WO2016061135A1 - Drug combinations with selective androgen receptor modulators (sarms) and methods of making and using them - Google Patents

Drug combinations with selective androgen receptor modulators (sarms) and methods of making and using them Download PDF

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Publication number
WO2016061135A1
WO2016061135A1 PCT/US2015/055383 US2015055383W WO2016061135A1 WO 2016061135 A1 WO2016061135 A1 WO 2016061135A1 US 2015055383 W US2015055383 W US 2015055383W WO 2016061135 A1 WO2016061135 A1 WO 2016061135A1
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optionally
equivalent
combination
cancer
therapeutic combination
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PCT/US2015/055383
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French (fr)
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John Maki
Newell Bascomb
Fredric Young
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Vicus Therapeutics, Llc
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Publication of WO2016061135A1 publication Critical patent/WO2016061135A1/en

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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
    • A61K31/40—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
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • 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

Definitions

  • This invention relates generally to medicine, pharmaceutical formulations and medical devices.
  • SARM selective androgen receptor modulator
  • additional drugs or active agents e.g., enobosarm or andarine
  • methods for making and using them for treating, ameliorating, reversing or preventing a cancer such as a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, a tumor, a burn or a short stature or related syndrome or condition.
  • SARM selective androgen receptor modulator
  • Chemotherapy is important in cancer treatment, but chemotherapy drugs act by damaging high proliferating cells, and damage to normal cells results in chemotherapy toxicities and side effects. Chemotoxicity can be seen most in actively dividing tissues such bone marrow, hair follicles and gastrointestinal mucosa. New approaches in cancer chemotherapeutics are needed to address these challenges.
  • therapeutic combinations of therapeutic agents or drugs for an individual in need thereof comprising or consisting of:
  • the SARM comprises or consists of:
  • enobosarm also called ostarine
  • ostarine or ((25)-3-(4-cyanophenoxy)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide), andarine, or 2,S')-3-(4-acetamido-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3- trifluoromethyl-phenyl)-propionamide
  • a paclitaxel or (2a,4a,5p,7p,10 ,13a)-4,10-Bis(acetyloxy)-13- ⁇ [(2i?,35)-3- (benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy ⁇ -l,7-dihydroxy-9-oxo-5,20- epoxytax-1 l-en-2-yl benzoate (or TAXOLTM) ; a docetaxel or equivalent, or
  • TAXOTERETM or a tamoxifen, or (Z)-2-[4-(l ,2-diphenylbut-l-enyl)phenoxy]-N,N- dimethylethanamine (or NOLVADEXTM, ISTUBALTM, VALODEXTM, GENOXTM), or an equivalent thereof or any combination thereof;
  • beta adrenergic receptor antagonist (a beta blocker), optionally a propranolol or equivalent, and optionally the propranolol is INDERALTM, AVLOCARDYLTM, DERALINTM, DOCITONTM, INDERALICITM, INNOPRAN XLTM, or SUMIALTM, or an equivalent thereof or any combination thereof;
  • NSAID non-steroidal anti-inflammatory drug
  • COX cyclooxygenase
  • prostaglandin synthase inhibitor or, optionally an etodolac, a naproxen; a celecoxib; a rofecoxib; a etoricoxib; a valdecoxib; a parecoxib; a
  • nabumetone a diclofenac (2-(2,6-dichloranilino) phenylacetic acid); or, a lumiracoxib, or an equivalent thereof or any combination thereof; (4) a combination of a beta adrenergic receptor antagonist (a beta blocker) and an NSAID, optionally a propranolol and an etodolac, optionally is a VT-122TM (Vicus Therapeutics, Morristown, NJ);
  • a growth hormone optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a HUMATROPETM (Eli Lilly);
  • SERM selective estrogen receptor modulator
  • an aromatase inhibitor or an aminoglutethimide, a 4-OH androstenedione, an anastrozole, a letrozole, an exemestane, or an equivalent thereof or any combination thereof;
  • (11) a combination of (10) and (2), (3) or (4);
  • a cyclophosphamide (cytophosphane), (i?5)-N,N-bis(2-chloroethyl)- 1,3,2- oxazaphosphinan-2-amine 2-oxide, or equivalent, or ENDOXANTM, CYTOXANTM,
  • (16) a combination of (13) and (14), and (2), (3) or (4);
  • a cytokine or a chemotherapeutic agent or a cytokine and a chemotherapeutic agent
  • the etodolac is a LODINETM, LODINE SRTM or ECCOXOLACTM; or the celecoxib is CELEBREXTM or CELEBRATM; or the rofecoxib is VIOXXTM, CEOXXTM or CEEOXXTM; or the etoricoxib is ARCOXIATM, ALGIXTM or TAUXIBTM; or the valdecoxib is BEXTRATM; the parecoxib is DYNAST ATTM; the naproxen is
  • XENOBIDTM ALEVETM
  • ANAPROXTM MIRANAXTM
  • NAPROGESICTM ANAPROXTM
  • DEDOLORTM DEFLAMATTM, VETAGESICTM or ZOLTEROLTM
  • the therapeutic combinations of therapeutic agents or drugs further comprises an anti-cancer or anti-tumor antibody, wherein optionally the anti-cancer or anti-tumor antibody is an alemtuzumab, a brentuximab vedotin, a cetuximab, a gemtuzumab ozogamicin, an abritumomab tiuxetan, a nimotuzumab, an ofatumumab, a panitumumab, a rituximab, a tositumomab, or a trastuzumab.
  • the anti-cancer or anti-tumor antibody is an alemtuzumab, a brentuximab vedotin, a cetuximab, a gemtuzumab ozogamicin, an abritumomab tiuxetan, a nimotuzumab, an ofat
  • the cytokine comprises an IL-2 or an interferon (IFN), wherein optionally the interferon is an alpha- IFN or a gamma-IFN; and optionally the IL-2 is a recombinant IL- 2, an aldesleukin, or a PROLEUKJN (Prometheus Laboratories), and optionally the IL-2, recombinant IL-2, or aldesleukin is dosages at about: 1 to 20, 2 to 10, 4 to 5, or 4.5 millions of IUs per cycle; or is dosaged for: 1 to 5, 2 to 4, or 3 cycles number of cycles of therapy.
  • IFN interferon
  • the chemotherapeutic agent comprises:
  • doxorubicin or a carboplatin or comprises an inducer of apoptosis or a mitotic inhibitor or anti-microtubule inhibitor, or an alkylating agent, or a topoisomerase inhibitor, or a glycopeptide antibiotic, or steroid receptor inhibitor, or a matrix metalloproteinase (MMP) inhibitor, or an mTOR (mammalian target of rapamycin) inhibitor, or a macrolide or a composition comprising a macrolide ring,
  • MMP matrix metalloproteinase
  • the inducer of apoptosis or a mitotic inhibitor or anti-microtubule inhibitor comprises or consists of a raltitrexed or equivalent, or TOMUDEXTM; a doxorubicin or equivalent, or ADRIAMYCINTM; a fluorouracil or 5-fluorouracil or equivalent; a paclitaxel or equivalent, or TAXOLTM or ABRAXANETM; a docetaxel or equivalent, or TAXOTERETM; a larotaxel, tesetaxel or ortataxel or equivalent; an epothilone or an epothilone A, B, C, D, E or F or equivalent; an ixabepilone (also known as azaepothilone B) or equivalent, or BMS-247550TM; a vincristine (also known as leurocristine) or equivalent, or ONCOVINTM; a vinblastin, vinblastine, vindesine, vinfluor
  • the topoisomerase inhibitor comprises or consists of an etoposide or equivalent, or EPOSINTM, ETOPOPHOSTM, VEPESIDTM or VP-16TM; an amsacrine or equivalent; a topotecan or equivalent, or HYC AMTINTM; a teniposide or equivalent, or VUMONTM or VM-26TM; an epipodophyllotoxin or equivalent; a camptothecin or equivalent; an irinotecan or equivalent, or CAMPTOSARTM; or, a combination thereof, and optionally the glycopeptide antibiotic comprises or consists of a bleomycin or equivalent or a bleomycin A 2 or B 2 or equivalent; a mitomycin or a mitomycin C or equivalent, a plicamycin (also known as mithramycin) or equivalent, or MITHRACINTM; or, a combination thereof,
  • the steroid receptor inhibitor comprises or consists of an estrogen receptor modulator (a SERM), and optionally the estrogen receptor modulator comprises or consists of a tamoxifen or equivalent, or NOLVADEXTM, ISTUBALTM or
  • VALODEXTM and optionally the steroid inhibitor or an anti-steroid comprises or consists of a finasteride or equivalent, or PROSCARTM, PROPECIATM, FINCARTM, FINPECIATM, FF AXTM, FINASTTM, FINARATM, FFNALOTM, PROSTERIDETM, GEFFNATM, APPECIATM, FFNASTERID IVAXTM, FFNASTERID or ALTERNOVATM
  • the macrolide or composition comprising a macrolide ring comprises or consists of a clarithromycin or equivalent, or ⁇ TM, KLARICIDTM, KLABAXTM, CLARIPENTM, CLARIDARTM, FROMILIDTM or CLACIDTM; an azithromycin or equivalent, or ZITHROMAXTM, ZITROMAXTM or SUMAMEDTM; a dirithromycin or equivalent; an erythromycin or equivalent; a roxithromycin or equivalent, or ROXOTM, SURLIDTM, R
  • ROXIMYCINTM or COROXINTM a telithromycin or equivalent or KETEKTM; a josamycin or equivalent; a kitasamycin or equivalent; a midecamycin or equivalent;
  • oleandomycin or equivalent a roxithromycin or equivalent
  • ROXOTM SURLIDTM, RULIDETM, BIAXSIGTM, ROXARTM, ROXIMYCINTM or COROXINTM
  • the chemotherapeutic agent comprises a sorafenib or equivalent, or NEXAVARTM; a sunitinib or equivalent, or SUTENTTM; an erlotinib or equivalent, or TARCEVATM; an imatinib or equivalent, or GLEEVECTM; a lapatinib or equivalent, or TYKERBTM; a toceranib or equivalent, or PALLADIATM; a masitinib or equivalent, or MASIVETTM, a bevacizumab or equivalent, or AVASTINTM; a sorafenib or equivalent, or NEXAVARTM; a sunitinib or equivalent, or SUTENTTM; an erlotinib or equivalent, or TARCEVATM; an imatinib or equivalent, or GLEEVECTM; a lapatinib or equivalent, or TYKERBTM; a toceranib or equivalent, or PALLADIATM; a masitin
  • trastuzumab or equivalent or HERCEPTINTM
  • cetuximab or equivalent or
  • ERBITUXTM a bevacizumab or equivalent, or AVASTINTM or BIBW 2992; a gefitinib or equivalent, or IRESSATM; a ranibizumab or equivalent, or LUCENTISTM; a pegaptanib or equivalent, or MACUGENTM; a dasatinib or equivalent, or BMS-354825TM; a sunitinib or equivalent, or SUTENTTM; a pazopanib or equivalent; a nilotinib or equivalent, or TASIGNATM; a panitumumab or equivalent, or VECTIBIXTM; a bandetinib or equivalent; a brivanib or equivalent, or E7080TM; a thalidomide or equivalent, or THALOMIDTM; lenalidomide or equivalent, or REVLIMIDTM; a bortezomib or equivalent, or
  • VELCADETM disulfiram or equivalent, or ANTABUSETM or ANTABUSTM; or an epigallocatechin gallate (EGCG) or equivalent; a demecolcine, an etoglucid or elsamitrucin, a lonidamine, a lucanthone, a mitotane or a mitoguazone or equivalent; or any combination thereof.
  • EGCG epigallocatechin gallate
  • the therapeutic agents or drugs formulated:
  • the therapeutic combination comprises or consists of a SARM or claim 1(a) with claim 1(b)(5), or a growth hormone, optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a
  • HUMATROPETM (Eli Lilly), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy, and optionally the therapeutic combination is formulated for controlled release dosing after about 12AM to achieve peak by about 6AM;
  • the therapeutic combination comprises or consists of a SARM with a propranolol and an growth hormone, or an hGH, or claim 1(b)(5), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy; and optionally is formulated as a combination pill comprising a SARM or claim 1(a) with a propranolol or claim 1(b)(2) (e.g., to enhance compliance), and optionally the propranolol comprises a sustained release propranolol plus, and optionally the therapeutic combination is formulated for treatment of severely burned children,
  • the therapeutic combination is formulated for controlled release propranolol and/or controlled release SARM or claim 1(a) dosing after about 12AM to achieve peak by about 6AM,
  • the therapeutic combination is formulated as a combination pill of sustained release propranolol and controlled release SARM or claim 1(a);
  • the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu,
  • TNBC triple-negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2/neu Her2/neu
  • the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1 (b)(2), 1(b) (3) or 1(b) (4),
  • the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage,
  • the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage,
  • the therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card;
  • the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic chemotherapy at standard dosing,
  • the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu,
  • TNBC triple-negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2/neu Her2/neu
  • the therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
  • a combination pill or packaging comprising or containing any combination of, or all of, (1), (2), (3), (4), (5), (6) and (7), optionally packaged on a blister card or equivalent, e.g., to enable metronomic dosing of one or all of the drugs, e.g., to enable metronomic dosing of cylcophosphomide and methotrexate or a claim l(b)(13),
  • the therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with: (1) VT-122 or claim 1(b)(4) and a docetaxel or claim 1(b)(1) or other cytotoxic chemotherapy, optionally at normal or metronomic low doses, or
  • the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer,, or an androgen receptor positive breast cancer, or a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu, such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
  • two or more therapeutic agents or drugs of the therapeutic combination are formulated as separate compositions, or two or more therapeutic agents or drugs of the therapeutic combination are formulated into one composition or drug formulation (two or more drugs of the therapeutic combination are formulated together).
  • one or two or more or all of the drugs of the therapeutic combination are packaged individually, or are packaged together, or packaged in any combination, in a single package, a plurality of packages or packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap.
  • one or two or more or all of the drugs of the therapeutic combination are packaged together or in any combination in a single package, a plurality of packages or packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap.
  • two or more or all of the drugs are released upon opening of the single package, plurality of packages or packettes, blister packet, lidded blister, blister card or packets or shrink wrap.
  • one or two or more or all of the drugs of the therapeutic combination are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a patch, a spray, an inhalant, a powder, a freeze-dried powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository or any combination thereof.
  • one or two or more or all of the drugs of the therapeutic combination are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one freeze-dried powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one adhesive, one spray, one powder, one freeze-dried powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel or one suppository.
  • the dosage of etodolac ranges from about 200 mg to 400 mg a day, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more; or (b) the dosage of propranolol ranges from 10 to 320 mg per day based on heart rate and blood pressure of the individual, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more.
  • the drug combination is packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day.
  • the beta adrenergic receptor antagonist or a beta blocker or equivalent, or a propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or equivalent, or etodolac or equivalent; and the therapeutic agent for the treatment of cancer are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day.
  • the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer are packaged in dosages that match a chrono-dosing regimen comprising:
  • beta adrenergic receptor antagonist e.g., a beta blocker
  • NSAID e.g., an etodolac or equivalent
  • 10 mg beta blocker, 400 mg NSAID in the AM, 20 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200mg NSAID, e.g., an etodolac or equivalent
  • 10 mg beta blocker 200 mg NSAID, e.g., an etodolac or equivalent
  • 10 mg beta blocker, 400 mg NSAID e.g., an etodolac or equivalent
  • beta adrenergic receptor antagonist e.g., a beta blocker
  • NSAID e.g., an etodolac or equivalent
  • beta adrenergic receptor antagonist e.g., a propranolol or equivalent, 200 mg NSAID
  • beta blocker 200 mg NSAID, in the evening 40 mg, NSAID; or
  • the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer are packaged in dosages that match a chrono-dosing regimen comprising:
  • Dose Escalation 1 AM 40 mg propranolol, 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etodolac; evening, 10 mg propranolol, 400 mg etodolac;
  • Dose escalation 2 AM 80 mg propranolol, 200 mg etodolac; afternoon 40 mg propranolol, 200 mg etodolac, evening 20 mg, etodolac.
  • the therapeutic drug combination is formulated for administration once a day, b.i.d. or t.i.d, or weekly, or biweekly, or monthly.
  • the therapeutic combination of drugs are formulated for administration intravenously, topically, orally, by inhalation, by infusion, by injection, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, for intra-articular administration, for intra-mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings.
  • the therapeutic drug combination is formulated for intermittent or alternated cycling of the drug or active agent or component, and optionally the intermittent or alternated cycling comprises administration weekly, bi-monthly, monthly or quarterly.
  • a device comprising a therapeutic combination of therapeutic agents or drugs as provided herein.
  • a pharmaceutical composition or formulation comprising the therapeutic combination as provided herein, alternatively further comprising a pharmaceutically acceptable excipient.
  • the pharmaceutical composition or formulation is formulated or manufactured as a feed, a food, a food or feed concentrate, a pellet, a lozenge, a liquid, a lotion, an implant, a nanoparticle, an elixir, an aerosol, a spray, an aerosol, an inhalant, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a patch, a microgel or a suppository.
  • provided are methods for treating, preventing or ameliorating a tumor or a cancer comprising: applying or administering to an individual in need thereof; or, applying or administering to an effected tissue: the therapeutic combination as provided herein, or a pharmaceutical composition or formulation as provided herein, wherein optionally the therapeutic agents or drugs are administered separately or together, or at the same time, or in synchrony, or by chrono-dosing, or one of the therapeutic agents or drugs is administered before another of the therapeutic agents or drugs, and optionally the therapeutic agents or drugs are formulated for administration intravenously (IV), parenterally, nasally, topically or locally, orally, or by liposome, implant or vessel-targeted nanoparticle delivery.
  • IV intravenously
  • the cancer or tumor is: a mastocytoma or a mast cell tumor, an ovarian cancer, pancreatic cancer, a non-small cell lung cancer, small cell lung cancer, hepatocarcinoma, melanoma, retinoblastoma, breast tumor or breast cancer (optionally a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), a basal-like carcinoma, a ductal carcinoma, colorectal carcinoma, leukemia, lymphoma, acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia, acute myeloid leukemia (AML), a histiocytic sarcoma, a brain tumor, an astrocytoma, a glioblastoma, a neuroma, a neuroblastoma, a colon carcinoma, cervical carcinoma, sarcoma, prostate tumor, bladder tumor
  • the therapeutic agents or drugs are administered separately or together, or at the same time, or in synchrony, or by chrono-dosing, or one of the therapeutic agents or drugs is administered before another of the therapeutic agents or drugs,
  • the therapeutic agents or drugs are formulated for administration intravenously (IV), parenterally, nasally, topically or locally, orally, or by liposome, implant or vessel-targeted nanoparticle delivery; and
  • systemic anti-cancer or anti-tumor treatment comprises administration of a drug, a biologic, a nutrient, an anti-cancer or anti-tumor dietary regimen, a radioactive agent, a tumor ablative agent, or
  • an anti-cancer or anti-tumor radiotherapy or a proton beam therapy wherein the therapeutic combination or pharmaceutical composition or formulation of (a) is administered before the anti-cancer or anti-tumor treatment of (b), or both are administered consecutively, or the therapeutic combination or pharmaceutical composition or formulation of (a) is administered after the anti-cancer or anti-tumor treatment of (b), or any combination thereof.
  • methods as provided herein further comprise: an anticancer or anti-tumor radiotherapy or a proton beam therapy.
  • a short stature a short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like
  • a burn a third degree burn, a large >10% total body surface area burn, a wound, a refractory large wound, a wound >10 cm 2 , a chronic wound, a diabetic foot ulcer, a venous leg ulcer, a pressure ulcer, or (c) a tumor or a cancer.
  • the cancer or tumor is: a mastocytoma or a mast cell tumor, an ovarian cancer, pancreatic cancer, a non-small cell lung cancer, small cell lung cancer, hepatocarcinoma, melanoma, retinoblastoma, breast tumor or breast cancer (optionally a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), a basal-like carcinoma, a ductal carcinoma, a colorectal carcinoma, leukemia, lymphoma, acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia, acute myeloid leukemia (AML), a Histiocytic sarcoma, a brain tumor, an astrocytoma, a glioblastoma, a neuroma, a neuroblastoma, a colon carcinoma, cervical carcinoma, sarcoma, prostate tumor,
  • TNBC
  • reticuloendothelial tissues Wilm's tumor, ovarian carcinoma, a bone cancer, an osteosarcoma, a renal cancer, or head and neck cancer, oral cancer, a laryngeal cancer, or an oropharyngeal cancer.
  • a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein, wherein optionally the therapeutic combination comprises or consists of a SARM or claim 1(a) with claim 1(b)(5), or a growth hormone, optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a HUMATROPETM (Eli Lilly), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy, and optionally the therapeutic combination is formulated for controlled release dosing after about 12AM to achieve peak by about 6AM.
  • a method for treating, ameliorating, preventing or reversing a burn, a third degree burn, a large >10% total body surface area burn, a wound, a refractory large wound, a wound >10 cm 2 , a chronic wound, a diabetic foot ulcer, a venous leg ulcer, a pressure ulcer, and the like comprising administering to an individual in need thereof a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein, wherein optionally the therapeutic combination comprises or consists of a SARM with a propranolol and an growth hormone, or an hGH, or claim 1(b)(5), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy; and optionally is formulated as a combination pill comprising a SARM or claim 1(a) with a propranolol or claim 1(b)(2) (e.g., to enhance compliance),
  • propranolol comprises a sustained release propranolol plus, and optionally the therapeutic combination is formulated for treatment of severely burned children,
  • the therapeutic combination is formulated for controlled release propranolol and/or controlled release SARM or claim 1(a) dosing after about 12AM to achieve peak by about 6AM,
  • the therapeutic combination is formulated as a combination pill of sustained release propranolol and controlled release SARM or claim 1(a).
  • the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
  • TNBC triple-negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2/neu Her2/neu
  • the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1(b)(2), 1(b) (3) or 1(b) (4),
  • the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage,
  • the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage,
  • the therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card; and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic chemotherapy at standard dosing, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
  • TNBC triple-negative breast cancer
  • the therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
  • capecitabine optionally at normal or metronomic low doses
  • a combination pill or packaging comprising or containing any combination of, or all of, (1), (2), (3), (4), (5), (6) and (7), optionally packaged on a blister card or equivalent, e.g., to enable metronomic dosing of one or all of the daigs, e.g., to enable metronomic dosing of cylcophosphomide and methotrexate or a claim l(b)(13),
  • the therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with:
  • VT-122 or claim 1(b)(4) and a docetaxel or claim 1(b)(1) or other cytotoxic chemotherapy optionally at normal or metronomic low doses
  • a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT 122 or claim 1(b)(4) and docetaxel or other cytotoxic chemotherapy optionally at normal or metronomic low doses
  • the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or androgen receptor positive breast cancer, and optionally the breast cancer is a triple- negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
  • two or more drugs of the therapeutic combination are formulated as separate compositions, or two or more drugs of the therapeutic combination are formulated into one composition or drug formulation, or two or more drugs of the therapeutic combination are formulated together.
  • formulations and/or a therapeutic combinations for use in a method for treating, ameliorating, preventing or reversing a tumor or a cancer
  • formulation or a therapeutic combination comprises a formulation or a therapeutic combination as set forth in any of claims 1 to 20, or comprises the pharmaceutical composition or formulation of any of claims 22 to 24,
  • the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
  • TNBC triple-negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2/neu Her2/neu
  • the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1(b)(2), 1(b) (3) or 1(b) (4), and optionally the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage,
  • the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage,
  • the formulation or a therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card;
  • the formulation or a therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic
  • the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
  • TNBC triple-negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • Her2/neu Her2/neu
  • formulation or a therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
  • capecitabine optionally at normal or metronomic low doses
  • the formulation or a therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with:
  • the formulation or a therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or androgen receptor positive breast cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
  • compositions, formulations, kits and devices for treating, preventing or ameliorating a short stature, short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like comprising use of a SARM and at least one other drug or active agent, including for example: a growth hormone, such as a human recombinant growth hormone (hrGH), somatropin or HUMATROPETM (Eli Lilly).
  • a growth hormone such as a human recombinant growth hormone (hrGH), somatropin or HUMATROPETM (Eli Lilly).
  • a SARM and at least one other drug or active agent, including for example, a beta adrenergic receptor antagonist, or a
  • the cancer is a dysfunctional cell condition.
  • the cancer or dysfunctional cell condition comprises (is) any metastatic or benign tumor, and the methods or uses as provided herein are used for ameliorating, treating (killing, eliminating, stopping the growth and/or metastasis of) cancer stem cells or cancer cells from: lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer (and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), a basal-like carcinoma, a ductal carcinoma, a carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the e
  • TNBC triple
  • the therapeutic combination or pharmaceutical composition or formulation are formulated (e.g., manufactured) as one dosage administration in the morning and one dosage administration in the evening; or are formulated as one dosage administration in the morning, one dosage mid-day and one dosage administration in the evening.
  • the dosage schedule provides a relatively higher dose of one drug in the morning (the AM) than in the evening, and a relatively higher dose of another medication in the evening than in the morning.
  • the therapeutic combination or the pharmaceutical composition are formulated for multiple
  • administrations e.g., at least two administrations, one in the morning and one in the evening, wherein the dosage schedule provides a relatively higher dose of beta blocker in the morning (the AM) than in the evening, and a relatively higher dose of an antiinflammatory medication in the evening than in the morning.
  • the products of manufacture or formulations as provided herein comprise a therapeutic combination as provided herein or the
  • composition or formulation as provided herein and a nutritional supplement, or food supplement or feed supplement.
  • therapeutic combinations of drugs are provided are therapeutic combinations of drugs, pharmaceutical compositions, preparations and kits, that can be administered by several routes, including intravenous, topical and oral, or combinations thereof.
  • one embodiment comprises a product of manufacture comprising a pharmaceutical composition or a formulation, a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a kit, comprising:
  • ingredients can be in one blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a kit
  • separate ingredients can be formulated e.g., for topical application, for oral or for topical application.
  • Each ingredient can be either separately packaged, or can be formulated as one unit dose, e.g., as one tube (e.g., with gel, lotion etc.), ampoule, blister packette and the like.
  • compositions, preparations and kits that can be administered by inhalation, infusion or injection, (e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intra-articular, intra-mammary, etc.), topical application (e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g. vaginal and other epithelial linings, gastrointestinal mucosa, etc.).
  • inhalation e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intra-articular, intra-mammary, etc.
  • topical application e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.
  • epithelial or mucocutaneous linings e.g. vaginal and other epithelial linings, gastrointestinal mucos
  • compositions, preparations and kits in liquid forms that can be administered orally.
  • the compositions, preparations and kits can be also prepared as capsules, gels, geltabs, tablets, powders, sprays, aerosols, pellets (e.g. for animal consumption), suppositories, lotions, patches or adhesives (e.g., for the skin), or creams and ointments.
  • the compositions, preparations and kits can be also prepared as physiological solutions suitable for I.V. administration or other parenteral administration.
  • a multi-ingredient kit as provided herein comprises (contains) two or more ingredients.
  • An amount may be determined, e.g. by mass or by weight or by molar amount.
  • a multi-ingredient kit may contain two or more ingredients in unequal amounts.
  • a multi-ingredient kit may contain two or more ingredients in approximately equal amounts and/or one or more ingredients that are not in unequal amounts.
  • said multi-ingredient kit may contain two or more ingredients that are admixed. In another aspect, said multi-ingredient kit may contain two or more ingredients that are not admixed. In another aspect, said multi-ingredient kit may contain two or more ingredients that are partially admixed. In another aspect, said multi- ingredient kit may contain two or more ingredients that are at least partially admixed, as well as one or more ingredients that are not admixed. An ingredient in a multi-ingredient kit may be liquid forms that can be administered orally.
  • one, two or three or more or all of the drugs of the therapeutic combination are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a patch, a spray, an inhalant, a powder, a freeze-dried powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository or any combination thereof.
  • one, two or three or more or all of the drugs of the therapeutic combination are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one freeze-dried powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one adhesive, one spray, one powder, one freeze-dried powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel or one suppository.
  • the dosage of etodolac ranges from about 200 mg to 400 mg a day, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more; or, (b) the dosage of propranolol ranges from 10 to 320 mg per day based on heart rate and blood pressure of the individual, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more.
  • the drug combinations are administered and/or packaged in dosages that match a chrono-dosing regimen, e.g., to match an optimal dose for the time of day.
  • a chrono-dosing regimen e.g., to match an optimal dose for the time of day.
  • the SARM and the beta adrenergic receptor antagonist or a beta blocker or equivalent, or the SARM and a propranolol or equivalent; or the SARAM and the non- steroidal anti -inflammatory drug or NSAID or equivalent, or etodolac or equivalent are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day.
  • combinations as provided herein are administered and/or packaged for"metronomic dosaging" or "metronomic chemotherapy”, e.g., where therapeutic combinations or the drug combinations as provided herein are dosed, administered and/or packaged for chronic, equally spaced administration of low doses, e.g., of chemotherapeutic drugs, without extended rest periods.
  • low doses e.g., of chemotherapeutic drugs
  • the low dosaging and administration without extended rest periods results in antitumor efficacy with very low toxicity.
  • the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal antiinflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer are packaged in dosages that match a chrono-dosing regimen comprising:
  • beta adrenergic receptor antagonist e.g., a beta blocker
  • NSAID e.g., an etodolac or equivalent
  • 10 mg beta blocker, 400 mg NSAID in the AM, 20 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200mg NSAID, e.g., an etodolac or equivalent
  • 10 mg beta blocker 200 mg NSAID, e.g., an etodolac or equivalent
  • 10 mg beta blocker, 400 mg NSAID e.g., an etodolac or equivalent
  • beta adrenergic receptor antagonist e.g., a beta blocker
  • NSAID e.g., an etodolac or equivalent
  • beta blocker 200 mg NSAID, in the evening 40 mg, NSAID; or
  • the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal antiinflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer are packaged in dosages that match a chrono-dosing regimen comprising:
  • Dose Escalation 1 AM 40 mg propranolol, 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etodolac; evening, 10 mg propranolol, 400 mg etodolac;
  • Dose escalation 2 AM 80 mg propranolol, 200 mg etodolac; afternoon 40 mg propranolol, 200 mg etodolac, evening 20 mg, etodolac.
  • the therapeutic drug combination is formulated for administration once a day, b.i.d. or t.i.d, or weekly, or biweekly, or monthly.
  • the beta adrenergic receptor antagonist (a beta blocker) or propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or etodolac or equivalent; and the therapeutic agent for the treatment of cancer are formulated for administration once a day, b.i.d. or t.i.d, or weekly, or biweekly, or monthly.
  • the therapeutic combination of drugs are formulated for administration intravenously, topically, orally, by inhalation, by infusion, by injection, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intra- aurally, for intra-articular administration, for intra-mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings.
  • a device comprising a therapeutic combination of therapeutic agents or drugs as provided herein.
  • kits comprising combinations of ingredients, as described herein.
  • each member of the combination of ingredients is manufactured in a separate package, kit or container; or, all or a subset of the combinations of ingredients are manufactured in a separate package or container.
  • the package, kit or container comprises a blister package, a clamshell, a tray, a shrink wrap and the like.
  • kits for manufacture comprising a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap comprising a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein.
  • the products of manufacture can comprise a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap comprising a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein, wherein the therapeutic combination or pharmaceutical composition or formulation are manufactured and/or formulated for at least two, three, four or five or more dosage administrations; or the therapeutic combination or pharmaceutical composition or formulation are manufactured and/or formulated for once a day, or bid (twice a day), or tid (three times a day), or four times a day, administration.
  • each compartment of the product of manufacture e.g., a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap
  • each compartment of the product of manufacture has all components or members of the drug combination to be administered at the same time, for example, all the components or members (e.g., pills, tablets, etc) to be taken in the morning are in one compartment, and all the components or members (e.g. , pills, tablets, etc) to be taken in the afternoon and/or evening are in another compartment, etc.
  • the components or members of the drug combination are in liquid form, then all the components or members of the drug combination to be taken at the same time are formulated as a liquid mixture in the same compartment, which can be appropriately sealed, but designed for easy opening, e.g., with a screw cap and the like.
  • drug combination as provided herein is formulated, packaged or designed for drug regimen compliance of a patient population, a pediatric or geriatric population, or a mentally compromised patient population.
  • drug combination(s) as provided herein are provided herein.
  • a patient population having mild or severe mental retardation, slow cognition, dementia, senility, Alzheimer's disease, traumatic brain injury, chemical brain damage, mental diseases (e.g., dissociative disorder, obsessive-compulsive disorder, delusional disorder, schizophrenia, mania, panic disorder, depression, dyslexia, any learning disability and the like) post-traumatic stress disorder, traumatic war neurosis, post-traumatic stress syndrome (PTSS), physical disability (e.g., blindness).
  • mental diseases e.g., dissociative disorder, obsessive-compulsive disorder, delusional disorder, schizophrenia, mania, panic disorder, depression, dyslexia, any learning disability and the like
  • post-traumatic stress disorder traumatic war neurosis
  • PTSS post-traumatic stress syndrome
  • physical disability e.g., blindness
  • the package, kit or container comprises a "blister package” (also called a blister pack, or bubble pack).
  • the blister package is made up of two separate elements: a transparent plastic cavity shaped to the product and its blister board backing. These two elements are then joined together with a heat sealing process which allows the product to be hung or displayed.
  • Exemplary types of "blister packages” include: Face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, slide blister packages.
  • Blister packs, clamshells or trays are forms of packaging used for goods; thus, provided are blister packs, clamshells or trays comprising a composition, e.g., a combination of active ingredients or the multi-ingredient combination of drugs as provided herein.
  • Blister packs, clamshells or trays can be designed to be non-reclosable, so consumers can tell if a package has already opened. They are used to package for sale goods where product tampering is a consideration, such as the pharmaceuticals as provided herein.
  • a blister pack as provided herein comprises a moulded PVC base, with raised areas (the "blisters") to contain the tablets, pills, etc. comprising the combinations as provided herein, covered by a foil laminate.
  • Tablets, pills, etc. are removed from the pack either by peeling the foil back or by pushing the blister to force the tablet to break the foil.
  • a specialized form of a blister pack is a strip pack.
  • blister packs adhere to British Standard 8404.
  • a blister packs also comprise a method of packaging where the compositions comprising combinations of ingredients as provided herein are contained in- between a card and a clear PVC.
  • the PVC can be transparent so the item (pill, tablet, geltab, etc.) can be seen and examined easily; and in one aspect, can be vacuum-formed around a mould so it can contain the item snugly and have room to be opened upon purchase.
  • the card is brightly colored and designed depending on the item (pill, tablet, geltab, etc.) inside, and the PVC is affixed to the card using pre-formed tabs where the adhesive is placed.
  • the adhesive can be strong enough so that the pack may hang on a peg, but weak enough so that this way one can tear open the join and access the item.
  • the card has a perforated window for access.
  • more secure blister packs e.g., for items such as pills, tablets, geltabs, etc. as provided herein are used, and they can comprise of two vacuum-formed PVC sheets meshed together at the edges, with the informative card inside. These can be hard to open by hand, so a pair of scissors or a sharp knife may be required to open.
  • blister packaging comprises at least two components (e.g., is a multi-ingredient combination of drugs as provided herein): a thermoformed "blister” which houses the product (e.g., a pharmaceutical combination as provided herein), and then a "blister card” that is a printed card with an adhesive coating on the front surface.
  • a thermoformed "blister” which houses the product (e.g., a pharmaceutical combination as provided herein)
  • a "blister card” that is a printed card with an adhesive coating on the front surface.
  • the blister component which is most commonly made out of PVC
  • This machine introduces heat to the flange area of the blister which activates the glue on the card in that specific area and ultimately secures the PVG blister to the printed blister card.
  • the thermoformed PVG blister and the printed blister card can be as small or as large as you would like, but there are limitations and cost considerations in going to an oversized blister card.
  • Conventional blister packs can also be sealed (e.g., using an AE GO 8 DUOTM, SCA Consumer Packaging, Inc., DeKalb IL) using regular heat seal tooling.
  • This alternative aspect, using heat seal tooling, can seal common types of thermoformed packaging.
  • therapeutic combinations, preparations, formulations and/or kits can be manufactured as "blister packages” or as a plurality of packettes, including as lidded blister packages, lidded blister or blister card or packets or packettes, or a shrink wrap.
  • laminated aluminum foil blister packs are used, e.g., for the preparation of drugs designed to dissolve immediately in the mouth of a patient.
  • This exemplary process comprises having the drug combinations as provided herein prepared as an aqueous solution(s) which are dispensed (e.g., by measured dose) into an aluminum (e.g., alufoil) laminated tray portion of a blister pack.
  • This tray is then freeze- dried to form tablets which take the shape of the blister pockets.
  • the alufoil laminate of both the tray and lid fully protects any highly hygroscopic and/or sensitive individual doses.
  • the pack incorporates a child-proof peel open security laminate.
  • the system give tablets an identification mark by embossing a design into the alufoil pocket that is taken up by the tablets when they change from aqueous to solid state.
  • individual 'push-through' blister packs/ packettes are used, e.g., using hard temper aluminum (e.g., alufoil) lidding material.
  • hermetically-sealed high barrier aluminum (e.g., alufoil) laminates are used.
  • any of the products of manufacture as provided herein including kits or blister packs, use foil laminations and strip packs, stick packs, sachets and pouches, peelable and non-peelable laminations combining foil, paper, and film for high barrier packaging.
  • any of the products of manufacture including kits or blister packs, as provided herein include memory aids to help remind patients when and how to take the drug. This safeguards the drug's efficacy by protecting each pill until it's taken; gives the product or kit portability, makes it easy to take a dose anytime or anywhere.

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Abstract

In alternative embodiments, provided are therapeutic combinations, pharmaceutical compositions, formulations, kits and devices comprising drug combinations including a selective androgen receptor modulator (SARM), e.g., such as enobosarm or andarine, with one or more additional drugs or active agents, and methods for making and using them for treating, ameliorating, reversing or preventing a cancer such as a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, a tumor, a burn or a short stature or related syndrome or condition.

Description

DRUG COMBINATIONS WITH SELECTIVE ANDROGEN RECEPTOR MODULATORS (SARMS) AND METHODS OF MAKING AND USING
THEM
RELATED APPLICATIONS
This Patent Convention Treaty (PCT) International Application claims the benefit of priority under 35 U.S.C. § 1 19(e) of U.S. Provisional Application Serial No. (USSN) 62/065,650, filed October 18, 2014. The aforementioned applications is expressly incorporated herein by reference in its and for all purposes.
FIELD OF THE INVENTION
This invention relates generally to medicine, pharmaceutical formulations and medical devices. In alternative embodiments, provided are therapeutic combinations, pharmaceutical compositions, formulations, kits and devices comprising drug
combinations including a selective androgen receptor modulator (SARM), e.g., such as enobosarm or andarine, with one or more additional drugs or active agents, and methods for making and using them for treating, ameliorating, reversing or preventing a cancer such as a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, a tumor, a burn or a short stature or related syndrome or condition.
BACKGROUND
Chemotherapy is important in cancer treatment, but chemotherapy drugs act by damaging high proliferating cells, and damage to normal cells results in chemotherapy toxicities and side effects. Chemotoxicity can be seen most in actively dividing tissues such bone marrow, hair follicles and gastrointestinal mucosa. New approaches in cancer chemotherapeutics are needed to address these challenges.
SUMMARY
In alternative embodiments, provided are therapeutic combinations of therapeutic agents or drugs for an individual in need thereof comprising or consisting of:
(a) a selective androgen receptor modulator (SARM),
wherein optionally the SARM comprises or consists of:
enobosarm (also called ostarine), or ((25)-3-(4-cyanophenoxy)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide), andarine, or 2,S')-3-(4-acetamido-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3- trifluoromethyl-phenyl)-propionamide,
(7R,7aS)-2-Chloro-4-(7-hydroxy- 1 ,3-dioxotetrahydropyrrolo[ 1 ,2-c]imidazol-2- yl)-3-methylbenzonitrile (or BMS-564,929),
4-[(2R)-2-[(lR)-2,2,2-trifluoro-l-hydroxyethyl]pyrrolidin-l-yl]-2- (trifluoromethyl)benzonitrile,
4-(3-Hydroxy-8-aza-bicyclo[3.2. l]octyl)-naphthalene-l-carbonitrile (or AC- 262,356),
6-(bis-(2,2,2-trifluoroethyl)amino)-4-trifluoromethyl-lH-quinolin-2-one (or LGD- 2226),
9-chloro-2-ethyl-l-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin- 7(6H)-one (or LGD-3303),
2-[4-(dimethylamino)-6-nitro-l,2,3,4-tetrahydroquinolin-2-yl]-2-methylpropan-l- ol (or S-40503),
2S)-N-(4-cyano-3-trifluoromethylphenyl)-3-(3-fluoro-4-chlorophenoxy)-2- hydroxy-2-methyl-propanamide (or S-23), or
an equivalent thereof or any combination thereof; and
(b) a therapeutic agent, compound or composition comprising:
(1) a paclitaxel, or (2a,4a,5p,7p,10 ,13a)-4,10-Bis(acetyloxy)-13-{[(2i?,35)-3- (benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-l,7-dihydroxy-9-oxo-5,20- epoxytax-1 l-en-2-yl benzoate (or TAXOL™) ; a docetaxel or equivalent, or
TAXOTERE™; or a tamoxifen, or (Z)-2-[4-(l ,2-diphenylbut-l-enyl)phenoxy]-N,N- dimethylethanamine (or NOLVADEX™, ISTUBAL™, VALODEX™, GENOX™), or an equivalent thereof or any combination thereof;
(2) a beta adrenergic receptor antagonist (a beta blocker), optionally a propranolol or equivalent, and optionally the propranolol is INDERAL™, AVLOCARDYL™, DERALIN™, DOCITON™, INDERALICI™, INNOPRAN XL™, or SUMIAL™, or an equivalent thereof or any combination thereof;
(3) a non-steroidal anti-inflammatory drug (a NSAID), optionally a
cyclooxygenase (COX) or prostaglandin synthase inhibitor; or, optionally an etodolac, a naproxen; a celecoxib; a rofecoxib; a etoricoxib; a valdecoxib; a parecoxib; a
nabumetone; a diclofenac (2-(2,6-dichloranilino) phenylacetic acid); or, a lumiracoxib, or an equivalent thereof or any combination thereof; (4) a combination of a beta adrenergic receptor antagonist (a beta blocker) and an NSAID, optionally a propranolol and an etodolac, optionally is a VT-122™ (Vicus Therapeutics, Morristown, NJ);
(5) a growth hormone, optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a HUMATROPE™ (Eli Lilly);
(6) a , or pentyl [l-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fiuoro-2-oxo- lH-pyrimidin-4-yl]carbamate, or XELODA™, or an equivalent thereof or any
combination thereof;
(7) a combination of (2), (3) or (4) and (6);
(8) a selective estrogen receptor modulator (SERM), or an equivalent thereof or any combination thereof;
(9) a combination of (8) and (2), (3) or (4);
(10) an aromatase inhibitor, or an aminoglutethimide, a 4-OH androstenedione, an anastrozole, a letrozole, an exemestane, or an equivalent thereof or any combination thereof;
(11) a combination of (10) and (2), (3) or (4);
(12) a combination of (2), (3) or (4) and (8) or (9), or a combination of (2), (3) or (4) and (10) or (1 1);
(13) a cyclophosphamide (cytophosphane), (i?5)-N,N-bis(2-chloroethyl)- 1,3,2- oxazaphosphinan-2-amine 2-oxide, or equivalent, or ENDOXAN™, CYTOXAN™,
NEOSAR™ or RE VIMMUNE™ ;
(14) a methotrexate, or (25)-2-[(4-{[(2,4-Diaminopteridin-6- yl)methyl](methyl)amino}benzoyl)amino]pentanedioic acid, or an equivalent thereof or any combination thereof;
(15) a combination of (13) and (14);
(16) a combination of (13) and (14), and (2), (3) or (4);
(17) a combination of (1) and (2), (3) or (4);
(18) a cytokine or a chemotherapeutic agent, or a cytokine and a chemotherapeutic agent;
(19) a combination of (1) and a cytokine or a chemotherapeutic agent;
(20) any combination of (1) to (19).
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs, the etodolac is a LODINE™, LODINE SR™ or ECCOXOLAC™; or the celecoxib is CELEBREX™ or CELEBRA™; or the rofecoxib is VIOXX™, CEOXX™ or CEEOXX™; or the etoricoxib is ARCOXIA™, ALGIX™ or TAUXIB™; or the valdecoxib is BEXTRA™; the parecoxib is DYNAST AT™; the naproxen is
XENOBID™, ALEVE™, ANAPROX™, MIRANAX™, NAPROGESIC™,
NAPROSYN™, NAPRELAN™, PROXEN™ or SYNFLEX™; the nabumetone is RELAFEN™, RELIFEX™ or a GAMBARAN™; or, the diclofenac is FLECTOR PATCH™, VOLTAREN™, VOLTAROL™, DICLON™, DICLOFLEX DIFEN™, DIFENE™, CATAFLAM™, PENNSAID™, PANAMOR™, RHUMALGAN™, MODIFENAC™, ABITREN™, OLFEN™, VOVERAN™, ARTHROTEC™,
DEDOLOR™, DEFLAMAT™, VETAGESIC™ or ZOLTEROL™;
In alternative embodiments the therapeutic combinations of therapeutic agents or drugs further comprises an anti-cancer or anti-tumor antibody, wherein optionally the anti-cancer or anti-tumor antibody is an alemtuzumab, a brentuximab vedotin, a cetuximab, a gemtuzumab ozogamicin, an abritumomab tiuxetan, a nimotuzumab, an ofatumumab, a panitumumab, a rituximab, a tositumomab, or a trastuzumab.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs, the cytokine comprises an IL-2 or an interferon (IFN), wherein optionally the interferon is an alpha- IFN or a gamma-IFN; and optionally the IL-2 is a recombinant IL- 2, an aldesleukin, or a PROLEUKJN (Prometheus Laboratories), and optionally the IL-2, recombinant IL-2, or aldesleukin is dosages at about: 1 to 20, 2 to 10, 4 to 5, or 4.5 millions of IUs per cycle; or is dosaged for: 1 to 5, 2 to 4, or 3 cycles number of cycles of therapy.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs, the chemotherapeutic agent comprises:
a doxorubicin or a carboplatin, or comprises an inducer of apoptosis or a mitotic inhibitor or anti-microtubule inhibitor, or an alkylating agent, or a topoisomerase inhibitor, or a glycopeptide antibiotic, or steroid receptor inhibitor, or a matrix metalloproteinase (MMP) inhibitor, or an mTOR (mammalian target of rapamycin) inhibitor, or a macrolide or a composition comprising a macrolide ring,
and optionally the inducer of apoptosis or a mitotic inhibitor or anti-microtubule inhibitor comprises or consists of a raltitrexed or equivalent, or TOMUDEX™; a doxorubicin or equivalent, or ADRIAMYCIN™; a fluorouracil or 5-fluorouracil or equivalent; a paclitaxel or equivalent, or TAXOL™ or ABRAXANE™; a docetaxel or equivalent, or TAXOTERE™; a larotaxel, tesetaxel or ortataxel or equivalent; an epothilone or an epothilone A, B, C, D, E or F or equivalent; an ixabepilone (also known as azaepothilone B) or equivalent, or BMS-247550™; a vincristine (also known as leurocristine) or equivalent, or ONCOVIN™; a vinblastin, vinblastine, vindesine, vinflunine, vinorelbine or NAVELBINE™ or equivalent; or, any combination thereof, and optionally the alkylating agent comprises or consists of a cisplatin or equivalent; a cisplatinum or equivalent; a cw-diamminedichloridoplatinum(II) (CDDP) or equivalent; a carboplatin or equivalent; a oxaloplatin or equivalent; a cyclophosphamide (cytophosphane) or equivalent, or ENDOXAN™, CYTOXAN™, NEOSAR™ or REVIMMUNE™; a mechlorethamine or equivalent; a chlormethine or equivalent; a mustine or equivalent; a nitrogen mustard or equivalent; a chlorambucil or equivalent, or LEUKERAN™; or, a combination thereof,
and optionally the topoisomerase inhibitor comprises or consists of an etoposide or equivalent, or EPOSIN™, ETOPOPHOS™, VEPESID™ or VP-16™; an amsacrine or equivalent; a topotecan or equivalent, or HYC AMTIN™; a teniposide or equivalent, or VUMON™ or VM-26™; an epipodophyllotoxin or equivalent; a camptothecin or equivalent; an irinotecan or equivalent, or CAMPTOSAR™; or, a combination thereof, and optionally the glycopeptide antibiotic comprises or consists of a bleomycin or equivalent or a bleomycin A2 or B2 or equivalent; a mitomycin or a mitomycin C or equivalent, a plicamycin (also known as mithramycin) or equivalent, or MITHRACIN™; or, a combination thereof,
and optionally the steroid receptor inhibitor comprises or consists of an estrogen receptor modulator (a SERM), and optionally the estrogen receptor modulator comprises or consists of a tamoxifen or equivalent, or NOLVADEX™, ISTUBAL™ or
VALODEX™, and optionally the steroid inhibitor or an anti-steroid comprises or consists of a finasteride or equivalent, or PROSCAR™, PROPECIA™, FINCAR™, FINPECIA™, FF AX™, FINAST™, FINARA™, FFNALO™, PROSTERIDE™, GEFFNA™, APPECIA™, FFNASTERID IVAX™, FFNASTERID or ALTERNOVA™, and optionally the macrolide or composition comprising a macrolide ring comprises or consists of a clarithromycin or equivalent, or ΒΙΑΧΓΝ™, KLARICID™, KLABAX™, CLARIPEN™, CLARIDAR™, FROMILID™ or CLACID™; an azithromycin or equivalent, or ZITHROMAX™, ZITROMAX™ or SUMAMED™; a dirithromycin or equivalent; an erythromycin or equivalent; a roxithromycin or equivalent, or ROXO™, SURLID™, RULIDE™, BIAXSIG™, ROXAR™,
ROXIMYCIN™ or COROXIN™; a telithromycin or equivalent or KETEK™; a josamycin or equivalent; a kitasamycin or equivalent; a midecamycin or equivalent;
oleandomycin or equivalent; a roxithromycin or equivalent, or ROXO™, SURLID™, RULIDE™, BIAXSIG™, ROXAR™, ROXIMYCIN™ or COROXIN™; a
troleandomycin or equivalent; or a tylosin or equivalent; or, any combination thereof, wherein optionally the chemotherapeutic agent comprises a sorafenib or equivalent, or NEXAVAR™; a sunitinib or equivalent, or SUTENT™; an erlotinib or equivalent, or TARCEVA™; an imatinib or equivalent, or GLEEVEC™; a lapatinib or equivalent, or TYKERB™; a toceranib or equivalent, or PALLADIA™; a masitinib or equivalent, or MASIVET™, a bevacizumab or equivalent, or AVASTIN™; a
trastuzumab or equivalent, or HERCEPTIN™; a cetuximab or equivalent, or
ERBITUX™; a bevacizumab or equivalent, or AVASTIN™ or BIBW 2992; a gefitinib or equivalent, or IRESSA™; a ranibizumab or equivalent, or LUCENTIS™; a pegaptanib or equivalent, or MACUGEN™; a dasatinib or equivalent, or BMS-354825™; a sunitinib or equivalent, or SUTENT™; a pazopanib or equivalent; a nilotinib or equivalent, or TASIGNA™; a panitumumab or equivalent, or VECTIBIX™; a bandetinib or equivalent; a brivanib or equivalent, or E7080™; a thalidomide or equivalent, or THALOMID™; lenalidomide or equivalent, or REVLIMID™; a bortezomib or equivalent, or
VELCADE™; disulfiram or equivalent, or ANTABUSE™ or ANTABUS™; or an epigallocatechin gallate (EGCG) or equivalent; a demecolcine, an etoglucid or elsamitrucin, a lonidamine, a lucanthone, a mitotane or a mitoguazone or equivalent; or any combination thereof.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs, the therapeutic agents or drugs formulated:
(a) for a short stature, short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like,
and optionally the therapeutic combination comprises or consists of a SARM or claim 1(a) with claim 1(b)(5), or a growth hormone, optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a
HUMATROPE™ (Eli Lilly), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy, and optionally the therapeutic combination is formulated for controlled release dosing after about 12AM to achieve peak by about 6AM;
(b) for a burn, and optionally the therapeutic combination comprises or consists of a SARM with a propranolol and an growth hormone, or an hGH, or claim 1(b)(5), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy; and optionally is formulated as a combination pill comprising a SARM or claim 1(a) with a propranolol or claim 1(b)(2) (e.g., to enhance compliance), and optionally the propranolol comprises a sustained release propranolol plus, and optionally the therapeutic combination is formulated for treatment of severely burned children,
and optionally the therapeutic combination is formulated for controlled release propranolol and/or controlled release SARM or claim 1(a) dosing after about 12AM to achieve peak by about 6AM,
and optionally the therapeutic combination is formulated as a combination pill of sustained release propranolol and controlled release SARM or claim 1(a);
(c) for a tumor or a cancer,
wherein optionally the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu,
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1 (b)(2), 1(b) (3) or 1(b) (4),
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage,
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage,
and optionally the therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card;
and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic chemotherapy at standard dosing,
and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu,
and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
(1) capecitabine or VT-122 or claim 1(b)(4), optionally at normal or metronomic low doses,
(2) VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(3) a SERM or claim 1(b)(8) or an aromatase inhibitor or claim l(b)(10); or, a SERM or claim 1(b)(8) or an aromatase inhibitor or claim l(b)(10) and VT-122 or claim 1(b)(4),
(4) a SERM or claim 1(b)(8) or an aromatase inhibitor or claim l(b)(10) and capecitabine or claim 1(b)(6),
(5) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(6) a VT-122 or claim 1(b)(4) and a cyclophosphamide or a claim l(b)(13), optionally at 50 mg per day, e.g., at 10 am, and methotrexate twice a day, optionally 2.5 mg twice a day, e.g., at 9 am and 5 pm, e.g., every 3rd or 4th day, e.g., on Monday and Thursday weekly, or
(7) a combination pill or packaging comprising or containing any combination of, or all of, (1), (2), (3), (4), (5), (6) and (7), optionally packaged on a blister card or equivalent, e.g., to enable metronomic dosing of one or all of the drugs, e.g., to enable metronomic dosing of cylcophosphomide and methotrexate or a claim l(b)(13),
and optionally the therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with: (1) VT-122 or claim 1(b)(4) and a docetaxel or claim 1(b)(1) or other cytotoxic chemotherapy, optionally at normal or metronomic low doses, or
(2) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT 122 or claim 1(b)(4) and docetaxel or other cytotoxic chemotherapy, optionally at normal or metronomic low doses,
and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer,, or an androgen receptor positive breast cancer, or a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu, such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
(1) treatment first on a SERM or claim 1(b)(8) or an aromatase inhibitor and then treatment with a SARM,
(2) 1 to 2 months on SERM or claim 1(b)(8) and then 1 to 2 months on a SARM, or
(3) 1 to 2 months on an aromatase inhibitor and then 1 to 2 months on a SARM.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs, two or more therapeutic agents or drugs of the therapeutic combination are formulated as separate compositions, or two or more therapeutic agents or drugs of the therapeutic combination are formulated into one composition or drug formulation (two or more drugs of the therapeutic combination are formulated together). Alternatively, one or two or more or all of the drugs of the therapeutic combination are packaged individually, or are packaged together, or packaged in any combination, in a single package, a plurality of packages or packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap. Alternatively, one or two or more or all of the drugs of the therapeutic combination are packaged together or in any combination in a single package, a plurality of packages or packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap. Alternatively, two or more or all of the drugs are released upon opening of the single package, plurality of packages or packettes, blister packet, lidded blister, blister card or packets or shrink wrap.
In alternative embodiments, one or two or more or all of the drugs of the therapeutic combination are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a patch, a spray, an inhalant, a powder, a freeze-dried powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository or any combination thereof. Alternatively, one or two or more or all of the drugs of the therapeutic combination are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one freeze-dried powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one adhesive, one spray, one powder, one freeze-dried powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel or one suppository.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs: (a) the dosage of etodolac ranges from about 200 mg to 400 mg a day, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more; or (b) the dosage of propranolol ranges from 10 to 320 mg per day based on heart rate and blood pressure of the individual, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs: the drug combination is packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs: the beta adrenergic receptor antagonist or a beta blocker or equivalent, or a propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or equivalent, or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day. Alternatively, the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are packaged in dosages that match a chrono-dosing regimen comprising:
(a) in the AM, 20 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200mg NSAID, e.g., an etodolac or equivalent; in the afternoon, 10 mg beta blocker, 200 mg NSAID, e.g., an etodolac or equivalent; in the PM, 10 mg beta blocker, 400 mg NSAID;
(b) in the AM 40 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200 mg NSAID, e.g., an etodolac or equivalent; in the afternoon 20 mg beta blocker, 200 mg NSAID; in the evening, 20 mg propranolol, 400 mg NSAID;
(c) in the AM 80 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200 mg NSAID; in the afternoon 40 mg
beta blocker, 200 mg NSAID, in the evening 40 mg, NSAID; or
(d) a dose escalation comprising a regimen of (a) to (b) to (c).
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs: the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are packaged in dosages that match a chrono-dosing regimen comprising:
Start: AM, 20 mg propranolol, 200mg etodolac; afternoon, 10 mg propranolol, 200 mg etodolac; PM 5 mg propranolol, 400 mg etodolac;
Dose Escalation 1 : AM 40 mg propranolol, 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etodolac; evening, 10 mg propranolol, 400 mg etodolac;
Dose escalation 2: AM 80 mg propranolol, 200 mg etodolac; afternoon 40 mg propranolol, 200 mg etodolac, evening 20 mg, etodolac.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs: the therapeutic drug combination is formulated for administration once a day, b.i.d. or t.i.d, or weekly, or biweekly, or monthly.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs: the therapeutic combination of drugs are formulated for administration intravenously, topically, orally, by inhalation, by infusion, by injection, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, for intra-articular administration, for intra-mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings.
In alternative embodiments of the therapeutic combinations of therapeutic agents or drugs: the therapeutic drug combination is formulated for intermittent or alternated cycling of the drug or active agent or component, and optionally the intermittent or alternated cycling comprises administration weekly, bi-monthly, monthly or quarterly.
In alternative embodiments, provided is: a device, a medical device, an implant, a breast implant, a prosthesis, a stent, a catheter, comprising a therapeutic combination of therapeutic agents or drugs as provided herein.
In alternative embodiments, provided is: a pharmaceutical composition or formulation comprising the therapeutic combination as provided herein, alternatively further comprising a pharmaceutically acceptable excipient. In alternative embodiments of the pharmaceutical composition or formulation as provided herein, the pharmaceutical composition or formulation is formulated or manufactured as a feed, a food, a food or feed concentrate, a pellet, a lozenge, a liquid, a lotion, an implant, a nanoparticle, an elixir, an aerosol, a spray, an aerosol, an inhalant, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a patch, a microgel or a suppository.
In alternative embodiments, provided are methods for treating, preventing or ameliorating a tumor or a cancer, comprising: applying or administering to an individual in need thereof; or, applying or administering to an effected tissue: the therapeutic combination as provided herein, or a pharmaceutical composition or formulation as provided herein, wherein optionally the therapeutic agents or drugs are administered separately or together, or at the same time, or in synchrony, or by chrono-dosing, or one of the therapeutic agents or drugs is administered before another of the therapeutic agents or drugs, and optionally the therapeutic agents or drugs are formulated for administration intravenously (IV), parenterally, nasally, topically or locally, orally, or by liposome, implant or vessel-targeted nanoparticle delivery. In alternative embodiments, the cancer or tumor is: a mastocytoma or a mast cell tumor, an ovarian cancer, pancreatic cancer, a non-small cell lung cancer, small cell lung cancer, hepatocarcinoma, melanoma, retinoblastoma, breast tumor or breast cancer (optionally a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), a basal-like carcinoma, a ductal carcinoma, colorectal carcinoma, leukemia, lymphoma, acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia, acute myeloid leukemia (AML), a histiocytic sarcoma, a brain tumor, an astrocytoma, a glioblastoma, a neuroma, a neuroblastoma, a colon carcinoma, cervical carcinoma, sarcoma, prostate tumor, bladder tumor, tumor of the reticuloendothelial tissues, Wilm's tumor, ovarian carcinoma, a bone cancer, an osteosarcoma, a renal cancer, or head and neck cancer, oral cancer, a laryngeal cancer, or an oropharyngeal cancer.
In alternative embodiments, provided are methods for treating, preventing or ameliorating a tumor or a cancer, comprising:
(a) applying or administering to an individual in need thereof; or, applying or administering to an effected tissue; the therapeutic combination of any one of claims 1 to 20, or a pharmaceutical composition or formulation of any of claims 22 to 24,
wherein optionally the therapeutic agents or drugs are administered separately or together, or at the same time, or in synchrony, or by chrono-dosing, or one of the therapeutic agents or drugs is administered before another of the therapeutic agents or drugs,
and optionally the therapeutic agents or drugs are formulated for administration intravenously (IV), parenterally, nasally, topically or locally, orally, or by liposome, implant or vessel-targeted nanoparticle delivery; and
(b) administering to the individual in need thereof:
(i) a systemic anti-cancer or anti-tumor treatment, wherein optionally the systemic anti-cancer or anti-tumor treatment comprises administration of a drug, a biologic, a nutrient, an anti-cancer or anti-tumor dietary regimen, a radioactive agent, a tumor ablative agent, or
(ii) an anti-cancer or anti-tumor radiotherapy or a proton beam therapy, wherein the therapeutic combination or pharmaceutical composition or formulation of (a) is administered before the anti-cancer or anti-tumor treatment of (b), or both are administered consecutively, or the therapeutic combination or pharmaceutical composition or formulation of (a) is administered after the anti-cancer or anti-tumor treatment of (b), or any combination thereof.
In alternative embodiments, methods as provided herein further comprise: an anticancer or anti-tumor radiotherapy or a proton beam therapy.
In alternative embodiments, also provided are uses of the therapeutic combination as provided herein, or a pharmaceutical composition or formulation as provided herein, in the manufacture of a medicament.
In alternative embodiments, provided are uses of the therapeutic combinations as provided herein, or a pharmaceutical composition or formulation as provided herein, in the manufacture of a medicament for treating, ameliorating, preventing or reversing: (a) a short stature, a short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like, (b) a burn, a third degree burn, a large >10% total body surface area burn, a wound, a refractory large wound, a wound >10 cm2, a chronic wound, a diabetic foot ulcer, a venous leg ulcer, a pressure ulcer, or (c) a tumor or a cancer. In alternative embodiments, the cancer or tumor is: a mastocytoma or a mast cell tumor, an ovarian cancer, pancreatic cancer, a non-small cell lung cancer, small cell lung cancer, hepatocarcinoma, melanoma, retinoblastoma, breast tumor or breast cancer (optionally a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), a basal-like carcinoma, a ductal carcinoma, a colorectal carcinoma, leukemia, lymphoma, acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia, acute myeloid leukemia (AML), a Histiocytic sarcoma, a brain tumor, an astrocytoma, a glioblastoma, a neuroma, a neuroblastoma, a colon carcinoma, cervical carcinoma, sarcoma, prostate tumor, bladder tumor, tumor of the
reticuloendothelial tissues, Wilm's tumor, ovarian carcinoma, a bone cancer, an osteosarcoma, a renal cancer, or head and neck cancer, oral cancer, a laryngeal cancer, or an oropharyngeal cancer.
In alternative embodiments, provided are methods for treating, ameliorating, preventing or reversing a short stature, short stature syndrome, Turner syndrome, Prader- Willi syndrome and the like, comprising administering to an individual in need thereof a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein, wherein optionally the therapeutic combination comprises or consists of a SARM or claim 1(a) with claim 1(b)(5), or a growth hormone, optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a HUMATROPE™ (Eli Lilly), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy, and optionally the therapeutic combination is formulated for controlled release dosing after about 12AM to achieve peak by about 6AM.
In alternative embodiments, provided are methods for treating, ameliorating, preventing or reversing a burn, a third degree burn, a large >10% total body surface area burn, a wound, a refractory large wound, a wound >10 cm2, a chronic wound, a diabetic foot ulcer, a venous leg ulcer, a pressure ulcer, and the like, comprising administering to an individual in need thereof a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein, wherein optionally the therapeutic combination comprises or consists of a SARM with a propranolol and an growth hormone, or an hGH, or claim 1(b)(5), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy; and optionally is formulated as a combination pill comprising a SARM or claim 1(a) with a propranolol or claim 1(b)(2) (e.g., to enhance compliance),
and optionally the propranolol comprises a sustained release propranolol plus, and optionally the therapeutic combination is formulated for treatment of severely burned children,
and optionally the therapeutic combination is formulated for controlled release propranolol and/or controlled release SARM or claim 1(a) dosing after about 12AM to achieve peak by about 6AM,
and optionally the therapeutic combination is formulated as a combination pill of sustained release propranolol and controlled release SARM or claim 1(a).
In alternative embodiments, provided herein are methods for treating,
ameliorating, preventing or reversing a tumor or a cancer, and the like, comprising administering to an individual in need thereof a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein,
wherein optionally the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1(b)(2), 1(b) (3) or 1(b) (4),
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage,
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage,
and optionally the therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card; and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic chemotherapy at standard dosing, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
(1) capecitabine, optionally at normal or metronomic low doses,
(2) VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(3) a SERM or claim 1(b)(8) and/or an aromatase inhibitor and VT-122 or claim 1(b)(4),
(4) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and capecitabine or claim 1(b)(6),
(5) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(6) a VT-122 or claim 1(b)(4) and a cyclophosphamide or a claim l(b)(13), optionally at 50 mg per day, e.g., at 10 am, and methotrexate twice a day, optionally 2.5 mg twice a day, e.g., at 9 am and 5 pm, e.g., every 3rd or 4th day, e.g., on Monday and Thursday weekly, or
(7) a combination pill or packaging comprising or containing any combination of, or all of, (1), (2), (3), (4), (5), (6) and (7), optionally packaged on a blister card or equivalent, e.g., to enable metronomic dosing of one or all of the daigs, e.g., to enable metronomic dosing of cylcophosphomide and methotrexate or a claim l(b)(13),
and optionally the therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with:
(1) VT-122 or claim 1(b)(4) and a docetaxel or claim 1(b)(1) or other cytotoxic chemotherapy, optionally at normal or metronomic low doses, or (2) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT 122 or claim 1(b)(4) and docetaxel or other cytotoxic chemotherapy, optionally at normal or metronomic low doses,
and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or androgen receptor positive breast cancer, and optionally the breast cancer is a triple- negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
(4) treatment first on a SERM or claim 1(b)(8) or an aromatase inhibitor and then treatment with a SARM,
(5) 1 to 2 months on SERM or claim 1(b)(8) and then 1 to 2 months on a SARM, or
(6) 1 to 2 months on an aromatase inhibitor and then 1 to 2 months on a SARM.
In alternative embodiment of methods as provided herein, two or more drugs of the therapeutic combination are formulated as separate compositions, or two or more drugs of the therapeutic combination are formulated into one composition or drug formulation, or two or more drugs of the therapeutic combination are formulated together.
In alternative embodiments, provided herein are formulations and/or a therapeutic combinations for use in a method for treating, ameliorating, preventing or reversing a tumor or a cancer,
wherein the formulation or a therapeutic combination comprises a formulation or a therapeutic combination as set forth in any of claims 1 to 20, or comprises the pharmaceutical composition or formulation of any of claims 22 to 24,
wherein optionally the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
and optionally the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1(b)(2), 1(b) (3) or 1(b) (4), and optionally the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage,
and optionally the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage,
and optionally the formulation or a therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card;
and optionally the formulation or a therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic
chemotherapy at standard dosing, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
and optionally the formulation or a therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
(1) capecitabine, optionally at normal or metronomic low doses,
(2) VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(3) a SERM or claim 1(b)(8) and/or an aromatase inhibitor and VT-122 or claim 1(b)(4),
(4) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and capecitabine or claim 1(b)(6),
(5) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(6) a VT-122 or claim 1(b)(4) and a cyclophosphamide or a claim l(b)(13), optionally at 50 mg per day, e.g., at 10 am, and methotrexate twice a day, optionally 2.5 mg twice a day, e.g., at 9 am and 5 pm, e.g., every 3rd or 4th day, e.g., on Monday and Thursday weekly, or (7) a combination pill or packaging comprising or containing any combination of, or all of, (1), (2), (3), (4), (5), (6) and (7), optionally packaged on a blister card or equivalent, e.g., to enable metronomic dosing of one or all of the drugs, e.g., to enable metronomic dosing of cyclophosphamide and methotrexate or a claim l(b)(13),
and optionally the formulation or a therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with:
(1) VT-122 or claim 1(b)(4) and a docetaxel or claim 1(b)(1) or other cytotoxic chemotherapy, optionally at normal or metronomic low doses, or
(2) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT 122 or claim 1(b)(4) and docetaxel or other cytotoxic chemotherapy, optionally at normal or metronomic low doses,
and optionally the formulation or a therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or androgen receptor positive breast cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
(7) treatment first on a SERM or claim 1(b)(8) or an aromatase inhibitor and then treatment with a SARM,
(8) 1 to 2 months on SERM or claim 1(b)(8) and then 1 to 2 months on a SARM, or
(9) 1 to 2 months on an aromatase inhibitor and then 1 to 2 months on a SARM. In alternative embodiments of the formulation or a therapeutic combination two or more drugs of the formulation or a therapeutic combination are formulated as separate compositions, or two or more drugs of the formulation or a therapeutic combination are formulated into one composition or drug formulation (two or more drugs of the therapeutic combination are formulated together). The details of one or more aspects of exemplary embodiments as provided herein are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and from the claims.
All publications, patents and patent applications cited herein are hereby expressly incorporated by reference for all purposes.
DETAILED DESCRIPTION
In alternative embodiments, provided are therapeutic combinations,
pharmaceutical compositions, formulations, kits and devices for treating, preventing or ameliorating a tumor or a cancer, and methods for treating, preventing or ameliorating a tumor or a cancer, comprising use of a SARM and at least one other drug or active agent, including for example: a paclitaxel or a tamoxifen; a capecitabine, a cyclophosphamide; a methotrexate, both a cyclophosphamide and a methotrexate; a beta adrenergic receptor antagonist (a "beta blocker") such as a propranolol, a non-steroidal anti-inflammatory drug (a NSAID) such as an etodolac, both a beta blocker and an NSAID (such as a propranolol and an etodolac), a H2-receptor antagonist (H2RA), a melatonin (or an N- acetyl-5-methoxytryptamine), a metformin, an immune checkpoint blockade agent, or an agent that blocks the interaction between a transmembrane programmed cell death- 1 protein (or PD1, or CD279), or any combination thereof.
In alternative embodiments, provided are therapeutic combinations,
pharmaceutical compositions, formulations, kits and devices for treating, preventing or ameliorating a short stature, short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like, and methods for treating, preventing or ameliorating a short stature, short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like, comprising use of a SARM and at least one other drug or active agent, including for example: a growth hormone, such as a human recombinant growth hormone (hrGH), somatropin or HUMATROPE™ (Eli Lilly).
In alternative embodiments, provided are therapeutic combinations,
pharmaceutical compositions, formulations, kits and devices for treating, preventing or ameliorating a burn, a third degree burn, a large >10% total body surface area burn, a wound, a refractory large wound, a wound >10 cm2, a chronic wound, a diabetic foot ulcer, a venous leg ulcer, a pressure ulcer, and methods for treating, preventing or ameliorating a burn, a third degree burn, a large >10% total body surface area burn, a wound, a refractory large wound, a wound >10 cm2, a chronic wound, a diabetic foot ulcer, a venous leg ulcer, a pressure ulcer, comprising use of a SARM and at least one other drug or active agent, including for example, a beta adrenergic receptor antagonist, or a beta blocker or equivalent, or a propranolol or equivalent.
In alternative embodiments the cancer is a dysfunctional cell condition. In alternative embodiments the cancer or dysfunctional cell condition comprises (is) any metastatic or benign tumor, and the methods or uses as provided herein are used for ameliorating, treating (killing, eliminating, stopping the growth and/or metastasis of) cancer stem cells or cancer cells from: lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer (and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), a basal-like carcinoma, a ductal carcinoma, a carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, a neoplasm of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma or pituitary adenoma, and any combination thereof.
In alternative embodiments of the products of manufacture as provided herein the therapeutic combination or pharmaceutical composition or formulation are formulated (e.g., manufactured) as one dosage administration in the morning and one dosage administration in the evening; or are formulated as one dosage administration in the morning, one dosage mid-day and one dosage administration in the evening. In one aspect, the dosage schedule provides a relatively higher dose of one drug in the morning (the AM) than in the evening, and a relatively higher dose of another medication in the evening than in the morning. For example, in alternative embodiments the therapeutic combination or the pharmaceutical composition are formulated for multiple
administrations, e.g., at least two administrations, one in the morning and one in the evening, wherein the dosage schedule provides a relatively higher dose of beta blocker in the morning (the AM) than in the evening, and a relatively higher dose of an antiinflammatory medication in the evening than in the morning.
In alternative embodiments, the products of manufacture or formulations as provided herein comprise a therapeutic combination as provided herein or the
pharmaceutical composition or formulation as provided herein, and a nutritional supplement, or food supplement or feed supplement.
Methods of administration
Provided are therapeutic combinations of drugs, pharmaceutical compositions, preparations and kits, that can be administered by several routes, including intravenous, topical and oral, or combinations thereof.
For example, one embodiment comprises a product of manufacture comprising a pharmaceutical composition or a formulation, a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a kit, comprising:
therapeutic combinations of drugs, pharmaceutical compositions or preparations as provided herein n. In alternative embodiments, although all ingredients can be in one blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, or a kit, separate ingredients can be formulated e.g., for topical application, for oral or for topical application. Each ingredient can be either separately packaged, or can be formulated as one unit dose, e.g., as one tube (e.g., with gel, lotion etc.), ampoule, blister packette and the like.
In alternative embodiments, provided are forms of compositions, preparations and kits that can be administered by inhalation, infusion or injection, (e.g., intraperitoneal, intramuscular, subcutaneous, intra-aural, intra-articular, intra-mammary, etc.), topical application (e.g., on areas, such as eyes, ears, skin or on afflictions such as wounds, burns, etc.), and by absorption through epithelial or mucocutaneous linings (e.g. vaginal and other epithelial linings, gastrointestinal mucosa, etc.). Methods are known for making compositions, preparations and kits containing the present components that are suitable for each of these methods of administration as well as other methods of administration that are known in the art.
In alternative embodiments, provided are compositions, preparations and kits in liquid forms that can be administered orally. The compositions, preparations and kits can be also prepared as capsules, gels, geltabs, tablets, powders, sprays, aerosols, pellets (e.g. for animal consumption), suppositories, lotions, patches or adhesives (e.g., for the skin), or creams and ointments. The compositions, preparations and kits can be also prepared as physiological solutions suitable for I.V. administration or other parenteral administration.
In one aspect, a multi-ingredient kit as provided herein comprises (contains) two or more ingredients. An amount may be determined, e.g. by mass or by weight or by molar amount. In another aspect, a multi-ingredient kit may contain two or more ingredients in unequal amounts. In another aspect, a multi-ingredient kit may contain two or more ingredients in approximately equal amounts and/or one or more ingredients that are not in unequal amounts.
In another embodiment, said multi-ingredient kit may contain two or more ingredients that are admixed. In another aspect, said multi-ingredient kit may contain two or more ingredients that are not admixed. In another aspect, said multi-ingredient kit may contain two or more ingredients that are partially admixed. In another aspect, said multi- ingredient kit may contain two or more ingredients that are at least partially admixed, as well as one or more ingredients that are not admixed. An ingredient in a multi-ingredient kit may be liquid forms that can be administered orally.
In alternative embodiments, one, two or three or more or all of the drugs of the therapeutic combination are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a patch, a spray, an inhalant, a powder, a freeze-dried powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository or any combination thereof.
In alternative embodiments, one, two or three or more or all of the drugs of the therapeutic combination are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one freeze-dried powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one adhesive, one spray, one powder, one freeze-dried powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel or one suppository.
In alternative embodiments: (a) the dosage of etodolac ranges from about 200 mg to 400 mg a day, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more; or, (b) the dosage of propranolol ranges from 10 to 320 mg per day based on heart rate and blood pressure of the individual, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more.
In alternative embodiments of the therapeutic combination, the drug combinations are administered and/or packaged in dosages that match a chrono-dosing regimen, e.g., to match an optimal dose for the time of day. For example, in exemplary alternative embodiments, the SARM and the beta adrenergic receptor antagonist or a beta blocker or equivalent, or the SARM and a propranolol or equivalent; or the SARAM and the non- steroidal anti -inflammatory drug or NSAID or equivalent, or etodolac or equivalent; are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day.
In alternative embodiments of the therapeutic combinations or the drug
combinations as provided herein are administered and/or packaged for"metronomic dosaging" or "metronomic chemotherapy", e.g., where therapeutic combinations or the drug combinations as provided herein are dosed, administered and/or packaged for chronic, equally spaced administration of low doses, e.g., of chemotherapeutic drugs, without extended rest periods. In practicing this treatment modality, the low dosaging and administration without extended rest periods results in antitumor efficacy with very low toxicity.
In exemplary alternative embodiments, the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal antiinflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are packaged in dosages that match a chrono-dosing regimen comprising:
(a) in the AM, 20 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200mg NSAID, e.g., an etodolac or equivalent; in the afternoon, 10 mg beta blocker, 200 mg NSAID, e.g., an etodolac or equivalent; in the PM, 10 mg beta blocker, 400 mg NSAID;
(b) in the AM 40 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200 mg NSAID, e.g., an etodolac or equivalent; in the afternoon 20 mg beta blocker, 200 mg NSAID; in the evening, 20 mg propranolol, 400 mg NSAID; (c) in the AM 80 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200 mg NSAID; in the afternoon 40 mg
beta blocker, 200 mg NSAID, in the evening 40 mg, NSAID; or
(d) a dose escalation comprising a regimen of (a) to (b) to (c).
In exemplary alternative embodiments, the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal antiinflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are packaged in dosages that match a chrono-dosing regimen comprising:
Start: AM, 20 mg propranolol, 200mg etodolac; afternoon, 10 mg propranolol,
200 mg etodolac; PM 5 mg propranolol, 400 mg etodolac;
Dose Escalation 1 : AM 40 mg propranolol, 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etodolac; evening, 10 mg propranolol, 400 mg etodolac;
Dose escalation 2: AM 80 mg propranolol, 200 mg etodolac; afternoon 40 mg propranolol, 200 mg etodolac, evening 20 mg, etodolac.
In exemplary alternative embodiments, the therapeutic drug combination is formulated for administration once a day, b.i.d. or t.i.d, or weekly, or biweekly, or monthly. In exemplary alternative embodiments, the beta adrenergic receptor antagonist (a beta blocker) or propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are formulated for administration once a day, b.i.d. or t.i.d, or weekly, or biweekly, or monthly.
In exemplary alternative embodiments, the therapeutic combination of drugs are formulated for administration intravenously, topically, orally, by inhalation, by infusion, by injection, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intra- aurally, for intra-articular administration, for intra-mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings.
In alternative embodiments, provided is: a device, a medical device, an implant, a breast implant, a prosthesis, a stent, a catheter, comprising a therapeutic combination of therapeutic agents or drugs as provided herein.
Packaging
In alternative embodiments, provided are therapeutic combinations, preparations, formulations and/or kits, comprising combinations of ingredients, as described herein. In one aspect, each member of the combination of ingredients is manufactured in a separate package, kit or container; or, all or a subset of the combinations of ingredients are manufactured in a separate package or container. In alternative aspects, the package, kit or container comprises a blister package, a clamshell, a tray, a shrink wrap and the like.
In alternative embodiments, provided are products of manufacture comprising a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap comprising a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein. In alternative embodiments the products of manufacture can comprise a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap comprising a therapeutic combination as provided herein, or the pharmaceutical composition or formulation as provided herein, wherein the therapeutic combination or pharmaceutical composition or formulation are manufactured and/or formulated for at least two, three, four or five or more dosage administrations; or the therapeutic combination or pharmaceutical composition or formulation are manufactured and/or formulated for once a day, or bid (twice a day), or tid (three times a day), or four times a day, administration.
In alternative embodiments, each compartment of the product of manufacture, e.g., a blister package, a lidded blister or a blister card or packet, a clamshell, a tray or a shrink wrap, has only one, or two or more components or members of the drug combination. In alternative embodiments, each compartment of the product of manufacture has all components or members of the drug combination to be administered at the same time, for example, all the components or members (e.g., pills, tablets, etc) to be taken in the morning are in one compartment, and all the components or members (e.g. , pills, tablets, etc) to be taken in the afternoon and/or evening are in another compartment, etc. If the components or members of the drug combination are in liquid form, then all the components or members of the drug combination to be taken at the same time are formulated as a liquid mixture in the same compartment, which can be appropriately sealed, but designed for easy opening, e.g., with a screw cap and the like.
In alternative embodiments, drug combination as provided herein is formulated, packaged or designed for drug regimen compliance of a patient population, a pediatric or geriatric population, or a mentally compromised patient population. In alternative embodiments drug combination(s) as provided herein are
formulated, packaged or designed for drug regimen compliance of a patient population having mild or severe mental retardation, slow cognition, dementia, senility, Alzheimer's disease, traumatic brain injury, chemical brain damage, mental diseases (e.g., dissociative disorder, obsessive-compulsive disorder, delusional disorder, schizophrenia, mania, panic disorder, depression, dyslexia, any learning disability and the like) post-traumatic stress disorder, traumatic war neurosis, post-traumatic stress syndrome (PTSS), physical disability (e.g., blindness).
In one aspect, the package, kit or container comprises a "blister package" (also called a blister pack, or bubble pack). In one aspect, the blister package is made up of two separate elements: a transparent plastic cavity shaped to the product and its blister board backing. These two elements are then joined together with a heat sealing process which allows the product to be hung or displayed. Exemplary types of "blister packages" include: Face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, slide blister packages.
Blister packs, clamshells or trays are forms of packaging used for goods; thus, provided are blister packs, clamshells or trays comprising a composition, e.g., a combination of active ingredients or the multi-ingredient combination of drugs as provided herein. Blister packs, clamshells or trays can be designed to be non-reclosable, so consumers can tell if a package has already opened. They are used to package for sale goods where product tampering is a consideration, such as the pharmaceuticals as provided herein. In one aspect, a blister pack as provided herein comprises a moulded PVC base, with raised areas (the "blisters") to contain the tablets, pills, etc. comprising the combinations as provided herein, covered by a foil laminate. Tablets, pills, etc. are removed from the pack either by peeling the foil back or by pushing the blister to force the tablet to break the foil. In one aspect, a specialized form of a blister pack is a strip pack. In one aspect, in the United Kingdom, blister packs adhere to British Standard 8404.
In one aspect, a blister packs also comprise a method of packaging where the compositions comprising combinations of ingredients as provided herein are contained in- between a card and a clear PVC. The PVC can be transparent so the item (pill, tablet, geltab, etc.) can be seen and examined easily; and in one aspect, can be vacuum-formed around a mould so it can contain the item snugly and have room to be opened upon purchase. In one aspect, the card is brightly colored and designed depending on the item (pill, tablet, geltab, etc.) inside, and the PVC is affixed to the card using pre-formed tabs where the adhesive is placed. The adhesive can be strong enough so that the pack may hang on a peg, but weak enough so that this way one can tear open the join and access the item. Sometimes with large items or multiple enclosed pills, tablets, geltabs, etc., the card has a perforated window for access. In one aspect, more secure blister packs, e.g., for items such as pills, tablets, geltabs, etc. as provided herein are used, and they can comprise of two vacuum-formed PVC sheets meshed together at the edges, with the informative card inside. These can be hard to open by hand, so a pair of scissors or a sharp knife may be required to open.
In one aspect, blister packaging comprises at least two components (e.g., is a multi-ingredient combination of drugs as provided herein): a thermoformed "blister" which houses the product (e.g., a pharmaceutical combination as provided herein), and then a "blister card" that is a printed card with an adhesive coating on the front surface. During the assembly process, the blister component, which is most commonly made out of PVC, is attached to the blister card using a blister machine. This machine introduces heat to the flange area of the blister which activates the glue on the card in that specific area and ultimately secures the PVG blister to the printed blister card. The thermoformed PVG blister and the printed blister card can be as small or as large as you would like, but there are limitations and cost considerations in going to an oversized blister card.
Conventional blister packs can also be sealed (e.g., using an AE GO 8 DUO™, SCA Consumer Packaging, Inc., DeKalb IL) using regular heat seal tooling. This alternative aspect, using heat seal tooling, can seal common types of thermoformed packaging.
Blister Packaging, Packettes, Shrink Wraps
Provided are therapeutic combinations, preparations, formulations and/or kits can be manufactured as "blister packages" or as a plurality of packettes, including as lidded blister packages, lidded blister or blister card or packets or packettes, or a shrink wrap.
In alternative embodiments, laminated aluminum foil blister packs are used, e.g., for the preparation of drugs designed to dissolve immediately in the mouth of a patient. This exemplary process comprises having the drug combinations as provided herein prepared as an aqueous solution(s) which are dispensed (e.g., by measured dose) into an aluminum (e.g., alufoil) laminated tray portion of a blister pack. This tray is then freeze- dried to form tablets which take the shape of the blister pockets. The alufoil laminate of both the tray and lid fully protects any highly hygroscopic and/or sensitive individual doses. In one aspect, the pack incorporates a child-proof peel open security laminate. In one aspect, the system give tablets an identification mark by embossing a design into the alufoil pocket that is taken up by the tablets when they change from aqueous to solid state. In one aspect, individual 'push-through' blister packs/ packettes are used, e.g., using hard temper aluminum (e.g., alufoil) lidding material. In one aspect, hermetically-sealed high barrier aluminum (e.g., alufoil) laminates are used. In one aspect, any of the products of manufacture as provided herein, including kits or blister packs, use foil laminations and strip packs, stick packs, sachets and pouches, peelable and non-peelable laminations combining foil, paper, and film for high barrier packaging.
In alternative embodiments, any of the products of manufacture, including kits or blister packs, as provided herein include memory aids to help remind patients when and how to take the drug. This safeguards the drug's efficacy by protecting each pill until it's taken; gives the product or kit portability, makes it easy to take a dose anytime or anywhere.
A number of aspects of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other aspects are within the scope of the following claims.

Claims

WHAT IS CLAIMED IS:
1. A therapeutic combination of therapeutic agents or drugs for an individual in need thereof comprising or consisting of:
(a) a selective androgen receptor modulator (SARM),
wherein optionally the SARM comprises or consists of:
enobosarm (also called ostarine), or ((25')-3-(4-cyanophenoxy)-N-[4-cyano-3- (trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide),
andarine, or 25)-3-(4-acetamido-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3- trifluoromethyl-phenyl)-propionamide,
(7R,7aS)-2-Chloro-4-(7-hydroxy-l ,3-dioxotetrahydropyrrolo[l ,2-c]imidazol-2- yl)-3-methylbenzonitrile (or BMS-564,929),
4-[(2R)-2-[( 1 R)-2,2,2-trifluoro- 1 -hydroxyethyl]pyrrolidin- 1 -yl]-2- (trifluoromethyl)benzonitrile,
4-(3-Hydroxy-8-aza-bicyclo[3.2. l]octyl)-naphthalene-l-carbonitrile (or AC-
262,356),
6-(bis-(2,2,2-trifluoroethyl)amino)-4-trifluoromethyl-lH-quinolin-2-one (or LGD-
2226),
9-chloro-2-ethyl-l-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-fJquinolin- 7(6H)-one (or LGD-3303),
2-[4-(dimethylamino)-6-nitro-l ,2,3,4-tetrahydroquinolin-2-yl]-2-methylpropan-l- ol (or S-40503),
2S)-N-(4-cyano-3-trifluoromethylphenyl)-3-(3-fluoro-4-chlorophenoxy)-2- hydroxy-2-methyl-propanamide (or S-23), or
an equivalent thereof or any combination thereof; and
(b) a therapeutic agent, compound or composition comprising:
(1) a paclitaxel, or (2a,4a,5p,7p,10 ,13a)-4, 10-Bis(acetyloxy)-13- {[(2i?,35)-3-
(benzoylamino)-2-hydroxy-3-phenylpropanoyl]oxy}-l ,7-dihydroxy-9-oxo-5,20- epoxytax-1 l -en-2-yl benzoate (or TAXOL™) ; a docetaxel or equivalent, or
TAXOTERE™; or a tamoxifen, or (Z)-2-[4-( 1 ,2-diphenylbut- 1 -enyl)phenoxy]-N,N- dimethylethanamine (or NOLVADEX™, ISTUBAL™, VALODEX™, GENOX™), or an equivalent thereof or any combination thereof; (2) a beta adrenergic receptor antagonist (a beta blocker), optionally a propranolol or equivalent, and optionally the propranolol is INDERAL™, AVLOCARDYL™, DERALIN™, DOCITON™, INDERALICI™, INNOPRAN XL™, or SUMIAL™, or an equivalent thereof or any combination thereof;
(3) a non-steroidal anti-inflammatory drug (a NSAID), optionally a
cyclooxygenase (COX) or prostaglandin synthase inhibitor; or, optionally an etodolac, a naproxen; a celecoxib; a rofecoxib; a etoricoxib; a valdecoxib; a parecoxib; a
nabumetone; a diclofenac (2-(2,6-dichloranilino) phenylacetic acid); or, a lumiracoxib, or an equivalent thereof or any combination thereof;
(4) a combination of a beta adrenergic receptor antagonist (a beta blocker) and an
NSAID, optionally a propranolol and an etodolac, optionally is a VT-122™ (Vicus Therapeutics, Morristown, NJ);
(5) a growth hormone, optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a HUMATROPE™ (Eli Lilly);
(6) a , or pentyl [l-(3,4-dihydroxy-5-methyltetrahydrofuran-2-yl)-5-fluoro-2-oxo- lH-pyrimidin-4-yl] carbamate, or XELODA™, or an equivalent thereof or any
combination thereof;
(7) a combination of (2), (3) or (4) and (6);
(8) a selective estrogen receptor modulator (SERM), or an equivalent thereof or any combination thereof;
(9) a combination of (8) and (2), (3) or (4);
(10) an aromatase inhibitor, or an aminoglutethimide, a 4-OH androstenedione, an anastrozole, a letrozole, an exemestane, or an equivalent thereof or any combination thereof;
(11) a combination of (10) and (2), (3) or (4);
(12) a combination of (2), (3) or (4) and (8) or (9), or a combination of (2), (3) or (4) and (10) or (1 1);
(13) a cyclophosphamide (cytophosphane) or equivalent, or ENDOXAN™, CYTOXAN™, NEOSAR™ or RE VIMMUNE™ ;
(14) a methotrexate, or (2S)-2-[(4-{[(2,4-Diaminopteridin-6- yl)methyl](methyl)amino}benzoyl)amino]pentanedioic acid, or an equivalent thereof or any combination thereof;
(15) a combination of (13) and (14);
(16) a combination of (13) and (14), and (2), (3) or (4); (17) a combination of (1) and (2), (3) or (4);
(18) a cytokine or a chemotherapeutic agent, or a cytokine and a chemotherapeutic agent;
(19) a combination of (1) and a cytokine or a chemotherapeutic agent;
(20) any combination of (l) to (19).
2. The therapeutic combination of therapeutic agents or drugs of claim 1 , wherein the etodolac is a LODINE™, LODINE SR™ or ECCOXOLAC™; or the celecoxib is CELEBREX™ or CELEBRA™; or the rofecoxib is VIOXX™, CEOXX™ or CEEOXX™; or the etoricoxib is ARCOXIA™, ALGIX™ or TAUXIB™; or the valdecoxib is BEXTRA™; the parecoxib is DYNAST AT™; the naproxen is
XENOBID™, ALEVE™, ANAPROX™, MIRANAX™, NAPROGESIC™,
NAPROSYN™, NAPRELAN™, PROXEN™ or SYNFLEX™; the nabumetone is RELAFEN™, RELIFEX™ or a GAMBARAN™; or, the diclofenac is FLECTOR PATCH™, VOLTAREN™, VOLTAROL™, DICLON™, DICLOFLEX DIFEN™, DIFENE™, CATAFLAM™, PENNSAID™, PANAMOR™, RHUMALGAN™, MODIFENAC™, ABITREN™, OLFEN™, VOVERAN™, ARTHROTEC™,
DEDOLOR™, DEFLAMAT™, VETAGESIC™ or ZOLTEROL™;
3. The therapeutic combination of therapeutic agents or drugs of claim 1, further comprising an anti-cancer or anti-tumor antibody,
wherein optionally the anti-cancer or anti-tumor antibody is an alemtuzumab, a brentuximab vedotin, a cetuximab, a gemtuzumab ozogamicin, an abritumomab tiuxetan, a nimotuzumab, an ofatumumab, a panitumumab, a rituximab, a tositumomab, or a trastuzumab.
4. The therapeutic combination of therapeutic agents or drugs of claim 1 , wherein the cytokine comprises an IL-2 or an interferon (IFN),
wherein optionally the interferon is an alpha-IFN or a gamma-IFN; and optionally the IL-2 is a recombinant IL-2, an aldesleukin, or a PROLEUKIN (Prometheus
Laboratories), and optionally the IL-2, recombinant IL-2, or aldesleukin is dosages at about: 1 to 20, 2 to 10, 4 to 5, or 4.5 millions of IUs per cycle; or is dosaged for: 1 to 5, 2 to 4, or 3 cycles number of cycles of therapy.
5. The therapeutic combination of therapeutic agents or drugs of claim 1 , wherein the chemo therapeutic agent comprises:
a doxorubicin or a carboplatin, or comprises an inducer of apoptosis or a mitotic inhibitor or anti-microtubule inhibitor, or an alkylating agent, or a topoisomerase inhibitor, or a glycopeptide antibiotic, or steroid receptor inhibitor, or a matrix metalloproteinase (MMP) inhibitor, or an mTOR (mammalian target of rapamycin) inhibitor, or a macrolide or a composition comprising a macrolide ring,
and optionally the inducer of apoptosis or a mitotic inhibitor or anti-microtubule inhibitor comprises or consists of a raltitrexed or equivalent, or TOMUDEX™; a doxorubicin or equivalent, or ADRIAMYCIN™; a fluorouracil or 5-fluorouracil or equivalent; a paclitaxel or equivalent, or TAXOL™ or ABRAXANE™; a docetaxel or equivalent, or TAXOTERE™; a larotaxel, tesetaxel or ortataxel or equivalent; an epothilone or an epothilone A, B, C, D, E or F or equivalent; an ixabepilone (also known as azaepothilone B) or equivalent, or BMS-247550™; a vincristine (also known as leurocristine) or equivalent, or ONCOVIN™; a vinblastin, vinblastine, vindesine, vinflunine, vinorelbine or NAVELBINE™ or equivalent; or, any combination thereof, and optionally the alkylating agent comprises or consists of a cisplatin or equivalent; a cisplatinum or equivalent; a c s-diamminedichloridoplatinum(II) (CDDP) or equivalent; a carboplatin or equivalent; a oxaloplatin or equivalent; a cyclophosphamide (cytophosphane) or equivalent, or ENDOXAN™, CYTOXAN™, NEOSAR™ or REVIMMUNE™; a mechlorethamine or equivalent; a chlormethine or equivalent; a mustine or equivalent; a nitrogen mustard or equivalent; a chlorambucil or equivalent, or LEUKERAN™; or, a combination thereof,
and optionally the topoisomerase inhibitor comprises or consists of an etoposide or equivalent, or EPOSIN™, ETOPOPHOS™, VEPESID™ or VP- 16™; an amsacrine or equivalent; a topotecan or equivalent, or HYCAMTIN™; a teniposide or equivalent, or VUMON™ or VM-26™; an epipodophyllotoxin or equivalent; a camptothecin or equivalent; an irinotecan or equivalent, or CAMPTOSAR™; or, a combination thereof, and optionally the glycopeptide antibiotic comprises or consists of a bleomycin or equivalent or a bleomycin A2 or B2 or equivalent; a mitomycin or a mitomycin C or equivalent, a plicamycin (also known as mithramycin) or equivalent, or MITHRACIN™; or, a combination thereof,
and optionally the steroid receptor inhibitor comprises or consists of an estrogen receptor modulator (a SERM), and optionally the estrogen receptor modulator comprises or consists of a tamoxifen or equivalent, or NOLVADEX™, ISTUBAL™ or
VALODEX™, and optionally the steroid inhibitor or an anti-steroid comprises or consists of a finasteride or equivalent, or PROSCAR™, PROPECIA™, FINCAR™, FINPECIA™, FINAX™, FINAST™, FINARA™, FINALO™, PROSTERIDE™, GEFINA™, APPECIA™, FINASTERID IV AX™, FINASTERID or ALTERNOVA™, and optionally the macrolide or composition comprising a macrolide ring comprises or consists of a clarithromycin or equivalent, or ΒΙΑΧΓΝ™, KLARICID™, KLABAX™, CLARIPEN™, CLARIDAR™, FROMILID™ or CLACID™; an azithromycin or equivalent, or ZITHROMAX™, ZITROMAX™ or SUMAMED™; a dirithromycin or equivalent; an erythromycin or equivalent; a roxithromycin or equivalent, or ROXO™, SURLID™, RULIDE™, BIAXSIG™, ROXAR™,
ROXIMYCIN™ or COROXIN™; a telithromycin or equivalent or KETEK™; a josamycin or equivalent; a kitasamycin or equivalent; a midecamycin or equivalent;
oleandomycin or equivalent; a roxithromycin or equivalent, or ROXO™, SURLID™, RULIDE™, BIAXSIG™, ROXAR™, ROXIMYCIN™ or COROXIN™; a
troleandomycin or equivalent; or a tylosin or equivalent; or, any combination thereof, wherein optionally the chemotherapeutic agent comprises a sorafenib or equivalent, or NEXAVAR™; a sunitinib or equivalent, or SUTENT™; an erlotinib or equivalent, or TARCEVA™; an imatinib or equivalent, or GLEEVEC™; a lapatinib or equivalent, or TYKERB™; a toceranib or equivalent, or PALLADIA™; a masitinib or equivalent, or MASIVET™, a bevacizumab or equivalent, or AVASTIN™; a
trastuzumab or equivalent, or HERCEPTIN™; a cetuximab or equivalent, or
ERBITUX™; a bevacizumab or equivalent, or AVASTIN™ or BIBW 2992; a gefitinib or equivalent, or IRESSA™; a ranibizumab or equivalent, or LUCENTIS™; a pegaptanib or equivalent, or MACUGEN™; a dasatinib or equivalent, or BMS-354825™; a sunitinib or equivalent, or SUTENT™; a pazopanib or equivalent; a nilotinib or equivalent, or TASIGNA™; a panitumumab or equivalent, or VECTIBIX™; a bandetinib or equivalent; a brivanib or equivalent, or E7080™; a thalidomide or equivalent, or THALOMID™; lenalidomide or equivalent, or REVLIMID™; a bortezomib or equivalent, or
VELCADE™; disulfiram or equivalent, or ANTABUSE™ or ANTABUS™; or an epigallocatechin gallate (EGCG) or equivalent; a demecolcine, an etoglucid or elsamitrucin, a lonidamine, a lucanthone, a mitotane or a mitoguazone or equivalent; or any combination thereof.
6. The therapeutic combination of any of claims 1 to 5, wherein the drugs of the therapeutic combination are formulated
(a) for a short stature, short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like,
and optionally the therapeutic combination comprises or consists of a SARM or claim 1(a) with claim 1(b)(5), or a growth hormone, optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a
HUMATROPE™ (Eli Lilly), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy,
and optionally the therapeutic combination is formulated for controlled release dosing after about 12AM to achieve peak by about 6AM;
(b) for a burn, and optionally the therapeutic combination comprises or consists of a SARM with a propranolol and an growth hormone, or an hGH, or claim 1(b)(5), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy; and optionally is formulated as a combination pill comprising a SARM or claim 1(a) with a propranolol or claim 1(b)(2) (e.g., to enhance compliance), and optionally the propranolol comprises a sustained release propranolol plus, and optionally the therapeutic combination is formulated for treatment of severely burned children,
and optionally the therapeutic combination is formulated for controlled release propranolol and/or controlled release SARM or claim 1(a) dosing after about 12AM to achieve peak by about 6AM,
and optionally the therapeutic combination is formulated as a combination pill of sustained release propranolol and controlled release SARM or claim 1(a);
(c) for a tumor or a cancer,
wherein optionally the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor
(ER), progesterone receptor (PR) or Her2/neu),
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1(b)(2), 1(b) (3) or 1(b) (4),
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage, and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage,
and optionally the therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card;
and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic chemotherapy at standard dosing, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu),
and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
(1) capecitabine or VT-122 or claim 1(b)(4), optionally at normal or metronomic low doses,
(2) VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(3) a SERM or claim 1(b)(8) or an aromatase inhibitor or claim l(b)(10); or, a SERM or claim 1(b)(8) or an aromatase inhibitor or claim l(b)(10) and VT-122 or claim 1(b)(4),
(4) a SERM or claim 1(b)(8) or an aromatase inhibitor or claim l(b)(10) and capecitabine or claim 1(b)(6),
(5) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(6) a VT-122 or claim 1(b)(4) and a cyclophosphamide or a claim l(b)(13), optionally at 50 mg per day, e.g., at 10 am, and methotrexate twice a day, optionally 2.5 mg twice a day, e.g., at 9 am and 5 pm, e.g., every 3rd or 4th day, e.g., on Monday and Thursday weekly, or
(7) a combination pill or packaging comprising or containing any combination of, or all of, (1), (2), (3), (4), (5), (6) and (7), optionally packaged on a blister card or equivalent, e.g., to enable metronomic dosing of one or all of the drugs, e.g., to enable metronomic dosing of cylcophosphomide and methotrexate or a claim l(b)(13),
and optionally the therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with:
(1) VT-122 or claim 1(b)(4) and a docetaxel or claim 1(b)(1) or other cytotoxic chemotherapy, optionally at normal or metronomic low doses, or
(2) a SERJV1 or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT 122 or claim 1(b)(4) and docetaxel or other cytotoxic chemotherapy, optionally at normal or metronomic low doses,
and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or androgen receptor positive breast cancer, and optionally the breast cancer is a triple- negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
(10) treatment first on a SERM or claim 1(b)(8) or an aromatase inhibitor and then treatment with a SARM,
(11) 1 to 2 months on SERM or claim 1(b)(8) and then 1 to 2 months on a
SARM, or
(12) 1 to 2 months on an aromatase inhibitor and then 1 to 2 months on a
SARM.
7. The therapeutic combination of any of claims 1 to 6, wherein two or more drugs of the therapeutic combination are formulated as separate compositions, or two or more drugs of the therapeutic combination are formulated into one composition or drug formulation (two or more drugs of the therapeutic combination are formulated together).
8. The therapeutic combination of any of claims 1 to 7, wherein one or two or more or all of the drugs of the therapeutic combination are packaged individually, or are packaged together, or packaged in any combination, in a single package, a plurality of packages or packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap.
9. The therapeutic combination of any of claims 1 to 8, wherein one or two or more or all of the drugs of the therapeutic combination are packaged together or in any combination in a single package, a plurality of packages or packettes, or a blister packet, lidded blister or blister card or packets, or a shrink wrap.
10. The therapeutic combination of claim 9, wherein two or more or all of the drugs are released upon opening of the single package, plurality of packages or packettes, blister packet, lidded blister, blister card or packets or shrink wrap.
11. The therapeutic combination of any of claims 1 to 10, wherein one or two or more or all of the drugs of the therapeutic combination are formulated or manufactured as a parenteral formulation, an aqueous solution, a liposome, an injectable solution, a tablet, a pill, a lozenge, a capsule, a caplet, a patch, a spray, an inhalant, a powder, a freeze-dried powder, an inhalant, a patch, a gel, a geltab, a nanosuspension, a nanoparticle, a nanoliposome, a microgel, a pellet, a suppository or any combination thereof.
12. The therapeutic combination of claim 11, one or two or more or all of the drugs of the therapeutic combination are formulated or manufactured together in one parenteral formulation, one aqueous solution, one liposome, one injectable solution, one freeze-dried powder, one feed, one food, one food supplement, one pellet, one lozenge, one liquid, one elixir, one aerosol, one inhalant, one adhesive, one spray, one powder, one freeze-dried powder, one patch, one tablet, one pill, one capsule, one gel, one geltab, one lozenge, one caplet, one nanosuspension, one nanoparticle, one nanoliposome, one microgel or one suppository.
13. The therapeutic combination of any of claims 1 to 12, wherein
(a) the dosage of etodolac ranges from about 200 mg to 400 mg a day, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more; or
(b) the dosage of propranolol ranges from 10 to 320 mg per day based on heart rate and blood pressure of the individual, or, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 75, 80, 85, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900 or 1000 mg or more.
14. The therapeutic combination of any of claims 1 to 13, the drug combination is packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day.
15. The therapeutic combination of claim 14, wherein the beta adrenergic receptor antagonist or a beta blocker or equivalent, or a propranolol or equivalent; the nonsteroidal anti-inflammatory drug or NSAID or equivalent, or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are packaged in dosages that match a chrono-dosing regimen to match an optimal dose for the time of day.
16. The therapeutic combination of any of claims 15, wherein the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the nonsteroidal anti-inflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are packaged in dosages that match a chrono-dosing regimen comprising:
(a) in the AM, 20 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200mg NSAID, e.g., an etodolac or equivalent; in the afternoon, 10 mg beta blocker, 200 mg NSAID, e.g., an etodolac or equivalent; in the PM, 10 mg beta blocker, 400 mg NSAID;
(b) in the AM 40 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200 mg NSAID, e.g., an etodolac or equivalent; in the afternoon 20 mg beta blocker, 200 mg NSAID; in the evening, 20 mg propranolol, 400 mg NSAID;
(c) in the AM 80 mg beta adrenergic receptor antagonist (a beta blocker), e.g., a propranolol or equivalent, 200 mg NSAID; in the afternoon 40 mg
beta blocker, 200 mg NSAID, in the evening 40 mg, NSAID; or
(d) a dose escalation comprising a regimen of (a) to (b) to (c).
17. The therapeutic combination of claim 16, wherein the beta adrenergic receptor antagonist or beta blocker or equivalent or propranolol or equivalent; the non-steroidal anti-inflammatory drug or NSAID or equivalent or etodolac or equivalent; and the therapeutic agent for the treatment of cancer, are packaged in dosages that match a chrono-dosing regimen comprising: Start: AM, 20 mg propranolol, 200mg etodolac; afternoon, 10 mg propranolol, 200 mg etodolac; PM 5 mg propranolol, 400 mg etodolac;
Dose Escalation 1 : AM 40 mg propranolol, 200 mg etodolac; afternoon 20 mg propranolol, 200 mg etodolac; evening, 10 mg propranolol, 400 mg etodolac;
Dose escalation 2: AM 80 mg propranolol, 200 mg etodolac; afternoon 40 mg propranolol, 200 mg etodolac, evening 20 mg, etodolac.
18. The therapeutic combination of any of claims 1 to 17, wherein the therapeutic drug combination is formulated for administration once a day, b.i.d. or t.i.d, or weekly, or biweekly, or monthly.
19. The therapeutic combination of any of claims 1 to 18, wherein the therapeutic combination of drugs are formulated for administration intravenously, topically, orally, by inhalation, by infusion, by injection, by inhalation, intraperitoneally, intramuscularly, subcutaneously, intra-aurally, for intra- articular administration, for intra-mammary administration, for topical administration or for absorption through epithelial or mucocutaneous linings.
20. The therapeutic combination of any of claims 1 to 20, wherein the therapeutic drug combination is formulated for intermittent or alternated cycling of the drug or active agent or component, and optionally the intermittent or alternated cycling comprises administration weekly, bi-monthly, monthly or quarterly.
21. A device, a medical device, an implant, a breast implant, a prosthesis, a stent, a catheter, comprising a therapeutic combination of therapeutic agents or drugs as set forth in any of claims 1 to 20.
22. A pharmaceutical composition or formulation comprising the therapeutic combination of any one of claims 1 to 20.
23. The pharmaceutical composition or formulation of claim 22, further comprising a pharmaceutically acceptable excipient.
24. The pharmaceutical composition or formulation of claim 22 or claim 23, wherein the pharmaceutical composition or formulation is formulated or manufactured as a feed, a food, a food or feed concentrate, a pellet, a lozenge, a liquid, a lotion, an implant, a nanoparticle, an elixir, an aerosol, a spray, an aerosol, an inhalant, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nanosuspension, a nanoparticle, a patch, a microgel or a suppository.
25. A method for treating, preventing or ameliorating a tumor or a cancer, comprising: applying or administering to an individual in need thereof; or, applying or administering to an effected tissue: the therapeutic combination of any one of claims 1 to 20, or a pharmaceutical composition or formulation of any of claims 22 to 24,
wherein optionally the therapeutic agents or drugs are administered separately or together, or at the same time, or in synchrony, or by chrono-dosing, or one of the therapeutic agents or drugs is administered before another of the therapeutic agents or drugs,
and optionally the therapeutic agents or drugs are formulated for administration intravenously (IV), parenterally, nasally, topically or locally, orally, or by liposome, implant or vessel-targeted nanoparticle delivery.
26. The method of claim 25, wherein the cancer or tumor is: a mastocytoma or a mast cell tumor, an ovarian cancer, pancreatic cancer, a non-small cell lung cancer, small cell lung cancer, hepatocarcinoma, melanoma, retinoblastoma, breast tumor or breast cancer (optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), a basal-like carcinoma, a ductal carcinoma, a colorectal carcinoma, leukemia, lymphoma, acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia, acute myeloid leukemia (AML), a histiocytic sarcoma, a brain tumor, an astrocytoma, a glioblastoma, a neuroma, a neuroblastoma, a colon carcinoma, cervical carcinoma, sarcoma, prostate tumor, bladder tumor, tumor of the reticuloendothelial tissues, Wilm's tumor, ovarian carcinoma, a bone cancer, an osteosarcoma, a renal cancer, or head and neck cancer, oral cancer, a laryngeal cancer, or an oropharyngeal cancer.
27. A method for treating, preventing or ameliorating a tumor or a cancer, comprising: (a) applying or administering to an individual in need thereof; or, applying or administering to an effected tissue; the therapeutic combination of any one of claims 1 to 20, or a pharmaceutical composition or formulation of any of claims 22 to 24,
wherein optionally the therapeutic agents or drugs are administered separately or together, or at the same time, or in synchrony, or by chrono-dosing, or one of the therapeutic agents or drugs is administered before another of the therapeutic agents or drugs,
and optionally the therapeutic agents or drugs are formulated for administration intravenously (IV), parenterally, nasally, topically or locally, orally, or by liposome, implant or vessel-targeted nanoparticle delivery; and
(b) administering to the individual in need thereof:
(i) a systemic anti-cancer or anti-tumor treatment, wherein optionally the systemic anti-cancer or anti-tumor treatment comprises administration of a drug, a biologic, a nutrient, an anti-cancer or anti-tumor dietary regimen, a radioactive agent, a tumor ablative agent, or
(ii) an anti-cancer or anti-tumor radiotherapy or a proton beam therapy, wherein the therapeutic combination or pharmaceutical composition or formulation of (a) is administered before the anti-cancer or anti-tumor treatment of (b), or both are administered consecutively, or the therapeutic combination or pharmaceutical composition or formulation of (a) is administered after the anti-cancer or anti-tumor treatment of (b), or any combination thereof.
28. The method of any of claims 25 to 27, further comprising: an anti-cancer or anti-tumor radiotherapy or a proton beam therapy.
29. Use of the therapeutic combination of any one of claims 1 to 20, or a pharmaceutical composition or formulation of any of claims 22 to 24, in the manufacture of a medicament.
30. Use of the therapeutic combination of any one of claims 1 to 20, or a pharmaceutical composition or formulation of any of claims 22 to 24, in the manufacture of a medicament for treating, ameliorating, preventing or reversing:
(a) a short stature, a short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like, (b) a burn, a third degree burn, a large >10% total body surface area burn, a wound, a refractory large wound, a wound >10 cm2, a chronic wound, a diabetic foot ulcer, a venous leg ulcer, a pressure ulcer, or
(c) a tumor or a cancer.
31. The use of claim 30, wherein the cancer or tumor is: a mastocytoma or a mast cell tumor, an ovarian cancer, pancreatic cancer, a non-small cell lung cancer, small cell lung cancer, hepatocarcinoma, melanoma, retinoblastoma, breast tumor or breast cancer (optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu), a basal-like carcinoma, a ductal carcinoma, a colorectal carcinoma, leukemia, lymphoma, acute lymphoblastic leukemia (ALL) or acute lymphoid leukemia, acute myeloid leukemia (AML), a Histiocytic sarcoma, a brain tumor, an astrocytoma, a glioblastoma, a neuroma, a neuroblastoma, a colon carcinoma, cervical carcinoma, sarcoma, prostate tumor, bladder tumor, tumor of the reticuloendothelial tissues, Wilm's tumor, ovarian carcinoma, a bone cancer, an osteosarcoma, a renal cancer, or head and neck cancer, oral cancer, a laryngeal cancer, or an oropharyngeal cancer.
32. A method for treating, ameliorating, preventing or reversing a short stature, short stature syndrome, Turner syndrome, Prader-Willi syndrome and the like, comprising administering to an individual in need thereof a therapeutic combination of any of claims 1 to 20, or the pharmaceutical composition or formulation of any of claims 22 to 24,
wherein optionally the therapeutic combination comprises or consists of a SARM or claim 1(a) with claim 1(b)(5), or a growth hormone, optionally a human growth hormone, optionally a human recombinant growth hormone (hrGH), a somatropin or a HUMATROPE™ (Eli Lilly), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy,
and optionally the therapeutic combination is formulated for controlled release dosing after about 12AM to achieve peak by about 6AM.
33. A method for treating, ameliorating, preventing or reversing a burn, a third degree burn, a large >10% total body surface area burn, a wound, a refractory large wound, a wound >10 cm2, a chronic wound, a diabetic foot ulcer, a venous leg ulcer, a pressure ulcer, and the like, comprising administering to an individual in need thereof a therapeutic combination of any of claims 1 to 20, or the pharmaceutical composition or formulation of any of claims 22 to 24,
wherein optionally the therapeutic combination comprises or consists of a SARM with a propranolol and an growth hormone, or an hGH, or claim 1(b)(5), and optionally the combination is formulated for chronodosing and/or metronomic dosaging to optimize therapy; and optionally is formulated as a combination pill comprising a SARM or claim 1(a) with a propranolol or claim 1(b)(2) (e.g., to enhance compliance),
and optionally the propranolol comprises a sustained release propranolol plus, and optionally the therapeutic combination is formulated for treatment of severely burned children,
and optionally the therapeutic combination is formulated for controlled release propranolol and/or controlled release SARM or claim 1(a) dosing after about 12AM to achieve peak by about 6AM,
and optionally the therapeutic combination is formulated as a combination pill of sustained release propranolol and controlled release SARM or claim 1(a).
34. A method for treating, ameliorating, preventing or reversing a tumor or a cancer, and the like, comprising administering to an individual in need thereof a therapeutic combination of any of claims 1 to 20, or the pharmaceutical composition or formulation of any of claims 22 to 24,
wherein optionally the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu,
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1(b)(2), 1 (b) (3) or 1(b) (4),
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage,
and optionally the therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage, and optionally the therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card;
and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic chemotherapy at standard dosing, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu,
and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
(1) capecitabine, optionally at normal or metronomic low doses,
(2) VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(3) a SERM or claim 1(b)(8) and/or an aromatase inhibitor and VT-122 or claim 1(b)(4),
(4) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and capecitabine or claim 1(b)(6),
(5) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(6) a VT-122 or claim 1(b)(4) and a cyclophosphamide or a claim l(b)(13), optionally at 50 mg per day, e.g., at 10 am, and methotrexate twice a day, optionally 2.5 mg twice a day, e.g., at 9 am and 5 pm, e.g., every 3rd or 4th day, e.g., on Monday and Thursday weekly, or
(7) a combination pill or packaging comprising or containing any combination of, or all of, (1), (2), (3), (4), (5), (6) and (7), optionally packaged on a blister card or equivalent, e.g., to enable metronomic dosing of one or all of the drugs, e.g., to enable metronomic dosing of cylcophosphomide and methotrexate or a claim l(b)(13),
and optionally the therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with: (1) VT-122 or claim 1(b)(4) and a docetaxel or claim 1(b)(1) or other cytotoxic chemotherapy, optionally at normal or metronomic low doses, or
(2) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT 122 or claim 1(b)(4) and docetaxel or other cytotoxic chemotherapy, optionally at normal or metronomic low doses,
and optionally the therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or androgen receptor positive breast cancer, and optionally the breast cancer is a triple- negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu, such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
(13) treatment first on a SERM or claim 1(b)(8) or an aromatase inhibitor and then treatment with a SARM,
(14) 1 to 2 months on SERM or claim 1(b)(8) and then 1 to 2 months on a SARM, or
(15) 1 to 2 months on an aromatase inhibitor and then 1 to 2 months on a
SARM.
35. The method of any of claims 32 to 34, wherein two or more drugs of the therapeutic combination are formulated as separate compositions, or two or more drugs of the therapeutic combination are formulated into one composition or drug formulation (two or more drugs of the therapeutic combination are formulated together).
36. A formulation or a therapeutic combination for use in a method for treating, ameliorating, preventing or reversing a tumor or a cancer,
wherein the formulation or a therapeutic combination comprises a formulation or a therapeutic combination as set forth in any of claims 1 to 20, or comprises the pharmaceutical composition or formulation of any of claims 22 to 24,
wherein optionally the cancer is a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu, and optionally the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a claim 1(b)(2), 1(b) (3) or 1(b) (4),
and optionally the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a capecitabine or a claim 1(b)(6), wherein optionally the or claim 1(b)(6) are formulated at a low dose, or a metronomic dosage,
and optionally the formulation or a therapeutic combination comprises or consists of a SARM or a claim 1(a), and a cyclophosphamide and a methotrexate, or a claim l(b)(13) and a claim l(b)(14), and optionally the cyclophosphamide and methotrexate are formulated at a low dose, or a metronomic dosage,
and optionally the formulation or a therapeutic combination is formulated in double, triple or quod combinations, or in a single pill or blister card;
and optionally the formulation or a therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or for androgen receptor positive breast cancer, optionally breast cancer in older women who are intolerant for chemotherapy or too frail to sustain cytotoxic
chemotherapy at standard dosing, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu,
and optionally the formulation or a therapeutic combination is formulated as a SARM or claim 1(a) with (or in combination with):
(1) capecitabine, optionally at normal or metronomic low doses,
(2) VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(3) a SERM or claim 1(b)(8) and/or an aromatase inhibitor and VT-122 or claim 1(b)(4),
(4) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and capecitabine or claim 1(b)(6),
(5) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT-122 or claim 1(b)(4) and capecitabine, optionally at normal or metronomic low doses,
(6) a VT-122 or claim 1(b)(4) and a cyclophosphamide or a claim l(b)(13), optionally at 50 mg per day, e.g., at 10 am, and methotrexate twice a day, optionally 2.5 mg twice a day, e.g., at 9 am and 5 pm, e.g., every 3rd or 4th day, e.g., on Monday and Thursday weekly, or (7) a combination pill or packaging comprising or containing any combination of, or all of, (1), (2), (3), (4), (5), (6) and (7), optionally packaged on a blister card or equivalent, e.g., to enable metronomic dosing of one or all of the drugs, e.g., to enable metronomic dosing of cyclophosphamide and methotrexate or a claim l(b)( 13),
and optionally the formulation or a therapeutic combination comprises or consists of an oral and an intravenous (IV) administered cytotoxic chemotherapy, and optionally the therapeutic combination is formulated as a SARM or claim 1(a) with:
(1) VT-122 or claim 1(b)(4) and a docetaxel or claim 1(b)(1) or other cytotoxic chemotherapy, optionally at normal or metronomic low doses, or
(2) a SERM or claim 1(b)(8) and/or an aromatase inhibitor or claim l(b)(10) and VT 122 or claim 1(b)(4) and docetaxel or other cytotoxic chemotherapy, optionally at normal or metronomic low doses,
and optionally the formulation or a therapeutic combination is formulated for the treatment of a breast cancer, a basal-like carcinoma, a ductal carcinoma or an ovarian cancer, or androgen receptor positive breast cancer, and optionally the breast cancer is a triple-negative breast cancer (TNBC), or any breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu, such that patients receive intermittent or alternated SERM or aromatase inhibitor and a SARM, wherein optionally the intermittent or alternated treatment comprises:
(16) treatment first on a SERM or claim 1(b)(8) or an aromatase inhibitor and then treatment with a SARM,
(17) 1 to 2 months on SERM or claim 1(b)(8) and then 1 to 2 months on a SARM, or
(18) 1 to 2 months on an aromatase inhibitor and then 1 to 2 months on a
SARM.
37. The formulation or a therapeutic combination of claim 36, wherein two or more drugs of the formulation or a therapeutic combination are formulated as separate compositions, or two or more drugs of the formulation or a therapeutic combination are formulated into one composition or drug formulation (two or more drugs of the therapeutic combination are formulated together).
PCT/US2015/055383 2014-10-18 2015-10-13 Drug combinations with selective androgen receptor modulators (sarms) and methods of making and using them WO2016061135A1 (en)

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