Compositions and methods for treating cancer diseases

Abstract

The present invention relates to pharmaceutical combinations for treating various cancer diseases. The present invention also relates to methods of treating cancers comprising use of a combination of drugs, targeting cancer cell metabolism (including glycolysis and mitochondrial substrate-level phosphorylation) and cancer stem cells and metastases.

Description

[0001] Compositions and methods for treating cancer diseases

[0002] TECHNICAL FIELD

[0003] The present invention relates to pharmaceutical combinations for treating various cancer diseases. The present invention also relates to methods of treating cancers comprising use of a combination of drugs, targeting cancer cell metabolism (including glycolysis and mitochondrial substrate-level phosphorylation) and cancer stem cells and metastases.

[0004] BACKGROUND

[0005] Cancer remains a significant global public health challenge, with 19.3 million new cases and 10 million deaths reported annually. Despite research investments exceeding $24 billion between 2016 and 2020, this multifactorial disease continues to challenge the scientific community due to the complexity and ambiguity of its underlying mechanisms. Several theories attempt to explain the origins of cancer, including the somatic mutation theory, the mitochondrial metabolic theory, the cancer stem cell theory, and the tissue organization field theory of cancer. Indeed, there are commonalities across all types of cancer. The most significant — and often overlooked — is that in nearly all advanced cancers, mitochondria exhibit alterations in their number, function, and structure. This mitochondrial dysfunction leads cancer cells to shift away from conventional energy production pathways, such as glucose metabolism and oxidative phosphorylation, and instead rely primarily on glucose and mitochondrial substrate-level phosphorylation. These two fermentable fuels are essential and sufficient for tumor survival and progression.

[0006] A more effective cure is needed to treat cancer, especially for metastatic and aggressive non-operable cancers, where the 5-year survival rate remains low.

[0007] An objective of the present invention is to provide a new method for treating cancer, targeting the connection between metabolism and cancer cells, including glycolysis and mitochondrial substrate-level phosphorylation in cancer cells including cancer stem cells, and metastases.

[0008] SUMMARY OF THE INVENTION

[0009] It is an object of the invention to provide effective pharmaceutical combinations for use in methods of treating cancer. To this end, the present invention provides a pharmaceutical combination for use in a method of treating a cancer in a subject, said combination comprising at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole, selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times. In a preferred embodiment, the benzimidazole is mebendazole.In some embodiments, the present invention provides a pharmaceutical combination for use in a method of treating a cancer in a subject, said combination comprising at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole, selected from mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times.

[0010] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, wherein the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof.

[0011] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein wherein the subject is a human.

[0012] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, preferably about 1.5 mg / kg / day.

[0013] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day, preferably 15 mg / kg / day to 200 mg / kg / day, more preferably about 100 mg / kg / day.

[0014] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, preferably about 1.5 mg / kg / day, and the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day, preferably 15 mg / kg / day to 200 mg / kg / day, more preferably about 100 mg / kg / day.

[0015] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the dose of the avermectin and benzimidazole is in a ratio of 1 :1 to 1 :600, preferably about 1 :67.

[0016] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 0.5 mg / kg / day to 100 mg / kg / day, preferably about 20 mg / kg / day.

[0017] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1 :1 to 1 :200, preferably about 1:13.

[0018] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the benzimidazole is fenbendazole and / oroxfendazole, and it is administered in a dose of 0.5 mg / kg / day to 100 mg / kg / day, preferably about 20 mg / kg / day, and wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1 :1 to 1 :200, preferably about 1:13.

[0019] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein wherein the subject is an animal, such as murine species, canids, and felids.

[0020] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day, preferably about 10 mg / kg / day.

[0021] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, preferably about 100 mg / kg / day.

[0022] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day, preferably about 10 mg / kg / day, and wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, preferably about 100 mg / kg / day.

[0023] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the dose of the avermectin and benzimidazole is in a ratio of 1 :1 to 1 :600, preferably about 1:10.

[0024] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg. In a preferred embodiment, the benzimidazole is mebendazole.

[0025] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg.

[0026] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :300, preferably about 1:10.

[0027] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, flubendazole,oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg, and wherein the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:300, preferably about 1:10.

[0028] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day.

[0029] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day.

[0030] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day.

[0031] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200, preferably about 1 :5.

[0032] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day, and wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200, preferably about 1 :5.

[0033] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day, and wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200, preferably about 1 :5.

[0034] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day, and wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200, preferably about 1 :5.

[0035] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, wherein the combination further comprises one or more of oleic acid,glycerol trioleate, Span 80, Tween 80, soybean oil, olive oil, coconut oil, fish oil, polyethylene glycol, natural phospholipids, and mannitol.

[0036] Another object of the present invention is to provide a method of treating a cancer in a subject. To this end, the present invention provides a method of treating a cancer in a subject, comprising administering an avermectin in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, to the subject, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect. In a preferred embodiment, the benzimidazole is mebendazole.

[0037] In some embodiments, the present invention provides a method of treating a cancer in a subject, comprising administering an avermectin in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and a benzimidazole selected from mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, to the subject, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect.

[0038] In some embodiments, the present invention provides a method of treating a cancer as described herein, wherein the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof.

[0039] In some embodiments, the present invention provides a method of treating a cancer as described herein, wherein the subject is a human.

[0040] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, preferably about 1.5 mg / kg / day.

[0041] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day, preferably 15 mg / kg / day to 200 mg / kg / day, more preferably about 100 mg / kg / day.

[0042] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, preferably about 1.5 mg / kg / day, and wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day, preferably 15 mg / kg / day to 200 mg / kg / day, more preferably about 100 mg / kg / day.In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :600, preferably about 1 :50.

[0043] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, preferably about 1.5 mg / kg / day, and wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day, preferably 15 mg / kg / day to 200 mg / kg / day, more preferably about 100 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :600, preferably about 1 :67.

[0044] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 0.5 mg / kg / day to 100 mg / kg / day, preferably about 20 mg / kg / day.

[0045] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1 :1 to 1 :200, preferably about 1:13.

[0046] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 0.5 mg / kg / day to 100 mg / kg / day, preferably about 20 mg / kg / day, and wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1 :1 to 1 :200, preferably about 1:13.

[0047] In some embodiments, the present invention provides a method of treating a cancer as described herein, wherein the subject is an animal, such as murine species, canids, and felids.

[0048] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day, preferably about 10 mg / kg / day.

[0049] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, preferably about 100 mg / kg / day.

[0050] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the avermectin is administered in a dose of of 5 mg / kg / day to 40 mg / kg / day, preferably about 10 mg / kg / day, and wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, preferably about 100 mg / kg / day.

[0051] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :600, preferably about 1:10.In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the avermectin is administered in a dose of of 5 mg / kg / day to 40 mg / kg / day, preferably about 10 mg / kg / day, and wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, preferably about 100 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:600, preferably about 1:10.

[0052] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole , febantel, netobimin, or mixtures thereof, and the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, the benzimidazole is mebendazole.

[0053] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole , febantel, netobimin, or mixtures thereof, and the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day.

[0054] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :300, preferably about 1:10.

[0055] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole , febantel, netobimin, or mixtures thereof, and the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :300, preferably about 1:10.

[0056] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day.

[0057] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day.

[0058] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day.In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200, preferably about 1 :5.

[0059] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200, preferably about 1 :5.

[0060] In another aspect, the present invention provides a method of treating a cancer in a subject, comprising administration of a suitable dose of a combination of an avermectin and a benzimidazole, simultaneously or at different times, resulting in concomitant therapeutically effective plasma concentration of each to induce a synergistic effect. In some embodiments, the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof. In some embodiments, the benzimidazole is selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof. In a preferred embodiment, the benzimidazole is mebendazole.

[0061] In some embodiments, the benzimidazole is selected from mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof.

[0062] In some embodiments, the combination could be used with standard conventional treatments (such as chemotherapy, radiotherapy, proton therapy, radioligand therapy, immunotherapy, CAR T-cell therapy, targeted therapy, surgery, hormone therapy, stem cell transplant, bone marrow transplant, cryotherapy, hyperthermia, histotripsy, photodynamic therapy, targeted radionuclide therapy, antibody drug conjugates, monoclonal antibody, and / or palliative care, amongst others).

[0063] In some embodiments, the combination could be used with standard conventional treatments, preferably immunotherapy.

[0064] In some embodiments, the combination could be used with standard conventional treatments, preferably histotripsy.

[0065] In some embodiments, the combination could be used with metabolic therapy, preferably ketogenic metabolic therapy.

[0066] In some embodiments, the present invention provides a method as described herein, such that the administration results in a synergistic therapeutic effect which is more than the sum of the individual effect of each compound.DETAILED DESCRIPTION

[0067] Cancers originate from chronic alterations in oxidative phosphorylation, leading to metabolic reprogramming essential for the survival of cancer cells. Ivermectin, in combination with benzimidazoles, could represent a promising therapeutic approach to target these metabolic alterations.

[0068] Cancer cells, like all cells, require energy for their survival. Recent studies have demonstrated that cancer cells have a similar energy supply to healthy cells. Specifically, the AG’ of ATP (the standard energy of ATP hydrolysis under physiological conditions) is relatively similar for both healthy and cancerous cells. It is approximately -56 kilojoules, indicating that the efficiency of ATP utilization is comparable in both cancer and normal cells. The primary energy supply for cancer cells comes from glycolysis and mitochondrial substrate-level phosphorylation, processes that help establish the tumor microenvironment via lactate and succinate production. Ivermectin has shown notable effects on various cancer cell lines, promoting apoptosis in cancer cells in vivo and significantly reducing tumor volume compared to control groups. Its apoptotic effect is mediated through mitochondrial pathways. Moreover, ivermectin influences cancer cell metabolism by targeting pyruvate kinase muscle isoforms, a critical enzyme in the final step of glycolysis. It inhibits glycolysis, inducing autophagy, and has been shown to exert a selective prooxidant effect on cancer cells. Ivermectin is believed to restore eubiosis and reverse the dysbiosis that is frequently observed in cancer patients. Additionally, ivermectin is capable of targeting cancer stem cells (CSCs) and metastases, as well as modulating macrophage activity. In vitro studies indicate that ivermectin is more effective than chemotherapy (paclitaxel) at inhibiting CSCs in breast cancer cells. In vivo studies further suggest that ivermectin, when used alone, outperforms standard chemotherapy (gemcitabine) in reducing tumor weight and volume in pancreatic cancer models. Another drug class, the benzimidazoles, has demonstrated significant anticancer properties, particularly Fenbendazole and Mebendazole. These two compounds are structurally similar and show comparable efficacy in fighting cancer in both in vitro and in vivo models.

[0069] Benzimidazoles exert anticancer effects by disrupting microtubule polymerization, inducing apoptosis, arresting the cell cycle at the G2 / M phase, inhibiting angiogenesis, and interfering with glucose and mitochondrial substrate-level phosphorylation. Mebendazole can inhibit mitochondrial substrate-level phosphorylation and reduce glutamate, a-KG, and succinate. This occurs without necessarily affecting glutamine levels, suggesting an action on GLS-C, and could potentially implicate one or more alternative pathways, including GDH, GOT2, and MDH2. These alternative pathways are non-essential for immune cells but essential for cancer cells, enabling Mebendazole to selectively target these pathways in cancer cells while preserving immune function in patients. Apoptosis induction is linked to mitochondrial damage and is regulated by p53 expression. Furthermore, benzimidazoles target cancer stem cells (CSCs) and metastases, as well as chemoresistant cancer cells, including those resistant to cisplatin. In vitro, Mebendazole has proven more potent than other widely used chemotherapeutic agents, such as 5-fluorouracil, oxaliplatin, gemcitabine, irinotecan,paclitaxel, cisplatin, etoposide, and doxorubicin, against gastric cancer cell lines. Moreover, in vivo studies show that Mebendazole significantly extends survival in glioblastoma multiform models when compared to standard chemotherapy with temozolomide.

[0070] We present for the first time the use of a specific combination of repurposed drugs that target the inhibition of cancer cell metabolism to treat cancer diseases. The inhibition of cancer cell metabolism includes the inhibition of two major fermentable pathways, namely glycolysis (and its involved enzymes: Hexokinase / Glucokinase, Phosphoglucose isomerase, Phosphofructokinase-1 (PFK-1), Aldolase, Triose phosphate isomerase, Glyceraldehyde-3-phosphate dehydrogenase, Phosphoglycerate kinase, Phosphoglycerate mutase, Enolase, Pyruvate kinase) and the mitochondrial substrate-level phosphorylation (and the various enzymes involved: Glutaminases (including GLS-C and GS) and Glutamate dehydrogenase (GDH), Transaminases (aminotransferases) including aspartate aminotransferase (GOT2), Glutamate synthetase, Alpha-ketoglutarate dehydrogenase, and Malate dehydrogenase (MDH). Targeting these pathways in combination with these two repurposed drugs simultaneously has not been reported to date as being beneficial for patients with cancer diseases.

[0071] Ivermectin, although its anticancer effects are known, has been little used and investigated in oncology in humans. However, its tolerance and safety are well known, making it a safe substance. Benzimidazoles, and more specifically mebendazole, are studied and well-known, and are also very safe products, even at very high doses.

[0072] Molecules are generally studied separately in oncology; the present invention combines them for a superior, surprising effect.

[0073] We present the use of specific repurposed drugs that target the inhibition of fermentable fuels in cancer cells as potential treatments for cancer diseases in humans (or animals). The inhibitors of cancer cell metabolism comprise unusually high doses of:

[0074] • Ivermectin and mebendazole;

[0075] • Or ivermectin and fenbendazole;

[0076] • Or ivermectin and oxfendazole;

[0077] • Or ivermectin and flubendazole;

[0078] • Or ivermectin and oxibendazole;

[0079] • Or ivermectin and thiabendazole;

[0080] • Or ivermectin and nocodazole;

[0081] • Or ivermectin and methiazole;

[0082] Or ivermectin and triclabendazole;

[0083] Or ivermectin and ciclobendazole;Or ivermectin and cambendazole;

[0084] • Or ivermectin and ricobendazole;

[0085] • Or ivermectin and febantel;

[0086] • Or ivermectin and netobimin;

[0087] • And / or a derivative thereof.

[0088] Those molecules can be administered orally.

[0089] Definitions

[0090] As used herein, ‘avermectin’ relates to a group of macrocyclic lactones produced by the Streptomyces avermitilis bacterium. These group of macrocyclic lactones belonging to the avermectin class may include abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof. Unless otherwise indicated, the present invention also encompasses any analogs or derivatives thereof.

[0091] As used herein, ‘benzimidazole’ refers to the heterocyclic aromatic parent structure comprising a fused benzene and imidazole ring system, including tautomeric forms thereof. Non-limiting examples include mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof. Unless otherwise indicated, the present invention also encompasses any analogs or derivatives thereof.

[0092] As used herein, ‘pharmaceutical combination’ refers to the specified active compounds being present together in a single formulation, or being present individually in separate formulations.

[0093] As used herein, ‘administered simultaneously’ means different compounds being present together in the same formulation for administration (for instance, in the same injection, tablet, etc.), or different compounds being present separately in different formulations wherein the formulations are administered at the same time, or administered at different times during the same hour, or administered at different times during the same part of the day (e.g. morning, afternoon, evening, night), or administered during the same day.

[0094] As used herein in reference to a numerical value (e.g. dosage, ratio, time), the term ‘about’ means approximately and includes the stated value plus or minus a range of variation that would be understood by a person of ordinary skill in the art in the context of the invention.

[0095] As used herein, ‘ratio’ refers to the proportional relationship between two doses, such as the doses of different components of a pharmaceutical combination, expressed as the quotient of one doses divided by another (e.g. A:B) such that the given ratio corresponds to fixed relative amounts of the active ingredients irrespective of the absolute dose levels. As will be understood from the above, any notation in the style of ‘A:B’ denotes the ratio of the dose of pharmaceutical compound A to the dose of pharmaceutical compound B, such that a combination havingcompounds A and B present in a ratio of A:B means the amount of A is to the amount of B as A is to B (e.g., 1:1 means equal amounts; 2:1 means twice as much A as B).

[0096] As used herein, ‘synergistic effect’ means an effect which is more than the sum of the individual effect of each compound.

[0097] For example, this can be measured using the Chou-Talalay method for calculating the Combination Index (Cl), which measures the interaction between the two substances. This calculation helps to determine whether the combined effect is greater than the sum of individual effects (synergy), equal to the sum (additive), or less (antagonism). Formula for Cl:

[0098] CI(£>1) + (g2)

[0099]

[0100] (Z?i + DT)

[0101] Where:

[0102] • D1 = Dose of the first drug in the combination.

[0103] • D2 = Dose of the second drug in the combination

[0104] • (D1 ) = Effect when using D1 alone

[0105] • (D2) = Effect when using D2 alone

[0106] • (D1 + D2) = Effect when using D1 + D2 together

[0107] The Cl is interpreted as follows:

[0108] • Cl = 1: There is an additive interaction (the combined effect is simply the sum of individual effects).

[0109] • Cl < 1 : There is synergy (the two drugs work better together than separately).

[0110] • Cl < 0.8: There is strong synergy (the two drugs work much better together than separately).

[0111] • Cl > 1 : There is antagonism (the two drugs neutralize each other or one prevents the effect of the other).

[0112] As used herein, ‘treating’ or ‘treat’ refers to any action intended to prevent, improve, ameliorate, stabilize, reduce, or otherwise affect a condition or its consequences. Non-limiting examples include prophylaxis, therapy, palliative care, maintenance therapy, rescue therapy, symptom management, and side-effect mitigation.

[0113] As used herein, ‘murine species’ refers to any member of the subfamily Murinae, typically including rodents of the genera Mus, Rattus, Apodemus, Neotoma, Peromyscus, andrelated taxa. Non-limiting examples include the house mouse, the brown rat, the black rat, the deer mouse, and the wood mouse.

[0114] As used herein, “canid” refers to any member of the family Canidae, encompassing both domestic and wild species that share a common lineage characterized by a elongated snout, non-retractile claws, and a primarily carnivorous diet. Non-limiting examples of canids include the domestic dog, the gray wolf, the coyote, the golden jackal, the dhole, the African wild dog, the red fox, the fennec fox, and the raccoon dog.

[0115] As used herein, “Felid” refers to any member of the family Felidae. Non-limiting examples include the lion, the tiger, the leopard, the jaguar, the snow leopard, the domestic cat, the African wildcat, the European wildcat, the lynx, the bobcat, the cougar / puma, the cheetah, the serval, the caracal, and the sand cat.

[0116] As used herein, the doses are defined in mg / kg / day, and mean the milligram amount of a particular compound intended per kilogram of the weight of the subject in a single day.

[0117] Pharmaceutical combinations

[0118] The present invention provides a pharmaceutical combination for use in a method of treating a cancer in a subject. According to the invention, the pharmaceutical combination comprises at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times. In a preferred embodiment, the benzimidazole is mebendazole. The inventors have surprisingly found that simultaneous administration of the specified active ingredients, in the specified dosage ranges, in methods of treating cancers demonstrate a remarkable therapeutic effect. Notably, it has been surprisingly observed that dosages within the specified ranges provide a synergistic anti-cancer effect, i.e. an effect which is more than the sum of the individual effects of the compounds.

[0119] In some embodiments, the present invention provides a pharmaceutical combination for use in a method of treating a cancer in a subject, wherein the pharmaceutical combination comprises at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole selected from mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times.

[0120] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, wherein the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixturesthereof. The inventors have surprisingly found that the specified avermectins are especially effective for use in a method of treating cancer.

[0121] In some embodiments, the present invention provides a pharmaceutical combination comprising at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times, for the manufacture of a medicament for treating a cancer. In a preferred embodiment, the benzimidazole is mebendazole.

[0122] In some embodiments, the present invention provides a pharmaceutical combination comprising at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole selected from mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times, for the manufacture of a medicament for treating a cancer. In a preferred embodiment, the benzimidazole is mebendazole.

[0123] In some embodiments, the pharmaceutical combination of the present invention further comprises one or more of oleic acid, glycerol trioleate, Span 80, Tween 80, soybean oil, olive oil, coconut oil, fish oil, polyethylene glycol, natural phospholipids, and mannitol.

[0124] Pharmaceutical combinations in humans

[0125] The present invention provides a pharmaceutical combination for use in a method of treating a cancer in a human. As such, in some embodiments, the present invention provides a pharmaceutical combination for use in a method of treating a cancer in a human, such that the pharmaceutical combination comprises at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times. In a preferred embodiment, the benzimidazole is mebendazole. It has been surprisingly found that the described pharmaceutical combination is particularly suitable for use in a method of treating a cancer in a human subject. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0126] In some embodiments, the present invention provides a pharmaceutical combination for use in a method of treating a cancer in a human, such that the pharmaceutical combination comprises at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) abenzimidazole selected from mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times.

[0127] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day. In a preferred embodiment, the avermectin is administered in a dose of 1.5 mg / kg / day.

[0128] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day. In a preferred embodiment, the benzimidazole is administered in a dose of 15 mg / kg / day to 200 mg / kg / day. In a more preferred embodiment, the benzimidazole is administered in a dose of 100 mg / kg / day. It has been surprisinglyfound that a pharmaceutical composition comprising benzimidazole in these specific doses is particularly suited for use in methods of treating a cancer in a human. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0129] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, and wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day. In a preferred embodiment, the avermectin is administered in a dose of 1.5 mg / kg / day and the benzimidazole is administered in a dose of 100 mg / kg / day.

[0130] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :600. In a preferred embodiment, the dose is in a ratio of 1 :67. It has been surprisingly found that the anti-cancer effect in humans is notable when avermectin and benzimidazole are in these specific ratios. Moreover, a synergistic effect has also been observed with these ratios of compounds, which is superior than the sum of effects by the individual components.

[0131] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, and wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :600. In a preferred embodiment, the dose is in a ratio of 1 :67.

[0132] The inventors have found particularly suitable pharmaceutical combinations comprising fenbendazole and / or oxfendazole for use in methods of treating cancer in humans. As such, in some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, comprising fenbendazole and / or oxfendazole as the benzimidazole, such that the fenbendazole and / or oxfendazole is administered in a dose of 0.5mg / kg / day to 100 mg / kg / day. In a preferred embodiment, the fenbendazole and / or oxfendazole is administered in a dose of 20 mg / kg / day. The inventors have found that these doses provide a surprisingly effective anti-cancer effect, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0133] In some embodiments, the present invention further provides a pharmaceutical combination for use in humans as described herein, wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1:1 to 1:200. In a preferred embodiment, the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1:13. The inventors have found that doses in these ratios provide a surprisingly effective anti-cancer effect, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0134] In some embodiments, the present invention provides a pharmaceutical combination for use in humans as described herein, comprising fenbendazole and / or oxfendazole as the benzimidazole, such that the fenbendazole and / or oxfendazole is administered in a dose of 0.5 mg / kg / day to 100 mg / kg / day, and wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1:1 to 1:200. In a preferred embodiment, the fenbendazole and / or oxfendazole is administered in a dose of 20 mg / kg / day. In a preferred embodiment, the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1:13.

[0135] In some embodiments, the present invention provides a pharmaceutical combination as described in any of the embodiments herein for the manufacture of a medicament for treating a cancer in a human.

[0136] Pharmaceutical combinations in animals

[0137] The present invention provides a pharmaceutical combination for use in a method of treating a cancer in an animal. As such, in some embodiments, the present invention provides a pharmaceutical combination for use in a method of treating a cancer in an animal, such as murine species, canids, and felids, such that the pharmaceutical combination comprises at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times. In a preferred embodiment, the benzimidazole is mebendazole. It has been surprisinglyfound that the described pharmaceutical combination is particularly suitable for use in a method of treating a cancer in an animal subject. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0138] In some embodiments, the present invention provides a pharmaceutical combination for use in a method of treating a cancer in an animal, such as murine species, canids, and felids,such that the pharmaceutical combination comprises at least (i) an avermectin, in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and (ii) a benzimidazole selected from mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that both (i) and (ii) are administered simultaneously or at different times.

[0139] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day. In a preferred embodiment, the avermectin is administered in a dose of 10 mg / kg / day.

[0140] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day. In a preferred embodiment, the benzimidazole is administered in a dose of 100 mg / kg / day. It has been surprisingly found that a pharmaceutical composition comprising benzimidazole in these specific doses is particularly suited for use in methods of treating a cancer in an animal. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0141] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day, and wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day. In a preferred embodiment, the avermectin is administered in a dose of 10 mg / kg / day and the benzimidazole is administered in a dose of 100 mg / kg / day.

[0142] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the dose of the avermectin and benzimidazole is in a ratio of 1:1 to 1:600. In a preferred embodiment, the dose is in a ratio of 1:10. It has been surprisingly found that the anti-cancer effect in animals is notable when avermectin and benzimidazole are in these specific ratios. Moreover, a synergistic effect has also been observed with these ratios of compounds, which is superior than the sum of effects by the individual components.

[0143] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day, and wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, such that the dose of the avermectin and benzimidazole is in a ratio of 1:1 to 1:600.

[0144] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, ormixtures thereof, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, when the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, the avermectin is administered in a dose of 10 mg / kg. The inventors have found that these doses provide a surprisingly effective anti-cancer effect in animals, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0145] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, when the benzimidazole is mebendazole, and the avermectin is administered in a dose of 10 mg / kg. The inventors have found that these doses provide a surprisingly effective anti-cancer effect in animals, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0146] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, when the benzimidazole is mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, the avermectin is administered in a dose of 10 mg / kg. The inventors have found that these doses provide a surprisingly effective anti-cancer effect in animals, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0147] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:300. In a preferred embodiment, the avermectin and the benzimidazole are in a ratio of 1:10. The inventors have found that doses in these ratios provide a surprisingly effective anti-cancer effect in animals, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0148] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, ormixtures thereof, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, and wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1:300. In a preferred embodiment, when the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, the avermectin is administered in a dose of 10 mg / kg, and the avermectin and the benzimidazole are in a ratio of 1 :10.

[0149] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, and wherein the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:300. In a preferred embodiment, when the benzimidazole is mebendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, the avermectin is administered in a dose of 10 mg / kg, and the avermectin and the benzimidazole are in a ratio of 1:10.

[0150] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is mebendazole, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, and wherein the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:300. In a preferred embodiment, when the benzimidazole is mebendazole, the avermectin is administered in a dose of 10 mg / kg, and the avermectin and the benzimidazole are in a ratio of 1 :10.

[0151] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day. In a preferred embodiment, the fenbendazole and / or oxfendazole is administered in a dose of 50 mg / kg / day. The inventors have found that these doses provide a surprisingly effective anti-cancer effect in animals, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0152] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, the avermectin is administered in a dose of 10 mg / kg / day. It has been surprisingly found that the anti-cancer effect in animals is particularly effective when the pharmaceutical composition comprises avermectin in specified doses. Moreover, a synergistic effect has also been observed with these doses of avermectin, which is superior than the sum of effects by the individual components.In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, the fenbendazole and / or oxfendazole is administered in a dose of 50 mg / kg / day and the avermectin is administered in a dose of 10 mg / kg / day.

[0153] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1:200. In a preferred embodiment, the dose of the avermectin and the benzimidazole is in a ratio of 1 :5. The inventors have found that doses in these ratios provide a surprisingly effective anti-cancer effect in animals, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0154] In some embodiments, the present invention provides a pharmaceutical combination for use in animals as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200.

[0155] In some embodiments, the present invention provides a pharmaceutical combination as described in any of the embodiments herein for the manufacture of a medicament for treating a cancer in an animal.

[0156] Method of treating a cancer

[0157] The present invention further provides a method of treating a cancer in a subject. As such, in some embodiments, the present invention provides a method of treating a cancer in a subject, comprising administering an avermectin in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, to the subject, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect. In a preferred embodiment, the benzimidazole is mebendazole. In some embodiments, the present invention provides a method of treating a cancer as described herein, wherein the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof. It has been surprisingly found that a method of treating a cancer with a pharmaceutical combination comprising an avermectin and a benzimidazole as per the present invention is particularly effective. It has been found that the method of treatment comprising administration of the particular pharmaceutical combinations, in the specified doses, is uniquely suited to provide a synergistic anti-cancer effect, which is more than the sum of individual effect of the components alone.In some embodiments, the present invention provides for use of a pharmaceutical composition comprising an avermectin and a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in doses as described herein, for the treatment of cancer in a subject. In a preferred embodiment, the benzimidazole is mebendazole. In some embodiments, the present invention provides for use of a pharmaceutical composition as described herein for the preparation / manufacture of a medicament for treatment of a cancer in a subject. In some embodiments, the present invention provides a method of treating a cancer in a patient comprising administering a pharmaceutical composition comprising an avermectin and a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in doses as described herein. In a preferred embodiment, the benzimidazole is mebendazole. In some embodiments, the present invention provides a method for treating a cancer, comprising administering a pharmaceutical composition comprising an avermectin and a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in doses as described herein, to a patient in need thereof. In a preferred embodiment, the benzimidazole is mebendazole.

[0158] Method of treating a cancer in humans

[0159] The present invention further provides a method of treating a cancer in a human. As such, in some embodiments, the present invention provides a method of treating a cancer in a human, comprising administering an avermectin in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / day to 300 mg / kg / day, to the human, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect. In a preferred embodiment, the benzimidazole is mebendazole.

[0160] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day. In a preferred embodiment, the avermectin is in a dose of 1.5 mg / kg / day. It has been surprisingly found that a method of treating a cancer in a human using these compounds at these doses is particularly effective at inducing a synergistic effect.

[0161] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day. In a preferred embodiment, the benzimidazole is in a dose of 15 mg / kg / day to 200 mg / kg / day. In a more preferred embodiment, the benzimidazole isadministered in a dose of about 100 mg / kg / day. It has been surprisingly found that these doses are uniquely effective at inducing a synergistic effect.

[0162] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, and wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day. In a preferred embodiment, the avermectin is in a dose of 1.5 mg / kg / day and the benzimidazole is in a dose of 100 mg / kg / day. It has been surprisingly found that a method of treating a cancer in a human using these compounds at these doses is particularly effective at inducing a synergistic effect.

[0163] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :600. In a preferred embodiment, the doses are in a ratio of 1 :67. The inventors have found that methods of treatment administering doses in these ratios provide a surprisingly effective anti-cancer effect in humans, whilst having low toxicity and being safer for use. Moreover, a synergistic effect has also been observed which is superior than the sum of effects by the individual components.

[0164] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, and wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1 :600. The inventors have found that methods of treatment administering doses in these ratios provide a surprisingly effective anti-cancer effect in humans, whilst having low toxicity and being safer for use, and demonstrating a synergistic effect.

[0165] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 0.5 mg / kg / day to 100 mg / kg / day. In a preferred embodiment, the fenbendazole and / or oxfendazole is administered in a dose of 20 mg / kg / day. Method of treating a cancer in a human comprising administration of these benzimidazoles at the specific doses is particularly effective, lower in toxicity, safer, and shows a synergistic effect.

[0166] In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1 :1 to 1 :200. In a preferred embodiment, the dose of avermectin and fenbendazole and / or oxfendazole is in a ratio of 1:13. In some embodiments, the present invention provides a method of treating a cancer in a human as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 0.5 mg / kg / day to 100 mg / kg / day, such that the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1:1 to 1:200. Method of treating a cancer in a human comprising administration of the avermectin and said benzimidazoles in specific ratios is particularly effective, lower in toxicity, safer, and shows a synergistic effect.Method of treating a cancer in animals

[0167] Another aspect of the present invention is a method of treating a cancer in an animal. As such, in some embodiments, the present invention provides a method of treating a cancer in an animal, such as murine species, canids, and felids, comprising administering an avermectin in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 10 mg / kg / day to 300 mg / kg / day, to the human, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect. In a preferred embodiment, the benzimidazole is mebendazole.

[0168] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the avermectin is administered in a dose of of 5 mg / kg / day to 40 mg / kg / day. In a preferred embodiment, the avermectin is administered in a dose of 10 mg / kg / day. It has been surprisingly found that a method of treating a cancer in an animal using avermectin at these doses is particularly effective at inducing a synergistic effect.

[0169] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day. In a preferred embodiment, the benzimidazole is in a dose of 100 mg / kg / day. It has been surprisingly found that a method of treating a cancer in an animal using these compounds at these doses is particularly effective at inducing a synergistic effect.

[0170] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day and wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day. In a preferred embodiment, the avermectin is administered in a dose of 10 mg / kg / day and the benzimidazole is in a dose of 100 mg / kg / day. It has been surprisingly found that a method of treating a cancer in an animal using avermectin at these doses is particularly effective at inducing a synergistic effect.

[0171] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:600. In a preferred embodiment, the dose of the avermectin and the benzimidazole is in a ratio of 1:10. It has been surprisingly found that these ratios are uniquely suited for inducing a synergistic anti-cancer effect in animals.

[0172] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day, and wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to1:600. It has been surprisingly found that these ratios are uniquely suited for inducing a synergistic anti-cancer effect in animals.

[0173] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole , febantel, netobimin, or mixtures thereof, and the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, the benzimidazole is mebendazole. It has been surprisingly found that a method of treating a cancer in an animal using these compounds at these doses is particularly effective at inducing a synergistic anti-cancer effect.

[0174] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:300. In a preferred embodiment, the dose of the avermectin and the benzimidazole is in a ratio of 1:10. It has been surprisingly found that the doses in these ratios are particularly effective at inducing a synergistic anti-cancer effect in animals.

[0175] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole , febantel, netobimin, or mixtures thereof, and the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, and wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :300. The doses in these ratios are uniquely effective at inducing a synergistic anti-cancer effect in animals.

[0176] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day. In a preferred embodiment, the benzimidazole is fenbendazole and / or oxfendazole, and is administered in a dose of 50 mg / kg / day. It has been surprisingly found that a method of treating a cancer in an animal using these compounds at these doses is particularly effective at inducing a synergistic anti-cancer effect.

[0177] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, the avermectin is administered in a dose of 10 mg / kg / day. It has been surprisingly found that a method of treating a cancer in an animal using these compounds at these doses is particularly effective at inducing a synergistic anti-cancer effect.

[0178] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole,and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, and the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day. In a preferred embodiment, the benzimidazole is fenbendazole and / or oxfendazole, and is administered in a dose of 50 mg / kg / day, and the avermectin is administered in a dose of 10 mg / kg / day. It has been surprisingly found that a method of treating a cancer in an animal using these compounds at these doses is particularly effective at inducing a synergistic anti-cancer effect.

[0179] In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1:200. In a preferred embodiment, the dose of the avermectin and the benzimidazole is in a ratio of 1:5. In some embodiments, the present invention provides a method of treating a cancer in an animal as described herein, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, and the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, such that the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200. Method of treating a cancer in an animal comprising administration of the avermectin and the benzimidazoles in specific ratios is particularly effective, lower in toxicity, safer, and shows a synergistic effect.

[0180] Method of treating, inducing a synergistic effect

[0181] In another aspect, the present invention provides a method of treating a cancer in a subject, comprising administration of a suitable dose of a combination of an avermectin and a benzimidazole, simultaneously or at different times, resulting in concomitant therapeutically effective plasma concentration of each to induce a synergistic effect. It has been surprisingly found that administration of a suitable dose of the avermectin and the benzimidazole, such that a therapeutically effective level of each is reached in the plasma, is important for inducing a synergistic anti-cancer effect in a subject.

[0182] In some embodiments, the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof. In some embodiments, the benzimidazole is selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof. In a preferred embodiment, the benzimidazole is mebendazole.

[0183] In some embodiments, the present invention provides a method as described herein, such that the administration results in a synergistic therapeutic effect which is more than the sum of the individual effect of each compound.Formulation and administration

[0184] In some embodiments, the pharmaceutical combination and / or its components are taken with meals. In some embodiments, the pharmaceutical combination and / or its components are taken on an empty stomach.

[0185] In some embodiments, the pharmaceutical combination and / or its components are taken with meals, including a fatty (i.e. lipid-rich) meal. In a preferred embodiment, the pharmaceutical combination and / or its components are taken before, with, or right after a meal.

[0186] In some embodiments, the pharmaceutical combination and / or its components are taken daily, or 6 days a week, or every other day, or every third day. In a preferred embodiment, the pharmaceutical combination and / or its components are taken daily.

[0187] In some embodiments, the pharmaceutical combination and / or its components are taken for a duration of 1 week to 5 years. In a preferred embodiment, the pharmaceutical combination and / or its components are taken for 6 months.

[0188] In some embodiments, the pharmaceutical combination and / or its components are in a suitable form for oral administration. Non-limiting examples of such forms include: paste, suspension, solution, capsules, gel, tablet, ingestible tablet, dispersible tablet, troche, elixir, syrup, wafer, emulsion, powder, granules, and lozenges.

[0189] In some embodiments, the formulation of the pharmaceutical combination and / or its components, further comprises a suitable carrier. In some embodiments, the components of the pharmaceutical combination are administered simultaneously. In some embodiments, the components of the pharmaceutical combination are administered at different times. In some embodiments, the components of the pharmaceutical combination are administered over a less than 12 hours interval.

[0190] In some embodiments, the pharmaceutical combination of the present invention is such that the avermectin and / or the benzimidazole is formulated to improve absorption (such as an improved Cmax and / or AUC0-24h). In a further embodiment, such formulation results in a reduction of effective doses by 2 to 10 times for avermectin. In a further embodiment, such formulation results in a reduction of effective doses by 2 to 30 times for the benzimidazole. Also disclosed herein are formulations of the pharmaceutical combinations. In some embodiments, the formulation may comprise one or more specific isomers, isomorphs, pseudo-polymorphs or polymorphs of avermectins. In some embodiments, the formulation may comprise one or more specific polymorphs of benzimidazoles, such as polymorphs B and / or C of mebendazole. In some embodiments, the formulation may comprise one or more specific isomers, isomorphs, pseudo-polymorphs or polymorphs of avermectins, and one or more specific polymorphs of benzimidazoles, such as polymorphs B and / or C of mebendazole.

[0191] In some embodiments, the formulation as described herein is prepared using one or more techniques / technologies, such as solid and / or liquid lipid nanoparticles, liposomesTl

[0192] (including nanoLiposomes), prodrugs, cyclodextrin-based formulations, ivermectin and benzimidazole salts, associations with excipients (e.g., oils or surfactants), co-administration with enzyme inhibitors (e.g., ritonavir, piperidine), oral suspensions, oral paste formulations, nanosuspension, polymer-based systems, PLGA nanoparticles / nanocapsules (Poly(Lactide-co-Glycolide)), polymer micelles of methoxy polyethylene glycol)-b-poly(caprolactone), polymer combined with PLGA, nanodroplet, self-emulsifying drug delivery system (SEDDS), self-microemulsifying drug delivery system (SMEDDS), SNEDDS (Self-Nanoemulsifying Drug Delivery System), SNEDDS (Self-Nanoemulsifying Drug Delivery System) with oils, SNEDDS (Self-Nanoemulsifying Drug Delivery System) with conter-ion, SNEDDS (Self-Nanoemulsifying Drug Delivery System) with polymer, SNEDDS (Self-Nanoemulsifying Drug Delivery System) with polymer, oils and conter-ion, redispersible microparticles with low-substituted hydroxypropylcellulose (L-HPC), crystal, nanocrystal, co-crystal, lipid nanoparticles, natural polymer nanoparticles, Nanostructured Lipid Carriers (NLCs), polymer micelles (amphiphilic), Metal-Organic Frameworks, chitosan-based nanoparticles, inclusion complexes with modified cyclodextrins, microspheres, lipid-core micelles, microencapsulation, lyophilized products, microspheres and microcapsules, encapsulation, solid dispersion, amorphous state, amorphous systems, co-amorphous system, amorphous complex, amorphous solid dispersion, amorphous salt solid dispersion, amorphous polymer solid dispersion, amorphous salt solid dispersion, amorphous salt-polymer solid dispersion (with / without oils), amorphous salt solid dispersion plus SNEDDS, amorphous salt solid dispersion plus SNEDDS and Lipid oils, amorphous salt-polymer solid dispersion plus SNEDDS, Mesoporous Silica Nanoparticles, or derivatives thereof, or a combination thereof.

[0193] It has been surprisingly found that the pharmaceutical combination of the present invention, when formulated in a suitable manner to improve absorption, results in reduction of the effective doses while maintaining an equivalent or greater therapeutic efficacy.

[0194] In a further embodiment, the ratio of the avermectin and the benzimidazole in the pharmaceutical combination according to the invention is adjusted to a range between 1 :5 and 1:25. It has been found that such a ratio adjustment compensates for an improvement in bioavailability of at least one order of magnitude for the avermectin and / or the benzimidazole, in order to achieve a plasma exposure ratio equivalent to in vitro data (i.e. 50-50 or 50 and greater of benzimidazole). The dosage of avermectin and benzimidazoles to achieve a plasma exposure ratio equivalent to in vitro data (i.e.50-50 or 50 and greater of benzimidazole) can vary depending on the absorption capacity of the formulation used. In a preferred embodiment, the avermectin is ivermectin and the benzimidazole is mebendazole.

[0195] In some embodiments, the pharmaceutical combination according to the invention comprises mebendazole in a dose of 3 to 300 mg / kg / day, preferably 15 to 250 mg / kg / day, more preferably about 200 mg / kg / day, and is administered in 1 to 4 doses with intervals of about 3 to 8 hours, during meals. In a preferred embodiment, it is administered in 3 doses, with intervals of about 6 hours, during meals.In some embodiments, the pharmaceutical combination according to the invention comprises mebendazole in an improved formulation with enhanced absorption (such as an improved Cmax and / or AUC0-24h) by 2 to 8-fold, such that Polymorph C and / or B of mebendazole is present at 60% or more in the formulation, and overall mebendazole dose is 3 to 200 mg / kg / day, preferably about 100 mg / kg / day, and is administered in 1 to 4 doses with intervals of about 3 to 8 hours, during meals. In a preferred embodiment, it is administered in 3 doses, with intervals of about 6 hours, during meals.

[0196] In some embodiments, the pharmaceutical combination according to the invention comprises mebendazole in a dose of 3 to 100 mg / kg / day, preferably about 25 mg / kg / day, administered during meal, including a high-fat meal with lipids, for enhanced absorption (such as an improved Cmax and / or AUC0-24h) by 5 to up to 8-fold administered in 1 to 4 doses with intervals of about 3 to 8 hours, during meals. In a preferred embodiment, it is administered in 3 doses, with intervals of about 6 hours, during meals.

[0197] In some embodiments, the pharmaceutical combination according to the invention comprises mebendazole in an improved formulation in a dose of 1 to 75 mg / kg / day, preferably about 25 mg / kg / day, for enhanced absorption (such as an improved Cmax and / or AUC0-24h) by 2 to up to 10-fold administered daily in 1 or 2 doses, or every other day, or every third day, during meals. In a preferred embodiment, it is administered in 1 dose per day, during meals.

[0198] In some embodiments, the pharmaceutical combination according to the invention comprises fenbendazole in a dose of 10 to 100 mg / kg / day, preferably about 20 mg / kg / day, administered in 1 to 3 doses, with intervals of about 6 to 12 hours, preferably about 8 hours, during meals. In a preferred embodiment, it is administered in 2 doses, with intervals of about 8 to 12 hours, during meals.

[0199] In some embodiments, the pharmaceutical combination according to the invention comprises fenbendazole in a dose of 10 to 100 mg / kg / day, preferably about 20 mg / kg / day, administered with a high-fat meal with lipids, for enhanced absorption, administered in 1 to 3 doses with intervals of about 6 to 12 hours, preferably about 8 hours, during meals. In a preferred embodiment, it is administered in 2 doses, with intervals of about 8 to 12 hours, during meals.

[0200] In some embodiments the pharmaceutical combination according to the invention comprises oxfendazole in a dose of 0.5 to 100 mg / kg / day, preferably about 3 mg / kg / day, administered daily in 1 or 2 doses, or every other day, or every third day, during meals. In a preferred embodiment, it is administered as 1 dose per day, during meals.

[0201] In some embodiments, the pharmaceutical combination according to the invention comprises oxfendazole in a dose of 0.5 to 100 mg / kg / day, preferably about 3 mg / kg / day, administered with a high-fat meal with lipids, for enhanced absorption, administered daily in 1 to 2, or every other day, or every third day, during meals. In a preferred embodiment, it is administered as 1 dose per day, during meals.In some embodiments, the pharmaceutical combination according to the invention comprises ricobendazole (also known as albendazole sulfoxide) administered daily in 1 to 3 doses, with intervals of about 8 to 14 hours, preferably 12 hours, during meals. In a preferred embodiment, it is administered daily in 2 doses with interval of about 8 to 12 hours, during meals.

[0202] In some embodiments, the pharmaceutical combination according to the invention comprises flubendazole, administered daily in 1 or 2 doses, or every other day, during meals. In a preferred embodiment, it is administered daily in 1 dose during meals.

[0203] In some embodiments, the present invention provides a pharmaceutical combination as described herein, such that it comprised ivermectin as the avermectin, and ivermectin is administered as a one dose daily or every other day, during meals.

[0204] Treating different stages of disease

[0205] Different stages of cancer disease require different treatment options. It has been found that different doses of the compounds in the pharmaceutical combination of the present invention are suited for use in methods aimed at treating different stages of cancer.

[0206] Stages l-ll

[0207] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage I or II, the pharmaceutical combination comprising avermectin between 0.1 mg / kg / day to 2 mg / kg / day and a benzimidazole between 15 mg / kg / day to 45 mg / kg / day, wherein the benzimidazole is mebendazole, such that both the avermectin and the benzimidazole are administered simultaneously or at different times. In a preferred embodiment, the avermectin is at a dose of 1 mg / kg / day and the said benzimidazole is at a dose of 20 mg / kg / day.

[0208] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage I or II, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:15 to 1:150, wherein the benzimidazole is mebendazole, and such that both the avermectin and the benzimidazole are administered simultaneously or at different times. In a preferred embodiment, the ratio is 1 :20.

[0209] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage I or II, the pharmaceutical combination comprising avermectin between 0.1 mg / kg / day to 2 mg / kg / day and a benzimidazole between 0.5 mg / kg / day to 10 mg / kg / day, wherein the benzimidazole is fenbendazole and / or oxfendazole, such that both the avermectin and the benzimidazole are administered simultaneously or at different times. In a preferred embodiment, the avermectin is at a dose of 1 mg / kg / day and the said benzimidazole is at a dose of 3 mg / kg / day.In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage I or II, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:3 to 1:100, wherein the benzimidazole is fenbendazole and / or oxfendazole, such that both the avermectin and the benzimidazole are administered simultaneously or at different times. In a preferred embodiment, the ratio is 1 :3.

[0210] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage I or II, the pharmaceutical combination comprising avermectin between 0.1 mg / kg / day to 2 mg / kg / day and a benzimidazole between 15 mg / kg / day to 45 mg / kg / day, wherein the benzimidazole is selected from the list flubendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, such that both the avermectin and the benzimidazole are administered simultaneously or at different times. In a preferred embodiment, the avermectin is at a dose of 1 mg / kg / day and the said benzimidazole is at a dose of 20 mg / kg / day.

[0211] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage I or II, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:15 to 1:200, wherein the benzimidazole is selected from the list mebendazole, flubendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, such that both the avermectin and the benzimidazole are administered simultaneously or at different times. In a preferred embodiment, the ratio is 1 :20.

[0212] The present invention further provides a method of treating a cancer at stage I or II in a subject. As such, in some embodiments, the present invention provides a method of treating a cancer at stage I or II in a subject, comprising administering an avermectin and a benzimidazole in the doses as described hereinabove, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect. It has been surprisingly found that a method of treating a stage I or II cancer with a pharmaceutical combination comprising an avermectin and a benzimidazole as per the present invention is particularly effective. It has been found that the method of treatment comprising administration of the particular pharmaceutical combinations, in the specified doses, is uniquely suited to provide a synergistic anti-cancer effect in treating stage I or II cancer, which is more than the sum of individual effect of the components alone.

[0213] In some embodiments, the present invention provides for use of a pharmaceutical composition comprising an avermectin and a benzimidazole, as described herein, for the treatment of stage I or II cancer in a subject. In some embodiments, the present invention provides for use of a pharmaceutical composition as described herein for the preparation / manufacture of a medicament for treatment of a stage I or II cancer in a subject. Insome embodiments, the present invention provides a method of treating a stage I or II cancer in a patient comprising administering a pharmaceutical composition comprising an avermectin and a benzimidazole as described herein. In some embodiments, the present invention provides a method for treating a stage I or II cancer, comprising administering a pharmaceutical composition comprising an avermectin and a benzimidazole as described herein, to a patient in need thereof.

[0214] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage III, the pharmaceutical combination comprising avermectin between 0.5 mg / kg / dayto 2 mg / kg / day and a benzimidazole between 20 mg / kg / day to 80 mg / kg / day, wherein the benzimidazole is mebendazole. In a preferred embodiment, the avermectin is at a dose of 1.5 mg / kg / day and the said benzimidazole is at a dose of 50 mg / kg / day.

[0215] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage III, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:18 to 1:160, wherein the benzimidazole is mebendazole. In a preferred embodiment, the ratio is 1 :33.

[0216] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage III, the pharmaceutical combination comprising avermectin between 0.5 mg / kg / day to 2 mg / kg / day and a benzimidazole between 0.5 mg / kg / day to 60 mg / kg / day, wherein the benzimidazole is fenbendazole and / or oxfendazole. In a preferred embodiment, the avermectin is at a dose of 1.5 mg / kg / day and the said benzimidazole is at a dose of 10 mg / kg / day.

[0217] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage III, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:13 to 1:120, wherein the benzimidazole is fenbendazole and / or oxfendazole. In a preferred embodiment, the ratio is 1 :17.

[0218] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage III, the pharmaceutical combination comprising avermectin between 0.5 mg / kg / dayto 2 mg / kg / day and a benzimidazole between 15 mg / kg / day to 45 mg / kg / day, wherein the benzimidazole is selected from the list flubendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof. In a preferred embodiment, the avermectin is at a dose of 1.5 mg / kg / day and the said benzimidazole is at a dose of 50 mg / kg / day.

[0219] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage III, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:18 to 1:160, wherein thebenzimidazole is selected from the list mebendazole, flubendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof. In a preferred embodiment, the ratio is 1:33.

[0220] The present invention further provides a method of treating a stage III cancer in a subject. As such, in some embodiments, the present invention provides a method of treating a stage III cancer in a subject, comprising administering an avermectin and a benzimidazole in the doses as described hereinabove, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect. It has been surprisingly found that a method of treating a stage III cancer with a pharmaceutical combination comprising an avermectin and a benzimidazole as per the present invention is particularly effective. It has been found that the method of treatment comprising administration of the particular pharmaceutical combinations, in the specified doses, is uniquely suited to provide a synergistic anti-cancer effect in treating stage III cancer, which is more than the sum of individual effect of the components alone.

[0221] In some embodiments, the present invention provides for use of a pharmaceutical composition comprising an avermectin and a benzimidazole, as described herein, for the treatment of stage III cancer in a subject. In some embodiments, the present invention provides for use of a pharmaceutical composition as described herein for the preparation / manufacture of a medicament for treatment of a stage III cancer in a subject. In some embodiments, the present invention provides a method of treating a stage III cancer in a patient comprising administering a pharmaceutical composition comprising an avermectin and a benzimidazole as described herein. In some embodiments, the present invention provides a method for treating a stage III cancer, comprising administering a pharmaceutical composition comprising an avermectin and a benzimidazole as described herein, to a patient in need thereof.

[0222] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage IV, the pharmaceutical combination comprising avermectin between 1 mg / kg / dayto 8 mg / kg / day and a benzimidazole between 10 mg / kg / day to 300 mg / kg / day, wherein the benzimidazole is mebendazole. In a preferred embodiment, the avermectin is at a dose of 1.5 mg / kg / day and the said benzimidazole is at a dose of 100 mg / kg / day.

[0223] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage IV, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:10 to 1:300, wherein the benzimidazole is mebendazole. In a preferred embodiment, the ratio is 1 :100.

[0224] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage IV, the pharmaceutical combinationcomprising avermectin between 1 mg / kg / dayto 8 mg / kg / day and a benzimidazole between 0.5 mg / kg / dayto 100 mg / kg / day, wherein the benzimidazole isfenbendazole and / or oxfendazole. In a preferred embodiment, the avermectin is at a dose of 1.5 mg / kg / day and the said benzimidazole is at a dose of 20 mg / kg / day.

[0225] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage IV, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:12.5 to 1:100, wherein the benzimidazole is fenbendazole and / or oxfendazole. In a preferred embodiment, the ratio is 1 :30.

[0226] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage IV, the pharmaceutical combination comprising avermectin between 1 mg / kg / dayto 8 mg / kg / day and a benzimidazole between 10 mg / kg / day to 200 mg / kg / day, wherein the benzimidazole is selected from the list flubendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof. In a preferred embodiment, the avermectin is at a dose of 1.5 mg / kg / day and the said benzimidazole is at a dose of 100 mg / kg / day.

[0227] In some embodiments, the present invention provides a pharmaceutical combination for use as described herein, for use in treating a cancer at stage IV, the pharmaceutical combination comprising avermectin and a benzimidazole in a ratio between 1:20 to 1:200, wherein the benzimidazole is selected from the list mebendazole, flubendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof. In a preferred embodiment, the ratio is 1:50.

[0228] The present invention further provides a method of treating a stage IV cancer in a subject. As such, in some embodiments, the present invention provides a method of treating a stage IV cancer in a subject, comprising administering an avermectin and a benzimidazole in the doses as described hereinabove, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect. It has been surprisingly found that a method of treating a stage IV cancer with a pharmaceutical combination comprising an avermectin and a benzimidazole as per the present invention is particularly effective. It has been found that the method of treatment comprising administration of the particular pharmaceutical combinations, in the specified doses, is uniquely suited to provide a synergistic anti-cancer effect in treating stage IV cancer, which is more than the sum of individual effect of the components alone.

[0229] In some embodiments, the present invention provides for use of a pharmaceutical composition comprising an avermectin and a benzimidazole, as described herein, for the treatment of stage IV cancer in a subject. In some embodiments, the present invention provides for use of a pharmaceutical composition as described herein for the preparation / manufacture of a medicament for treatment of a stage IV cancer in a subject. In some embodiments, thepresent invention provides a method of treating a stage IV cancer in a patient comprising administering a pharmaceutical composition comprising an avermectin and a benzimidazole as described herein. In some embodiments, the present invention provides a method for treating a stage IV cancer, comprising administering a pharmaceutical composition comprising an avermectin and a benzimidazole as described herein, to a patient in need thereof.

[0230] Dosage adjustment

[0231] It is believed that dosages can be absorbed and tolerated differently between male and female. Accordingly, any dosages mentioned in this specification may be adapted for administration to a male or female. For example, higher dosages may be administered to male subjects compared with female subjects.

[0232] Embodiments

[0233] In some embodiments, the present invention provides a method of treating cancer diseases in humans or animals comprising: administering fixed combinations of unusually high doses of repurposed drugs to said humans or animals:

[0234] • Ivermectin and Mebendazole;

[0235] • Or ivermectin and Fenbendazole;

[0236] • Or ivermectin and Oxfendazole;

[0237] • Or ivermectin and Albendazole;

[0238] • And / or a derivative thereof.

[0239] In some embodiments, the present invention provides a method of treating cancer diseases in humans or animals comprising: administering to said humans or animals a specific range of combinations of drugs selected from the group consisting of:

[0240] • Ivermectin and Mebendazole;

[0241] • Or ivermectin and Fenbendazole;

[0242] • Or ivermectin and Oxfendazole;

[0243] • Or ivermectin and Albendazole;

[0244] • And / or a derivative thereof.

[0245] In some embodiments, the present invention provides a method of treating cancer diseases in humans or animals comprising: administering to said humans or animals a combination comprising pharmaceutically acceptable excipients and two active ingredients selected from the group consisting of:

[0246] • Ivermectin and Mebendazole;

[0247] Or ivermectin and Fenbendazole;• Or ivermectin and Oxfendazole;

[0248] • Or ivermectin and Albendazole;

[0249] • And / or a derivative thereof,

[0250] wherein the anti-cancer activity of the combination being superior to the activity of a high dose of either active ingredient alone.

[0251] In some embodiments, the present invention provides a treatment method for all types and grades of cancer.

[0252] In some embodiments, the present invention provides a method of treatment targeting the inhibition of cancer cell metabolism (particularly glycolysis and glutaminolysis), as well as targeting cancer stem cells and metastases.

[0253] In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, comprising: a combination of ivermectin and one benzimidazole (mebendazole, fenbendazole, oxfendazole, or albendazole), where the distribution of the quantities of the two active compounds is adjusted such that one constitutes between 1 % and 99% of the total, with the other accounting for the remainder.

[0254] In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, comprising:

[0255] Ivermectin (Ivm); and

[0256] Mebendazole (MBZ),

[0257] wherein a dosage combination of Ivermectin (Ivm) and Mebendazole (MBZ) is as follows, Medication Ivermectin (Ivm) Mebendazole (MBZ)

[0258] Dose 2 mg / kg / day 100 mg / kg / day

[0259] Cmax (Plasma) 247.8 ng / ml at 1 mg / kg / day 261 ng / ml at 100 mg / kg / day AUCO-oo 4547.7 ng-h / ml at 1 mg / kg / day 493.34 ng-h / ml at 100mg / kg / day Half-life (t1 / 2) 19.1 hours 3 to 6 hours

[0260] Toxicity Not detected up to 2.5 mg / kg / day Non-serious at 200 mg / kg / day

[0261] In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, comprising: a combination of ivermectin and a benzimidazole (mebendazole, fenbendazole, oxfendazole, or albendazole), wherein the concentration of each active compound can vary between 1 % and 99%.

[0262] Respective doses being selected based on relative efficacy of the combination on tumors in animal models.In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, comprising: a combination of ivermectin and a benzimidazole, with a dosage regimen ranging from 1 to 10 daily administrations.

[0263] In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, comprising: a combination of ivermectin and a benzimidazole, with a treatment duration ranging from one day to three years.

[0264] In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, including: ivermectin and a benzimidazole, wherein the composition targets the enzymes involved in glycolysis: Hexokinase / Glucokinase, Phosphoglucose isomerase, Phosphofructokinase-1 (PFK-1), Aldolase, Triose phosphate isomerase, Glyceraldehyde-3-phosphate dehydrogenase, Phosphoglycerate kinase, Phosphoglycerate mutase, Enolase, or Pyruvate kinase.

[0265] In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, including: ivermectin and a benzimidazole, wherein the composition targets the enzymes involved in glutaminolysis: Glutaminases, Glutamate dehydrogenase (GDH), Transaminases (aminotransferases), Glutamate synthetase, or Alphaketoglutarate dehydrogenase.

[0266] In some embodiments, the present invention provides the composition as described herein, wherein the dosage combination is:

[0267] - ivermectin: 0.01 mg / kgto 15 mg / kg;

[0268] - mebendazole: 0.01 mg / kgto 300 mg / kg,

[0269] In some embodiments, the present invention provides the composition as described herein, further comprising: the option to select from all Mebendazole polymorphs, including polymorphs A, B, and C, with a preference for polymorph C, and optionally in combination with polymorph B, wherein the composition comprises a high proportion of polymorphs C and B.

[0270] In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, comprising:

[0271] - ivermectin: 0.01 mg / kgto 15 mg / kg; and

[0272] - fenbendazole: 0.01 mg / kgto 100 mg / kg,

[0273] In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, comprising:

[0274] - ivermectin: 0.01 mg / kgto 15 mg / kg;

[0275] - oxfendazole: 0.01 mg / kg to 100 mg / kg,In some embodiments, the present invention provides a composition for treating cancer diseases in humans or animals, comprising:

[0276] - ivermectin: 0.01 mg / kgto 15 mg / kg;

[0277] - albendazole: 0.01 mg / kg to 200 mg / kg,

[0278] In some embodiments, the present invention provides a method of orally administering the composition described herein.

[0279] In some embodiments, the present invention provides a method of improving absorption of ivermectin and benzimidazoles through:

[0280] - Oily suspensions;

[0281] - General lipid-based formulations;

[0282] - A derivative thereof; or

[0283] - a combination thereof.

[0284] In some embodiments, the present invention provides a method of improving absorption of ivermectin and benzimidazoles through formulations based on oils (lipids) and / or co-solvents (oleic acid, glycerol trioleate, Span 80, Tween 80, soybean oil, olive oil, coconut oil, fish oil, polyethylene glycol, natural phospholipids, mannitol, etc.); a derivative thereof; or a combination thereof.

[0285] In some embodiments, the present invention provides a method of creating derivatives of ivermectin or benzimidazoles, such as mebendazole salts (mesylate) for mebendazole, and combining them together; a derivative thereof; or a combination thereof.

[0286] In some embodiments, the present invention provides a method of improving absorption, rapid and / or prolonged release, and effectiveness of ivermectin in combination with benzimidazoles using techniques such as: Solid Lipid Nanoparticles (SLNs), Liposomes, Cyclodextrin-based formulations, Ivermectin and benzimidazole salts, associations with excipients (e.g., oils or surfactants), co-administration with enzyme inhibitors (e.g., ritonavir, piperidine), oral suspensions, oral paste formulations, nanosuspension for solubility enhancement, polymer-based systems, PLGA nanoparticles (Poly(Lactide-co-Glycolide)), polymer micelles of methoxy polyethylene glycol)-b-poly(caprolactone), polymer combined with PLGA, SNEDDS (Self-Nanoemulsifying Drug Delivery System), SNEDDS (Self-Nanoemulsifying Drug Delivery System) with oils, redispersible microparticles with low-substituted hydroxypropylcellulose (L-HPC), Solid dispersion and nanocrystal techniques, Lipid nanoparticles, natural polymer nanoparticles, Nanostructured Lipid Carriers (NLCs), polymer micelles (amphiphilic), chitosan-based nanoparticles, inclusion complexes with modified cyclodextrins, microspheres, lipid-core micelles, microencapsulation, encapsulation, derivatives thereof, or a combination thereof.In some embodiments, the present invention provides any method as described herein, further comprising: a step of optimizing efficacy of the ivermectin-benzimidazole combination of any of the embodiments herein by modulating their release profiles, wherein the step of optimizing includes: rapid or prolonged release of ivermectin, benzimidazole, or both to maximize their combined therapeutic efficacy against cancer cells.

[0287] In some embodiments, the present invention provides a method of optimizing absorption of ivermectin and benzimidazoles to ensure a stable and therapeutic plasma concentration, while avoiding sharp plasma peaks, promoting prolonged release, and leveraging protective hepatic metabolism, in order to enhance their efficacy without increasing toxicity.

[0288] For example, the doses of ivermectin may be based on references 1 -3, of mebendazole on 4-8, of fenbendazole on 9-12 and oxfendazole on 13-15.

[0289] In some embodiments, provided is a method of treating cancer diseases in humans or animals, comprising: orally administering to said humans or animals a specific highly dosed combination of ivermectin and a benzimidazole (including mebendazole, fenbendazole, or oxfendazole). High doses administered simultaneously would allow for a synergistic effect on the metabolism of cancer cells, particularly targeting the glycolysis and glutaminolysis pathways for all types and grades of cancer, inducing cancer cells death.

[0290] References

[0291] 1. Guzzo CA, Furtek Cl, Porras AG, et al. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects. J Clin Pharmacol. Oct 2002;42(10) : 1122-33. doi:10.1177 / 009127002401382731. 2. de Castro CG, Jr., Gregianin LJ, Burger JA. Continuous high-dose ivermectin appears to be safe in patients with acute myelogenous leukemia and could inform clinical repurposing for COVID-19 infection. Leuk Lymphoma. Oct 2020;61(10):2536-2537. doi:10.1080 / 10428194.2020.1786559. 3. Chung K, Yang CC, Wu ML, Deng JF, Tsai WJ. Agricultural avermectins: an uncommon but potentially fatal cause of pesticide poisoning. Ann EmergMed. Jul 1999;34(1 ):51 -7. doi: 10.1016 / s0196-0644(99)70271 -4. 4. Gôçmen A, Toppare MF, Kiper N. Treatment of hydatid disease in childhood with mebendazole. Eur Respir J. Feb 1993;6(2):253-7. 5. Mansoori S, Fryknàs M, Alvfors C, Loskog A, Larsson R, Nygren P. A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer. Sci Rep. Apr 262021 ;11 (1 ):8981. doi: 10.1038 / s41598-021 -88433-y.6. Patil VM, Bhelekar A, Menon N, et al. Reverse swing-M, phase 1 study of repurposing mebendazole in recurrent high-grade glioma. Cancer Med. Jul 2020, ’9(13):4676-4685. doi:10.1002 / cam4.3094. 7. Krystal J, Hanson D, Donnelly D, Atlas M. A phase 1 study of mebendazole with bevacizumab and irinotecan in high-grade gliomas. Pediatr Blood Cancer. Apr 2024;71 (4):e30874. doi:10.1002 / pbc.30874. 8. Gallia GL, Holdhoff M, Brem H, et al. Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: results of a phase 1 clinical trial. Neurooncol Adv. Jan-Dec 2021;3(1):vdaa154. doi:10.1093 / noajnl / vdaa154. 9. Nguyen J, Nguyen TQ, Han BO, Hoang BX. Oral Fenbendazole for Cancer Therapy in Humans and Animals. Anticancer Res. Sep 2024;44(9):3725-3735.doi:10.21873 / anticanres.17197. 10. Wang X, Tian W, Wang N, et al. Transcriptome analysis reveals the anticancer effects of fenbendazole on ovarian cancer: an in vitro and in vivo study. BMC Cancer. Dec 3016 / 172024;24(1 ):1593. doi: 10.1186 / s12885-024-13361 -9. 11. Chung I, Zhou K, Barrows C, et al. Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer. Front Oncol. 2020; 10:594141. doi:10.3389 / fonc.2020.594141. 12. Duan Q, Liu Y, Rockwell S. Fenbendazole as a potential anticancer drug. Anticancer Res. Feb 2013;33(2):355-62. 13. An G, Murry DJ, Gajurel K, et al. Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Volunteers: a Randomized, Placebo-Controlled First-in-Human Single-Dose Escalation Study. Antimicrob Agents Chemother. Apr 2019;63(4)doi:10.1128 / aac.02255-18. 14. Moreno L, Lopez-Urbina MT, Farias C, et al. A high oxfendazole dose to control porcine cysticercosis: pharmacokinetics and tissue residue profiles. Food Chem Toxicol. Oct 2012, ’50(10):3819-25. doi: 10.1016 / j.fct.2O12.07.023.

[0292] 15. Bach T, Galbiati S, Kennedy JK, et al. Pharmacokinetics, Safety, and Tolerability of Oxfendazole in Healthy Adults in an Open-Label Phase 1 Multiple Ascending Dose and Food Effect Study. Antimicrob Agents Chemother. Oct 20 2020;64(11)doi:10.1128 / aac.01018-20.

[0293] 16. Bai RY, Staedtke V, Aprhys CM, Gallia GL, Riggins GJ. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro Oncol. Sep 2011;13(9):974-82. doi:10.1093 / neuonc / nor077. 17. Chai JY, Jung BK, Hong SJ. Albendazole and Mebendazole as Anti-Parasitic and Anti-Cancer Agents: an Update. Korean J Parasitol. Jun 2021 ;59(3): 189-225. doi: 10.3347 / kjp.2O21.59.3.189

[0294] EXAMPLES

[0295] Example 1 : Anti-cancer activity of pharmaceutical combinations in vitro in cell lines

[0296] Cells were grown as adherent at 37°C in a humidified atmosphere (5% CO2, 95% air), in an appropriate culture medium as described hereunder. For experimental use, tumor cells were detached from the culture flask by a 5 minute treatment with trypsin-versene and neutralized by addition of complete culture medium. The cells were counted and viability assessed by 0.25% trypan blue exclusion assay. Cancer cells were then seeded in 384-well flat-bottom microtitration plates at the adequate cell density, in 20 pL of the culture medium and incubated at 37°C under 5% CO2. Day after the seeding, cells were treated with the test compounds as described hereunder.

[0297] The plating of the VM-M3 cell line was done in DMEM + 12 mM Glucose + 2 mM Glutamine in the absence of serum.

[0298] Cisplatin was used as a positive control. Cisplatin was prepared as a stock solution of 1.5 mM in NaCl, and diluted 2-fold from stock solution in culture medium. 5 pL of the diluted solution was added to the cells.

[0299] 5 pL of NaCl was used as negative control.Mebendazole (MBZ) was used as an exemplary benzimidazole (Mebendazole Polymorph C, Batch CS-25-18838-01 ). MBZ was prepared as a stock solution of 64 mM in 100% DMSO, and diluted in culture medium as described hereunder.

[0300] Ivermectin (IVE) was used as an exemplary avermectin (Ivermectin, Bacth 230PAV). IVE was prepared as a stock solution of 150 mM in 100% DMSO, and diluted in culture medium as described hereunder.

[0301] Unless otherwise indicated, 5 pL of test combination was added to the cells.

[0302] The final concentration of DMSO in cell cultures was 0.1 %, which was also used as additional negative control. Cells were incubated with treatment for 72 hours, except for the VM-M3 cell line, which was incubated for 48 hours.

[0303] Data analysis

[0304] Compound toxicity was monitored by using the CellTiter-Glo Luminescent Cell Viability Assay (Promega, Ref: G7572). Plates were read using EnVision Multilabel Reader (PerkinElmer). The IC50 for cell viability was calculated with the XLfit software using the 4 Parameter Logistic Model or Sigmoidal Dose-Response Model (model 205).

[0305] A combination index (Cl) was calculated using CompuSyn Software (https: / / www.combosyn.com). This software is based on the Chou-Talalay’s Cl calculation method. The latter indicates that a Cl less than 1 indicates a synergy between 2 drugs, a Cl greater than 1 indicates an antagonism between 2 drugs, and a Cl equals 1 indicates an additivity between 2 drugs.

[0306] Example 2: Cytotoxicity of avermectin and benzimidazole combination on murine glioma cell line

[0307] Murine glioma cell line GL261 from DSMZ-ACC 802 was cultured in DMEM + 2 mM L-Glutamine + 10 % FCS (heat inactivated) medium, as described under Example 1.

[0308] Combination with doses of IVE and MBZ in a ratio of 1:9 and 1:1 were tested, using various concentrations. For 1:9, IVE doses used were 52 nM and 104 nM. Correspondingly, the MBZ doses used were 466.9 nM and 933.8 nM. For 1 :1 ratio, the tested doses were 129.7 nM, 259.4 nM, 518.8 nM, and 1037.5 nM.

[0309] These combinations showed cytotoxic activity against the murine glioma cancer cell line, with a Cl of less than 0.95 demonstrating synergistic effect of the pharmaceutical combinations. In particular, the 1:9 ratio combinations, and the 1:1 combination with 259.4 nM, 518.8 nM, and 1037.5 nM demonstrated a very strong effect on viability of the murine glioma cancer cells between 10% and 90%.Example 3: Cytotoxicity of avermectin and benzimidazole combination on human glioblastoma cell line

[0310] Human glioblastoma cell line U-87 MG from ATCC-HTB-14 was cultured in DMEM + 10 % FCS medium, as described under Example 1.

[0311] Combination with doses of IVE and MBZ in a ratio of 1:9 and 1:1 were tested, using various concentrations. For 1:9, IVE doses used were 6.5 nM, 13 nM, 415 nM, and 830 nM. Correspondingly, the MBZ doses used were 58.4 nM, 116.7 nM, 3735 nM, and 7470 nM. For 1 :1 ratio, the tested doses were 32.4 nM, 64.8 nM, 2075 nM, and 4150 nM.

[0312] These combinations showed cytotoxic activity against the human glioblastoma cell line, with a Cl of less than 0.95 demonstrating synergistic effect of the pharmaceutical combination. In particular, the 1:9 ratio combination with 415 nM and 830 nM of IVE, as well as 1:1 ratio with 2075 and 4150 nM, demonstrated a very strong effect on viability of the human glioblastoma cancer cells.

[0313] Example 4: Cytotoxicity of avermectin and benzimidazole combination on murine breast cancer cell line

[0314] Murine breast cancer cell line 4T1 from ATCC-CRL-2539 was cultured in RPMI-1640 + 2.5 g / l glucose + 1.0 mM Sodium pyruvate + 10 mM Hepes + 10 % FCS (20% at thawing) medium, as described under Example 1.

[0315] Combination with doses of IVE and MBZ in a ratio of 1:9 and 1:1 were tested, using various concentrations. For 1:9, IVE doses used were 6.5 nM and 52 nM. Correspondingly, the MBZ doses used were 58.4 nM and 466.9 nM. For 1 :1 ratio, the tested doses were 32.4 nM, 64.8 nM, 259.4 nM, and 518.8 nM.

[0316] These combinations showed cytotoxic activity against the murine breast cancer cell line, with a Cl of less than 0.95 demonstrating synergistic effect of the pharmaceutical combination. In particular, the 1:9 ratio combination with 52:466.9 nM demonstrated a very strong effect on viability.

[0317] Example 5: Cytotoxicity of avermectin and benzimidazole combination on human breast cancer cell line

[0318] Human breast cancer cell line MDA-MB-231 from ATCC-HTB-26 was cultured in DMEM + non-essential amino acid + 10 % FCS medium, as described under Example 1.

[0319] Combination with doses of IVE and MBZ in a ratio of 1:9 and 1:1 were tested, using various concentrations. For 1:9, IVE doses used were 52 nM and 104 nM. Correspondingly, the MBZdoses used were 466.9 nM, and 933.8 nM. For 1:1 ratio, the tested doses were 32.4 nM, 64.8 nM, 129.7 nM, 259.4 nM, 518.8 nM, and 1037.5 nM.

[0320] These combinations showed cytotoxic activity against the human breast cancer cell line, with a Cl of less than 0.95 demonstrating synergistic effect of the pharmaceutical combination. In particular, the 1:1 combination with 259.4 nM, 518.8 nM, and 1037.5 nM, as well as both of the 1 :9 ratio combinations, demonstrated a very strong effect on viability between 20% and 90%.

[0321] Example 6: Cytotoxicity of avermectin and benzimidazole combination on human large cell lung cancer cell line

[0322] Human large cell lung cancer cell line NCI-H460 from ATCC-HTB-177 was cultured in RPMI-1640 + 10 % FCS medium, as described under Example 1.

[0323] Combination with doses of IVE and MBZ in a ratio of 1:9 and 1:1 were tested, using various concentrations. For 1 :9, IVE doses used were 52 nM, 104 nM, and 208 nM. Correspondingly, the MBZ doses used were 466.9 nM, 933.8 nM, and 1867 nM. For 1 :1 ratio, the tested doses were 32.4 nM, 64.8 nM, 129.7 nM, 259.4 nM, 518.8 nM, 1037.5 nM, and 2075 nM.

[0324] These combinations showed cytotoxic activity against the human large cell lung cancer cell line, with a Cl of less than 0.95 demonstrating synergistic effect of the pharmaceutical combination. In particular, the 1 :9 combinations tested, and the 1 :1 combinations with 259.4 nM and 1037.5 nM demonstrated a very strong effect on viability of the human large cell lung cancer cells between 10% and 90%.

[0325] Example 7: Cytotoxicity of avermectin and benzimidazole combination on murine glioblastoma cell line

[0326] Murine glioblastoma cell line VM-M3 from ABM-T8016 was cultured in PriGrow 111 + 10 % FCS for thawing and culture start. Once culture is established, it was switched to DMEM + 10 % FCS + 25 mM glucose + 4 mM Glutamine medium, as described under Example 1.

[0327] Combination with doses of IVE and MBZ in a ratio of 1:9 and 1:1 were tested, using various concentrations. For 1 :9, IVE doses used were 6.5 nM, 52 nM, and 415 nM. Correspondingly, the MBZ doses used were 58.4 nM, 466.9 nM, and 3735 nM. For 1:1 ratio, the tested doses were 32.4 nM, 64.8 nM, 129.7 nM, and 259.4 nM. In particular, the 1:9 combinations with 52.0 nM and 466.9 nM, and the 1 :1 with 259.4 nM and 259.4 nM demonstrated a very strong effect These combinations showed cytotoxic activity against the murine glioma cell line, with a Cl of less than 0.95 demonstrating synergistic effect of the pharmaceutical combination.

[0328] Example 8: Anti-cancer effect in human subjectsHuman subjects with various types and stages of cancer were treated with different pharmaceutical combinations according to the invention. Unless otherwise indicated, the pharmaceutical combinations were taken with meals (mainly with a high-fat diet), avermectin administered in a single dose, and benzimidazole administered in 2 or 3 doses.

[0329] I. A female with non-small cell lung cancer, adenocarcinoma type, Stage 4 cancer, was treated with ivermectin 1mg / kg / day and fendendazole 1776 mg / day (« 25 mg / kg / day). Adjuvant chemotherapy was also administered (carboplatin + Paclitaxel). A complete metabolic response was observed after 1.5 months of treatment.

[0330] II. A female with Stage4TNBC breast cancer, metastatic to brain, was treated with ivermectin 1 mg / kg / day and mebendazole 1500 mg / day

[0331]

[0332] 20 mg / kg / day), in addition to the ongoing administration of Keytruda and Xeloda. After 3 months of treatment with the pharmaceutical combination according to the invention, all tumors and metastases, including brain metastases, were observed to be shrinking.

[0333] III. A female with Stage 4 non-small cell lung cancer was treated with ivermectin 48 mg / day (equivalent to 1 mg / kg / day) and mebendazole 1500 mg / day 25 mg / kg / day). Additionally, she was also taking Tagrisso 80 mg / day. After 2.5 months, almost 74% tumor volume shrinkage was observed (i.e. PET Sep. 20, 2025: LUL mass 5.5x3.0 cm SUVmax 13.9 shrunk to 2.8x2.6 cm SUVmax 6.3 on PET Dec. 9, 2025). Moreover, cancer marker CEA reduced from 66.4 ng / mL to a surprising 9.5 ng / mL.

[0334] IV. A female with glioblastoma, previously treated with chemoradiation with Temodar, was administered ivermectin 1.5 mg / kg / day and mebendazole 1500 mg / day (~ 20 mg / kg / day). Adjuvant Temodar was also administered alongside. After 6 months, no tumor growth was observed, and no recurrence was observed.

[0335] V. A male with Stage 4 melanoma with extensive metastases, was administered ivermectin 1 mg / kg / day, fenbendazole 1500 mg / day (« 20 mg / kg / day), and mebendazole 1500 mg / day (« 20 mg / kg / day), alongside immunotherapy. After 3 months, no evidence of disease was observed. VI. Afemale with NHL lymphoma with multiple neck lymph nodes, was administered ivermectin 1 mg / kg / day and fenbendazole 1500 mg / day 20 mg / kg / day), alongside chemotherapy. After 2 months of treatment and 2 cycles of R-CHOP chemotherapy, no evidence of disease was observed.

[0336] VII. A male with 8 cm Stage 3 small cell lung cancer, was administered ivermectin 1.5 mg / kg / day and Fenbendazole 1500 mg / day (~ 20 mg / kg / day), alongside chemotherapy. After 2 months, no evidence of disease was observed.

Claims

45CLAIMS1. A pharmaceutical combination for use in a method of treating a cancer in a subject, said combination comprising at least:(i) an avermectin, in a dose of 0.5 mg / kg / dayto 20 mg / kg / day, and(ii) a benzimidazole, selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 0.5 mg / kg / dayto 300 mg / kg / day,such that both (i) and (ii) are administered simultaneously or at different times.

2. A pharmaceutical combination for use according to claim 1 , wherein the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof.

3. A pharmaceutical combination for use according to anyone of claims 1-2, wherein the subject is a human.

4. A pharmaceutical combination for use accordingto claim 3, wherein the avermectin is administered in a dose of 0.5 mg / kg / dayto 10 mg / kg / day, preferably about 1.5 mg / kg / day.

5. A pharmaceutical combination for use according to claim 3 or 4, wherein the benzimidazole is administered in a dose of 0.5 mg / kg / dayto 300 mg / kg / day, preferably 15 mg / kg / dayto 200 mg / kg / day, more preferably about 100 mg / kg / day.

6. A pharmaceutical combination for use according to any one of claims 3 - 5, wherein the dose of the avermectin and benzimidazole is in a ratio of 1 :1 to 1 :600, preferably about 1:67.

7. A pharmaceutical combination for use according to any one of claims 3 - 6, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 0.5 mg / kg / dayto 100 mg / kg / day, preferably about 20 mg / kg / day.

8. A pharmaceutical combination for use according to claim 7, wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1:1 to 1:200, preferably about 1:13.

9. A pharmaceutical combination for use accordingto anyone of claims 1-2, wherein the subject is an animal, such as murine species, canids, and felids.

10. A pharmaceutical combination for use accordingto claim 9, wherein the avermectin is administered in a dose of 5 mg / kg / dayto 40 mg / kg / day, preferably about 10 mg / kg / day.4611. A pharmaceutical combination for use according to claim 9 or 10, wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, preferably about 100 mg / kg / day.

12. A pharmaceutical combination for use according to any one of claims 9- 11, wherein the dose of the avermectin and benzimidazole is in a ratio of 1 :1 to 1 :600, preferably about 1:10.

13. A pharmaceutical combination for use according to anyone of claims 9- 12, wherein the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, or mixtures thereof, and wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg.

14. A pharmaceutical combination for use accordingto claim 13, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:300, preferably about 1:

10.

15. A pharmaceutical combination for use accordingto anyone of claims 9- 12, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day.

16. A pharmaceutical combination for use accordingto claim 15, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day.

17. A pharmaceutical combination for use accordin to anyone of claims 15-16, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200, preferably about 1 :5.

18. A pharmaceutical combination for use accordingto anyone of claims 1 - 17, wherein the combination further comprises one or more of oleic acid, glycerol trioleate, Span 80, Tween 80, soybean oil, olive oil, coconut oil, fish oil, polyethylene glycol, natural phospholipids, and mannitol.

19. A method of treating a cancer in a subject, comprising administering an avermectin in a dose of 0.5 mg / kg / day to 20 mg / kg / day, and a benzimidazole selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof, in a dose of 10 mg / kg / day to 300 mg / kg / day, to the subject, such that the avermectin and the benzimidazole are administered simultaneously or at different times to induce a synergistic effect.

20. The method according to claim 19, wherein the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof.4721. The method according to any one of claims 19-20, wherein the subject is a human.

22. The method according to claim 21, wherein the avermectin is administered in a dose of 0.5 mg / kg / day to 10 mg / kg / day, preferably about 2 mg / kg / day.

23. The method according to claim 21 or 22, wherein the benzimidazole is administered in a dose of 0.5 mg / kg / day to 300 mg / kg / day, preferably 15 mg / kg / day to 200 mg / kg / day, more preferably about 100 mg / kg / day.

24. The method according to any one of claims 21 - 23, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :600, preferably about 1 :

50.

25. The method according to any one of claims 21 - 24, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 5 mg / kg / day to 100 mg / kg / day, preferably about 20 mg / kg / day.

26. The method according to claim 25, wherein the dose of the avermectin and fenbendazole and / or oxfendazole is in a ratio of 1 :1 to 1 :200, preferably about 1:10.

27. The method according to any one of claims 19-20, wherein the subject is an animal, such as murine species, canids, and felids.

28. The method according to claim 27 , wherein the avermectin is administered in a dose of 5 mg / kg / day to 40 mg / kg / day, preferably about 10 mg / kg / day.

29. The method according to any one of claim 27 - 28, wherein the benzimidazole is administered in a dose of 20 mg / kg / day to 300 mg / kg / day, preferably about 100 mg / kg / day.

30. The method according to any one of claims 27 - 29, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1:1 to 1:600, preferably about 1:

10.

31. The method according to any one of claims 27 - 30, wherein the benzimidazole is mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole , febantel, netobimin, or mixtures thereof, and the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day.

32. The method according to claim 31, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1 :1 to 1 :300, preferably about 1 :10.

33. The method according to any one of claims 27 - 30, wherein the benzimidazole is fenbendazole and / or oxfendazole, and it is administered in a dose of 15 mg / kg / day to 100 mg / kg / day, preferably about 50 mg / kg / day.

34. The method according to claim 33, wherein the avermectin is administered in a dose of 1 mg / kg / day to 20 mg / kg / day, preferably about 10 mg / kg / day.

35. The method according to any one of claims 33 - 34, wherein the dose of the avermectin and the benzimidazole is in a ratio of 1.3:1 to 1 :200, preferably about 1 :

5.

36. A method of treating a cancer in a subject, comprising administration of a suitable dose of a combination of an avermectin and a benzimidazole, simultaneously or at different times, resulting in concomitant therapeutically effective plasma concentration of each to induce a synergistic effect.

37. The method according to claim 36, wherein the avermectin is selected from abamectin, doramectin, emamectin, eprinomectin, ivermectin, selamectin, milbemycins, moxidectin, and mixtures thereof.

38. The method according to any one of claims 36-37, wherein the benzimidazole is selected from mebendazole, fenbendazole, flubendazole, oxfendazole, oxibendazole, thiabendazole, nocodazole, methiazole, triclabendazole, ciclobendazole, cambendazole, ricobendazole, febantel, netobimin, and mixtures thereof.

39. The method according to any one of claims 19 - 38, such that the administration results in a synergistic therapeutic effect which is more than the sum of the individual effect of each compound.

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