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WO2005117864A1 - Produit combine comprenant de l'anastrozole et un inhibiteur double de la prenyl transferase - Google Patents

Produit combine comprenant de l'anastrozole et un inhibiteur double de la prenyl transferase Download PDF

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Publication number
WO2005117864A1
WO2005117864A1 PCT/GB2005/002079 GB2005002079W WO2005117864A1 WO 2005117864 A1 WO2005117864 A1 WO 2005117864A1 GB 2005002079 W GB2005002079 W GB 2005002079W WO 2005117864 A1 WO2005117864 A1 WO 2005117864A1
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Prior art keywords
transferase
dual
anastrozole
treatment
azd3409
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PCT/GB2005/002079
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English (en)
Inventor
Trevor Charles Stephens
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority claimed from GB0412004A external-priority patent/GB0412004D0/en
Priority claimed from GB0417722A external-priority patent/GB0417722D0/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2005117864A1 publication Critical patent/WO2005117864A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid

Definitions

  • the present invention relates to a combination therapeutic product comprising anastrozole and a dual prenyl transferase inhibitor that inhibits both famesyl transferase and geranylgeranyl transferase- 1, for use in a new method for the treatment or prophylaxis of breast cancer.
  • the invention also relates to a pharmaceutical composition comprising anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase- 1, and to the use thereof in the treatment or prophylaxis of breast cancer. Cancer is believed to involve alteration in expression or function of genes controlling cell growth and differentiation.
  • prenyl transferase inhibitors in cancer.
  • prenyl transferase enzymes farnesyl transferase and geranylgeranyl transferase- 1 that catalyse the addition of lipid moieties (farnesyl and geranylgeranyl respectively) to a cysteine residue at the 4 l position from the C-terminus of a range of proteins.
  • Post-translational prenylation of target proteins is required for their biological activity (see below for example).
  • Prenylated proteins may either be exclusive substrates for farnesyl transferase, exclusive substrates for geranylgeranyl transferase- 1, or capable of being prenylated by either enzyme.
  • the specificity and affinity of proteins for these two prenyl transferase enzymes is dictated by the CAAX box, which is a sequence of 4 amino acids at the C-terminus of the target protein.
  • CAAX box is a sequence of 4 amino acids at the C-terminus of the target protein.
  • Many of the proteins that are prenylated by these enzymes are regulatory proteins involved in cell growth and differentiation and prevention of their biological functions by inhibiting their prenylation may provide a useful intervention in tumourigenesis.
  • the ras proteins are small GTP binding proteins that participate in the MAP-kinase growth signalling pathway. Ras proteins require prenylation to relocate from the cytoplasm to the cell membrane where they perform their biological function. As the ras proteins have different selectivities for farnesyl and geranylgeranyl transferases, they provide an example where "dual" prenyl transferase inhibition may be advantageous. H-ras is exclusively farnesylated and its function may be inhibited by a pure farnesyl transferase inhibitor.
  • K- and N-ras although preferentially farnesylated, may be geranylated in presence of a farnesyl transferase inhibitor.
  • a farnesyl transferase inhibitor As the geranylated forms of K- and N-ras are relocated in the membrane they retain biological activity and may allow cell growth to continue. However, the biological function of these ras forms can be prevented by administration of a "dual" prenylation inhibitor. It is known that farnesyl transferase and geranylgeranyl transferase- 1 are frequently present in common human cancers such as breast cancer (Kelland, Expert. Opin. Investig. Drugs [2003] 12, 413-421; Grace & Adjei [2002] Cancer Investigation 20, Suppl. 2, 30-37).
  • an inhibitor of farnesyl transferase and/or geranylgeranyl transferase- 1 should be of value as a selective inhibitor of the growth of tumours in the breast. It is known that certain compounds possess inhibitory activity against farnesyl transferase.
  • one such compound is isopropyl (2S)-2-( ⁇ 2-(4-fluorophenethyl)-5- [( ⁇ 2S,4S)-4-[(3-pyridinylcarbonyl)sulfanyl]tetrahydro-lH-pyrrol-2- yl ⁇ methyl)amino]benzoyl ⁇ amino-4-(methylsulfanyl)butanoate (hereinafter referred to as AZD3409) or a salt thereof, which is disclosed in International Patent Publication No. WO-A- 01/46137.
  • the corresponding structure of AZD3409 is shown below in Formula I:
  • Formula I AZD3409 has also been shown to possess inhibitory activity against geranylgeranyl transferase- 1 (Stephens et al, Proc AACR-NCI-EORTC Intl. Conf. Mol. Targets and Cancer Therap. [2003] pp95 Antibodies A183).
  • the compound AZD3409 can be used as a selective inhibitor of the growth of tumours in the breast.
  • AZD3409 is a pro-pro-drug.
  • the biotransformation of orally administered AZD3409 is shown in Figure 1.
  • the pro-pro-drug (I) the thiol and carboxy groups of the thiol-acid drug (lb), are both protected as esters.
  • the pro-pro-drug is rapidly transformed in plasma to the thiol-ester pro-drug (la), which is then transformed to the thiol-acid drug (lb), as shown in Figure 1.
  • the thiol-acid drug is formed intracellularly via intracellular esterase and is the intracellular active species. It should be appreciated that all references herein to AZD3409 include all of the aforementioned forms, i.e. the AZD3409 pro-pro-drug, the thiol-ester pro- drug and the thiol-acid drug / intracellular active species.
  • FIG. 1 Another approach to breast cancer treatment is endocrine therapy. It is known that tumours of the breast are often hormone-dependent and, thereby, sensitive, at least for an initial period, to levels of oestrogen. Intra-tumoral oestrogen is known to stimulate tumour growth in hormone-sensitive breast tumours. Additionally, it is known that deficiency of oestrogen leads to degeneration of tumours in the breast. Substances that block the effects of oestrogen in cells, as well as substances that inhibit the generation of oestrogen, therefore, are useful for the treatment of breast cancer. It is known that certain compounds inhibit the generation of oestrogen.
  • one such compound is 2,2'-[5-(lH-l,2,4-triazol-l-ylmethyl)-l,3-phenylene]di(2-methyl- propionitrile), which is disclosed in EP-B-0,296,749 and in US patent re-issue number
  • an alternative name for this compound is 2,2'-dimethyl-2,2'-[5-(lH-l,2,4-triazol-l- ylmethyl)-l,3-phenylene]bis(propiononitrile).
  • This compound is also known as "anastrozole” or by the AstraZeneca tradename "Arimidex ® " and will hereinafter be referred to as anastrozole.
  • AstraZeneca tradename "Arimidex ®” The corresponding structure of anastrozole is shown below in Formula II:
  • Anastrozole is an aromatase inhibitor that can result in near maximal suppression of serum and intra-tumoural oestrogen.
  • anastrozole can be used to inhibit the generation of oestrogen, which leads to degeneration of tumours in the breast.
  • One side effect associated with the use of anastrozole is a reduction in bone mineral density among patients, as well as an increased risk of bone fractures.
  • the compounds disclosed therein, such as AZD3409 may be administered as a sole therapy or may involve, in addition to the compounds disclosed therein, one or more other substances and/or treatments.
  • such conjoint treatment may be achieved by way of surgery, radiotherapy or chemotherapy in addition to the cell cycle inhibitory treatment achieved with compounds such as AZD3409.
  • Such chemotherapy may cover three main categories of therapeutic agent: (i) other cell cycle inhibitory agents that work by the same or different mechanisms from the dual prenylation inhibitors (such as AZD3409) discussed previously; (ii) cytostatic agents such as antioestrogens (for example fulvestrant, tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example anastrozole, letrazole, vorazole, exemestane), antiprogestogens, antiandrogens (for example flutamide, nilutamide, bicalutamide, cyproterone acetate), LHRH agonists and antagonists (for example goserelin acetate, luprolide), inhibitors of testosterone 5 ⁇ -dihydroreductase (for example finasteride), anti- invasion agents
  • the combination use of anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase- 1 in the treatment of breast cancer can have a beneficial and/or synergistic effect on the treatment or prophylaxis of breast cancer.
  • the combination use of anastrozole and the dual prenyl transferase inhibitor may have a beneficial and/or synergistic effect in terms of one or more of the extent of the response, the response rate, the time to disease progression and the survival rate.
  • the combination use of anastrozole and the dual prenyl transferase inhibitor may induce greater tumour regression ' than either treatment alone.
  • the combination use of anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase- 1 may have a beneficial or advantageous effect in terms of reducing or substantially preventing reduction in bone mineral density and in terms of reducing or substantially preventing bone fractures. It is further expected that the combination use of anastrozole and the dual prenyl transferase inhibitor may have a beneficial effect in preventing the onset of breast cancer in humans genetically predisposed to the disease.
  • the beneficial and/or synergistic effects of the combination use of anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase- 1 in the treatment or prophylaxis of breast cancer may be due to the combination of the different modes of action of anastrozole and the dual prenyl transferase inhibitor.
  • the dual prenyl transferase inhibitor is believed to be a selective inhibitor of the growth of breast tumours by means of inhibition of both farnesylation and geranylation.
  • the dual prenyl inhibitor is believed to delay growth of tumours in breast and induce tumour regression in breast cancer.
  • Anastrozole is believed to inhibit the generation of oestrogen, which leads to degeneration of tumours in the breast. It is believed that these different modes of action produce an unexpected beneficial and/or synergistic effect in the treatment or prophylaxis of breast cancer. Additionally, it is believed that protein geranylgeranylation is required for osteoclast formation, function and survival (see, for example, Coxon et al., Journal of Bone and Mineral Research, voL 15, 8, 2000, pages 1467-1476). Inhibition of geranylgeranyl transferase- 1, therefore, may reduce or substantially prevent osteoclast formation, function and survival and in turn reduce or substantially prevent reduction in bone mineral density and reduce or substantially prevent fractures.
  • a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase- 1 in combination with anastrozole may have a beneficial effect on bone mineral density and fractures as discussed above in view of the action of the geranylgeranyl transferase- 1 inhibitor.
  • This effect would be expected to be particularly beneficial in view of the side effects associated with anastrozole, as previously discussed. It would not be expected that such an effect would be observed with the combination use of a single farnesyl transferase inhibitor and anastrozole.
  • a combination therapeutic product comprising anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase- 1 for use simultaneously, sequentially or separately in the treatment or prophylaxis of breast cancer.
  • the dual prenyl transferase inhibitor is particularly AZD3409. It should be appreciated that there is no requirement that the anastrozole and the dual prenyl transferase inhibitor components of the combination therapeutic product of the invention must be dosed simultaneously. Sequential or separate use of these components may also provide the desired beneficial and/or synergistic effect and such use is to be understood to fall within the definition of a product of the invention.
  • a combination therapeutic product is defined as affording a beneficial effect if the effect is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that achievable on dosing one or other of the components of the combination therapeutic product at its conventional dose.
  • the effect of the combination therapeutic product is beneficial if the effect is therapeutically superior to the effect achievable with anastrozole alone or with the dual prenyl transferase inhibitor alone. Further, the effect of the combination therapeutic product is beneficial if a beneficial effect is obtained in a group of patients that does not respond (or responds poorly) to anastrozole alone or to the dual prenyl transferase inhibitor alone.
  • the effect of the combination therapeutic product is defined as affording a beneficial effect if one of the components is dosed at its conventional dose and the other component is dosed at a reduced dose and the therapeutic effect, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, is equivalent to that achievable on dosing conventional amounts of the components of the combination therapeutic product.
  • a combination therapeutic product is defined as affording a synergistic effect if the effect is therapeutically superior, as measured by, for example, the extent of the response, the response rate, the time to disease progression or the survival period, to that expected to be achievable on dosing both of the components of the combination therapeutic product together at their conventional dose (for example the combination effect is greater than the sum of the single agent effects).
  • a combination therapeutic product comprising anastrozole and AZD3409 for use simultaneously, sequentially or separately in the treatment or prophylaxis of breast cancer.
  • a combination therapeutic product of the invention may be administered in the form of a pharmaceutical composition.
  • a pharmaceutical composition for use in the treatment or prophylaxis of breast cancer which comprises anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase- 1 in conjunction or admixture with pharmaceutically-acceptable diluents or carriers.
  • the dual prenyl transferase inhibitor is particularly AZD3409.
  • the pharmaceutical composition according to the present invention includes a composition comprising anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase- 1 and a pharmaceutically-acceptable diluent or carrier.
  • compositions conveniently provides the combination therapeutic product of the invention for simultaneous use in the treatment or prophylaxis of breast cancer.
  • a pharmaceutical composition according to the present invention also includes separate compositions comprising a first composition comprising anastrozole and a pharmaceutically-acceptable diluent or carrier, and a second composition comprising a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and a pharmaceutically-acceptable diluent or carrier.
  • a composition conveniently provides the combination therapeutic product of the invention for sequential or separate use in the treatment or prophylaxis of breast cancer but the separate compositions may also be administered simultaneously.
  • such a pharmaceutical composition of the invention comprises a kit comprising a first container with a suitable composition containing the anastrozole and a second container with a suitable composition containing a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409).
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, capsules, aqueous or oily suspensions, emulsions or dispersible powders or granules), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions; for example for use within a transdermal patch), for parenteral administration (for example as a sterile aqueous or oily solution or suspension for intravenous, subcutaneous, intramuscular or intravascular dosing) or as a suppository for rectal dosing.
  • the compositions of the invention are in a form suitable for oral use, for example as tablets or capsules.
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutically-acceptable diluents or carriers that are well known in the art.
  • suitable pharmaceutically-acceptable diluents or carriers for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as gelatin or starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binding agents such as gelatin or starch
  • lubricating agents such as magnesium stearate
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
  • a pharmaceutical composition as defined hereinbefore comprising anastrozole and AZD3409 in conjunction or admixture with pharmaceutically-acceptable diluents or carriers.
  • the amount of each active ingredient of the present combination therapeutic product in such pharmaceutical compositions will necessarily vary depending upon the host treated and the particular route of administration.
  • a tablet or capsule formulation intended for oral administration will generally contain, for example, from about 0.1 to 100 mg, particularly, from about 0.25 to 25 mg, of active ingredient.
  • a conventional tablet formulation may be used for daily oral administration containing about 1 mg of active ingredient.
  • a tablet or capsule formulation intended for oral administration will also generally contain, for example, from about 250 to 2500 mg, particularly from about 500 to 1750 mg, more particularly from about 500 to 1250 mg, of active ingredient.
  • a conventional tablet formulation may be used for oral administration containing about 500, 750, 1000, 1250, 1500 or 1750 mg of active ingredient.
  • the daily oral dose of AZD3409 is above about 500 mg, for example about 1750 mg.
  • the active ingredients may be compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 20 mg to about 500 mg of each active ingredient.
  • each active ingredient may be combined separately with one or more excipients to produce a two-part dosage form.
  • the pharmaceutical composition of the invention comprises a kit comprising a first container with a suitable composition containing the anastrozole and a second container with a suitable composition containing the dual prenyl transferase inhibitor.
  • a kit may, for example, allow the physician wishing to treat his patient's breast cancer to select the appropriate amounts of each active ingredient and the sequence and timing of the administration thereof.
  • Those skilled in the art of treating breast cancer patients can readily select the appropriate conventional amounts of each active ingredient and a suitable dosing schedule.
  • a method for the treatment or prophylaxis of breast cancer which comprises the administration simultaneously, sequentially or separately to a warm-blooded animal such as a human of an effective amount of the combination therapeutic product as defined hereinbefore or of an effective amount of the pharmaceutical composition as defined hereinbefore.
  • a combination treatment as defined herein may be applied as a sole therapy or may involve surgery or radiotherapy or an additional chemotherapeutic agent in addition to a combination treatment of the invention.
  • Surgery may comprise the step of partial or complete tumour resection, prior to, during or after the administration of the combination treatment.
  • Other chemotherapeutic agents for optional use with a combination treatment of the present invention include those described in WO 01/46137, which is incorporated herein by reference.
  • a combination therapeutic product comprising anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 and a bisphosphonate drug for use simultaneously, sequentially or separately in the treatment or prophylaxis of breast cancer.
  • the bisphosphonate drug may help to reduce or substantially prevent osteoclast formation, function and survival and in turn reduce or substantially prevent reduction in bone mineral density and reduce or substantially prevent fractures.
  • the bisphosphonate drug may be selected from, for example, alendronate, etidronate, risedronate, tiludronate and pamidronate.
  • a combination therapeutic product comprising anastrozole, AZD3409 and a bisphosphonate drug for use simultaneously, sequentially or separately in the treatment or prophylaxis of breast cancer.
  • a pharmaceutical composition for use in the treatment or prophylaxis of breast cancer which comprises anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and a bisphosphonate drug in conjunction or admixture with pharmaceutically-acceptable diluents or carriers.
  • a combination therapeutic product comprising anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and a bisphosphonate drug for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal such as a human for the treatment or prophylaxis of breast cancer.
  • a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1
  • a bisphosphonate drug for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal such as a human for the treatment or prophylaxis of breast cancer.
  • a method for the treatment or prophylaxis of breast cancer which comprises the administration simultaneously, sequentially or separately to a warm-blooded animal such as a human of an effective amount of a combination therapeutic product comprising anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and a bisphosphonate drug.
  • a warm-blooded animal such as a human of an effective amount of a combination therapeutic product comprising anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and a bisphosphonate drug.
  • a pharmaceutical composition comprising anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and a bisphosphonate drug in conjunction or admixture with pharmaceutically-acceptable diluents or carriers for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal such as a human for the treatment or prophylaxis of breast cancer.
  • a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1
  • a bisphosphonate drug in conjunction or admixture with pharmaceutically-acceptable diluents or carriers for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal such as a human for the treatment or prophylaxis of breast cancer.
  • a method for the treatment or prophylaxis of breast cancer which comprises the administration simultaneously, sequentially or separately to a warm-blooded animal such as a human of an effective amount of a pharmaceutical composition comprising anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and a bisphosphonate drug in conjunction or admixture with pharmaceutically-acceptable diluents or carriers.
  • a warm-blooded animal such as a human of an effective amount of a pharmaceutical composition comprising anastrozole, a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and a bisphosphonate drug in conjunction or admixture with pharmaceutically-acceptable diluents or carriers.
  • a combination therapeutic product comprising anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409), for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal such as a human for the treatment or prophylaxis of breast cancer.
  • a pharmaceutical composition comprising anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) in conjunction or admixture with pharmaceutically-acceptable diluents or carriers, for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal such as a human for the treatment or prophylaxis of breast cancer.
  • a pharmaceutical composition comprising anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) in conjunction or admixture with pharmaceutically-acceptable diluents or carriers, for the manufacture of a medicament for administration simultaneously, sequentially or separately to a warm-blooded animal such as a human for the treatment or prophylaxis of breast cancer.
  • a method for the treatment or prophylaxis of breast cancer which comprises the combination of surgical removal of a tumour together with the administration simultaneously, sequentially or separately to a warm-blooded animal such as a human of an effective amount of a combination therapeutic product comprising anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409).
  • a method for the treatment or prophylaxis of breast cancer which comprises the combination of surgical removal of a tumour together with the administration simultaneously, sequentially or separately to a warm-blooded animal such as a human of an effective amount of a pharmaceutical composition comprising anastrozole and a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) in conjunction or admixture with pharmaceutically-acceptable diluents or carriers.
  • a warm-blooded animal such as a human of an effective amount of a pharmaceutical composition
  • a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) in conjunction or admixture with pharmaceutically-acceptable diluents or carriers.
  • the administration of a triple combination of a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409), anastrozole and ionising radiation may produce effects, such as anti-tumour effects, greater than those achieved with any of a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409), anastrozole and ionising radiation used alone, greater than those achieved with the combination of a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and anastrozole, greater than those achieved with the combination of a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD340
  • a method for the treatment of breast cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of anastrozole and before, after or simultaneously with an effective amount of ionising radiation.
  • a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of anastrozole and before, after or simultaneously with an effective amount of ionising radiation.
  • a method for the treatment of breast cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of anastrozole and before, after or simultaneously with an effective amount of ionising radiation, wherein the dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and anastrozole may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
  • a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) or a pharmaceutically acceptable salt thereof and anastrozole in the manufacture of a medicament for use in the treatment of breast cancer in a warm-blooded animal such as a human which is being treated with ionising radiation.
  • a therapeutic combination treatment comprising the administration of an effective amount of a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and the administration of an effective amount of anastrozole, optionally together with a pharmaceutically acceptable excipient or carrier, and the administration of an effective amount of ionising radiation, to a warm-blooded animal such as a human in need of such therapeutic treatment wherein the dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409), anastrozole and ionising radiation may be administered simultaneously, sequentially or separately and in any order.
  • a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase
  • a warm-blooded animal such as a human which is being treated with ionising radiation means a warm-blooded animal such as a human which is treated with ionising radiation before, after or at the same time as the administration of a medicament or combination treatment comprising a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and anastrozole.
  • said ionising radiation may be given to said warm-blooded animal such as a human within the period of a week before to a week after the administration of a medicament or combination treatment comprising a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and anastrozole.
  • a dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 such as AZD3409
  • anastrozole and ionising radiation may be administered separately or sequentially in any order, or may be administered simultaneously.
  • the warm-blooded animal may experience the effect of each of the dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409), anastrozole and radiation simultaneously.
  • the ionising radiation is administered before one of the dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and anastrozole or after one of the dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and anastrozole.
  • the ionising radiation is administered before both the dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and anastrozole or after both the dual prenyl transferase inhibitor that inhibits both farnesyl transferase and geranylgeranyl transferase-1 (such as AZD3409) and anastrozole.
  • Experimental Methods Both in vitro experimental methods and in vivo experimental methods in animals and/or appropriate clinical trials in humans can be used to assess the activity of the combination therapeutic product of the present invention. In Vitro Methods Breast tumour cell lines with varying ER status may be used in these studies.
  • cells may be treated with single agents, or combinations, for various times up to about 6 days, and growth measured using an MTT (Mossman [1983] J. Immunol. Methods 65, 55-63), Sulforhodamine B (Skehan et al [1990] J. Natl. Cancer Inst. 82, 1107- 1112) or cell counting endpoint.
  • MTT Mossman [1983] J. Immunol. Methods 65, 55-63
  • Sulforhodamine B Skehan et al [1990] J. Natl. Cancer Inst. 82, 1107- 1112
  • cell counting endpoint Cell counting endpoint.
  • Experimental designs and mathematical analysis methods such as "Median Effect Analysis” (Chou & Talalay Adv. Enz. Regul. [1984] 22, 27-55) may be used to assess interactions with combinations of drugs.
  • In vivo animal models such as human breast tumour xenografts growing in immunocompromised rodents may be used to examine the effects of single agents and combinations.
  • Tumours will usually be implanted subcutaneously and tumour growth may be assessed by caliper measurements every few days.
  • Drugs may be administered to tumour bearing animals by various routes including oral, intravenous, or intraperitoneal. Effects of treatment may be assessed by endpoints such as growth delay or %T/C.
  • Beneficial combinations may be identified by, for example, demonstrating that a well tolerated combination produces greater inhibition than its most active single agent component. Synergistic combinations may be identified by demonstrating that a combination produces inhibition that is greater than the sum of the effects of the single agents administered alone.

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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention porte sur un produit thérapeutique combiné comprenant de l'anastrozole et un inhibiteur double de la prényl transférase inhibant à la fois la farnésyl transférase et la géranylgéranyl transférase-1, et s'utilisant simultanément, séquentiellement ou séparément pour le traitement ou la prophylaxie du cancer du sein.
PCT/GB2005/002079 2004-05-28 2005-05-25 Produit combine comprenant de l'anastrozole et un inhibiteur double de la prenyl transferase WO2005117864A1 (fr)

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GB0412004A GB0412004D0 (en) 2004-05-28 2004-05-28 Combination product
GB0412004.4 2004-05-28
GB0417722A GB0417722D0 (en) 2004-08-10 2004-08-10 Combination product
GB0417722.6 2004-08-10

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007092285A3 (fr) * 2006-02-02 2008-10-09 Link Medicine Corp Traitement de synucléinopathies
US8232402B2 (en) 2008-03-12 2012-07-31 Link Medicine Corporation Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications
US8343996B2 (en) 2008-11-13 2013-01-01 Astrazeneca Ab Azaquinolinone derivatives and uses thereof
WO2015168648A1 (fr) * 2014-05-01 2015-11-05 Eiger Biopharmaceuticals, Inc. Traitement d'infection de virus d'hépatite delta
US10076512B2 (en) 2014-05-01 2018-09-18 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US10835496B2 (en) 2015-04-21 2020-11-17 Eiger Biopharmaceuticals, Inc. Pharmaceutical compositions comprising lonafarnib and ritonavir
US11311519B2 (en) 2014-05-01 2022-04-26 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001046137A1 (fr) * 1999-12-22 2001-06-28 Astrazeneca Ab Inhibiteurs de farnesyltransferase
WO2003053438A1 (fr) * 2001-12-10 2003-07-03 Astrazeneca Ab Utilisation de l'anastrozole pour le traitement du cancer du sein a un stade precoce chez les femmes menopausees
WO2004012728A1 (fr) * 2002-07-30 2004-02-12 Novartis Ag Combinaison d'un inhibiteur de l'aromatase et d'un biphosphonate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001046137A1 (fr) * 1999-12-22 2001-06-28 Astrazeneca Ab Inhibiteurs de farnesyltransferase
WO2003053438A1 (fr) * 2001-12-10 2003-07-03 Astrazeneca Ab Utilisation de l'anastrozole pour le traitement du cancer du sein a un stade precoce chez les femmes menopausees
WO2004012728A1 (fr) * 2002-07-30 2004-02-12 Novartis Ag Combinaison d'un inhibiteur de l'aromatase et d'un biphosphonate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STEPHENS TREVOR C ET AL: "AZD3409, a novel, oral, protein prenylation inhibitor with promising preclinical antitumor activity.", PROCEEDINGS OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH ANNUAL MEETING, vol. 44, July 2003 (2003-07-01), & 94TH ANNUAL MEETING OF THE AMERICAN ASSOCIATION FOR CANCER RESEARCH; WASHINGTON, DC, USA; JULY 11-14, 2003, pages 970, XP001207255, ISSN: 0197-016X *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007092285A3 (fr) * 2006-02-02 2008-10-09 Link Medicine Corp Traitement de synucléinopathies
US8232402B2 (en) 2008-03-12 2012-07-31 Link Medicine Corporation Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications
US8343996B2 (en) 2008-11-13 2013-01-01 Astrazeneca Ab Azaquinolinone derivatives and uses thereof
WO2015168648A1 (fr) * 2014-05-01 2015-11-05 Eiger Biopharmaceuticals, Inc. Traitement d'infection de virus d'hépatite delta
US10076512B2 (en) 2014-05-01 2018-09-18 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US10828283B2 (en) 2014-05-01 2020-11-10 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US11311519B2 (en) 2014-05-01 2022-04-26 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US11793793B2 (en) 2014-05-01 2023-10-24 Eiger Biopharmaceuticals, Inc. Treatment of hepatitis delta virus infection
US12290509B2 (en) 2014-05-01 2025-05-06 Eit Pharma, Inc. Treatment of hepatitis delta virus infection
US10835496B2 (en) 2015-04-21 2020-11-17 Eiger Biopharmaceuticals, Inc. Pharmaceutical compositions comprising lonafarnib and ritonavir
US11517532B2 (en) 2015-04-21 2022-12-06 Eiger Biopharmaceuticals, Inc. Methods of treating hepatitis delta virus infection
US12029819B2 (en) 2015-04-21 2024-07-09 Eiger Biopharmaceuticals, Inc. Pharmaceutical compositions comprising lonafarnib and ritonavir

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