68(6), 943-8. Diitzmann et al. conclude:“ While the resulting intratumoral concentration might not be sufficient to cause significant short-term antitumor effects, it may be high enough to achieve long-term tumor control. The reason for the low bioavailability of curcumin in the tumor tissue despite high serum concentrations unfortunately remains speculative Thus, no immediate effect on the tumour could be observed, and earlier reports of the in vitro effect of curcumin on the glioblastoma cell line U-251 did not show any effect on the proliferation at all (see WO 95/18606, Table I on pages 10 and 11, “relative cell viability (% of control)” for glial U-251 cells of 103±3). Thus, there is no reliable clinical evidence that curcumin (or a curcuminoid) is indeed capable of treating in particular a glioblastoma, if curcumin (or a

curcuminoid) is administered as the sole pharmaceutically active agent or as sole adjunct therapy to conventionally used cancer therapies, such as e.g. chemotherapy or radiotherapy.

The present invention is based on the surprising finding that it is the combination of a centrally acting m-opioid receptor agonist, in particular methadone, and a

curcuminoid, in particular curcumin (optionally administered together with one or more curcuminoid bioavailability enhancer) that is indeed capable of achieving the effect, which neither of said pharmaceutically active agents is capable of achieving alone, namely the treatment of a tumour of the central nervous system, in particular a glioblastoma.

4. Prior art discussion US 2016/0324843 discloses an anticancer supplement containing loperamide as an active ingredient, wherein this supplement is used together with a proteasome inhibitor for the treatment of cancer. Curcumin is listed as a potential proteasome inhibitor in this prior art document.

The present invention is distinguished over US 2016/0324843 at least in that loperamide as peripherally acting m-opioid receptor agonist is not encompassed by the term“centrally acting m-opioid receptor agonist”. Clearly, when treating a tumour of the central nervous system, a peripherally acting m-opioid receptor agonist such as loperamide would not be feasible in the combination of the present invention.

EP 2 716 291 discloses novel strategies for the treatment of cancer patients based on a combination of an opioid receptor agonist and an anticancer compound. EP 2 716 291 in particular focuses on methadone as the opioid receptor agonist. Anticancer compounds are inter alia disclosed in claim 9 of E 2716 291 as published.

The present invention is distinguished over EP 2 716 291 at least in that a

curcuminoid is not disclosed in EP 2 716 291 as anticancer compound. While the “usual suspects” of anticancer compounds are stated in EP 2 716 291, namely intercalating substances, topoisomerase inhibitors, nitrosourea compounds, nitrogen mustards, alkyl sulfonates, alkylating agents, platinum analogues, microtubule disruptive drugs, antifolates, purine analogues, pyrimidine analogues, steroid hormones, anti-cancer antibodies, anti-cancer peptides, irradiation, electron particles, and radioactively labelled chemical compounds, a curcuminoid, let alone curcumin, is not disclosed therein.

5. Examples

5 1 Example 1 : 58-year old male patient suffering from glioblastoma

A glioblastoma was surgically removed from the patient, followed by standard radiotherapy and chemotherapy with temozolomide. A few months after surgery, a significant re-growth of the tumour was measured and confirmed during the following months.

2 x 5 mg of methadone hydrochloride per day (one pill in the morning, one in the evening) were then administered to the patient for more than two months. After a methadone-only administration for one month, the patient received orally, in addition to the afore-mentioned methadone administration, a mixture of 90 mg of curcumin, 4.5 mg of piperine, and gamma-cyclodextrin (in an about 1 : 1-molar ratio of curcumimgamma-cyclodextrin) in three pills each containing 1/3 of above listed amounts of components per day (morning, noon, evening) for more than a month.

The treatment scheme of the combination for more than one month as outlined above resulted in a significant regression of the tumour size, which made it necessary to re calculate the radiation dose in the subsequent radiotherapy, reducing the dose by a factor of about three compared to the originally planned dose. Thus, the combination of methadone, curcumin and curcumin bioavailability enhancers resulted in a decrease of the tumour size as measured by standard gadolinium contrast agent- enhanced MRI. Furthermore, the above treatment scheme using the combination led to significantly reduced side effects and to almost normalized blood parameters such as the number of neutrophilic granulocytes and the number of thrombocytes. The patient himself as well as people knowing the patient observed a significantly improved agility, well feeling and positive attitude after the above combination treatment scheme. Thus, the combination of methadone, curcumin and curcumin bioavailability enhancers resulted in an improved side effect profile.

Contrary to the original prediction of a residual lifetime of at maximum three to four months, the patient could surprisingly add more than 1.5 years on top of the initial three to four months lifetime expectation. Thus, the combination of methadone, curcumin and curcumin bioavailability enhancers at least significantly increased the lifetime.

5.2. Example 2: 5-vear old male patient suffering from glioblastoma

The above patient was presented with glioblastoma and a history of radiotherapy and chemotherapy.

After the standard radiotherapy and chemotherapy, methadone and

curcumin/piperine/gamma-cyclodextrin were administered to the child for several weeks: 2.5 mg of methadone hydrochloride once per day plus one separate pill with 30 mg of curcumin, 1.5 mg of piperine, and gamma-cyclodextrin (in an about 1 : 1- molar ratio of curcumimgamma-cyclodextrin) once per day. It was only after the additional therapy with methadone and

curcumin/piperine/gamma-cyclodextrin that a regression of the tumour could be observed. Further, only after this additional therapy, the child very rapidly regained physical activity and obviously felt much more comfortable, in sharp contrast to the time before administration of methadone and curcumin/piperine/gamma- cyclodextrin.

Thus, the combination of methadone, curcumin and curcumin bioavailability enhancers resulted in a decrease of the tumour size and an overall improved side effect profile taking into account that the combination was used as adjunct therapy.

Claims

1. A combination of a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and a curcuminoid or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, wherein said cancer is a tumour of the central nervous system.

2. The combination for use according to claim 1, wherein said tumour of the central nervous system is a glioblastoma.

3. The combination for use according to claim 1 or 2, wherein said treatment results in a reduction in tumor size and/or increased survival time in a human patient, preferably a human glioblastoma patient, more preferably the treatment results in a reduction in tumor size of at least 25 % compared to treatment start.

4. The combination for use according to any one of claims 1 to 3, wherein the patient to be treated is a chemotherapy-resistant glioblastoma patient.

5. The combination for use according to any one of claims 1 to 4, wherein said centrally acting m-opioid receptor agonist or pharmaceutically acceptable salt thereof is selected from the group consisting of alfentanil,

allylprodine, alphaprodine, anileridine, benzylmorphine, buprenorphine, codeine, dextromoramide, dextropropoxyphene, dezocine, dihydrocodeine, dihydroetorphine, dihydromorphine, dimethylthiambutene, ethylmethylthiambutene, ethylmorphine, etorphine, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levacetylmethadol, levorphanol, meptazinol, metazocine, methadone, metopon, mitragynine, morphine, myrophine, nicomorphine, norlevorphanol, normethadone, oxycodone, oxymorphone, pethidine, phenomorphan, piritramide, remifentanil, sufentanil, tapentadol, tilidine, tramadol, an endorphin, an endomorphin, an enkephalin, dynorphin A_I.8, pharmaceutically acceptable salts thereof and combinations thereof.

6. The combination for use according to any one of claims 1 to 5, wherein said centrally acting m-opioid receptor agonist or pharmaceutically acceptable salt thereof is methadone or a pharmaceutically acceptable salt thereof, preferably methadone hydrochloride.

7. The combination for use according to any one of claims 1 to 6, wherein said curcuminoid or pharmaceutically acceptable salt thereof is a linear diarylheptanoid, wherein said linear diarylheptanoid is preferably selected from the group consisting of curcumin, dem ethoxy curcumin, bisdem ethoxy curcumin, dimethoxycurcumin, tetrahydrocurcumin, pharmaceutically acceptable salts thereof and combinations thereof.

8. The combination for use according to any one of claims 1 to 7, wherein said curcuminoid or pharmaceutically acceptable salt thereof is curcumin or a pharmaceutically acceptable salt thereof, preferably curcumin.

9. The combination for use according to any one of claims 1 to 8, wherein said curcuminoid or pharmaceutically acceptable salt thereof is used together with a curcuminoid bioavailability enhancer.

10. The combination for use according to claim 9, wherein said curcuminoid bioavailability enhancer is selected from the group consisting of a liposome, an organic solvent, a cyclodextrin, a polymeric micelle, a surfactant, an alkaloid and combinations thereof.

11. The combination for use according to any one of claims 1 to 3, wherein said centrally acting m-opioid receptor agonist is methadone or a pharmaceutically acceptable salt thereof, preferably methadone hydrochloride; wherein said curcuminoid is curcumin or a pharmaceutically acceptable salt thereof, preferably curcumin; and wherein said curcuminoid or pharmaceutically acceptable salt thereof is used together with piperine and/or gamma-cyclodextrin as

curcuminoid bioavailability enhancer.

12. The combination for use according to claim 11, wherein a human glioblastoma patient is administered a daily dosage of 1 mg to 100 mg centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof, 10 to 1000 mg curcuminoid or a pharmaceutically acceptable salt thereof, 0.5 mg to 5000 mg curcumin bioavailability enhancer, preferably the dosage is administered orally.

13. The combination for use according to claim 11 or 12, wherein a human glioblastoma patient is administered a daily dosage of 8 to 12 mg methadone or a salt thereof, 70 to 110 mg curcumin, 3 to 5 mg piperine and gamma-cyclodextrin (1 : 1 molar ratio of curcumimgamma-cyclodextrin), preferably the daily dosage consists of 10 mg methadone hydrochloride, 90 mg curcumin and 4.5mg piperine, and gamma-cyclodextrin (1 : 1 molar ratio of curcumimgamma-cyclodextrin).

14. The combination for use according to claim 11, wherein a human glioblastoma patient who is a child from 1 to 15 years, preferably 4 to 10 years is administered a daily dosage of 1 to 10 mg of a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof, 10 to 100 mg of a curcuminoid or a pharmaceutically acceptable salt thereof, and 0.5 to 500 mg of a curcumin bioavailability enhancer, preferably the dosage is administered orally.

15. The combination for use according to claim 14, wherein said patient being from 1 to 15 years is administered a daily dosage from 1 to 6 mg methadone or a salt thereof, 20 to 50 mg curcumin and 0.5 to 3 mg piperine, and gamma- cyclodextrin (1 :1 molar ratio of curcumimgamma-cyclodextrin), preferably the daily dosage is 2.5 mg methadone hydrochloride, 30 mg curcumin and 1.5 mg piperine, and gamma-cyclodextrin (1 : 1 molar ratio of curcumimgamma-cyclodextrin).

16. The combination for use according to any one of claims 11 to 15, wherein the daily dosage is administered once daily, twice daily or three times daily, preferably orally.

17. A method for the prevention and/or treatment of a cancer of the central nervous system, preferably a human glioblastoma, comprising administering a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 16, a curcuminoid or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 16 and a curcumin bioavailability enhancer as defined in any one of claims 1 to 16 to a patient in need thereof.

18. The method according to claim 17, wherein said treatment results in a reduction in tumor size and/or increased survival time in a human patient, preferably a human glioblastoma patient.

19. The method according to claim 17 or 18, wherein the patient to be treated is a chemotherapy -resistant glioblastoma patient.

20. The method according to any one of claims 17 to 19 comprising administering a daily dosage of 1 mg to 100 mg centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof, 10 mg to 1000 mg a curcuminoid or a pharmaceutically acceptable salt thereof, and 0.5 mg to 5000 mg curcumin bioavailability enhancer, preferably the dosage is administered orally.

21. The method according to any one of claims 17 to 20 comprising administering a daily dosage of 8 to 12 mg methadone or a salt thereof, 70 to 110 mg curcumin, 3 to 5 mg piperine, and gamma-cyclodextrin (in an 1 : 1 molar ratio of curcumimgamma-cyclodextrin), preferably the daily dosage consists of 10 mg methadone hydrochloride, 90 mg curcumin, 4.5 mg piperine, and gamma- cyclodextrin (in an 1 : 1 molar ratio of curcumimgamma-cyclodextrin).

22. The method according according to any one of claims 17 to 19, wherein a human glioblastoma patient who is a child from 1 to 15 years, preferably 4 to 10 years is administered a daily dosage of 1 to 10 mg of a centrally acting m- opioid receptor agonist or a pharmaceutically acceptable salt thereof, 10 to 100 mg of a curcuminoid or a pharmaceutically acceptable salt thereof, and 0.5 to 500 mg of a curcumin bioavailability enhancer, preferably the dosage is administered orally.

23. The combination for use according to claim 22, wherein said patient being from 1 to 15 years is administered a daily dosage from 1 to 6 mg of methadone or a salt thereof, 20 to 50 mg of a curcumin and 0.5 to 3 mg of piperine and gamma- cyclodextrin (1 :1 molar ratio of curcumimgamma-cyclodextrin), preferably the daily dosage is 2.5 mg methadone hydrochloride, 30 mg curcumin and 1.5 mg piperine and gamma-cyclodextrin (1 : 1 molar ratio of curcumimgamma-cyclodextrin).

24. The method according to any one of claims 17 to 23, wherein the daily dosage is administered once daily, twice daily or three times daily, preferably orally.

25. A kit of dosage forms comprising a. a dosage form comprising a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof; and

b. a dosage form comprising a curcuminoid or a pharmaceutically

acceptable salt thereof.

26. The kit according to claim 25, further comprising a dosage form comprising a curcuminoid bioavailability enhancer.

27. The kit according to claim 25 or 26 comprising a. a dosage form comprising methadone or a pharmaceutically acceptable salt thereof, preferably methadone hydrochloride;

b. a dosage form comprising curcumin or a pharmaceutically acceptable salt thereof, preferably curcumin; and

c. a dosage form comprising pipeline and/or gamma-cyclodextrin as curcuminoid bioavailability enhancer.

28. A dosage form comprising a centrally acting m-opioid receptor agonist or a pharmaceutically acceptable salt thereof and a curcuminoid or a

pharmaceutically acceptable salt thereof.

29. The dosage form according to claim 28, wherein said dosage form further comprises a curcuminoid bioavailability enhancer.

30. The dosage form according to claim 28 or 29 comprising methadone or a pharmaceutically acceptable salt thereof, preferably methadone hydrochloride; curcumin or a pharmaceutically acceptable salt thereof, preferably curcumin, and pipeline and/or gamma-cyclodextrin as curcuminoid bioavailability enhancer.