WO2018069924A1 - Polythérapies non cytotoxiques et leurs utilisations dans le traitement du cancer - Google Patents

Polythérapies non cytotoxiques et leurs utilisations dans le traitement du cancer Download PDF

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WO2018069924A1
WO2018069924A1 PCT/IL2017/051126 IL2017051126W WO2018069924A1 WO 2018069924 A1 WO2018069924 A1 WO 2018069924A1 IL 2017051126 W IL2017051126 W IL 2017051126W WO 2018069924 A1 WO2018069924 A1 WO 2018069924A1
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combination therapy
cancer
inhibitor
container
carcinoma
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PCT/IL2017/051126
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English (en)
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Shmuel Ben-Sasson
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Tiltan Pharma Ltd.
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Publication of WO2018069924A1 publication Critical patent/WO2018069924A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the field of treatment and/or prevention of cancer using a combination of agents.
  • Cancer generally refers to one of a group of more than 100 diseases caused by the uncontrolled, abnormal growth of cells that can spread to adjoining tissues or other parts of the body.
  • Cancer cells can form a solid tumor, in which the cancer cells are massed together, or exist, as dispersed cells, as in leukemia. Normal cells divide until maturation is attained and then only as necessary for replacement of damaged or dead cells. Cancer cells are often referred to as "malignant", because they divide endlessly, eventually crowding out nearby tissues and spreading to other parts of the body. The tendency of cancer cells to invade and spread from one organ to another or from one part of the body to another distinguishes them from benign tumor cells, which overgrow but do not spread to other organs or parts of the body. Malignant cancer cells eventually metastasize and spread to other parts of the body via the bloodstream or lymphatic system, where they can multiply and form new tumors. This sort of tumor progression makes cancer a deadly disease.
  • cytotoxic agents selective for dividing cells.
  • These drugs are effective because cancer cells generally divide more frequently than normal cells.
  • cancer cells can acquire mutations that confer drug resistance.
  • Another is that not all cancer cells divide more frequently than normal cells, and slowly- dividing cancer cells can be as, or even more, insensitive to such cytotoxic agents as normal cells.
  • Some cancer cells divide slowly, because they reside in a poorly vascularized, solid tumor and are unable to meet the needs required for cell division.
  • cytotoxic agents such as cyclophosphamide have been used to treat cancer.
  • any single agent may only target a subset of the total population of malignant cells present, leaving a subpopulation of cancerous cells to continue growing.
  • cells develop resistance upon prolonged exposure to a drug.
  • Combination therapies which employ two or more agents with differing mechanisms of action and differing toxicities, have been useful for circumventing drug resistance and increasing the target cell population, but have not proven effective in the treatment of all cancers.
  • certain combinations of agents may be synergistic: their combined effect is larger than that predicted based on their individual activities. Thus, combining different agents can be a powerful strategy for treating cancer.
  • cytotoxic agents which typically disrupt cell proliferation by interfering with the synthesis or integrity of DNA.
  • alkylating agents such as cyclophosphamide, antimetabolites (e.g. purine and pyrimidine analogues), and platinum coordination complexes.
  • cytotoxic agents which function by disrupting cell division are that they do not discriminate between normal and malignant cells: any dividing cell is a potential target for their action.
  • any dividing cell is a potential target for their action.
  • cell populations which normally exhibit high levels of proliferation are affected, leading to the toxic side effects commonly associated with cancer treatments.
  • Angiogenesis is a process of tissue vascularization that involves the growth of new developing blood vessels into a tissue, and is also referred to as neovascularization. Blood vessels are the means by which oxygen and nutrients are supplied to living cells.
  • Inhibitors of pro-angiogenic growth factors are agents used to inhibit the signaling of known pro-angiogenic factors like VEGF or FGF. Currently, these agents by themselves failed to demonstrate sufficient efficacy in the treatment of cancer.
  • a combination comprising at least one angiogenesis inhibitor, at least one non-steroidal anti-inflammatory agent (NSAID), at least one NFkB inhibitor, at least one H2 blocker, however devoid of any cvtoxotic agents could provide anti-cancer treatment.
  • NSAID non-steroidal anti-inflammatory agent
  • NFkB inhibitor at least one NFkB inhibitor
  • H2 blocker at least one H2 blocker
  • the present invention provides a combination therapy comprising at least one angiogenesis inhibitor, at least one non-steroidal anti-inflammatory agent (NSAID), at least one NFkB inhibitor, at least one H2 blocker and a pharmaceutically acceptable carrier.
  • NSAID non-steroidal anti-inflammatory agent
  • NFkB inhibitor at least one NFkB inhibitor
  • H2 blocker at least one H2 blocker
  • combination therapy refers to a combination of therapeutically active agents (at least one angiogenesis inhibitor, at least one NSAID, at least one angiogenesis inhibitor, at least NFkB inhibitor, at least one H2 blocker, at least one non-steroidal anti-inflammatory agent) encompassed in a single or multiple compositions.
  • said combination therapy of the invention comprises at least one angiogenesis inhibitor, at least one non-steroidal antiinflammatory agent (NSAID), at least one NFkB inhibitor, at least one H2 blocker being administered together at the same time to a patient in need thereof or separately (each or in any combinations thereof) in any sequential manner prescribed by a medical care taker.
  • NSAID non-steroidal antiinflammatory agent
  • said at least one angiogenesis inhibitor is a protein kinase inhibitor. In other embodiments, said at least one angiogenesis inhibitor is an inhibitor of angiopoietin-1/2 signaling through the Tie2 receptor.
  • said at least one angiogenesis inhibitor is selected from vatalanib, bevacizumab, aflibercept (VEGF-Trap), vandetanib, cediranib, axitinib, sorafenib, regorafenib, brivanib, sunitinib, motesanib, pazopanib, Apatinib, BIBF and any combination thereof.
  • the invention provides a combination therapy comprising vatalanib, sorafenib or regorafenib, at least one non-steroidal anti-inflammatory agent and a pharmaceutically acceptable carrier.
  • angiogenesis inhibitor relates to agents which are used to inhibit the signaling of known pro-angiogenic factors such as VEGF, FGF or PDGF. Without wishing to be bound by theory, it was shown that these agents can act extracellularly, by the inhibition of the interaction of an angiogenic factor with its receptor or can act intracellularly via the inhibition of the protein-kinase activity of the corresponding receptors. Non limiting examples of these agents include anti- VEGF or anti-VEGF- Receptor antibodies or inhibitors of the protein-kinase domain of VEGF-R, FGF-R or PDGF-R.
  • anti-inflammatory agent relates to any agents capable of reducing and/or inhibiting and/or preventing inflammation disease cased by either response to infection, injury, irritation, or surgery.
  • the anti-inflammatory drug is a steroidal anti-inflammatory drug selected from a group consisting of dexamethasone and betamethasone.
  • the antiinflammatory agent is a non-steroidal anti inflammatory drug.
  • the non-steroidal anti- inflammatory drug may be selected from a COX-1 inhibitor, a COX-2 inhibitor and a non-selective COX-1 and COX-2 inhibitor.
  • the COX- 1 and COX-2 inhibitors may be selected from the group consisting of diclofenac, piroxicam and indomethacin.
  • the composition in addition to the non-steroidal anti-inflammatory drug, the composition further comprises a steroidal anti- inflammatory drug such as, but not limited to, dexamethasone and betamethasone.
  • said at least one non-steroidal anti-inflammatory agent is selected from diclofenac, piroxicam, indomethacin and any combinations thereof.
  • pharmaceutically acceptable carrier relates to pharmaceutically-acceptable, nontoxic carriers or diluents, which are defined as vehicles commonly used to formulate pharmaceutical compositions for animal or human administration.
  • Such carriers may include, however not limited to, buffering agents, solubilizing agents, stabilizing agents or taste additives.
  • a combination therapy of the invention further comprises at least one of an NFkB inhibitor, an H2-blocker, levamisol, at least one agent that enhances intracellular accumulation of NADH + H + , an inhibitor of a matrix metalloproteinase, a redox quinine or any combination thereof.
  • a combination therapy of the invention further comprises an NFkB inhibitor.
  • NFkB inhibitor as used herein relates to any agent used for the inhibition of the Nuclear Factor kappa B (NFkB) intracellular transcription factor.
  • the NFkB inhibitor is selected from sulfasalazine, rapamycin, caffeic acid phenethylester, SN50 (a cell-permeable inhibitory peptide), parthenolide, triptolide, wedelolactone, lactacystin and MG-132 [Z-Leu-Leu-Leu-H].
  • the NFkB inhibitor is selected from sulfasalazine and rapamycin or their derivatives.
  • rapamycin derivatives are selected from temsirolimus and everolimus.
  • said NFkB inhibitor is sulfasalazine.
  • a combination therapy of the invention further comprises an H2-blocker.
  • H2-blocker as referred to in the present invention relates to an Histamine type 2-receptor antagonist, used to block the action of histamine on parietal cells in the stomach, decreasing acid production by these cells.
  • the H2-blocker may be any H2-blocker known to those skilled in the art.
  • the H2-blocker may be selected from the group consisting of Cimetidine, Ranitidine, Famotidine and Nizatidine.
  • said H-2 blocker is cimetidine.
  • a combination therapy of the invention further comprises levamisol.
  • a combination therapy of the invention further comprises at least one agent that enhances intracellular accumulation of NADH + H + .
  • a combination therapy of the invention further comprises an inhibitor of a matrix metalloproteinase.
  • matrix metalloproteinase (MMP) inhibitor relates to any chemical compound that inhibits by at least 5%, the hydrolytic activity of at least one matrix metalloproteinase enzyme that is naturally occurring in a mammal.
  • the MMP inhibitor may be any MMP inhibitor known in the art, such as AG- 3340, RO 32-3555, RS 13-0830, Tissue Inhibitors of metalloproteinases (TIMPs) (e.g. TIMP-1, TIMP-2, TIMP-3, or TIMP-4), alpha 2- macroglobulin, tetracyclines (e.g., tetracycline, minocycline, and doxycycline), hydroxamates (e.g.
  • TIMP-1, TIMP-2, TIMP-3, or TIMP-4 Tissue Inhibitors of metalloproteinases
  • alpha 2- macroglobulin e.g., tetracyclines, minocycline, and doxycycline
  • hydroxamates e.g.
  • the MMP inhibitor is an MMP2 or an MMP9 inhibitor.
  • a combination therapy of the invention further comprises a redox quinone.
  • said redox quinone is Vitamin 3 ⁇ 4.
  • said Vitamin 3 ⁇ 4 is selected from a group consisting of menadione and menadione sodium bisulfite.
  • Vitamin K 3 is a redox quinone , known as a prothrombogenic agent, mainly in supplement of veterinary diet. Studies have shown that Vitamin K 3 has failed to demonstrate beneficial anti-cancer properties (Tetef M. et al. /. Cancer Res. Clin. Oncol. 121 :103-6 (1995)).
  • said combination therapy of the invention is being contained in at least one container. In other embodiments, said combination therapy of the invention is being contained in at least two containers.
  • container refers to any receptacle capable of holding at least one component of a composition of the combination therapy of the invention.
  • a container may be any jar, vial or box known to a person skilled in the art and may be made of any material suitable for the components contained therein and additionally suitable for short or long term storage under any kind of temperature.
  • the present invention further provides a formulation consisting of an aqueous or oily suspension or solution comprising compositions of the combination therapy of the invention.
  • the formulation is formulated for oral administration.
  • Such oral administration may allow for treatment to take place, for example, at the patient's home.
  • the formulation further comprises a flavoring agent (e.g. menthol, anethol and/or salt).
  • a flavoring agent e.g. menthol, anethol and/or salt.
  • part of the constituents of the aqueous or oily suspension or solution of the formulation may be supplied in a dry form and reconstituted (e.g. solubilized) prior to oral administration.
  • compositions may be provided as sustained release or timed release formulations.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostrearate or glyceryl distearate, alone or mixed with a wax. Micro-encapsulation may also be used.
  • the timed release formulation can provide a pharmaceutical composition of immediate and pulsed release throughout the day.
  • the diluent is selected so as not to affect the biological activity of a composition of the combination therapy of the invention. Examples of such diluents are distilled water, physiological saline, Ringer's solution, dextrose solution, and Hank' s solution.
  • a composition or formulation of the combination therapy of the invention may include carriers, adjuvants and emulsifiers such as poloxamers, or nontoxic, non- therapeutic, non-immunogenic stabilizers and the like. Effective amounts of such diluent or carrier will be those amounts which are effective to obtain a pharmaceutically acceptable formulation in terms of solubility of components, biological activity, and the like.
  • the formulations include a controlled- release device or composition where one or several of the components comprised in a composition of a combination therapy of the invention are being released in a delayed fashion.
  • Such formulation may be in the form of a tablet (or a pill) which releases different doses of components comprised in a composition of a combination therapy of the invention, in different time intervals after being administered orally.
  • a composition of a combination therapy of the invention may be formulated in a solid, semi-solid, or liquid form such as, e.g. suspensions, aerosols, or the like or any other formulation known to a person skilled in the art.
  • the compositions are administered in unit dosage forms suitable for single administration of precise dosage amounts.
  • the compositions may also include, depending on the formulation desired, pharmaceutically-acceptable carriers as defined above.
  • composition of a combination therapy of the invention may be administered in a single dosage form comprising all the therapeutically active agents together.
  • said combination therapy of the present invention comprises more than two compositions contained in separate containers
  • said at least two compositions/containers may be separately administered, simultaneously or sequentially.
  • administered sequentially refers to ordered and successive administration of said compositions of a combination therapy of the invention. Said sequential administration may be 1, 2 or 3 days apart.
  • a combination therapy of the invention consists of: a first container comprising Vatalanib, sorafenib or regorafenib, diclofenac, cimetidine and sulfasalazine; and a second container comprising Vatalanib, cimetidine and sulfasalazine.
  • said first container is administered twice a week and said second container is administered five times a week, on non-overlapping days.
  • said first and said second containers are formulated in a liquid form suitable for oral administration.
  • said first container comprises Vatalanib, Sorafenib or Regorafenib, in the range of 200-1 , 500mg; diclofenac in the range of 100-300 mg; cimetidine in the range of 200-1,000 mg; sulfasalazine in the range of 200-1 ,000 mg.
  • said second container comprises Vatalanib in the range of 300- l ,500mg; cimetidine in the range of 200-1,000 mg; sulfasalazine in the range of 400- 2,000 mg.
  • the dose-range for Vatalanib, Sorafenib or Regorafenib, in a combination therapy of the invention is 100mg-2000mg administered once or twice a day. In some embodiments the total daily dose of Vatalanib, Sorafenib or Regorafenib, in a combination therapy of the invention is in the range of 500mg- 1250mg administered once or twice a day.
  • the invention provides a combination therapy as disclosed herein above and below for use in the treatment of at least one type of cancer disease or any condition or symptom associated therewith.
  • said at least one type of cancer disease is selected from lung cancer (e.g. adenocarcinoma and including non-small cell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), nasopharyngeal cancer, gastric cancer, liver cancer (e.g. hepatocellular carcinoma), biliary-tract cancer, prostate cancer including the advanced disease, hematopoietic tumors of lymphoid lineage (e.g.
  • lung cancer e.g. adenocarcinoma and including non-small cell lung cancer
  • pancreatic cancers e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma
  • colon cancers e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and
  • acute lymphocytic leukemia B-cell lymphoma, Burkitt's lymphoma
  • myeloid leukemias for example, acute myelogenous leukemia (AML)
  • thyroid follicular cancer myelodysplastic syndrome (MDS)
  • tumors of mesenchymal origin e.g. fibrosarcomas and rhabdomyosarcomas
  • melanomas teratocarcinomas
  • neuroblastomas gliomas, glioblastoma
  • benign tumor of the skin e.g. keratoacanthomas
  • breast carcinoma e.g. advanced breast cancer
  • kidney carcinoma ovary carcinoma
  • bladder carcinoma epidermal carcinoma and any combinations thereof.
  • the present invention provides a method of inhibiting and/or treating at least one type of cancer disease or any condition or symptom associated therewith in a mammal comprising administering to the mammal a combination therapy of the invention.
  • cancer as referred to in the present invention relates to any type of neoplastic disease which is characterized by abnormal and uncontrolled cell division causing malignant growth or tumor.
  • Cancer cells unlike benign tumor cells, exhibit the properties of invasion and metastasis and are highly anaplastic.
  • Cancer includes the two broad categories of carcinoma and sarcoma.
  • the cancer is a solid tumor or tumor metastasis.
  • said cancer may be selected from, however not limited to, the group consisting of lung cancer (e.g. adenocarcinoma and including non-small cell lung cancer), pancreatic cancers (e.g.
  • pancreatic carcinoma such as, for example exocrine pancreatic carcinoma
  • colon cancers e.g. colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma
  • prostate cancer including the advanced disease, hematopoietic tumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g.
  • fibrosarcomas and rhabdomyosarcomas melanomas, teratocarcinomas, neuroblastomas, gliomas, glioblastoma, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer), kidney carcinoma, ovary carcinoma, bladder carcinoma, epidermal carcinoma and any combinations thereof.
  • the term "inhibiting any type of cancer disease or any condition or symptom associated therewith” and/or “treating any type of cancer disease or any condition or symptom associated therewith” as used in the context of the present invention relates to a decrease in tumor size; decrease in rate of tumor growth; stasis of tumor size; decrease in the number of metastasis; decrease in the number of additional metastasis; decrease in invasiveness of the cancer; decrease in the rate of progression of the tumor from one stage to the next, inhibition of tumor growth in a tissue of a mammal having a malignant cancer, control of establishment of metastases, inhibition of tumor metastases formation, regression of established tumors as well as decrease in the angiogenesis induced by the cancer.
  • inhibiting cancer can also refer to prophylaxis such as prevention as cancer reoccurs after previous treatment (including surgical removal) and prevention of cancer in an individual prone (genetically, due to life style, chronic inflammation and so forth) to develop cancer.
  • administering or its other lingual forms as used in the context of the present invention relates to the path by which a pharmaceutically active component, a drug, fluid or other substance is brought into contact with the body. The pharmaceutical composition is transported from the site of entry to the part of the body where its action is desired to take place.
  • said administering may be achieved via any medically acceptable means suitable for a composition of a combination therapy of the invention or any component thereof, including oral, rectal, vaginal, nasal, topical, transdermal, or parenteral (including subcutaneous, intramuscular, intrasynovial, intraperitoneal, intradermal and intravenous) administration.
  • any medically acceptable means suitable for a composition of a combination therapy of the invention or any component thereof including oral, rectal, vaginal, nasal, topical, transdermal, or parenteral (including subcutaneous, intramuscular, intrasynovial, intraperitoneal, intradermal and intravenous) administration.
  • composition of a combination therapy of the present invention can thus be administered by any means known in the art, such as oral (including buccal and sublingual), rectal, vaginal, nasal, topical, transdermal, or parenteral (including subcutaneous, intramuscular, intravenous, intrasynovial, intraperitoneal and intradermal) administration.
  • compositions, methods and systems of the present invention may be used either alone, or in conjunction with other cancer treatment methods known to those of skill in the art. Such methods may include, but are not limited to chemotherapy, radiation therapy or surgery.
  • the administration of a composition of a combination therapy of the present invention may be conducted before, during or after other cancer therapies.
  • a composition of a combination therapy of the present invention may be administered concurrently with other cancer treatments known to those of skill in the art.
  • oral administration requires a higher dose than intravenous administration.
  • the administration route will depend upon the situation: the skilled artisan must determine which form of administration is best in a particular case, balancing dose needed versus the number of times per month administration is necessary.
  • the components of a composition of a combination therapy of the invention are administered using the normal dose of each component as known to a person skilled in the art.
  • the dosages and administration schedule of components of a composition of a combination therapy of the invention may vary depending on the component, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose and administration scheduled should be sufficient to result in slowing and/or regressing, the growth of the tumor(s) and may also cause complete regression of the cancer. In some cases, regression may be monitored via direct imaging (e.g. MRI) or by a decrease in blood levels of tumor specific markers.
  • An effective amount of the pharmaceutical composition is that which provides a medical benefit as noted by the clinician or other qualified observer. Regression of a tumor in a patient is typically measured with reference to the diameter of a tumor.
  • the present invention allows for the administration of a composition of a combination therapy of the present invention, either prophylactically or therapeutically or in the context of adjuvant or neo-adjuvant treatment.
  • a composition of a combination therapy of the invention may be administered in advance of any symptom.
  • Prophylactic administration of compositions may serve to prevent or inhibit cancer.
  • a composition of a combination therapy of the invention may prophylactically be administered to a patient with, for example, a family history of cancer.
  • the risk for developing cancer may be determined by measuring levels of cancer marker proteins in the biological fluids (i.e. blood, urine) of a patient or by genetic markers.
  • administration of a composition of a combination therapy of the invention may be administered to a patient with rising cancer marker protein levels.
  • Such markers include, for example, rising PSA, CEA, thymosin ⁇ -15, thymosin ⁇ -16, calcitonin, and matrix metalloproteinase (MMP).
  • MMP matrix metalloproteinase
  • compositions or compositions of a combination therapy of the invention may be administered at (or after) the onset of a symptom or indication of a cancer.
  • a composition of a combination therapy of the present invention may be provided either prior to the anticipated tumor growth at a site or after the malignant growth has begun at a site.
  • mammal as used in the context of the present invention relates to warm blooded vertebrate animals characterized by the presence of mammary glands, which produce milk in females for the nourishment of young, and in addition are covered with hair or fur.
  • said mammal may be selected from the group consisting of a human, a cat, a dog and a horse.
  • compositions of a combination therapy of the invention were tested in vivo for the purpose of suppression of tumor growth in mice.
  • the control group received a vehicle containing only non-active ingredients which was compared to groups which received pharmaceutical compositions comprising different active ingredients as described in detail below.
  • Example 1 Anti-cancer and synergistic activity of the combination of the invention
  • EMT 6JCTX a breast carcinoma cells derived from Balb/c mice, known for Cyclophosphamide resistance (Dr. Beverly Teicher, Dena Farber Cancer Institute).
  • Animals-Species-Strain Mouse-CB6 Fl.
  • Gender /Number /Age Males /8 mice per group/ 7-8 weeks.
  • Source Harlan Laboratories, Israel.
  • DMEM Dulbecco's Modified Eagle Medium
  • EMT6/CTX were cultured in growth medium and diluted 1 :2 or 1 :4 every 2-3 days by harvesting in Trypsin. Mice were injected with 3.5 x 10 5 EMT6/CTX mammary carcinoma cells in a volume of 0.1 ml per mouse at a concentration of 3.5 x 10 6 cells/ml.
  • test article were diluted 1 :2 with DDW, prior to administration i.e. again, 0.2 ml i.p. administration for 25g mouse.
  • TL-118 comprised two sets of drug combinations, each formulated as a liquid dosage form.
  • the one containing the cytotoxic agent is Green-labeled while the non-cytotoxic formulation is White-labeled.
  • the Green-labeled drug-combination is administered twice a week while the White one is administered during the rest of the week, according to the schedule specified below.
  • TL-118 Green-labeled Vial content is administered twice a week while the White one is administered during the rest of the week, according to the schedule specified below.
  • the dosing solutions Prior to administration, the dosing solutions were brought to room temperature and mixed. The solutions were diluted 1 :1 with DDW.
  • Subcutaneous Tumour Tumor implantation was done on Wednesday to enable starting of treatment on Sunday.
  • CB6F1 mice were injected SC into the right flank with EMT6/CTX cells in a volume of 100 ⁇ .
  • Subcutaneous tumors were measured in two perpendicular diameters starting on Day 5 (1 st day of treatment), at least once a week, until study termination at day 34..
  • Sorafenib was administered at a dose of 20mg/kg. Sorafenib was dissolved in 50% Solutol HS-15 50% absolute Ethanol solution and diluted in DDW prior to injection.
  • SRF Sorafenib

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Abstract

L'invention concerne une polythérapie non cytotoxique comprenant: au moins un inhibiteur de l'angiogenèse; au moins un anti-inflammatoire non stéroïdien; au moins un inhibiteur de NFk B; au moins un H2-bloquant; et un véhicule pharmaceutiquement acceptable. Elle concerne également des utilisations de cette polythérapie dans le traitement du cancer.
PCT/IL2017/051126 2016-10-10 2017-10-03 Polythérapies non cytotoxiques et leurs utilisations dans le traitement du cancer WO2018069924A1 (fr)

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WO2007053573A2 (fr) * 2005-10-31 2007-05-10 Bayer Pharmaceuticals Corporation Traitement du cancer au moyen de sorafenib
WO2008004231A1 (fr) 2006-07-07 2008-01-10 Tiltan Pharma Ltd. Traitement anticancéreux faisant appel à un h2-bloquant, à au moins un agent anti-inflammatoire et à un agent cytotoxique
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