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WO2019090141A1 - Thérapies par association médicamenteuse contre le cancer et leurs procédés de fabrication et d'utilisation - Google Patents

Thérapies par association médicamenteuse contre le cancer et leurs procédés de fabrication et d'utilisation Download PDF

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Publication number
WO2019090141A1
WO2019090141A1 PCT/US2018/059047 US2018059047W WO2019090141A1 WO 2019090141 A1 WO2019090141 A1 WO 2019090141A1 US 2018059047 W US2018059047 W US 2018059047W WO 2019090141 A1 WO2019090141 A1 WO 2019090141A1
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WO
WIPO (PCT)
Prior art keywords
propranolol
optionally
formulation
etodolac
cancer
Prior art date
Application number
PCT/US2018/059047
Other languages
English (en)
Inventor
John Maki
Newell Bascomb
Fredric Young
Original Assignee
Vicus Therapeutics, Llc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vicus Therapeutics, Llc filed Critical Vicus Therapeutics, Llc
Publication of WO2019090141A1 publication Critical patent/WO2019090141A1/fr

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

  • This invention relates generally to medicine, pharmaceutical formulations and medical devices.
  • a beta- adrenergic receptor antagonist such as propranolol
  • a nonsteroidal anti-inflammatory drug such as etodolac
  • the therapeutic combinations of therapeutic agents or drugs comprise an anti-cancer or anti-tumor antibody, a cytokine, and/or another
  • 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 and in non-dividing, but toxicity sensitive, nerves. New approaches in cancer chemotherapeutics are needed to address these challenges.
  • coxibs nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase-2 (COX-2) but not cyclooxygenase-1 (COX-1)
  • beta adrenergic receptor antagonists beta blockers
  • COX-1 cycl
  • compositions, drug delivery devices or products of manufacture comprising:
  • the first formulation is formulated or manufactured as having the delayed (or controlled) release (DR) propranolol formulation, and/or the immediate release (IR) propranolol formulation, on or coated on the surface of or contained: in a bead, a powder, a particle, or a multilayered bead or particle,
  • DR delayed (or controlled) release
  • IR immediate release
  • the second formulation is formulated or manufactured as having the immediate release (IR) etodolac formulation, on or coated on the surface of or contained in: a bead, a powder, a particle, or a multilayered bead or particle,
  • IR immediate release
  • the bead, powder, particle or the multilayered bead or particle is contained in a pill, a capsule, a tablet, or a geltab, or equivalents, for oral delivery,
  • pill, capsule, tablet, geltab or equivalent for oral delivery is a hard gelatin capsule or equivalent, or comprises a hard gelatin or equivalent
  • the delayed (or controlled) release (DR) propranolol formulation comprises a racemic R(+) and S(-) mixture of propranolol, a substantially pure (S)-enantiomer of propranolol, or a pharmaceutically acceptable salt thereof, or mixtures thereof,
  • the immediate release (IR) propranolol formulation comprises a racemic R(+) and S(-) mixture of propranolol, a substantially pure (S)-enantiomer of propranolol, or a pharmaceutically acceptable salt thereof, or mixtures thereof, and
  • the immediate release (IR) etodolac formulation comprises a racemic R(+) and
  • the immediate release (TR) propranolol formulation comprises particles, powders, pellets, or beads (or a core comprising particles, powders, pellets, or beads), and the particles, powders, pellets, or beads are coated with or have contained therein:
  • the immediate release (IR) etodolac formulation comprises particles, powders, pellets, or beads (or a core comprising particles, powders, pellets, or beads), and the particles, powders, pellets, or beads are coated with or have contained therein:
  • the delayed (or controlled) release (DR) propranolol formulation comprises particles, pellets, or beads (or a core comprising particles, pellets, or beads), and the particles, pellets, or beads are coated with or have contained therein:
  • the optionally particles, powders, pellets, or beads comprise a membrane or a coating comprising a water insoluble polymer or a combination of a water insoluble polymer and a water soluble polymer,
  • the pharmaceutical dosage form, the drug delivery device or the product of manufacture exhibits the following in vitro dissolution profile, or in vivo human dissolution profile,
  • the in vitro dissolution profile is determined by testing according to United States Pharmacopoeia dissolution test method USP Apparatus 1, Baskets @ 100 rpm, Drug Release Test 1 using 900 mL of pH 1.2 buffer for 1.5 hours followed by testing in 900 mL of pH 6.8 at 4, 8, 14, and 24 hours,
  • the in vivo human dissolution profile is based on an oral administration to an individual in need thereof: after 1.0 hour: not less than about 35%, 40%, 45% or 50% of the total propranolol is released (or dissolved); or, about 50% +/- 15%, of the total propranolol is released (or dissolved);
  • the dissolution profile corresponds to the following pattern:
  • the first formulation, the amount of propranolol in the delayed (or controlled) release (DR) propranolol formulation and the amount of propranolol in the immediate release (IR) propranolol formulation are present in a ratio of from:
  • the first formulation the immediate release (IR) propranolol formulation substantially releases all of the racemic R(+) and S(-) mixture of propranolol, the substantially pure (S)-enantiomer of propranolol, or the pharmaceutically acceptable salt thereof, or mixtures thereof, contained therein during the first hour of dissolution testing, or during the first hour after oral administration.
  • the first formulation and/or the second formulation the immediate release (IR) etodolac formulation substantially releases all of the racemic R(+) and S(-) mixture of etodolac, the substantially pure (S)-enantiomer of etodolac, or the pharmaceutically acceptable salt thereof, or mixtures thereof, contained therein during the first hour of dissolution testing, or during the first hour after oral administration.
  • the water insoluble polymer comprises an
  • the water-insoluble polymer and water-soluble polymer are present in a weight ratio of from about 0: 100 to 60:40.
  • the core particles or beads comprise or are
  • the core particles or beads further comprise: (a) a polymeric binder; (b) a seal coating; or, (c) non-pareil seeds and a polymeric binder in the immediate release (IR) propranolol formulation or the immediate release (IR) etodolac formulation.
  • the water-soluble polymer comprises a
  • the pharmaceutical dosage form, the drug delivery device or the product of manufacture is configured or manufactured as a blister card or equivalent, wherein at least one day, or between about one to two weeks, or 7 to 8 days, of:
  • the first formulation for administration in the morning or breakfast (or AM, or afternoon) are formulated in a single orally administrable carrier, or 2 or 3 orally administrable carriers (optionally one, two or three or more tablets, capsules, geltabs, or pills or equivalents), and,
  • the second formulation for administration at dinnertime or the evening (or in the PM or at bedtime) comprising an immediate release (IR) etodolac, formulated in a single orally administrable carrier, or 2 or 3 orally administrable carriers (optionally one, two or three or more tablets, capsules, geltabs, or pills or equivalents),
  • IR immediate release
  • the blister card or equivalent are packaged in the blister card or equivalent in separate compartments (wherein the one, two or three or more orally administrable carriers of (a) and the one, two or three or more orally administrable carriers (b) are in separate compartments on the blister card), and optionally, between about two days and one to two weeks, or about 8 days, of the one, two or three or more orally administrable carriers of the first formulation, and separately the one, two or three or more orally administrable carriers of the second formulation, are packaged and configured or spaced on the blister card or equivalent in relation to each other to reflect an administration regimen wherein the one, two or three or more orally administrable carriers of the first formulation is to be taken in the AM
  • the blister card or equivalent comprises at least a first and a second blister strip
  • the first blister strip contains or comprises between about two days and one to two weeks, or about 7 or 8 days, of the one, two or three or more orally administrable carriers of the first formulation to be taken in the AM (morning or afternoon); and the second blister strip contains or comprises between about two days and one to two weeks, or about 7 to 8 days, of the one, two or three or more orally
  • administrable carriers of the second formulation to be taken at dinnertime or in the evening (or in the PM or at bedtime), and optionally the one, two or three or more orally administrable carriers of the second formulation comprise immediate release (IR) etodolac formulation contained in or on or coated on a plurality of particles, a powder, pellets, or beads (or contained in or on or coated on a core comprising particles, a powder, pellets, or beads), and the IR etodolac formulation comprises:
  • each administrable carrier has or all the administrable carriers in total have: between about 100 and 500 mg, between about 200 and 400 mg, between about 250 and 350 mg, about 270, or about 200, 210, 220, 225, 230, 240, 250, 260, 270, 275, 280, 290, 300, 310, 320, 330, 340, 350 mg, IR etodolac, or up to three times these amounts, or between about 300 mg and 1,050 mg immediate release (IR) etodolac,
  • the blister card or equivalent is a thermoformed polyvinyl chloride (PVC) blister card or equivalent with a push-through lidding (optionally a foil-lined paper push-through lidding, or any air-impermeable lidding), optionally comprising a sealing layer and a moisture barrier, wherein optionally the sealing layer comprises APPEEL ® , and optionally the moisture barrier comprises ACLAR ® .
  • PVC polyvinyl chloride
  • the pharmaceutical dosage form, the drug delivery device or the product of manufacture comprises a therapeutic combination comprising:
  • IR etodolac about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130 or 140 mg IR etodolac, or up to triple these amounts, or between about 150 and 420 IR etodolac,
  • IR and DR propranolol optionally about 16 mg IR and about 16 mg DR propranolol for a racemic mixture, totaling 32 mg propranolol in each tablet, or 32 mg total for all the tablets for a particular dose (e.g., all in one blister card container), or about 4 to 12 mg or 6 to 10 mg IR and about 4 to 12 mg or 6 to 10 mg DR propranolol in each tablet, or these totals for all the tablets for a particular dose (e.g., all in one blister card container), for a substantially pure (S)- enantiomer, of propranolol),
  • each set of morning or AM one, two or three or more tablets, pills, geltabs, capsules or equivalents are in one blister card or equivalent compartment and the compartments are arranged in the blister card or equivalent for morning or afternoon, or AM consumption, administration or use by a user (or a patient),
  • IR propranolol between about 2 to 80 mg, 4 to 40 mg, 5 to 25 mg, or 10 to 20 mg IR propranolol, or about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg of DR propranolol, or up to triple these amounts, or between about 6 and 240 mg, and optionally the morning or breakfast, or AM, tablet has approximately equal amounts of IR and DR propranolol;
  • the membrane or coating comprises between about 1% to 10% based on the weight of the bead, particle or the multilayered bead or particle; (b) comprises approximately 1.5% to 6% based on the weight of the bead, particle or the multilayered bead or particle in a delayed (or controlled) release (DR) propranolol formulation.
  • the water-insoluble polymer comprises an ethylcellulose having a viscosity of not more than 30 cps when tested on a 5% solution at 25°C.
  • the delayed (or controlled) release (DR) propranolol formulation and/or the immediate release (IR) propranolol formulation in the first formulation are each or are in total from between about 2 to 80 mg, between about 4 to 40 mg, between about 5 to 25 mg, or between about 10 to 20 mg, or about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg, or up to triple of each of these amounts, or between about 6 mg to about 240 mg DR propranolol,
  • the DR and IR formulations are present in the first formulation in approximately equal amounts; and/or
  • the immediate release (IR) etodolac formulation in the first formulation is from between about 25 mg to 200 mg, 50 mg to 175 mg, 60 mg to 160 mg, or 70 mg to 150 mg, or about 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160 or 170 mg, or up to triple of each of these amounts, or between about 75 mg and 450 mg,
  • the first formulation comprises:
  • the immediate release (IR) propranolol formulation comprises the racemic R(+) and S(-) mixture of propranolol, the substantially pure (S)-enantiomer of propranolol, or the pharmaceutically acceptable salt thereof, or mixtures thereof, coated on microbeads or microparticles or equivalents, optionally polysaccharide microbeads, and optionally the delayed (or controlled) release (DR) propranolol formulation comprises the racemic R(+) and S(-) mixture of propranolol, the substantially pure (S)- enantiomer of propranolol, or the pharmaceutically acceptable salt thereof, or mixtures thereof, coated on microbeads or microparticles or equivalents, optionally polysaccharide microbeads or microparticles, and further comprising an ammonio methacrylate
  • copolymer dispersion or equivalents (optionally a EUDRAGIT polymer or equivalents) also coated on the microbeads or microparticles or equivalents,
  • the water-soluble polymer has a viscosity of not more than 200 cps when tested on a 2% aqueous solution at 25°C.
  • racemic R(+) and S(-) mixture of propranolol, the substantially pure (S)-enantiomer of propranolol, or the pharmaceutically acceptable salt thereof, or mixtures thereof, in the delayed (or controlled) release (DR) propranolol formulation and/or the immediate release (IR) propranolol formulation are contained in or adsorbed to or onto a core, wherein optionally the core comprises a plurality of sugar spheres, wherein optionally the sugar spheres comprise sugar spheres PF006 or
  • SUGLETS® and optionally the amount of sugar spheres in the formulation or in each dosage unit is about 21%(w/w), or is between about 20 to 22%(w/w), or is between about 18 to 25%(w/w).
  • the racemic R(+) and S(-) mixture of propranolol, the substantially pure (S)-enantiomer of propranolol, or the pharmaceutically acceptable salt thereof, or mixtures thereof, in the delayed (or controlled) release (DR) propranolol formulation and/or the immediate release (IR) propranolol formulation is coated with a coating agent,
  • the delayed (or controlled) release (DR) propranolol formulation and/or the immediate release (IR) propranolol formulation forms a bead or a pellet
  • the coating agent comprises a water soluble cellulose ether and/or OPADRY ® ,
  • the water soluble cellulose ether comprises a hypromellose, optionally a METHOCEL E5 PREMIUM LVTM,
  • the coating agent comprises both the hypromellose and the OPADRY ® , and optionally the hypromellose and the OPADRY ® are present in approximately equal amounts in the formulation or each dosage unit;
  • the coating agent further comprises about 2.5% (w/w), or between about 2% (w/w) to 3% (w/w), or between about 1% (w/w) to 4% (w/w), of the formulation or each dosage unit.
  • the coating agent in the delayed (or controlled) release (DR) propranolol formulation further comprises a triethyl citrate, an ammonio methacrylate copolymer dispersion Type A (optionally EUDRAGIT ® RL-30D), an ammonio methacrylate copolymer dispersion Type B (optionally EUDRAGIT ® RS-30D), or a mixture thereof,
  • the coating agent comprises: the hypromellose at between about 1 %(w/w) and 1.5%(w/w); the OPADRY® at between about 1 %(w/w) and 1.5%(w/w); the ammonio methacrylate copolymer dispersion Type A at between about 0.5%(w/w) to 1.5%(w/w); the ammonio methacrylate copolymer dispersion Type B at between about 8%(w/w) to 9%(w/w) or 7%(w/w) to 10%(w/w); and the tri ethyl citrate at between about l%(w/w) to 2%(w/w), of the formulation or each dosage unit,
  • the formulation or each dosage unit further comprises a neutral filler, optionally at an amount of between about 5%(w/w) to 6%(w/w), or about 3%(w/w) to 8%(w/w), of the formulation or each dosage unit,
  • the neutral filler comprises a talc or a hydrated magnesium silicate.
  • the racemic R(+) and S(-) mixture of etodolac, the substantially pure (S)-enantiomer of etodolac, or the pharmaceutically acceptable salt thereof, or mixtures thereof, in the immediate release (IR) etodolac formulation comprises a granulated etodolac, or is comprised substantially of granulated etodolac.
  • the immediate release (IR) etodolac formulation comprises or is formulated with a filler, a disintegrant a glidant and/or a lubricant,
  • the filler comprises a microcrystalline cellulose (optionally an
  • the disintegrant comprises a croscarmellose sodium (optionally an Ac-Di-Sol ® );
  • the glidant comprises a colloidal silicon dioxide (optionally a Cab-O-Sil ® M5P ® ), and/or the lubricant comprises magnesium stearate or equivalent thereof,
  • the filler is in an amount at between about 4%(w/w) to 5%(w/w) or 3%(w/w) to 6%(w/w);
  • the disintegrant is in an amount at between about 2%(w/w) to 3%(w/w) or l%(w/w) to 4%(w/w);
  • the glidant is in an amount at between about 0. l%(w/w) to 0.5%(w/w); and/or, the lubricant is in an amount at between about 0.1%(w/w) to 0.5%(w/w).
  • LMR lymphocyte-to-monocyte ratio
  • CRP C- reactive protein
  • NLR neutrophil-to-lymphocyte ratio
  • the pharmaceutical dosage form, drug delivery device or product of manufacture is administered is delivered or administered to the individual in need thereof before, at the same time and/or after the other treatment for cancer.
  • the therapeutic combination is administered at a dosage regimen of:
  • each tablet, pill, geltab, capsule or equivalent has, or all tablets, pills, geltabs, capsules or equivalent in a compartment in total have: 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 mg of immediate release (IR) propranolol; 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 mg of delayed (or controlled) release (DR) propranolol; and about 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250 mg IR etodolac,
  • IR immediate release
  • DR delayed (or controlled) release
  • one, two or three or more tablets, pills, capsules, geltabs or equivalents have approximately equal amounts of IR and DR propranolol (optionally about 16 mg IR and 16 mg DR propranolol for a racemic mixture, or 4 to 8 mg IR and 4 to 8 mg DR propranolol for a substantially pure (S)-enantiomer, of propranolol); and one, two or three or more tablets, pills, capsules, geltabs or equivalents for administration in at dinnertime or the evening (e.g., PM or bedtime) each having or in total having between about 100 and 250 mg, between about 200 and 400 mg, between about 250 and 300 mg, about 270 mg, or about 200, 210, 220, 225, 230, 240, 250, 260, 270, 275, 280, 290, 300, 310, 320, 330, 340 or 350 mg, IR etodolac; or
  • IR propranolol between about 2 to 80 mg, 4 to 40 mg, 5 to 25 mg, or 10 to 20 mg IR propranolol, or about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg of DR propranolol, or up to triple these amounts, or between about 6 and 240 mg, and optionally the morning or breakfast, or AM, tablet has approximately equal amounts of IR and DR propranolol;
  • the water insoluble polymer comprises an ethylcellulose having a viscosity of not more than 30 cps when tested on a 5% solution at 25°C.
  • drug delivery devices or packages comprising a pharmaceutical dosage form or formulation of any of the preceding claims, wherein the drug delivery device or package, blister pack, clamshell or tray comprises a plurality of compartments spatially arranged on the drug delivery device or package, blister pack, clamshell or tray to follow a dosage administration regimen,
  • the spatially arranged plurality of compartments are in at least two rows, each row marked for the time for which the tablets, pills, capsules, geltabs or equivalents are to be taken by a user (optionally a patient), optionally one row marked for morning, breakfast or AM administration, and one row marked for evening, dinnertime or PM administration, and optionally the row or rows marked for morning, breakfast or AM administration is or are positioned above the row or rows marked for evening, dinnertime or PM administration,
  • the spatially arranged plurality of compartments are in four rows, two rows marked for morning, breakfast or AM administration, and two rows marked for evening, dinnertime or PM administration,
  • each row comprises seven compartments for one dosage administration for each day of the week, or eight compartments for one dosage administration for each day of the week and one spare, and optionally each vertically arranged set of compartments, or columns, are marked for which day of the week the dosage formulations contained therein are to be taken by the user, and optionally where the drug delivery device or package, blister pack, clamshell or tray has one row for morning, breakfast or AM administration, and one row marked for evening, dinnertime or PM administration, each column or day will have two compartments, optionally where the compartment for morning, breakfast or AM administration is above the compartment for evening, dinnertime or PM administration, and optionally the rows of compartments on the drug delivery device or package, blister package, clamshell or tray is arranged as set forth in FIG. 2,
  • each compartment has a foil or equivalent backing, or each compartment is an environmentally- (optionally moisture-, pathogen-, and/or light-) protected or sealed storage unit, and optionally the foil backing requires minimal finger strength to remove a dosage formulation (optionally one, two or three or more capsules, tablets, pills, geltabs or equivalents) in the compartment;
  • the blister package is a face seal blister package, a gang run blister package, a mock blister package, an interactive blister package or a slide blister package, and optionally the drug delivery device or package, blister package, clamshell or tray is joined with board material which allows the product to be packaged, handled, hung, displayed and/or shipped without damaging the blister protection or seal, and optionally also provided with child resistant features,
  • the drug delivery device or package, blister package, clamshell or tray comprises a medical electronic monitory system that records administration time and transmits information to near-field communication (NFC) enabled mobile phone.
  • NFC near-field communication
  • compositions in alternative embodiment, provided are pharmaceutical dosage forms, drug delivery devices or packages, blister packages, clamshells or trays, or products of manufacture as provided herein, optionally for use in treating or ameliorating a cancer, tumor or a dysfunctional cell condition, or a symptom of cancer, tumor or a dysfunctional cell condition, further comprising an additional drug or active agent,
  • the additional drug or active agent comprises a (optionally an additional) cancer drug or a cancer adjunctive or support therapy
  • the cancer drug or a cancer adjunctive or (as a drug or pharmaceutical) support therapy comprises (or further comprises, or comprises use of):
  • an anti-microtubule agent including at least one of, or any one of: a paclitaxel (e.g. TAXOLTM or GENEXOLTM), a paclitaxel protein bound particles (e.g. ABRAXANETM), a polymeric micelle paclitaxel (GENEXOL PMTM), a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B), a liposomal paclitaxel (e.g. LIPUSUTM), a docetaxel (e.g., TAXOTERETM), a DHP107, an oral paclitaxel and P-gp inhibitor HM30181 A (e.g.
  • ORAXOLTM a polymeric micelle docetaxel (e.g. NANOXEL PMTM), a cabazitaxel (e.g. JEVTANATM), a polymeric micelle cabazitaxel, a vincristine, a vinblastine, a vinorelbine (e.g. NAVELBINETM), a vinflunine, and/or an eribulin (e.g. HALAVENTM), or any combination thereof,
  • an alkylating agent including at least one of, or any one of: a cisplatin (e.g.
  • PLATINOLTM a carboplatin (e.g. PARAPLATINTM), oxaliplatin (e.g., ELOXATINTM), a NC-6004 (e.g. LIPOPLATINTM), an oxaliplatin (e.g., ELOXATINTM), a bendamustine (e.g., TREA DATM), a cyclophosphamide, an ifosfamide, a chlorambucil, a melphalan, a dacarbazine, a mitozalomide, and/or a temozolomide, or any combination thereof,
  • a carboplatin e.g. PARAPLATINTM
  • oxaliplatin e.g., ELOXATINTM
  • NC-6004 e.g. LIPOPLATINTM
  • an oxaliplatin e.g., ELOXATINTM
  • a bendamustine e.g., TREA DA
  • a cytotoxic antibiotic including at least one of, or any one of: a doxorubicin (e.g. ADRIAMYCINTM or RUBEXTM), a pegylated liposomal doxorubicin (e.g. DOXILTM or LIPODOXTM), a non-pegylated liposomal doxorubicin (e.g. MYOCETTM), a polymeric micelle doxorubicin, a daunorubicin, a liposomal daunorubicin, an epirubicin (e.g.
  • a doxorubicin e.g. ADRIAMYCINTM or RUBEXTM
  • a pegylated liposomal doxorubicin e.g. DOXILTM or LIPODOXTM
  • a non-pegylated liposomal doxorubicin e.g. MYOCETTM
  • ELLENCETM an idararubicin, a piranubicin, an aclarubicin, a mitoxantrone, a bleomycin, and/or a mitomycin, or any combination thereof
  • a topisom erase inhibitor including at least one of, or any one of: an irinotecan (e.g., CAMPTOSARTM), a liposomal irinotecan (e.g., ONIVYDETM), an etirinotecan pegol, (e.g. ONZEALDTM), a liposomal encapsulated irinotecan and 5FU (e.g. CPX-1), a topotecan, a camptothecin and/or an etoposide (e.g. ETOPOPHOSTM), or any combination of: an irinotecan (e.g., CAMPTOSARTM), a liposomal irinotecan (e.g., ONIVYDETM), an etirinotecan pegol, (e.g. ONZEALDTM), a liposomal encapsulated irinotecan and 5FU (e.g. CPX-1), a topotecan, a camp
  • an anti-metabolite including at least one of, or any one of: a methotrexate, a pemetrexed (e.g. ALIMTATM), a pralatrexate (e.g. FOLOTYNTM), a 5-fluorouracil or 5- FU (e.g. ADRUCILTM), a capecitabine (e.g., XELODATM), a tegafur/gimeracil/oteracil (e.g. TEYSUNOTM or S-lTM), a trifluridine/tipiracil (e.g. LONSURFTM), a gemcitabine (e.g. GEMZARTM), a NUC-1031 (e.g. ACELARINTM), and/or a azacytidine (e.g.
  • a methotrexate e.g. ALIMTATM
  • a pralatrexate e.g. FOLOTYNTM
  • VIDAZATM VIDAZATM
  • a hydroxycarbamide or any combination thereof
  • a cisplatin and paclitaxel a cisplatin and paclitaxel
  • a cisplatin and a paclitaxel protein bound particles a cisplatin and a polymeric micelle paclitaxel (GE EXOL PMTM)
  • a cisplatin and a liposomal paclitaxel e.g. LIPUSUTM
  • a carboplatin and paclitaxel a carboplatin and paclitaxel
  • a carboplatin and a paclitaxel protein bound particles a carboplatin and a polymeric micelle paclitaxel (GENEXOL PMTM)
  • a carboplatin and a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd as described, e.g., in China patent no. CN 102218027 B
  • a carboplatin and a liposomal paclitaxel e.g. LIPUSUTM
  • an oxaliplatin and paclitaxel an oxaliplatin and paclitaxel; an oxaliplatin and a paclitaxel protein bound particles; an oxaliplatin and a polymeric micelle paclitaxel (GENEXOL PMTM); an oxaliplatin and a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B); and/or, an oxaliplatin and a liposomal paclitaxel, (e.g. LIPUSUTM);
  • a polymeric micelle doxorubicin and a paclitaxel protein bound particle a cisplatin and a polymeric micelle paclitaxel (GENEXOL PMTM); a cisplatin and a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B); and/or a cisplatin and a liposomal paclitaxel, (e.g. LIPUSUTM);
  • a gemcitabine and paclitaxel a gemcitabine and paclitaxel
  • a gemcitabine and a paclitaxel protein bound particles a gemcitabine and a polymeric micelle paclitaxel (GENEXOL PMTM)
  • a gemcitabine and a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd as described, e.g., in China patent no. CN 102218027 B
  • a gemcitabine and a liposomal paclitaxel e.g. LIPUSUTM
  • a gemcitabine a paclitaxel and a cisplatin
  • a gemcitabine a paclitaxel protein bound particles and a cisplatin
  • a gemcitabine a polymeric micelle paclitaxel
  • a gemcitabine a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B) and a cisplatin
  • a gemcitabine a liposomal paclitaxel, (e.g. LIPUSUTM) and a cisplatin
  • a gemcitabine a paclitaxel and a NC-6004
  • a gemcitabine a paclitaxel protein bound particles and a NC-6004
  • a gemcitabine a polymeric micelle paclitaxel
  • a gemcitabine a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B) and a NC-6004; and/or a gemcitabine, a liposomal paclitaxel, (e.g. LIPUSUTM) and a NC-6004;
  • FOLFIRI a combination of folinic acid, or leucovorin, a vitamin B derivative; 5-flurouracil; irinotecan, optionally with liposomal irinotecan);
  • FOLFOX a combination of folinic acid, or leucovorin; 5- fluorouracil; oxaliplatin
  • FOLFIRINOX a combination of folinic acid, or leucovorin
  • irinotecan optionally with liposomal irinotecan; oxaliplatin
  • a calcitriol also called 1,25-dihydroxycholecalciferol
  • a ROCALTROLTM also called 1,25-dihydroxycholecalciferol
  • CALCIJEXTM CALCIJEXTM
  • DECOSTRIOLTM a tyrosine kinase inhibitor
  • the TKI comprises a sorafenib (e.g. EXAVARTM), regorafenib (e.g. STIVARGATM), levantinib (e.g., LENVIMATM), cabozanitinib (e.g., CABOMETYXTM, COMETRIQTM), ibrutinib (e.g.
  • IMBRUVICATM afatinib, axitinib, cabimetinib, crizotinib, eradafitinib, erlotinib, gefitinib, lapatinib, pazopanib, sunitinib, vandetantib, vemuraferib, apatinib, savolitinib, fruquinitinib, sulfatinib, epitinib, theliatinib, lifirafenib, zanubrutinib, ivosidenib, avapritinib, CS3006, CS3008, CS3009, CBT101, CBT102, or any combination thereof,
  • a PARP inhibitor inhibitors of the enzyme poly ADP ribose polymerase), optionally olaparib (LYNPARZATM); rucaparib (e.g., RUBRACATM); niraparib (e.g., ZEJULATM); talazoparib; fluzoparib; AZD2281 (e.g., OLAPARIBTM); ABT-888 (e.g., VELIPAPJBTM); AG014699 (e.g., RUCAPARIBTM), simmiparib, SC-10914, CEP-8983, and/or pamiparib, or any combination thereof,
  • LYNPARZATM olaparib
  • rucaparib e.g., RUBRACATM
  • niraparib e.g., ZEJULATM
  • talazoparib e.g., fluzoparib
  • AZD2281 e.g.,
  • a Programmed cell death protein 1 (PD1) inhibitor optionally a nivolumab (e.g., OPDIVOTM); pembrolizumab (e.g., KEYTRUDATM), cemiplimab, genolimzumab, dostarlimab, PDR001, AMP-224; LZM-009; BL-754091; JNJ-63723283; AJ0103;
  • a nivolumab e.g., OPDIVOTM
  • pembrolizumab e.g., KEYTRUDATM
  • cemiplimab cemiplimab
  • genolimzumab genolimzumab
  • dostarlimab PDR001, AMP-224
  • LZM-009 BL-754091
  • JNJ-63723283 AJ0103
  • a Programmed death-ligand 1 (PDL1) inhibitor optionally atezolizumab (e.g., TECENTRIQTM); avelumab (e.g., BAVENCIOTM); durvalumab (e.g., IMFINZITM); LY- 3300054;CX-072; FAZ-053; SHR-1316; TQB2450; LZM009; KL-A167; STI-A1014; AK104; HLZ-10; BGB-A333; MSB-2311; HLX-20; CSlOOl; CBT-502; KN-035; and/or WBT3155, or any combination thereof,
  • PDL1 Programmed death-ligand 1
  • atezolizumab e.g., TECENTRIQTM
  • avelumab e.g., BAVENCIOTM
  • durvalumab e.g., IMFINZITM
  • CTLA-4 inhibitor a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor
  • CTLA-4 inhibitor comprises: ipilimumab (e.g., YERVOYTM); tremelimumab; JS007; CS3002 ; and/or CBT-509, or any combination thereof,
  • a cisplatin, pemetrexed and a Programmed cell Death protein 1 (PD1) inhibitor comprises: nivolumab; pembrolizumab; cemiplimab; genolizmzumab; dostarlimab; PDR001; AMP-224; LZM-009; BL-754091; JNJ- 63723283; AJ0103; AGEN-2034; JSOOl; tislelizumab; MGA-012; GLS-010; SHR-120; CK-301; HTI-1316; JSOOl; IBI308; KN035; CS1003; CBT-501 and/or BAT- 1306, or any combination thereof, a cisplatin, a pemetrexed and a programmed death-ligand 1 (PDLl) inhibitor, and optionally the PDLl inhibitor comprises: atezolizumab, avelumab, durvalumab,
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • CTLA-4 inhibitor comprises: ipilimumab, tremelimumab, JS007, CS3002, and/or CBT-509, or any combination thereof,
  • a carboplatin, a pemetrexed and a Programmed cell Death protein 1 (PD1) inhibitor comprises: nivolumab, pembrolizumab, cemiplimab, genolizmzumab, dostarlimab, PDR001, AMP-224, LZM-009, BL-754091, JNJ-63723283, AJ0103, AGEN-2034, JS001, tislelizumab, MGA-012, GLS-010, SHR- 120, CK-301, HTI-1316, JS001, IBI308, KN035, CS1003, CBT-501 and/or BAT- 1306 a carboplatin, a pemetrexed and a programmed death-ligand 1 (PDLl) inhibitor, and optionally the PDLl inhibitor comprises: atezolizumab, avelumab, durvalumab, LY- 3300054, CX-072, F
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • CTLA-4 inhibitor comprises ipilimumab, tremelimumab, JS007, CS3002 , and/or CBT-509, or any combination thereof
  • a polymeric micelle doxorubicin and a Programmed cell Death protein 1 (PD1) inhibitor comprises: nivolumab, pembrolizumab, cemiplimab, genolizmzumab, dostarlimab, PDR001, AMP-224, LZM-009, BL-754091, JNJ-63723283, AJ0103, AGEN-2034, JS001, tislelizumab, MGA-012, GLS-010, SHR- 120, CK-301, HTI-1316, JS001, IBI308, KN035, CS1003, CBT-501 and/or BAT- 1306, or any combination thereof,
  • PD1 inhibitor comprises: nivolumab, pembrolizumab, cemiplimab, genolizmzumab, dostarlimab, PDR001, AMP-224, LZM-009, BL-754091, JNJ-63723283, AJ0
  • a polymeric micelle doxorubicin and a programmed death-ligand 1 (PDLl) inhibitor comprises: atezolizumab, avelumab, durvalumab; LY-3300054; CX-072; FAZ-053; SHR-1316; TQB2450; LZM009; KL- A167; STI-A1014; AK104; HLZ-10; BGB-A333; MSB-2311; HLX-20; CSlOOl; CBT- 502; KN-035; and/or WBT3155, or any combination thereof, a polymeric micelle doxorubicin and a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no.
  • CN 102218027 B and a Programmed cell Death protein 1 (PDl) inhibitor
  • PDl Programmed cell Death protein 1
  • the PDl inhibitor comprises: nivolumab, pembrolizumab, cemiplimab, genolizmzumab, dostarlimab, PDR001, AMP-224, LZM-009, BL-754091, JNJ-63723283, AJ0103,
  • a polymeric micelle doxorubicin and a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B) and a programmed death-ligand 1 (PDL1) inhibitor
  • the PDL1 inhibitor comprises: atezolizumab, avelumab, durvalumab, LY-3300054, CX-072, FAZ-053, SHR-1316, TQB2450, LZM009, KL-A167, STI-A1014, AK104, HLZ-10, BGB-A333, MSB-2311, HLX-20, CSlOOl, CBT-502, KN-035, and/or WBT3155, or any combination thereof,
  • the anti -microtubule agent comprises a paclitaxel (e.g. TAXOLTM or GENEXOLTM); a paclitaxel protein bound particles (e.g. ABRAXANETM); a polymeric micelle paclitaxel (GENEXOL PMTM); a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B); a liposomal paclitaxel, (e.g. LIPUSUTM); a DHP107, an oral paclitaxel and P-gp inhibitor HM30181 A (e.g.
  • ORAXOLTM a Programmed cell Death protein 1 (PDl) inhibitor
  • PDl Programmed cell Death protein 1
  • the PDl inhibitor comprises nivolumab; pembrolizumab; cemiplimab;
  • the anti -microtubule agent comprises a paclitaxel (e.g. TAXOLTM or GENEXOLTM); a paclitaxel protein bound particles (e.g. ABRAXANETM); a polymeric micelle paclitaxel (GENEXOL PMTM); a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B); a liposomal paclitaxel, (e.g. LIPUSUTM); a DHP107, an oral paclitaxel and P-gp inhibitor HM30181 A (e.g.
  • PDL1 inhibitor comprises atezolizumab; avelumab; durvalumab; LY-3300054; CX-072; FAZ-053; SHR-1316; TQB2450; LZM009; KL-A167; STI-A1014; AK104; HLZ-10; BGB-A333; MSB-2311; HLX-20; CSlOOl; CBT-502; KN-035; and/or WBT3155, or any combination thereof,
  • an anti-microtubule agent wherein optionally the anti -microtubule agent comprises a paclitaxel (e.g. TAXOLTM or GENEXOLTM); a paclitaxel protein bound particles (e.g. ABRAXANETM); a polymeric micelle paclitaxel (GENEXOL PMTM); a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B); a liposomal paclitaxel, (e.g. LIPUSUTM), a DHP107, an oral paclitaxel and P-gp inhibitor HM30181 A (e.g.
  • a paclitaxel e.g. TAXOLTM or GENEXOLTM
  • a paclitaxel protein bound particles e.g. ABRAXANETM
  • GENEXANETM paclitaxel protein bound particles
  • CTLA-4 cytotoxic T-lymphocyte-associated protein 4
  • CTLA-4 inhibitor comprises ipilimumab; tremelimumab; JS007; CS3002 ; and/or CBT-509, or any combination thereof
  • the anti-microtubule agent comprises a paclitaxel (e.g. TAXOLTM or GENEXOLTM); a paclitaxel protein bound particles (e.g. ABRAXANETM); a polymeric micelle paclitaxel (GENEXOL PMTM); a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B); a liposomal paclitaxel, (e.g.
  • the alkylating agent comprises a cisplatin, a carboplatin; oxaliplatin; a NC-6004, an oxaliplatin; and, a Programmed cell Death protein 1 (PD1) inhibitor, wherein optionally the PD1 inhibitor comprises nivolumab; embrolizumab; cemiplimab; genolizmzumab; dostarlimab; PDR001; AMP- 224; LZM-009; BL-754091; JNJ-63723283; AJ0103; AGEN-2034; JS001; tislelizumab; MGA-012; GLS-010; SHR-120; CK-301; HTI-1316; JS001; IBI308; KN035; CS1003; CBT-501 and/or BAT-1306, or any combination thereof,
  • PD1 inhibitor comprises nivolumab; embrolizumab; cemiplimab; geno
  • an anti-microtubule agent wherein optionally the anti-microtubule agent comprises a paclitaxel (e.g. TAXOLTM or GENEXOLTM); a paclitaxel protein bound particles (e.g. ABRAXANETM), or any combination thereof; a polymeric micelle paclitaxel (GENEXOL PMTM); a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd (as described, e.g., in China patent no. CN 102218027 B); a liposomal paclitaxel, (e.g.
  • LIPUSUTM alkylating agents
  • alkylating agents optionally, a cisplatin; or optionally a carboplatin; oxaliplatin; a NC-6004; an oxaliplatin; and a programmed death-ligand 1 (PDL1) inhibitor
  • PDL1 inhibitor comprises atezolizumab; avelumab; durvalumab; LY-3300054; CX-072; FAZ-053; SHR-1316; TQB2450; LZM009; KL-A167; STI-A1014; AK104; HLZ-10; BGB-A333; MSB-2311; HLX-20; CSIOOI; CBT-502; KN-035; and/or WBT3155, or any combination thereof, an anti-microtubule agent, wherein optionally the anti -microtubule agent comprises a paclitaxel (e.g.
  • TAXOLTM or GE EXOLTM a paclitaxel protein bound particles
  • a paclitaxel protein bound particles e.g. ABRAXA ETM
  • a polymeric micelle paclitaxel GENEXOL PMTM
  • a polymeric micelle paclitaxel manufactured by Shanghai Yizhong Biotechnology Co., Ltd as described, e.g., in China patent no. CN 102218027 B
  • a liposomal paclitaxel e.g.
  • the alkylating agent comprises a cisplatin,, a carboplatin, oxaliplatin, a NC-6004, an oxaliplatin; and, a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor, wherein optionally the CTLA-4 inhibitor comprises ipilimumab; tremelimumab; JS007; CS3002 ; and/or CBT-509, or any combination thereof,
  • CTLA-4 inhibitor comprises ipilimumab; tremelimumab; JS007; CS3002 ; and/or CBT-509, or any combination thereof
  • a treatment or amelioration for a neuroendocrine tumor or a carcinoid or a side effect caused by the carcinoid or neuroendocrine tumor optionally, a drug that is an analog of somatostatin such as e.g., the peptide H-D-2Nal-Cys(l)-Tyr-D-Trp-Lys-Val- Cys(l)-Thr-NH2, or lanreotide or lanreotide acetate or lanreotide SR (e.g.,
  • SOMATULINETM manufactured e.g., by Ipsen (Paris, France); or, octreotide (e.g., SANDOSTATINTM) or octreotide acetate LAR (SANDOSTATIN LARTM, Novartis Pharma AG), or any combination thereof;
  • cancer drug or a cancer adjunctive or as a drug or
  • support therapy is formulated with the first formulation and/or the second formulation, or the cancer drug or a cancer adjunctive or (as a drug or
  • the cancer drug or a cancer adjunctive or (as a drug or pharmaceutical) support therapy is separately formulated, for example, the cancer drug or a cancer adjunctive or (as a drug or pharmaceutical) support therapy is formulated in the form of a tablet, pill, geltab, capsule and the like which is placed or inserted in the same compartment on a blister card, clamshell or tray or equivalent with one or more tablets, pills, geltabs, capsules and the like comprising a first formulation and/or second formulation as provided herein, wherein all tablets, pills, geltabs, capsules and the like in the same compartment are to be taken at the same time by the user, e.g., a patient.
  • cancer or tumor or dysfunctional cell condition(s) is or are: neuroendocrine tumors, cancers of the endocrine system, and pancreatic cancer, including gastroenteropancreatic neuroendocrine tumors (GEP- ET), pancreatic neuroendocrine tumors (Pan ETs), islet cell tumors or non-islet hypoglycemic cell tumor, intestinal endocrine tumors, carcinoids, adenocarcinoma pancreatic tumors, pheochromocytoma (PCC) or cancer of the adrenal gland, or cancer of the medulla of the adrenal glands, paraganglioma or chemodectoma, a gastrinoma (a gastrin secreting tumor), primary neuroendocrine carcinoma of the skin; hepatocellular carcinoma and liver cancers; brain and nerve cell cancers
  • GEP- ET gastroenteropancreatic neuroendocrine tumors
  • Pancreatic neuroendocrine tumors Pancreatic neuroendocrine tumors
  • osteosarcoma including bone and soft tissue sarcomas, chondrosarcoma, liposarcoma, rhabdomyosarcoma, Kaposi's sarcoma, desmoid tumor, epithelioid sarcoma, lymphangiosarcoma, and lymphosarcoma; familial adenomatous polyposis; lung cancers including small cell lung cancer and non-small cell lung cancer; skin cancer and melanomas, including cutaneous or intraocular melanoma, merkel-cell carcinoma (MCC); cancers of the head and neck; uterine cancer; rectal and colorectal cancer, including colon cancer and cancer of the anal region; stomach cancer; breast cancer; carcinoma of the fallopian tubes; carcinoma of the endometrium; carcinoma of the cervix; carcinoma of the vagina; carcinoma of the vulva; lymphomas, including chronic or acute leukemia, lymphocytic lymphomas, Hodgkin's
  • FIG. 1 graphically illustrates the concept of an inverted dose response, as discussed in further detail, below.
  • FIG. 2 schematically illustrates an exemplary drug delivery device, blister package, clamshell or tray as provided herein, as discussed in further detail, below.
  • FIG. 3 and FIG. 4 schematically illustrate a randomized, double-blind, placebo- controlled two-staged study using the exemplary therapeutic combination VT-1 ICR with GemNab for untreated, metastatic pancreatic cancer, as described in detail in Example 2, below.
  • FIG. 5 graphically illustrates overall survival of GemNab ⁇ propranolol and etodolac in patients with locally advanced / metastatic pancreatic cancer in the studies illustrated in FIG. 3 and FIG. 4, as described in detail in Example 2, below.
  • FIG. 6 schematically illustrates a two-staged study using the exemplary therapeutic combination VT-1 ICR with paclitaxel and gemcitabine for metastatic adenocarcinoma, as described in detail in Example 2, below.
  • FIG. 7 graphically illustrates data demonstrating that propranolol and/or etodolac show inverted dose responses in immunocompetent animal models B16F10 melanoma in mice (for a propranolol study) (graph on left) and hepatocellular carcinoma (HCC) in Shionogi mice (for etodolac) (right graph).
  • FIG. 8, FIG. 9, FIG. 10 and FIG. 11 graphically illustrate dissolution profiles of propranolol (individual product) at 5°C / ambient RH, 25°C / 60% RH, 30 °C / 65% RH and 40°C /75% RH (relative humidity), as described in detail in Example 3, below.
  • FIG. 13, FIG. 14, FIG. 15 and FIG. 16 graphically illustrate dissolution profiles of propranolol (solid lines) and etodolac (dashed lines) at 5 °C / ambient RH, 25 °C / 60% RH, 30 °C / 65% RH and 40 °C / 75% RH, as described in detail in Example 3, below.
  • FIG. 18 illustrates in tabular form the dissolution profile of Propranolol HC1, 16 mg IR and 16 mg DR, in combination with Etodolac 70 mg - specifically observing the 240 minutes - 360 minutes on stability up to 6 months.
  • FIG. 19 schematically illustrates an exemplary universal multi-drug delivery system as provided herein, where a week of pharmaceutical dosage forms are stored on four rows, two rows for administration for morning or breakfast, or AM administration, and two rows are for evening, dinnertime or PM administration, as discussed in detail, below.
  • 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.
  • a beta adrenergic receptor antagonist a "beta blocker”
  • a non-steroidal anti-inflammatory drug a NSAID
  • compositions, formulations, kits and devices as provided herein are designed to exploit an inverted dose response, as illustrated in FIG. 1, using: a fixed dose combination capsule; delayed or controlled release (DR) microparticles or microbeads (e.g., as in Level 1 VT-1 ICR AM or which comprises a formulation of polysaccharide microbeads or microparticles coated with propranolol and EUDRAGIT® polymer and etodolac power with excipients (see Table 1, below); and, as in Level 2 VT-1 ICR PM capsules which is comprised of a formulation of etodolac (as the only active ingredient, i.e., no propranolol) and excipients as listed in Table 2, below); low non-standard dose strengths; optimized non-standard timing, with propranolol (e.g., INDERALTM) in the daytime (e.g., in the morning, at breakfast or afternoon) only, and optionally also with etodolac
  • compositions, formulations and kits as provided herein comprise an easy to use blister card with a seven day supply, with a spare, of propranolol (including e.g., a racemic R(+) and S(-) mixture of propranolol, a substantially pure (S)-enantiomer of propranolol, or a pharmaceutically acceptable salt thereof, or mixtures thereof) and etodolac (including e.g., a racemic R(+) and S(-) mixture of etodolac, a substantially pure (S)-enantiomer of etodolac, or a pharmaceutically acceptable salt thereof, or mixtures thereof), e.g., as illustrated in FIG. 2, wherein:
  • the packaging of the therapeutic combinations, pharmaceutical compositions, formulations for morning (or AM) administration include: one, two or three (or more) tablets, pills, capsules, geltabs or equivalents comprising: immediate release
  • IR propranolol powder, particles or equivalent IR formulation
  • DR delayed (or controlled) release propranolol particles or equivalent DR formulation, and IR etodolac powder, particles or equivalent IR formulation
  • each morning (or AM) administration is contained in one compartment of a blister card or equivalent, and arranged on the blister card or equivalent as an AM dosage, versus an evening dose;
  • compositions, formulations for evening or bed-time (e.g., dinnertime or PM) administration include: one, two or three (or more) tablets, pills, capsules, geltabs or equivalents comprising IR etodolac powder, particles or equivalent IR formulation, wherein optionally each evening or bed-time (e.g., dinnertime or PM) administration is contained in one compartment of a blister card or equivalent, and arranged on the blister card or equivalent as a PM dosage, versus an AM dose.
  • the therapeutic combination, pharmaceutical composition, formulation and kits as provided herein are packaged in easy to use "titration packages", such as blister cards or equivalents, having one, two or three (or more) tablets, pills, capsules, geltabs or equivalents in the morning (or AM), and one, two or three (or more) tablets, pills, capsules, geltabs or equivalents in the evening or bedtime (or dinnertime or PM).
  • titration packages such as blister cards or equivalents, having one, two or three (or more) tablets, pills, capsules, geltabs or equivalents in the morning (or AM), and one, two or three (or more) tablets, pills, capsules, geltabs or equivalents in the evening or bedtime (or dinnertime or PM).
  • the therapeutic combination comprises:
  • a low dose of one, two or three (or more) tablets, pills, capsules, geltabs or equivalents for administration in the morning, or breakfast or AM that comprises: about 4 to 32, 8 to 24, 12 to 20, 14 to 18 or 15 to 17 mg of IR propranolol hydrochloride; about 4 to 32, 8 to 24, 12 to 20, 14 to 18 or 15 to 17 mg of DR propranolol hydrochloride; and about 0 to 180, 40 to 120, 60 to 100, 65 to 80 mg IR etodolac, or
  • a high dose of one, two or three (or more) tablets, pills, capsules, geltabs or equivalents for administration in the morning, or breakfast or AM that comprises: about 8 to 64, 16 to 48, 24 to 40, 28 to 36 or 30 to 34 mg of IR propranolol hydrochloride; about 8 to 64, 16 to 48, 24 to 40, 28 to 36 or 30 to 34 mg of DR propranolol hydrochloride; and about 0 to 360, 80 to 240, 120 to 200, 130 to 160 mg IR etodolac,
  • IR and DR propranolol e.g., 16 mg IR and 16 mg DR propranolol;
  • - one tablet, pill, capsule or equivalent for administration in the evening or bedtime having between about 200 and 400 mg, between about 250 and 300 mg, about 270 mg, or about 340 mg, IR etodolac, wherein in one embodiment the evening or bedtime IR 270 mg formulation of etodolac is designated "VT- 11CR PM");
  • the therapeutic combination is designated "Level 1 VT-1 ICR AM” (for example, see Example 1, below, where "low dose cards” comprise a one morning (AM) blister strip containing 8 VT-1 ICR capsules and one evening (PM) blister strip containing 8 etodolac capsules);
  • the therapeutic combination is designated "Level 2 VT-1 ICR AM" (for example, see Example 1, below, where "high dose cards” are comprised of two morning (AM) blister strips containing a total of 16 VT-1 ICR capsules and two evening (PM) blister strips containing a total of 16 etodolac capsules).
  • the therapeutic combination comprises:
  • - one tablet, pill, capsule or equivalent for administration in the morning, or AM that comprises: about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg of IR propranolol hydrochloride; about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 mg of DR propranolol (e.g., propranolol hydrochloride), and optionally the morning tablet has approximately equal amounts of IR and DR propranolol, e.g., 16 mg IR and 16 mg DR propranolol (e.g., propranolol hydrochloride);
  • one tablet, pill, capsule or equivalent for administration in the afternoon or evening having between about 200 and 400 mg, between about 250 and 300 mg, about 270 mg, or about 340 mg, IR etodolac;
  • the therapeutic combination comprises dose ranges and percent release splits comprise release profiles, where for propranolol: 35% to 60% of the administered dosage is released in the morning (AM) and 40% to 65% is released in the afternoon; and for etodolac, 0 to 30% of the administered dosage is released in the morning (AM) and 70% to 100% is released in the afternoon or evening (PM).
  • the therapeutic combination comprises dosage amounts that target release of high amounts of propranolol in the AM, e.g., 64 mg propranolol and release of high amounts of etodolac in the PM, e.g., 680 mg etodolac.
  • the therapeutic combination comprises dosage amounts that target release of, or administration of, 32 mg propranolol in the AM and 340 mg etodolac in the PM. In alternative embodiments, the therapeutic combination comprises dosage amounts that target release of, or administration of, 32 mg propranolol in the AM and 680 mg etodolac in the PM. In alternative embodiments, the therapeutic combination comprises dosage amounts that target release of, or administration of, 64 mg propranolol in the AM and 340 mg etodolac in the PM. In alternative embodiments, equal amounts IR and DR are administered.
  • the therapeutic combination comprises dosage amounts that include a higher dose range for propranolol, e.g., a total of between about 80 and 110 mg, or about 96 mg (e.g., equal amounts IR and DR) administered in the AM (or breakfast, or afternoon).
  • a higher dose range for propranolol e.g., a total of between about 80 and 110 mg, or about 96 mg (e.g., equal amounts IR and DR) administered in the AM (or breakfast, or afternoon).
  • the therapeutic combination comprises a substantially pure (S)-enantiomer (versus a racemic mixture) of propranolol, and in these embodiments dosages of propranolol is lowered by as much as half, or less.
  • dosages of propranolol is lowered by as much as half, or less.
  • the therapeutic combination comprises a substantially pure (S)-enantiomer (versus a racemic mixture) of etodolac, and in these embodiments dosages of propranolol can be lowered by as much as half, or less.
  • the therapeutic combination comprises dosage amounts that target release of, or administration of about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 total mg propranolol (including e.g., equal amounts of IR and DR formulations) in the AM, and etodolac in the PM.
  • the therapeutic combination comprises dosage amounts that target release of, or
  • administration of etodolac is halved to about 10 to 100 mg of IR etodolac in the AM and between about 200 to 300 mg IR etodolac in the PM, or evening or dinnertime.
  • equal amounts IR and DR propranolol are administered.
  • low dosage administration of propranolol and/or etodolac take advantage of their inverted dose-responses to maximize efficacy and safety, as graphically illustrated e.g., in FIG.
  • the therapeutic combination comprises another beta blocker at the same effective dosage in place of propranolol, or comprises another beta blocker in combination with propranolol adding up the same effective dosage as the exemplary formulations provided herein.
  • the other or additional beta blocker comprises for example: timolol (e.g., BETEVIOLTM), bupranolol, nadolol (e.g., CORGARDTM), or, the other or additional beta blocker comprises a selective adrenergic beta-2 receptor inhibitor such as butoxumine or 3-(isopropylamino)- l-[(7-methyl-4-indanyl)oxy]butan-2-ol (also called ICI-118,551).
  • the therapeutic combination comprises in place of etodolac another NSAID or another coxib at the same or equivalent dosage, or comprises another NSAID or another coxib in combination with etodolac adding up the same effective dosage as the exemplary formulations provided herein.
  • the other or additional NSAID or coxib comprises for example: imrecoxib; apricoxib; nimesulide; diclofenac (e.g., CATAFLAMTM, VOLTARENTM); sulindac (e.g., CLINORILTM); meloxicam (e.g., MOBICTM, METACAMTM), polmacoxib or
  • CG100649 e.g., ACELEXTM
  • a microsomal PGE-2 synthase inhibitor such as e.g., NX-580, and the like.
  • a rational for the exemplary propranolol and etodolac therapeutic combinations as provided herein is driven by the recent advances in understanding the tumor biology including the macrophage contribution to the inflammatory component which promotes tumor growth, metastases, immune evasion and a negative impact on Natural Killer (NK) cell and T- lymphocyte (e.g., CTLs) anti-tumor functions.
  • NK Natural Killer
  • T- lymphocyte e.g., CTLs
  • Ml macrophages inhibit cancer growth and metastasis, stimulate immune function, co-ordinate the anti -cancer Thl response and inhibit angiogenesis; while the M2 macrophages can suppress immune function, promote cancer growth and the Th2 inflammatory response and support angiogenesis.
  • the therapeutic combination comprises the "VT-1 ICR drug product", which consists of two individual dosage forms: a VT-1 ICR AM capsule and a VT-1 ICR PM capsule.
  • a VT-1 ICR AM capsule for oral administration combines two active ingredients: propranolol hydrochloride, a beta- adrenergic blocking agent, and etodolac, a NSAID.
  • the VT-1 ICR AM capsule, 32/70 mg contains 32 mg propranolol hydrochloride (as 16 mg immediate release (IR) beads and 16 mg delayed (or controlled) release (DR) beads), and 70 mg etodolac immediate release (IR) drug product.
  • the VT-1 ICR PM capsule for oral administration contains one active ingredient: etodolac.
  • the quantitative composition of a VT-1 ICR AM capsule is presented in Table 1.
  • the film coating agent used in manufacture of propranolol HC1 IR beads is OPADRY CLEARTM (Colorcon, Inc., Harleysville, PA).
  • novel formulations and dosaging regiments that solve existing problems when using the therapeutic combination of coxibs and beta blockers, for example: these problems can comprise side effects that limit the ability to chronodose the co-administration of beta blockers and coxibs; the complexity of the titration of individual pills needed to determine a tolerable dose limits their use and efficacy; and, it is difficult to get patients to comply or adhere to a TDD (three times a day) or more dosing regimen.
  • NSCLC non-small-cell-lung cancer
  • NCT00527319 etodolac and propranolol
  • Propranolol 20 mg in AM and 20 mg in afternoon increased to 40 mg AM and 40 mg in afternoon based on heart rate change.
  • Etodolac at 600 mg in PM and dose titrated down if GI discomfort to 400 mg in PM or increased to 200 mg in AM and 600mg PM if pain exists in AM:
  • the treatment group showed an 8.3 increase in overall survival versus control and the survival benefit was consistent across subpopulations of patients.
  • VT-1 ICR propranolol 64 mg/pilot study maximum 80mg 20% difference
  • VT-1 ICR etodolac 340mg vs pilot study of 400mg 15% difference
  • VT-12CR etodolac 680mg vs pilot study maximum 800mg 15% difference
  • VT-1 ICR dosage amounts and release profiles are predicted to offer equal or greater safety and efficacy than Bhattacharyya 2015 based on in vitro dissolution, in vitro in vivo correlations and comparison by pharmacokinetic simulations.
  • VT-1 ICR's propranolol and etodolac have similar "drug-free" intervals (below an active concentration) compared to Bhattacharyya 2015.
  • the VT-1 ICR's etodolac has C ma x, and t ma x within 80% to 125% of the Bhattacharyya 2015.
  • VT-1 ICR propranolol AM releases occur in one hour and the afternoon release occurs over three hours.
  • Bhattaryya 2015 propanolol AM release occurs within 1 ⁇ 4 hour of administration.
  • VT-1 ICR dosing has lower Cmax and delayed tmax that minimizes the hypotensive risks compared to a spike in beta adrenergic blockade from immediate release propranolol.
  • the VT-1 ICR dosing initiates all patients at Level 1 (low dosage) of propranolol and etodolac and then escalates all patients to Level 2 (high dosage) of propranolol and etodolac.
  • Level 1 low dosage
  • Level 2 high dosage
  • the VT1 ICR dose escalation algorithm enables most patients to benefit from high dosage of propranolol and etodolac (e.g., 66 mg propranolol and 680 mg etodolac).
  • only 30% (6 of 20) patients in Bhattacharyya 2015 benefited from a dosages greater than 40 mg propranolol and 600 mg etodolac.
  • VT-1 ICR Dosing Regimen level 1 and Level 2
  • VT-1 ICR improves titration by reducing the titration complexity from five to only two options and improves the ease of adherence by reducing dose frequency from three (TID) (including a difficult to adhere afternoon dose) to two (BID) doses per day, e.g., as depicted below:
  • one tablet, pill, capsule or equivalent is formulated designated (e.g., packaged) for administration in the morning, or AM, and comprises a total dosage of: 16 mg of IR propranolol hydrochloride; 16 mg of DR propranolol hydrochloride; and 70 mg IR etodolac, the therapeutic combination is designated "Level 1 VT-1 ICR AM” (for example, see Example 1, below, where "low dose cards” comprise a one morning (AM) blister strip containing 8 VT-1 ICR capsules and one evening (PM) blister strip containing 8 etodolac capsules).
  • AM one morning
  • PM evening
  • one or two tablet(s), pill(s), capsule(s) or equivalent is/are formulated or designated (e.g., packaged) for administration in the morning, or AM, and comprise a total dosage of: 32 mg of IR propranolol hydrochloride; 32 mg of DR propranolol hydrochloride; and 140 mg IR etodolac, the therapeutic combination is designated "Level 2 VT-1 ICR AM” (for example, see Example 1, below, where "high dose cards” are comprised of two morning (AM) blister strips containing a total of 16 VT-1 ICR capsules and two evening (PM) blister strips containing a total of 16 etodolac capsules).
  • one tablet, pill, capsule or equivalent is formulated or designated (e.g., packaged) for administration in the evening or bedtime (e.g., PM) having between about 200 and 400 mg, between about 250 and 300 mg, about 270 mg, or about 340 mg, IR etodolac, wherein in one embodiment the evening or bedtime IR 270 mg formulation of etodolac is designated "VT-1 ICR PM").
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein are used for primary or supportive treatment of a cancer, wherein the treatment of a cancer can be a drug treatment or other therapy such as radiotherapy or a surgery.
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein are administered before, during and/or after the cancer treatment, e.g., the drug treatment, surgery and/or radiotherapy.
  • 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) dysfunctional cell conditions, cancer stem cells or cancer cells from: neuroendocrine tumors, cancers of the endocrine system, and pancreatic cancer, including
  • gastroenteropancreatic neuroendocrine tumors GEP- ET
  • pancreatic neuroendocrine tumors Pan ETs
  • islet cell tumors or non-islet hypoglycemic cell tumor intestinal endocrine tumors, carcinoids, adenocarcinoma pancreatic tumors, pheochromocytoma (PCC) or cancer of the adrenal gland, or cancer of the medulla of the adrenal glands, paraganglioma or chemodectoma, a gastrinoma (a gastrin secreting tumor), primary neuroendocrine carcinoma of the skin; hepatocellular carcinoma and liver cancers; brain and nerve cell cancers including neuroblastomas, brain stem glioma and glioblastoma multiforme; ovarian cancer; angiosarcoma; bone cancer and osteosarcoma; sarcomas, including bone and soft tissue sarcomas, chondrosarcoma, liposarcoma,
  • rhabdomyosarcoma Kaposi's sarcoma, desmoid tumor, epithelioid sarcoma,
  • iymphangiosarcoma, and lymphosarcoma fami lial adenomatous polyposis
  • lung cancers including small cell lung cancer and non-small cell lung cancer
  • skin cancer and melanomas including cutaneous or intraocular melanoma, merkel-cell carcinoma (MCC); cancers of the head and neck; uterine cancer; rectal and colorectal cancer, including colon cancer and cancer of the anal region; stomach cancer; breast cancer; carcinoma of the fallopian tubes; carcinoma of the endometrium; carcinoma of the cervix; carcinoma of the vagina; carcinoma of the vulva
  • lymphomas including chronic or acute leukemia, lymphocytic lymphomas, Hodgkin's Disease, primary CNS lymphoma; cancer of the esophagus; cancer of the small intestine; cancer of the thyroid gland or parathyroid gland, medullary thyroid cancer (MTC) or cancer of the parafollicular cells (C cells); cancer of the urethr
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein are administered before, during or after a therapeutic administration of a dysfunctional cell condition therapy, or another cancer drug or a cancer adjunctive or support therapy.
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: calcitriol (also called 1,25- dihydroxycholecalciferol), or ROCALTROLTM, CALCUEXTM, or DECOSTRIOLTM.
  • calcitriol also called 1,25- dihydroxycholecalciferol
  • ROCALTROLTM also called 1,25- dihydroxycholecalciferol
  • CALCUEXTM also called DECOSTRIOLTM.
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: a gemcitabine-based therapy, e.g., gemcitabine (e.g., GEMZARTM) alone; gemcitabine and paclitaxel; gemcitabine, paclitaxel and platinum; gemcitabine and lipo-platinum (e.g., NC-6004, a micellar nanoparticle product of cisplatin); gemcitabine and capecitabine; gemcitabine and SI (SI is the combination drug tegafur/ gimeracil/ oteracil, trade name TEYSUNOTM); and/or, a nucleoside analog of gemcitabine such as NUC-1031 (ACELARIN®).
  • a gemcitabine-based therapy e.g., gemcitabine (e.g., GEMZARTM) alone; gemcitabine and paclitaxel; gemcitabine, paclitaxel and platinum; gem
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: e.g., a 5-flurouracil (5-FU) based therapy, e.g., capecitabine (e.g., XELODATM) alone; "FOLFIRT' treatment (a combination of folinic acid, or leucovorin, a vitamin B derivative; 5-flurouracil; and, irinotecan (e.g., CAMPTOSARTM), a topoisomerase inhibitor), optionally with liposomal irinotecan (e.g., ONIVYDETM); "FOLFOX” treatment (a combination of folinic acid, or leucovorin, a vitamin B derivative; 5-flurouracil; and, oxaliplatin (e.g., ELOXATINTM); "FOLFIRINOX” treatment (a combination of folinic acid, or leucovorin
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: a tyrosine kinase inhibitor (TKI) such as sorafenib (e.g. NEXAVARTM), regorafenib (e.g. STIVARGATM), levantinib (e.g., LENVIMATM), cabozanitinib (e.g., CABOMETYXTM, COMETRIQTM), ibrutinib (e.g. FMBRUVICATM), apatinibi and/or BGB-3111.
  • TKI tyrosine kinase inhibitor
  • sorafenib e.g. NEXAVARTM
  • regorafenib e.g. STIVARGATM
  • levantinib e.g., LENVIMATM
  • cabozanitinib e.g., CABOMET
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: a PARP inhibitors (inhibitors of the enzyme poly ADP ribose polymerase), e.g., olaparib (LYNPARZATM); rucaparib (e.g., RUBRACATM); niraparib (e.g., ZEJULATM); talazoparib; fluzoparib; AZD2281 (e.g., OLAPARIBTM); ABT-888 (e.g., VELIPARIBTM); AG014699 (e.g.,
  • a PARP inhibitors inhibitors of the enzyme poly ADP ribose polymerase
  • LYNPARZATM olaparib
  • rucaparib e.g., RUBRACATM
  • niraparib e.g., ZEJULATM
  • talazoparib
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: a Programmed cell Death protein 1 (PD1) inhibitor, e.g., nivolumab (e.g., OPDIVOTM); pembrolizumab (e.g., KEYTRUDATM); avelumab (e.g., BAVENCIOTM); durvalumab (e.g., IMFINZITM);
  • PD1 inhibitor e.g., nivolumab (e.g., OPDIVOTM); pembrolizumab (e.g., KEYTRUDATM); avelumab (e.g., BAVENCIOTM); durvalumab (e.g., IMFINZITM);
  • PD1 inhibitor e.g., nivolumab (e.g., OPDIVOTM)
  • pembrolizumab
  • Atezolizumab e.g., TECENTRIQTM
  • BGB-A317 MGA012; GLS-010; SHR-120; CK- 301 and/or HTI-1316.
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: a programmed death-ligand 1 (PDL1) inhibitor, e.g., atezolizumab (e.g., TECENTRIQTM); avelumab (e.g.,
  • durvalumab e.g., IMFINZITM
  • HTI-1316 HTI-1316
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: a drug that inhibits cytotoxic T- lymphocyte-associated protein 4 (CTLA-4), e.g., ipilimumab (e.g., YERVOYTM) or tremelimumab.
  • CTLA-4 cytotoxic T- lymphocyte-associated protein 4
  • ipilimumab e.g., YERVOYTM
  • tremelimumab e.g., tremelimumab.
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: an "immuno-oncology" therapy, including e.g., treatment for an oncolytic virus, or an autologous formula fixed tissue vaccine, or immune checkpoint inhibitors such as e.g., ipilimumab; tremelimumab; and/or nivolumab (e.g., OPDIVOTM).
  • an "immuno-oncology" therapy including e.g., treatment for an oncolytic virus, or an autologous formula fixed tissue vaccine, or immune checkpoint inhibitors such as e.g., ipilimumab; tremelimumab; and/or nivolumab (e.g., OPDIVOTM).
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises: a treatment or amelioration for a neuroendocrine tumor or a carcinoid or a side effect caused by the carcinoid or neuroendocrine tumor; for example, a drug that is an analog of somatostatin such as e.g., the peptide H-D-2Nal-Cys(l)-Tyr-D-Trp-Lys-Val-Cys(l)-Thr-NH2, or lanreotide or lanreotide acetate or lanreotide SR (e.g., SOMATULINETM), manufactured e.g., by Ipsen (Paris, France); or, octreotide (e.g., SANDOSTATINTM) or octreotide acetate LAR (SANDOSTATIN LARTM, Novartis Pharma AG).
  • compositions, formulations and kits as provided herein are used with protein-bound paclitaxel and gemcitabine for the treatment of a metastatic pancreatic cancer.
  • patients before administration of therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein, patients are provided a run-in period to stabilize patients with substantial and pre-emptive supportive care, and then to continue substantial and pre-emptive supportive care after treatment for e.g., dysfunctional cell conditions or cancers (e.g., with therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein).
  • pre-emptive support care comprises use of anti- thrombic therapy, stents (e.g., when at risk of obstruction), and drugs such as granulocyte- colony stimulating factor (G-CSF or GCSF, also known as colony-stimulating factor 3, or CSF 3); and others are used in response to deficiencies and/or for symptoms as they arise.
  • stents e.g., when at risk of obstruction
  • drugs such as granulocyte- colony stimulating factor (G-CSF or GCSF, also known as colony-stimulating factor 3, or CSF 3); and others are used in response to deficiencies and/or for symptoms as they arise.
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprises, or the cancer drug or a cancer adjunctive or support therapy comprises, or the pre-emptive support care or post-treatment support care comprises:
  • LMWH low molecular weight heparin
  • direct factor Xa inhibitors such as e.g., rivaroxaban
  • XARELTOTM apixaban
  • ELIQUISTM dabigatran etexilate
  • GCSF e.g., immediately after chemo to prevent neutropenia
  • Vitamin D e.g., administered as an injection
  • Diabetes management e.g., metformin, GLUCOPHAGETM, insulin, and/or
  • LANTUSTM often associated with pancreas cancer due to pancreas endocrine organ failure/type 3 diabetes, and/ or general diabetes control;
  • - Biliary stents e.g., metal coated
  • - H2 antagonists for GI bleeding e.g., famotidine, PEPCIDTM
  • this can synergize with administrations of an exemplary drug combination as provided herein, e.g., VT-11CR;
  • VT-1 ICR VT-1 ICR
  • the therapeutic combinations, pharmaceutical compositions, formulations and kits as provided herein further comprise, or the cancer drug or a cancer adjunctive or support therapy comprises (or comprises use of):
  • LAG Lymphocyte- Activation Gene
  • LAG-3 Lymphocyte- Activation Gene 3
  • the LAG or LAG-3 modulator comprises:
  • Eftilagimod Alpha or LAG-3 Ig or IMP 321) (Prima BioMed Ltd, Australia)
  • LAG525 (Novartis), optionally in combination with PDR001, an anti-PD-1 monoclonal antibody,
  • Relatlimab (or BMS-986016) (Bristol-Myers Squibb), a LAG inhibitor,
  • GSK2831781 (GlaxoSmithKline (GSK)
  • GSK GlaxoSmithKline
  • MGD013 MicroGenics
  • 3 ⁇ 4G4K bispecific antibody that binds PD-1 and LAG-3 concomitantly or independently
  • REGN3767 (Regeneron Pharmaceuticals), optionally with REGN2810 (Anti- PD1), and/or
  • TSR-033 (Tesaro, Inc.), an anti-LAG-3 Monoclonal Antibody, optionally in combination with an anti-PD-1 molecule or antibody;
  • an IL-10 optionally a recombinant IL-10, optionally pegilodecakin (or AMOOIO) (ARMO Biosciences) (an IL-10 linked to polyethylene glycol (PEG), or PEG-IL-10), and optionally in combination with folinic acid, 5-fluorouracil, and/or oxaliplatin; - an IL-2 or analog thereof, optionally an IL-2 receptor agonist, or an interferon (IFN), and optionally the interferon is an alpha-IFN or a gamma-IFN; and optionally the IL-2 or analog thereof or IL-2 receptor agonist is a recombinant IL-2, an aldesleukin or a PROLEUKIN® (made by genetically engineered E.
  • coli strain containing an analog of the human interleukin-2 gene (Prometheus Laboratories), wherein 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, and optionally the IL-2 or analog thereof or IL-2 receptor agonist is NKTR-214 (Nectar), a CD122-biased agonist designed to stimulate the patient's own immune system;
  • NKTR-222 an IL-15 or analog thereof, optionally NKTR-222 (Nektar);
  • T-cell immunoglobulin and mucin-domain containing-3 (“TIM-3") antagonist
  • TIM-3 a T-cell immunoglobulin and mucin-domain containing-3
  • belizatinib or TSR-011 an orally available inhibitor of both the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) and the tropomyosin-related kinases (TRK) TRKA, TRKB, and TRKC
  • ALK receptor tyrosine kinase anaplastic lymphoma kinase
  • TRK tropomyosin-related kinases
  • MBG453 Novartis
  • Tim- 3 is an immune checkpoint, or protein that ensures that the immune system does not mistakenly attack healthy cells
  • an oncolytic virus optionally a genetically oncolytic virus, for example:
  • a genetically engineered herpes virus optionally talimogene laherparepvec, or T-VECTM, or FMLYGICTM, or ONCOVEXTM, or RP1, RP2 or RP3 (Replimune);
  • vaccinia virus • a genetically engineered vaccinia virus, optionally PEXA-VECTM; or
  • PRRs pattern recognition receptors
  • NLRs NOD-like receptors
  • RIG-I-like receptors RLRs
  • CLRs C-type lectin receptors
  • CDSs cytosolic sdDNA sensors
  • TLRs Toll-like receptors
  • provided herein are therapeutic combinations of drugs, pharmaceutical compositions, preparations and kits, that can be administered by several routes, for formulated for administration by any of 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.
  • 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.
  • the package, kit or container comprises a "blister package” (also called a blister pack, or bubble pack).
  • a "blister package” also called a blister pack, or bubble pack.
  • the blister package is made up of two separate elements: a transparent or occlusive plastic cavity shaped to the product and its blister foil backing. These two elements are then sealed together into a blister strip of one or more blister with each blister an environmentally (e.g. moisture, pathogen, light) protected unit dose.
  • One or more blister strips can be further joined with board material which allows the product to be package, handled, hung, displayed or shipped without damaging the blister seal and provided child resistant features.
  • 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 (the multi-ingredient combination of drugs as provided herein) combination of active ingredients) 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 molded PVC base, with raised areas (the "blisters") to contain the tablets, pills, etc.
  • a specialized form of a blister pack is a strip pack.
  • blister packs adhere to British Standard 8404.
  • 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 fireeze- 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 gives 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 products of manufacture as provided herein, including kits or blister packs 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.
  • MultiRexTM Universal Oral Anti-Cancer Drug Delivery System
  • a universal oral anti-cancer drug delivery system comprising use of pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein.
  • the universal oral anti-drug delivery system addresses the significant challenges posed when using complex oral anti-cancer therapies, including: the challenges to the prescriber to accurately prescribe, titrate and modify dosing; and e.g., for the pharmacists to fill the prescription; for the physician, oncology nurse and/or pharmacist to train and manage the patient/primary care adherence to therapy and to address side effects that may arise with use of the drug.
  • Complex oral therapy regimens are defined as two or more anti-cancer drugs, prescribed three-or more times per day at different amounts between AM and PM and may also be prescribed at different dosage amounts by day of week and week of a cycle of anti-cancer therapy.
  • a cycle of anti-cancer therapy ranges from one to twelve weeks with most from two to six and most common four weeks or one-month.
  • a complex regimen also is one prescribed at different dose strengths and requiring dose
  • oral anti-cancer drug delivery systems provided herein as provided herein, e.g., MULTIREXTM, addresses the problems of compliance for complex oral therapy regimens. For example, studies show that for just single oral cancer which are prescribed three or more times per day, only 25% to 50% of patients are able to adhere 80% or more to time-interval administration within two hours of the indicated time. Studies show that adherence rates decline further with use of multi-oral agents, that vary over course of a treatment cycle and in in elderly, symptomatic, single patients and/or with other risk factors of poor adherence. Alternative embodiments of universal multi-drug delivery system are designed address these problems.
  • Alternative embodiments of oral anti-cancer drug delivery systems provided herein as provided herein, e.g., MULTIREXTM, overcome the challenges of complex oral anti-cancer therapies by preserving the pharmacokinetic/pharmacodynamic (PK/PD) profile of a complex regimen of any complex oral therapy, and translate the regimen into a single fixed dose combination drug product that can be accurately prescribed by the oncologist and adhered to by the patient.
  • PK/PD pharmacokinetic/pharmacodynamic
  • the universal multi-drug delivery systems provided herein comprise, e.g., Level 1 VT-1 ICR AM and/or Level 2 VT-1 ICR AM, and, VT- 1 ICR PM; for example, the universal multi-drug delivery systems as provided herein can comprise:
  • Immediate release e.g., etodolac
  • DR delayed (or controlled) release
  • BID a twice a day
  • PK/PD profile of a three times a day (TID), four times a day (QID) or more dosing of the agents;
  • Combination morning (or AM) capsule, tablet, pill or the like comprised of one or more active agents in an IR and/or DR release forms
  • PM (evening or bedtime) capsule, tablet, pill or the like comprised of one or more active agents with IR and/or DR release profile.
  • the capsules, tablets, pills or the like are placed on a blister card or equivalent providing multi-day, e.g., a seven day, supply with/without a spare dose;
  • composition of the AM and PM capsules, tablets, pills or the like may vary by day of week and week within cycle of therapy;
  • the capsules, tablets, pills or the like are contained in unit dose blister card or equivalent with foil backing that requires minimal finger strength to remove the capsules, tablets, pills or the like;
  • the blister card or equivalent is in a child resistant enclosure system that is elderly friendly and requires minimal grip strength to release the blister card or equivalent;
  • a telephone number for 24/7 healthcare professional support and/or a QR code (abbreviated from Quick Response Code, is the trademark for a type of matrix barcode or two-dimensional barcode) for 24/7 mobile phone access to patient support material and a healthcare
  • the blister card or equivalent will function as a physical data capture device for use by the patient and/or primary care as a reminder system to improve adherence and avoid both missed dosing as well as double dosing;
  • the blister card or equivalent will also function as physical data capture device for use by the healthcare professional to monitor adherence on daily, weekly or cycle basis, identify lack of adherence by time of day/day of week/week in cycle and then through dialogue with the patients and/or caregiver; and to identify barriers to adherence, propose interventions to overcome barriers to adherence and then monitor interventions to assure adherence;
  • a medical electronic monitory system that records administration time
  • NFC near-field communication
  • a database system that captures data from by manual or automated loading of compliance data; the database system is linked to pharmacy and other healthcare information systems; the database can track and compare adherence rates by healthcare professional, by site and by payer;
  • HCP health care provider
  • a payer adherence rate data will support outcomes based reimbursement.
  • universal multi-drug delivery systems as provided herein e.g., MULTIREXTM
  • pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein comprise use of non-steroidal antiinflammatory drugs (NSAIDs) and Beta Blockers (or beta-adrenergic blocking agents; these are competitive antagonists that block the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system), e.g., propranolol (which blocks the action of epinephrine (adrenaline) and norepinephrine (noradrenaline) at both ⁇ - and p 2 -adrenergic receptors) and etodolac (blocks or inhibits cyclooxygenase, or "COX", and therefore is called a "coxib”), which over the last thirty years
  • MO A agents' mode of action
  • the investigator was able to titrate, separately, propranolol and etodolac, based on changes in heart rate, liver function, pain, among other responses of each patient during a one-week titration period to five different dose combination of propranolol and etodolac administrated three times per day; in a community setting, titration of etodolac and propranolol, separately is not possible given the limited time to observe the patient, the frequent treatment of
  • an effective therapy needs e.g., to use a robust biomarker to identify M2 macrophage high patients; to simplify dosing for easy titration and dose modification; and/or to improve drug deliver and packaging to improve adherence, which problems are significantly addressed by the specific dose amounts and dose release profile of propranolol/ etodolac (PE) as provided herein, and the universal multi-drug delivery systems provided herein, e.g., MULTIREXTM, and the pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein.
  • PE Propranolol-Etodolac
  • MULTIREXTM universal multi-drug delivery systems
  • a robust biomarker is used to identify M2
  • LMR lymphocyte- to-monocyte ratio
  • markers for selecting an individual (e.g., patient) in need of treatment using a therapeutic combination as provided herein include: C-reactive protein (CRP /Albumin of greater than 0.05 or greater than 0.8 or greater than 0.10 or greater than 0.12 or greater than 0.15 or greater 0.18, and neutrophil-to-lymphocyte ratio (LR) of greater than 2.0 or greater than 3.0 or greater than 4.0 or greater than 5.0.
  • CRP /Albumin C-reactive protein
  • LR neutrophil-to-lymphocyte ratio
  • use of the universal multi-drug delivery systems provided herein, e.g., MULTIREXTM, and the pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein are drug delivery systems that can improve adherence to optimized dosage amounts and timing by converting from QID or TIE) to a BID dosage regimen by using delayed (DR) (or controlled) "pulsatile" release beads or tablets or equivalents, e.g., using Dose Level 1 VT-1 ICR AM or Dose Level 2 VT-1 ICR AM, as provided herein.
  • DR delayed
  • Use of a delayed "pulsatile" release regimen eliminates the need for difficult to adhere to time-interval dosing, and retains intermittent release of drug to minimize risk of tachyphylaxis.
  • the delayed "pulsatile" release regimen combines the desired drug combination, e.g., propranolol and etodolac (PE), into one single AM and one PM pill to reduce pill burden and improve adherence.
  • desired drug combination e.g., propranolol and etodolac (PE)
  • universal multi-drug delivery systems provided herein, e.g., MULTIREXTM, and pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein, use child resistant and elderly friendly packaging, e.g., packaging compliant to U.S. Government child resistant packaging regulation that requires minimal finger and grip strength.
  • child resistant and elderly friendly packaging e.g., packaging compliant to U.S. Government child resistant packaging regulation that requires minimal finger and grip strength.
  • foil-only containment of pills is used.
  • universal multi-drug delivery systems provided herein, e.g., MULTIREXTM, and pharmaceutical dosage forms, drug delivery devices and products of manufacture as provided herein, place AM and PM tablets, capsules, pills or equivalents on a blister card or equivalent to track usage.
  • the blister card monitor can remind the patient and/or the primary care-giver to take medication (or that medication has been taken) in AM and PM; and can facilitate discussion with health care professionals to identify and overcome barriers to adherence.
  • patient usage is monitored by use of customized blister cards or equivalents using an Electronic Compliance Monitor (ECM) system (Intelligent Devices SEZC Inc. (DDI), Grand Cayman, Cayman Islands), or equivalents.
  • ECM Electronic Compliance Monitor
  • the blister cards or equivalents comprise an electronic component that detects, records, safeguards and/or transmits medication removal from the blister cards or equivalents.
  • a sensor detects medication removal from the blister cards or equivalents, and this information can be transferred to a remote location for review by e.g., the drug provider and/or the primary care institution or individuals.
  • the data transfer can be by hard contact downloading of data to a transmitting and/or storage device, and can be scanned and data downloaded remotely using a radio-frequency identification (RFID) chip, tag or device or equivalent, which can be operatively connected to a computer and/or a mobile phone or other device.
  • RFID radio-frequency identification
  • Radio- frequency identification uses electromagnetic fields to automatically identify and track tags attached to objects, where the tags contain electronically stored information, which in this embodiment is transmitting whether and/or when medication is removed from each compartment of the blister cards or equivalents, or by Near-Field Communication (NFC) to a NFC-enabled mobile device or mobile phone.
  • NFC Near-Field Communication
  • the NFC is a set of communication protocols that enable two electronic devices, one of which is usually a portable device such as a smartphone, to establish communication by bringing them within 4 cm (1.6 in) of each other.
  • universal multi-drug delivery systems e.g., MULTIREXTM, comprises use of a box to house or enclose drug delivery devices or packages, blister packages, clamshells or trays, as provided herein, as illustrated in FIG. 19, where in this exemplary delivery system a week of pharmaceutical dosage form (e.g., one, two or three or more tablets, pills, capsules, geltabs or
  • the blister packages, clamshells or trays are physical linked to a storage box, wherein the blister packages, clamshells or trays slide into and out of the storage box, and in alternative embodiments if needed the PM set of rows can be folded over the AM set of rows for reinsertion of the blister packages, clamshells or trays into the storage box.
  • the storage box comprises sensors to detect medication removal from each of the compartments (e.g., which compartment is opened and when), and this information can be transferred to a remote location, e.g., by Near- Field Communication (NFC) to a NFC-enabled mobile device or mobile phone, for review by e.g., the drug provider and/or the primary care institution or individuals.
  • NFC Near- Field Communication
  • Example 1 Container Closure System for VT-1 ICR Capsules
  • This example demonstrates an exemplary formulation and packaging delivery system as provided herein.
  • exemplary formulations or drug combinations as provided herein are packaged into 8-count thermoformed polyvinyl chloride (PVC) blisters with foil-lined paper push- through lidding. Both the blister and lidding are constructed of materials that provide a barrier to oxygen and moisture. All products utilize the same packaging components.
  • PVC polyvinyl chloride
  • cards are assembled in a child resistant and elderly friendly box enclosure system that requires minimal finger and grip strength to release card from box and capsules from blister.
  • cards are assembled for low dose (e.g., designated “Level 1”) and high dose (e.g., designated “Level 2”) as described below, using 8-capsule blister strips of etodolac and 8-capsule blister strips of VT-1 ICR:
  • Level 1 cards comprise one morning (AM) blister strip containing 8 VT-1 ICR capsules and one evening (PM) blister strip containing 8 etodolac capsules.
  • Level 2 cards comprise two morning (AM) blister strips containing a total of 16 VT-1 ICR capsules and two evening (PM) blister strips containing a total of 16 etodolac capsules.
  • This exemplary embodiment also applies to the placebo presentation (VT-1 ICR placebo capsules + etodolac placebo capsules).
  • This example demonstrates an exemplary therapeutic protocol using the exemplary VT-1 ICR formulation and packaging delivery system as provided herein with protein-bound paclitaxel (albumin-bound paclitaxel, or nab-paclitaxel, or ABRAXANE®) and gemcitabine (GEMZAR®), or "GemNab", for metastatic pancreatic cancer.
  • protein-bound paclitaxel albumin-bound paclitaxel, or nab-paclitaxel, or ABRAXANE®
  • GEMZAR® gemcitabine
  • Patients take their morning dose in the morning within one hour after breakfast (target between 8:00 AM and 10:00 AM).
  • the evening dose should be taken within one hour after the evening meal (target 7:00 PM to 10:00 PM), approximately 12 hours after the morning dose.
  • Patients should consume food prior to taking the VT-1 ICR
  • VT-1 ICR medication In the evening, a small snack should be sufficient pre-dose but the VT-1 ICR medication should be taken right after eating. A mid-day meal or snack is also
  • VT-1 ICR study medication can continue until intolerable adverse events, patient refusal to continue treatment or withdrawal of consent for the study, PD or the patient starts a new anti -cancer treatment. If GemNab has been discontinued and the patient's disease has not yet progressed, treatment with VT-1 ICR study medication can continue per the Investigator's discretion until the patient starts a new anti-cancer treatment. The patient will undergo an End-of- Treatment visit when the VT-1 ICR study medication has been discontinued.
  • Standard of care chemotherapy will consist of protein-bound paclitaxel 125 mg/m2 given intravenously Days 1, 8 and 15 of a 28-day cycle) and gemcitabine 1,000 mg/m2 (given intravenously Days 1, 8 and 15 of a 28-day cycle).
  • GemNab can continue until intolerable adverse events, patient refusal to continue treatment or withdrawal of consent for the study, PD or the patient starts a new anti- cancer treatment. If treatment with one of the components of GemNab is discontinued (e.g. for toxicity reasons), the other component should also be discontinued.
  • VT-1 ICR study medication has been discontinued and the patient's disease has not yet progressed, treatment with GemNab can continue per the Investigator's discretion. The patient will undergo an End-of-Treatment visit when the VT-1 ICR study medication has been discontinued.
  • PK parameters for assessment can include maximum concentration (Cmax), time to reach maximum concentration (tmax), half-life (t1 ⁇ 2), area under the curve (AUC)0-12, AUCO-t, total clearance after oral administration (CL/F), apparent volume of distribution after non-intravenous administration (Vd/F), and terminal disposition rate constant ( ⁇ ).
  • Cmax maximum concentration
  • tmax time to reach maximum concentration
  • t1 ⁇ 2 half-life
  • AUC area under the curve
  • AUCO-t area under the curve
  • CL/F total clearance after oral administration
  • Vd/F apparent volume of distribution after non-intravenous administration
  • ⁇ terminal disposition rate constant
  • CSF granulocyte colony-stimulating factor
  • opioids for pain and other supportive care as needed.
  • CSF granulocyte colony-stimulating factor
  • VT-1 ICR study As summarized in FIGs. 3-5, a randomized, double-blind, placebo-controlled two-staged study in which patients is randomized on a 1 : 1 basis to receive the standard of care GemNab, with VT-1 ICR study medication consisting of either VT-1 ICR (Treatment Arm 1) or placebo (Treatment Arm 2). Patients will have previously untreated, metastatic pancreatic cancer with documented measurable disease according to RECIST 1.1.
  • VT-1 ICR study medication After confirmation of eligibility and randomization, patients initiate VT-1 ICR study medication at Dose Level 1 on study Day -7. Upon completing of at least two days of treatment and in the absence of any related > Grade 2 adverse events, treatment with VT-1 ICR study medication at Dose Level 2. Upon completing at least 3 hours of treatment and in the absence of any related > Grade 2 adverse events, GemNab will start on study Day 1. VT-1 ICR study medication and GemNab can continue until intolerable adverse events, patient refusal to continue treatment or withdrawal of consent for the study, PD or the patient starts a new anti -cancer treatment.
  • VT- 11 CR study medication can continue per the Investigator's discretion until the patient starts a new anti -cancer treatment. Similarly, if VT-1 ICR study medication has been
  • Example 3 Stability and Dissolution Profiles of Exemplary VT-1 ICR Capsules
  • This example describes stability and dissolution profiles of the exemplary VT-
  • Combination Product - The combination product is tested as a single gelatin capsule containing propranolol (32 mg active) in the same two formulations described above (16 mg IR + 16 mg DR) with etodolac (70 mg active).
  • the dissolution profiles of propranolol (individual product) at 5°C / ambient RH, 25°C / 60% RH, 30 °C / 65% RH and 40°C /75% RH are shown in FIGs. 8 to 11, respectively.
  • the long-term storage condition was initially assigned as refrigerated (2 to 8°C). Based on this assignment, the other stability storage temperatures/humidities represent accelerated conditions that may be used to provide an extrapolated shelf life at the long-term storage condition or to support high-temperature excursions from the long- term storage condition (such as those that may occur during shipment or day-to-day patient use).
  • error bars utilize ⁇ %RSD; also, for clarity, the 24-hour dissolution time point is not provided in the graphical presentation, as complete dissolution was consistently achieved by 12 hours.
  • SI 6 capsules tested
  • S2 The average value of the 12 units (SI + S2) lies within each of the stated ranges and is not less than the stated amount at the final time point. None is more than 10% of labeled content outside each of the stated ranges. None is more than 10% of labeled content below the stated amount at the final time point.
  • the 5°C dissolution profiles are sufficiently consistent across all stability time points and satisfy the three critical parameters for the mixture of IR and DR propranolol formulations contained in the gelatin capsule: (1) the 1-hour time point verifies that the IR formulation of propranolol has fully released, and that dose dumping of propranolol from the DR formulation has not occurred, (2) the intermediate time points exhibit a consistent release rate of propranolol from the DR formulation, and (3) the final time point ensures complete propranolol release from the DR formulation. As additional batches of product are generated, acceptance criteria may be reviewed and tightened as appropriate.
  • Enzymes can be added to the dissolution medium to overcome this problem.2
  • One way to assess this would be to separately encapsulate the IR and DR formulations and perform stability testing on each type of capsule, and compare to the un-encapsulated formulations stored in a sealed non-reactive container.
  • dissolution specifications may be proposed for propranolol and etodolac (combination product).
  • Proposed Propranolol (16 mg IR + 16 mg DR) w/ Etodolac 70 mg Combination Product, Dissolution Acceptance Criteria: Propranolol meets SI, S2 or S3 at each time point, according to the criteria specified below:
  • SI 6 capsules tested
  • S2 The average value of the 12 units (S I + S2) lies within each of the stated ranges and is not less than the stated amount at the final time point. None is more than 10% of labeled content outside each of the stated ranges. None is more than 10% of labeled content below the stated amount at the final time point.
  • SI + S2 + S3 is > 85% (> Q). Not more than 2 of the 24 units are ⁇ 70% ( ⁇ Q - 15%), and no unit is ⁇ 60% ( ⁇ Q - 25%). Dissolution testing is continued through the three levels S I, S2 and S3 unless the results conform at either SI or S2.
  • the 5°C dissolution profiles are sufficiently consistent across all stability time points and satisfy three critical parameters for the combination of propranolol IR/DR formulations and etodolac contained in a single gelatin capsule: (la) the 1-hour time point for propranolol verifies that the release of propranolol from the IR formulation is complete, and that dose dumping of propranolol from the DR formulation has not occurred, (lb) the 1-hour time point for etodolac verifies immediate release of this active moiety, (2) after a 4-hour delay, the intermediate time points exhibit a consistent release rate of propranolol from the DR formulation, and (3) the final time point ensures complete propranolol release from the DR formulation. As additional batches of combination product are generated, acceptance criteria may be reviewed and tightened as appropriate.
  • FIG. 18 illustrates in tabular form the dissolution profile of Propranolol HC1, 16 mg IR and 16 mg DR, in combination with Etodolac 70 mg - specifically observing the 240 minutes - 360 minutes on stability up to 6 months.

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Abstract

Selon d'autres modes de réalisation, la présente invention concerne des combinaisons thérapeutiques, des compositions pharmaceutiques, des préparations, des trousses et des dispositifs de traitement, de prévention ou d'amélioration d'une tumeur ou d'un cancer, ainsi que des procédés de traitement, de prévention ou d'amélioration d'une tumeur ou d'un cancer. Selon d'autres modes de réalisation, la présente invention concerne des combinaisons thérapeutiques, des compositions pharmaceutiques, des préparations, des trousses et des dispositifs qui comprennent : un antagoniste du récepteur bêta-adrénergique (un « bêta-bloquant », tel que le propanolol) ; un médicament anti-inflammatoire non stéroïdien (un AINS, tel que l'étodolac) conditionné ou formulé pour une libération chronodosée et pulsatile de telle sorte qu'il peut être administré deux fois par jour (BID ), et des procédés de fabrication et d'utilisation de ceux-ci, par exemple, dans des régimes de traitement. Selon d'autres modes de réalisation, les combinaisons thérapeutiques d'agents thérapeutiques ou de médicaments comprennent en outre un anticorps anticancéreux ou antitumoral, une cytokine et/ou un autre agent chimiothérapeutique.
PCT/US2018/059047 2017-11-02 2018-11-02 Thérapies par association médicamenteuse contre le cancer et leurs procédés de fabrication et d'utilisation WO2019090141A1 (fr)

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CN113631166A (zh) * 2018-12-14 2021-11-09 慧源香港创新有限公司 用于治疗癌症的口服给药的伊立替康和P-gp抑制剂的治疗组合
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CN115025245A (zh) * 2022-05-18 2022-09-09 齐齐哈尔医学院 一种联载氟尿嘧啶和亚叶酸钙的pH响应型纳米递药体系
CN115105484A (zh) * 2019-05-31 2022-09-27 百济神州有限公司 一种parp抑制剂微丸制剂及其制备工艺
WO2023039568A1 (fr) * 2021-09-10 2023-03-16 Athenex, Inc. Combinaisons thérapeutiques de paclitaxel administré par voie orale, d'un inhibiteur de p-gp et d'un inhibiteur de point de contrôle pour le traitement de tumeurs solides

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US11253603B2 (en) 2018-09-17 2022-02-22 The Children's Hospital Of Philadelphia Polymer-based macromolecular prodrugs
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CN113631166A (zh) * 2018-12-14 2021-11-09 慧源香港创新有限公司 用于治疗癌症的口服给药的伊立替康和P-gp抑制剂的治疗组合
CN112007011A (zh) * 2019-05-31 2020-12-01 百济神州(苏州)生物科技有限公司 一种parp抑制剂微丸胶囊及其制备工艺
CN115105484A (zh) * 2019-05-31 2022-09-27 百济神州有限公司 一种parp抑制剂微丸制剂及其制备工艺
EP3977984A4 (fr) * 2019-05-31 2023-01-11 BeiGene, Ltd. Préparation de pastille d'inhibiteur de parp et procédé de préparation correspondant
WO2023039568A1 (fr) * 2021-09-10 2023-03-16 Athenex, Inc. Combinaisons thérapeutiques de paclitaxel administré par voie orale, d'un inhibiteur de p-gp et d'un inhibiteur de point de contrôle pour le traitement de tumeurs solides
CN115025245A (zh) * 2022-05-18 2022-09-09 齐齐哈尔医学院 一种联载氟尿嘧啶和亚叶酸钙的pH响应型纳米递药体系

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