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WO2010061208A2 - Traitement therapeutique 555 - Google Patents

Traitement therapeutique 555 Download PDF

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Publication number
WO2010061208A2
WO2010061208A2 PCT/GB2009/051471 GB2009051471W WO2010061208A2 WO 2010061208 A2 WO2010061208 A2 WO 2010061208A2 GB 2009051471 W GB2009051471 W GB 2009051471W WO 2010061208 A2 WO2010061208 A2 WO 2010061208A2
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WO
WIPO (PCT)
Prior art keywords
cancer
compound
combination
treatment
taxane
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Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2009/051471
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English (en)
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WO2010061208A3 (fr
Inventor
Daniel Mark Hickinson
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AstraZeneca UK Ltd
AstraZeneca AB
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AstraZeneca UK Ltd
AstraZeneca AB
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Publication of WO2010061208A2 publication Critical patent/WO2010061208A2/fr
Publication of WO2010061208A3 publication Critical patent/WO2010061208A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a combination comprising 4-(3-chloro-2- fluoroanilino)-7-methoxy-6- ⁇ [ 1 -(N-methylcarbamoylmethyl)piperidin-4-yl ]oxy ⁇ quinazoline, or a pharmaceutically acceptable salt thereof, hereafter "Compound (I)", and a taxane.
  • the combination is expected to be useful for the treatment or prophylaxis of cancer.
  • the invention also relates to a pharmaceutical composition comprising such combinations and to the use thereof in the manufacture of a medicament for use in the treatment or prophylaxis of cancer, such as breast cancer.
  • the erbB family of receptor tyrosine kinases which include EGFR, erbB2, erbB3 and erbB4, are frequently involved in driving the proliferation and survival of tumour cells and as such the erbB family of receptors is implicated in a number of epithelial cancers (reviewed in Olayioye et al., EMBO J., 2000, 1_9, 3159), including for example breast cancer (Sainsbury et al., Brit. J.
  • NSCLCs non-small cell lung cancers
  • adenocarcinomas Cerny et al., Brit. J. Cancer. 1986, 54, 265; Reubi et al., Int. J. Cancer. 1990, 45, 269; Rusch et al., Cancer Research.
  • gastrointestinal cancer such as colon, rectal or stomach cancer
  • gastrointestinal cancer such as colon, rectal or stomach cancer
  • gastrointestinal cancer such as colon, rectal or stomach cancer
  • Kapitanovic et al. Gastroenterology, 2000, 112, 1103; Ross et al.. Cancer Invest., 2001, 19. 554
  • cancer of the prostate (Visakorpi et al., Histochem. J.. 1992, 24, 481; Kumar et al.. 2000, 32, 73; Scher et al.. J. Natl. Cancer Inst.. 2000, 92, 1866), leukaemia (Konaka et al., CeU, 1984, 37, 1035, Martin-Subero et al..
  • an inhibitor of erbB receptor tyrosine kinases should be of value as a selective inhibitor of the growth of certain carcinomas.
  • a number of erbB tyrosine kinase inhibitors have demonstrated clinical benefit and a number of erbB tyrosine kinase inhibitors have been approved for use in the treatment of cancer.
  • the EGFR tyrosine kinase inhibitors gefitinib and erlotinib for the treatment of advanced non-small cell lung cancer and lapatinib, which has erbB2 tyrosine kinase inhibitory activity, for use in metastatic breast cancer.
  • Several other EGFR and erbB2 tyrosine kinase inhibitors are currently in development.
  • WO2005/028469 then goes on to describe examples of such conjoint treatment including surgery, radiotherapy and many different types of chemotherapeutic agent.
  • Compound (I) is an erbB receptor tyrosine kinase inhibitor, in particular Compound (I) is a potent inhibitor of EGFR, erbB2 and erbB3 receptor signalling.
  • erbB3 does not have an intrinsic tyrosine kinase activity, activation of the erbB3 receptor is achieved only through the formation of heterodimeric receptor complexes with other kinase-active receptors including particularly EGFR and erbB2.
  • EGFR and erbB2 heterodimers formed with erbB3 are thought to drive tumour growth in tumours where these receptors are expressed.
  • Compound (I) inhibits erbB3 mediated signalling through the inhibition of phosphorylation of erbB3 following ligand stimulated EGFR/erbB3 and/or erbB2/erbB3 heterodimerisation. Accordingly, Compound (I) exhibits a unique erbB tyrosine kinase inhibitory effect compared to other erbB tyrosine kinase inhibitors such as gef ⁇ tinib or erlotinib that act primarily as EGFR tyrosine kinase inhibitors and lapatinib which is primarily an erbB2 inhibitor with some EFGR inhibitory activity.
  • Compound (I) exhibits improved anti-tumour effects compared to EGFR tyrosine kinase inhibitors such as gef ⁇ tinib, erlotinib, herceptin and lapatinib. Without wishing to be bound by theory, it is thought that the improved properties may result from the inhibition of the erbB3 mediated signalling by Compound (I).
  • Taxanes are anti-mitotic agents that bind to tubulin and act to stabilise microtubule polymerisation thereby disrupting the normal equilibrium involved in microtubule assembly and deconstruction and therefore retards microtubule functioning.
  • Microtubules are essential to cell division and cells exposed to taxanes are arrested in the premitotic G2 phase and fail to divide. Cells treated with these drugs are held in mitosis, i.e. they interfere with the cell division process, this may eventually result in cell death due to unsuccessful mitosis.
  • Taxanes such as paclitaxel and docetaxel have been approved for use in the treatment of a number of cancers, including ovary, breast, lung, head and neck, prostate and gastric carcinomas.
  • the present inventors have unexpectedly found that the combination of Compound (I) and a taxane can have a particular beneficial and/or synergistic anti-tumour effect and may therefore be useful in the treatment of cancer.
  • a combination comprising Compound (I) and a taxane.
  • taxane refers to any chemical analogue which exerts its anticancer effect by stabilization of the tubulin microtubules involved in cell division.
  • taxanes include: • (2aR,3aR,4aR,6R,9S,l lS,12S,12aR,12bS)-6,12b-diacetoxy-9-[3(S)-(tert- butoxycarbonylamino)-2(R)-hydroxy-3-phenylpropionyloxy]-12-benzoyloxy-l l- hydroxy-8,13,13-trimethyl-2a,3,3a,4,5,6,9,10,l l,12,12a,12b-dodecahydro-lH-7,l l- methanocyclodeca[3,4]-cyclopropa[4,5]benz[l,2-b]oxet-5-one dihydrate;
  • Paclitaxel (Taxol), • BMS- 184476 (7-methylthiomethylpaclitaxel);
  • taxanes such as paclitaxel and docetaxel.
  • Particular examples of such formulations include: • conventional formulations of paclitaxel or docetaxel, for example the currently approved Taxol and Taxotere formulations;
  • biocompatible polymers particularly proteins such as albumin, more particularly nano-particle or micro-particle formulations of paclitaxel or docetaxel with albumin, for example Abraxane (described in US 5,439,686 and US 6,749,868) or NAB-docetaxel (described in, for example US 20080161382, US20070117744 and US
  • polymer conjugates particularly polymer conjugates of paclitaxel or docetaxel, more particularly conjugates of docetaxel or paclitaxel with poly-L-glutamate, for example Opaxio (also known as Xyotax, paclitaxel poliglumex, CT-2103 and described in for example Li C; Poly ( L -glutamic acid) - anticancer drug conjugates; Adv. Drug Deliv.
  • Opaxio also known as Xyotax, paclitaxel poliglumex, CT-2103 and described in for example Li C; Poly ( L -glutamic acid) - anticancer drug conjugates; Adv. Drug Deliv.
  • conjugates of docetaxel or paclitaxel with a fatty acid particularly conjugates of paclitaxel or docetaxel with docosahexaenoic acid (DHA), for example, Taxoprexin (DHA-paclitaxel, described in for example Bradley MO et al. Tumor targeting by covalent conjugation of a natural fatty acid to paclitaxel; Clin. Cancer Res. 2001; 7:
  • microparticle compositions such as the porous microparticle formulations described in US 6,645,528, for example the microparticle formulation of paclitaxel AI-850, comprising paclitaxel nanoparticles in a porous, hydrophilic matrix, composed primarily of a sugar; and
  • emulsions of paclitaxel or docetaxel in vitamin E for example Tocosol.
  • Further formulations of paclitaxel and docetaxel are also known, further examples of which are mentioned hereafter.
  • Such formulations of taxanes may also be used as the taxane component of the combinations according to the present invention.
  • the taxane is selected from paclitaxel, docetaxel and Abraxane.
  • the taxane is paclitaxel.
  • the taxane is docetaxel.
  • the taxane is Abraxane. Therefore according to a further aspect of the invention there is provided a combination comprising Compound (I) and a taxane selected from paclitaxel, docetaxel and Abraxane.
  • a combination comprising Compound (I) and a Abraxane. According to a further aspect of the invention there is provided a combination comprising Compound (I) and NAB-docetaxel.
  • a compound or a pharmaceutically acceptable salt thereof is referred to this refers to the compound only. In another aspect this refers to a pharmaceutically acceptable salt of the compound.
  • cancer refers to, for example, tumours expressing one or more of the erbB family of receptors, such as EFGR, erbB2 and/or erbB3 receptors.
  • cancer refers to oesophageal cancer, myeloma, hepatocellular, pancreatic, cervical cancer, Ewing's tumour, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer - non small cell lung cancer (NSCLC), and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, brain cancer, renal cancer, lymphoma and leukaemia.
  • NSCLC non small cell lung cancer
  • SCLC small cell lung cancer
  • cancer refers to breast cancer, lung cancer (for example NSCLC), gastric cancer, head and neck cancer, colorectal cancer and/or ovarian cancer.
  • cancer refers to SCLC, NSCLC, colorectal cancer, ovarian cancer and/or breast cancer.
  • SCLC refers to SCLC.
  • NSCLC refers to colorectal cancer.
  • head and neck cancer refers to gastric cancer.
  • gastric cancer refers to ovarian cancer.
  • breast cancer more particularly it refers to breast cancer.
  • hormone receptor positive breast cancer especially to hormone receptor positive breast cancer in post-menopausal women.
  • non-metastatic hormone receptor positive breast cancer for example non-metastatic hormone receptor positive breast cancer in post-menopausal women. Still furthermore it refers to non- metastatic estrogen and/or progesterone receptor positive breast cancer, especially to non- metastatic estrogen and/or progesterone receptor positive breast cancer in post-menopausal women. In addition, more particularly it refers to metastatic hormone receptor positive breast cancer, especially to metastatic hormone receptor positive breast cancer in postmenopausal women. Still furthermore it refers to metastatic estrogen and/or progesterone receptor positive breast cancer, especially to metastatic estrogen and/or progesterone receptor positive breast cancer in post-menopausal women.
  • bladder cancer, oesophageal cancer, gastric cancer, melanoma, cervical cancer and/or renal cancer In addition it refers to endometrial, liver, stomach, thyroid, rectal and/or brain cancer.
  • the cancer is in a non-metastatic state.
  • particularly the cancer is in a metastatic state.
  • particularly the cancer is in a metastatic state, and more particularly the cancer produces skin metastases.
  • the cancer is in a metastatic state, and more particularly the cancer produces lymphatic metastases.
  • particularly the cancer is in a metastatic state, and more particularly the cancer produces brain metastases.
  • particularly the cancer is in a metastatic state, and more particularly the cancer produces bone metastases.
  • the term "low over-expression of erbB2" refers to tumours which express low levels of erbB2, for example those tumours that are not eligible for treatment with the drug Herceptin, more particularly tumours that are Her2 fluorescent in-situ hybridization (FISH) negative. Such tumours are those tumours which have non-amplified levels of erbB2.
  • FISH Her2 fluorescent in-situ hybridization
  • the cancer is a cancer with low over-expression of erbB2 selected from one or more of:
  • the cancer is a cancer with non-amplified levels of erbB2 selected from one or more of:
  • a breast cancer which is Her2++by IHC and Her2 FISH negative.
  • the term "advanced cancer” refers to a cancer that is locally advanced (where the cancer has spread from the primary tumour to surrounding tissues) or metastatic cancer. Particularly “advanced cancer” refers to metastatic cancer. Testing for Her2 in breast cancer is described in the Journal of Clinical Oncology, VoI 25, No 1 (January 1), 2007, pi 18-145, A. C. Wolff et al.
  • the anti-cancer effect of the combination according to the invention may be measured in terms of one or more of an anti-tumour effect, the extent of the response (for example reduced tumour volume or reduced tumour burden), the response rate, the clinical benefit rate (the sum of complete response, partial response and stable disease) the time to disease progression, progression-free survival and the overall survival rate.
  • an anti-tumour effect for example reduced tumour volume or reduced tumour burden
  • the response rate for example reduced tumour volume or reduced tumour burden
  • the response rate for example reduced tumour volume or reduced tumour burden
  • the clinical benefit rate the sum of complete response, partial response and stable disease
  • the anti-tumour effects of the combination according to the invention may be for example one or more of inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment or slowing of disease progression.
  • the combination use of Compound (I) and a taxane may also have a beneficial effect in preventing the onset of cancer in warm-blooded animals, such as man.
  • Pharmaceutically-acceptable salts mentioned herein include, for example, salts with alkali metals (such as sodium, potassium or lithium), alkaline earth metals (such as calcium or magnesium), ammonium salts, and salts with organic bases affording physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine and morpholine.
  • examples of pharmaceutically-acceptable salts include, pharmaceutically-acceptable acid-addition salts with hydrogen halides, sulphuric acid, phosphoric acid and with organic acids such as citric acid, maleic acid, methanesulphonic acid and p-toluenesulphonic acid.
  • the compounds may exist in zwitterionic form.
  • a particular pharmaceutically acceptable salt of Compound (I) is a di-fumarate salt of Compound (I).
  • a combination comprising Compound (I) and a taxane, for use as a medicament.
  • a combination comprising Compound (I) and a taxane, for use in the treatment of a cancer.
  • a combination comprising Compound (I) and a taxane, for use in the treatment of hormone receptor positive breast cancer, for example estrogen receptor positive breast cancer.
  • a combination comprising Compound (I) and a taxane, for use in the treatment of hormone receptor negative breast cancer, for example estrogen receptor negative breast cancer.
  • a combination comprising Compound (I) and a taxane, for use in the treatment of breast cancer with low over-expression of erbB2.
  • a combination comprising Compound (I) and a taxane, for use in the treatment of advanced breast cancer with low over-expression of erbB2.
  • a combination comprising Compound (I) and a taxane, for use in the first line treatment of advanced breast cancer with low over-expression of erbB2.
  • a combination comprising Compound (I) and a taxane, for use in the treatment of advanced breast cancer with low over-expression of erbB2 in a patient that has not received prior chemotherapy.
  • a combination comprising Compound (I) and a taxane, for use in the treatment of hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2.
  • hormone receptor positive for example ER and/or PR receptor positive
  • a combination comprising Compound (I) and a taxane, for use in the treatment of advanced hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2.
  • advanced hormone receptor positive for example ER and/or PR receptor positive
  • a combination comprising Compound (I) and a taxane, for use in the first-line treatment of advanced hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2.
  • advanced hormone receptor positive for example ER and/or PR receptor positive
  • a combination comprising Compound (I) and a taxane, for use in the treatment of advanced hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2 in a patient that has not received prior chemotherapy.
  • advanced hormone receptor positive for example ER and/or PR receptor positive
  • a combination comprising Compound (I) and a taxane, for use in the treatment of hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2.
  • hormone receptor negative for example ER and/or PR receptor negative
  • a combin Laattiioonn,, ccoommpprriissiinngg Compound (I) and a taxane for use in tthhee ttrreeaattmmeenntt ooff advanced hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2.
  • a combination comprising Compound (I) and a taxane, for use in the first-line treatment of advanced hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2.
  • advanced hormone receptor negative for example ER and/or PR receptor negative
  • a combination comprising Compound (I) and a taxane, for use in the treatment of advanced hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2 in a patient that has not received prior chemotherapy.
  • advanced hormone receptor negative for example ER and/or PR receptor negative
  • the combination according to the invention is the first chemotherapy used to treat the patient.
  • the patient may however have recieved other non-chemotherapeutic treatments of the cancer prior to, during or after use of the combination according to the invention.
  • the patient may undergo surgery to remove some or all of the tumour and/or radiotherapy prior to treatment with a combination according to the invention.
  • Compound (I) and the taxane may be used as a single composition containing Compound (I) and the taxane. Accordingly, a further aspect of the invention provides a pharmaceutical composition which comprises Compound (I) and a taxane in association with a pharmaceutically acceptable diluent or carrier.
  • Compound (I) and the taxane may be used as two individual compositions, one containing Compound (I) and one containing the taxane, wherein the two compositions are administered simultaneously, separately or sequentially.
  • a further aspect of the invention provides a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises a taxane in association with a pharmaceutically acceptable diluent or carrier.
  • a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • a method of treating hormone receptor positive breast cancer for example estrogen receptor positive breast cancer, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • a method of treating breast cancer with low over-expression of erbB2 in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • a method of treating advanced breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • a method for the first-line treatment of advanced breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • a method of treating advanced breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man, that has not received prior chemotherapy, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • a method of treating hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • hormone receptor positive for example ER and/or PR receptor positive
  • a method of treating advanced hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • advanced hormone receptor positive for example ER and/or PR receptor positive
  • a method of treating advanced hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man that has not received prior chemotherapy, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • advanced hormone receptor positive for example ER and/or PR receptor positive
  • a method for the first-line treatment of advanced hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • advanced hormone receptor positive for example ER and/or PR receptor positive
  • a method of treating hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • a method of treating advanced hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2 in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • a method of treating advanced hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man that has not received prior chemotherapy, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • advanced hormone receptor negative for example ER and/or PR receptor negative
  • a method for the first-line treatment of advanced hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane.
  • advanced hormone receptor negative for example ER and/or PR receptor negative
  • erbB2 for example ER and/or PR receptor negative breast cancer with low over-expression of erbB2
  • administering to said animal an effective amount of Compound (I) in combination with an effective amount of a taxane for the avoidance of doubt, where the treatment of cancer is indicated, it is to be understood that this also refers to the prevention of metastases and the treatment of metastases, i.e. cancer spread.
  • the combination of the present invention could be used to treat a patient who has no metastases to stop them occurring, or to lengthen the time period before they occur, and to a patient who already has metastases to treat the metastases themselves.
  • the combination of the present invention could be used to treat a patient with a cancer where the cancer is either in a metastatic or a non-metastatic state.
  • the treatment of cancer also refers to treatment of an established primary tumour or tumours and developing primary tumour or tumours.
  • the treatment of cancer relates to the prevention of metastases.
  • the treatment of cancer relates to the treatment of metastases.
  • the treatment of cancer relates to treatment of an established primary tumour or tumours or developing primary tumour or tumours.
  • the treatment of cancer relates to an adjuvant treatment.
  • the treatment of cancer refers to the neo-adjuvant treatment of cancer.
  • the treatment of cancer relates to first- line treatment of cancer.
  • the combination according to the invention is used as an adjuvant treatment of breast cancer which has a tumour with low over- expression of erbB2, for example as an adjuvant treatment of estrogen receptor positive breast cancer which has a tumour with low over-expression of erbB2.
  • the combination is used as a first line treatment of advanced breast cancer, which has a tumour with low over-expression of erbB2.
  • the combination according to the invention is used as a neo-adjuvant treatment of breast cancer, for example advanced breast cancer, which has a tumour with low over-expression of erbB2.
  • adjuvant therapy refers to a treatment given following removal of the primary tumour.
  • removal of the primary tumour may be effected by, for example, surgery (for example lumpectomy or mastectomy) and/or radiotherapy.
  • non-adjuvant therapy refers to a treatment given prior to removal of the primary tumour by surgery or radiotherapy.
  • the treatment of the cancer refers to the first- line treatment of the cancer. In another embodiment the treatment of the cancer refers to the second- line treatment of the cancer (a treatment administered following failure of the first- line treatment of the cancer).
  • the treatment of cancer also refers to the prevention of cancer per se.
  • the effect of a method of treatment of the present invention is expected to be at least equivalent to the addition of the effects of each of the components of said treatment used alone, that is, of each of Compound (I) and the taxane used alone.
  • the effect of a method of treatment of the present invention is expected to be greater than the addition of the effects of each of the components of said treatment used alone, that is, of each of Compound (I) and the taxane used alone.
  • the effect of a method of treatment of the present invention is expected to be a synergistic effect.
  • a treatment using the combination according to the invention 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 achievable on dosing one or other of the components of the combination treatment at its conventional dose.
  • the effect of the combination treatment is synergistic if the effect is therapeutically superior to the effect achievable with Compound (I) or the taxane alone.
  • the effect of the combination treatment is synergistic if a beneficial effect is obtained in a group of patients that does not respond (or responds poorly) to Compound (I) or the taxane alone.
  • the effect of the combination treatment is defined as affording a synergistic effect if one of the components is dosed at its conventional dose and the other component(s) is/are 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 treatment.
  • synergy is deemed to be present if the conventional dose of Compound (I) or the taxane may be reduced without detriment to one or more of the extent of the response, the response rate, the time to disease progression and survival data, in particular without detriment to the duration of the response, but with fewer and/or less troublesome side-effects than those that occur when conventional doses of each component are used.
  • kits comprising Compound (I) and a taxane; optionally with instructions for use.
  • kits comprising: a) Compound (I), in a first unit dosage form; b) a taxane, in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • kits comprising: a) Compound (I), together with a pharmaceutically acceptable diluent or carrier, in a first unit dosage form; b) a taxane, together with a pharmaceutically acceptable diluent or carrier, in a second unit dosage form; and c) container means for containing said first and second dosage forms; and optionally d) with instructions for use.
  • a pharmaceutical composition which comprises Compound (I), in association with a pharmaceutically acceptable diluent or carrier, in combination with a pharmaceutical composition which comprises a taxane in association with a pharmaceutically acceptable diluent or carrier for use in the treatment of cancer.
  • the pharmaceutical compositions of compound (I) described herein may be in a form suitable for oral administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
  • a suitable dosage form for a taxane such as docetaxel or paclitaxel is for example a formulation suitable for parenteral, particularly intravenous administration.
  • parenteral compositions of paclitaxel and docetaxel are well known in the art.
  • the above compositions may be prepared in a conventional manner.
  • Compound (I) is suitably formulated as a tablet using the following excipients:
  • Tablet Core Compound (I); lactose; microcrystalline cellulose; crospovidone; polyvidone (PVP); and magnesium stearate
  • the tablet core may be coated with a conventional film-coating such as an HPMC based film coating which optionally contains one or more colorants and/or light protective agents.
  • a conventional film-coating such as an HPMC based film coating which optionally contains one or more colorants and/or light protective agents.
  • Compound (I) is used in the tablet as the Compound (I) difumarate salt, more specifically the Compound (I) difumarate salt.
  • the Compound (I) may be milled prior to formulation into the tablet to provide a uniform particle size distribution of the Compound (I) in the tablet.
  • Compound (I) difumarate may be milled to provide an average particle size of about 5 ⁇ m. Suitable milling methods are well known.
  • the tablets may be prepared using conventional methods and as illustrated in the Examples. The taxane may be formulated according to known procedures.
  • Paclitaxel for example various formulations of Paclitaxel are known, including the currently approved intravenous formulations of paclitaxel and docetaxel.
  • taxane formulations include those mentioned hereinbefore, including Abraxane; AI-850; DO/NDR/02 (a cremophor- free paclitaxel formulation); EndoTag-1; liposome encapsulated paclitaxel; LPE/PLP Paclitaxel; MPI-5019; NK-105; OncoGel; Paclimer Microspheres; S-8184; ABI-007; NOVA- 12005; SP-IOlOC-O; Pacligel; SP-IOlOC; Paxoral, Xorane; Genexol; Tocosol; PacoExtra; Yewtaxan; Taxosomes; Atrigel; Xyotax (paclitaxel polyglumex; polyglutamated paclitaxel) and SP 101OC.
  • kits comprising Compound (I) and a taxane; optionally with instructions for use; for use in the treatment of cancer.
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the treatment of cancer, in a warm-blooded animal, such as man.
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the treatment of hormone receptor positive breast cancer, for example estrogen receptor positive breast cancer, in a warm-blooded animal, such as man.
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the treatment of breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man.
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use as the first-line treatment of advanced breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man.
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the treatment of advanced breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man that has not received prior chemotherapy.
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the treatment of hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man.
  • hormone receptor positive for example ER and/or PR receptor positive
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the treatment of advanced hormone receptor positive (for example ER and/or PR receptor positive) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man that has not received prior chemotherapy.
  • advanced hormone receptor positive for example ER and/or PR receptor positive
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the treatment of hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man.
  • hormone receptor negative for example ER and/or PR receptor negative
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the treatment of advanced hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man that has not received prior chemotherapy.
  • advanced hormone receptor negative for example ER and/or PR receptor negative
  • Compound (I) in combination with a taxane, in the manufacture of a medicament for use in the first- line treatment of advanced hormone receptor negative (for example ER and/or PR receptor negative) breast cancer with low over-expression of erbB2, in a warm-blooded animal, such as man.
  • advanced hormone receptor negative for example ER and/or PR receptor negative
  • a combination treatment comprising the administration of an effective amount of Compound (I), optionally together with a pharmaceutically acceptable diluent or carrier, in combination with an effective amount of a taxane, optionally together with a pharmaceutically acceptable diluent or carrier to a warm-blooded animal, such as man in need of such therapeutic treatment, for use in the treatment of cancer.
  • Compound (I), or a pharmaceutically acceptable salt thereof, administered would be that sufficient to provide the desired pharmaceutical effect.
  • Compound (I) could be administered to a warm-blooded animal orally, at a unit dose less than Ig daily but more than lmg.
  • Particularly Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 250 mg per day.
  • Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 160 mg per day.
  • Compound (I) could be administered to a warm-blooded animal orally, at a unit dose less than Ig daily but more than lmg.
  • Particularly Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 250 mg per day.
  • Compound (I) could be administered to a warm-blooded animal, at a
  • Compound (I) could be administered to a warm-blooded animal, at a unit dose of less than 50 mg per day.
  • the dose of Compound (I) may be administered as a single daily dose or as multiple fractions of the total daily dose.
  • the total daily dose of Compound (I) may be administered as two doses, which may be the same or different.
  • each fraction of the total daily dose would be approximately equal.
  • compound (I) may be administered as a one or more tablets containing, for example 1, 2.5, 10, 40 or lOOmg of Compound (I).
  • the taxane will normally be administered in accordance with approval guidelines. Suitable doses are both species and schedule dependent with respect to their maximum tolerated doses.
  • the taxane when it is paclitaxel, it may be administered intravenously on a 4-week cycle, wherein the paclitaxel is administered once a week for three weeks, followed by one week without treatment. The cycle may then be repeated as required, for example to the point of disease progression or treatment failure.
  • the paclitaxel is intravenous infusion is administered over a 3 or 24 hour period.
  • compound (I) is administered 2 times daily and paclitaxel is administered using the 4-week cycle described above.
  • the dose of compound (I) and the taxane will necessarily be varied depending upon the host treated, the particular route of administration, and the severity of the illness being treated. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient. The dosage of each of the drugs and their proportions have to be composed so that the best possible treatment effects, as defined by national and international guidelines (which are periodically reviewed and re-defined), will be met.
  • Compound (I) may be prepared as described in Example 1 of WO2005/028469. Alternatively Compound (I) may be prepared as described in the Examples.
  • Figures 1, 2 and 3 show the effect on cell viability of treating MCF-7, SKBr3 and BT474c cells respectively with a combination of Compound (I) (0.2 ⁇ M) + Taxol (2 OnM/ 100OnM) compared to either compound (I) alone or Taxol alone.
  • the y-axis shows the optical density (OD) measured using a spectrophotometer at a wavelength of 49OnM.
  • NTC optical density
  • Figure 4 shows the combination index (CI) for MCF-7, SKBr3 and BT474c cell lines tested with a combination of Compound (I) and Taxol relative to the use of either Compound (I) or Taxol alone.
  • Figure 5 shows the results of an anti tumour study in a BT474c xenograft in female
  • Control A 1% Polysorbate 80 p.o. twice daily
  • Control B 5% Cremaphor/5% Ethanol/90% PBS i.p. once weekly (trace with black squares).
  • Group 2 Compound (I) @ 12.5mg/kg p.o. twice daily (trace with circles)
  • Group 3 Taxol @ 15mg/kg i.p. once weekly (trace with triangles pointing up)
  • Group 4 Taxol @ 7.5mg/kg i.p. once weekly (trace with triangles pointing down)
  • Group 5 Compound (I) @ 12.5mg/kg p.o. twice daily + Taxol @ 15mg/kg i.p. once weekly (trace with triangle pointing left)
  • Group 6 Compound (I) @ 12.5mg/kg po twice daily + Taxol @ 7.5mg/kg i.p. once weekly (trace with triangle pointing right).
  • the x-axis shows the days of dosing.
  • the y- axis shows the mean tumour volume on cm 3 +/- the standard experimental measurement error (SEM).
  • Figure 6 shows an X-ray powder diffraction pattern (XRPD) for Compound (I) difumarate Form A.
  • the x-axis shows the 2-theta value and the y-axis the counts.
  • Step 1 6-Acetoxy-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride 6-Acetoxy-4-hydroxy-7-methoxyquinazoline (21.4 kg, 89.3 mol) was suspended in toluene (150 kg). To this was added N-ethyldiisopropylamine (13.3 kg, 103 mol). The brown suspension was heated to 70 0 C then phosphorus oxychloride (36.0 kg, 228 mol) was charged. The reaction mixture was stirred at 70 0 C for 5 hours. Further toluene 84.0 kg) was added followed by 3-chloro-2-fluoraniline (14.88 kg, 102 mol).
  • reaction mixture was stirred at 70 0 C for 2 hours during which time a solid precipitated.
  • the suspension was cooled to 25°C and held at this temperature for 93 hours.
  • the reaction mixture was filtered and the filter cake washed with toluene (2 x 55.5 kg).
  • 6-Acetoxy-4-(3 -chloro-2-fluoroanilino)-7-methoxyquinazoline hydrochloride from step 1 (33.5 kg, 82.2 mol) was suspended in methanol (198 kg). To the stirred suspension at 25°C was added water (86 kg) and sodium hydroxide (31.5 kg, 32%). The resulting solution was stirred at 60 0 C for 4.5 hours and then cooled to 25°C. Acetic acid (approximately 16.0 kg) was added until a pH of 5.5-6.0 was achieved at which point the product precipitates from solution. After the addition of further methanol (5.5 kg) the suspension was stirred for 90 minutes.
  • the product was filtered then washed with 25% aqueous methanol (39.0 kg MeOH + 17.0 kg Water) and then methanol (55.5 kg).
  • the crude solid was dried under vacuum at 40 0 C.
  • the crude solid was slurried with water (145 kg) and stirred for 2 hours at 65°C.
  • the slurry was cooled to 20 0 C and filtered.
  • Step 3 ⁇ -ird-fert-ButoxycarbonvDpiperidin ⁇ -ylioxyl- ⁇ Q-chloro ⁇ -fluoroanilino)-?- methoxy quinazoline 4-(3-Chloro-2-fluoroanilino)-6-hydroxy-7-methoxy quinazoline from Step 2
  • the batch was stirred at 80 0 C for a further 60 minutes then cooled to 20 0 C over 2 hours, during which time the product crystallized.
  • the product was isolated by filtration.
  • the product was dissolved in hot (reflux) methanol (200 L). To this mixture was added water (20 L), which induced crystallization. The suspension was cooled to 0 0 C and filtered.
  • Step 4 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-r(piperidin-4-yl)oxy1 ⁇ uinazoline
  • the batch was stirred at 65 0 C for a further 2 hours to establish crystallisation.
  • the slurry was cooled to 20 0 C over 6 hours.
  • the product was isolated by filtration.
  • the filter cake was slurried with aqueous ethanol (ethanol 117 ml, water 58 ml) and then displacement washed with aqueous ethanol (ethanol 117 ml, water 58 ml).
  • the filter cake was then slurried with water (175 ml) and then displacement washed with water (175 ml).
  • Aqueous sodium hydroxide (15.51g 182.2 mmoles) was charged followed by 2-methyltetrahydrofuran (58.Og). The reaction mixture was heated to 60 0 C, which upon settling gave two layers and the lower aqueous layer was discarded. The volume of the reaction mixture was reduced by vacuum distillation and methyl tert-butyl ether (18.54g) was added to give a slurry which was cooled to 10 0 C. and then the solid was collected by filtration.
  • Isopropanol (15.8 kg was added and the reaction mixture distilled to remove 15.6 kg of distillates. Crystallisation occurred during the distillation. Isopropanol (21 kg) was added and the reaction cooled to 0 0 C over 8 hours and held for 1 hour before isolation by filtration.
  • the filter used to clarify the fumaric acid solution was then washed with isopropanol (37 ml). After holding for 1 hour at 40 0 C the reaction was cooled to 20 0 C over 1 hour. The reaction mixture was held for 13.5 hours before isolating the product by filtration.
  • the solution was distilled such that 25.2 ml of distillates were collected.
  • the solution was cooled to 40 0 C.
  • a clarified solution of fumaric acid (1.38 g, 11.90 mmol) in isopropanol (21 ml) was then added over 1 hour.
  • Compound (I) difumarate Form A seed was added (3.7 mg, 5.3 ⁇ mol).
  • the filter used to clarify the fumaric acid solution was then washed with isopropanol (2 ml). After holding for 1 hour at 40 0 C the reaction was cooled to 20 0 C over 2 hours. The reaction mixture was held for 15 hours before isolating the product by filtration.
  • Compound (I) difumarate Form A is a free flowing powder.
  • X-ray powder diffraction of Compound (I) difumarate ( Figure 6) indicates that the material is crystalline.
  • the X-Ray Powder Diffraction analysis was carried out using a Siemens D5000 powder X- ray diffractometer fitted with a scintillation detector; the X-Ray source was Cu IQ x , giving a wavelength of 1.54A; data were collected over the range 2-theta 2 - 40°, in increments of 2-theta 0.02°, with 1 second per increment and was categorised into the categories identified in the table below:
  • Compound (I) tablets may be manufactured using, for example, a wet granulation, compression and film coating process.
  • the powdered ingredients are charged to a mixer and mixed to produce a uniform distribution of drug substance.
  • a binder solution is prepared and added to the powders with further mixing until a suitable wet mass is formed.
  • the wet mass is passed through a screen and the resultant granules dried to an appropriate moisture content.
  • the dried granules are passed through an appropriately sized screen and blended with magnesium stearate before compressing into tablet cores using conventional tabletting equipment.
  • the compressed cores are coated with an aqueous suspension of film coating components using a conventional perforated drum coater.
  • Suitable film-coated tablets containing the equivalent of 2.5, 10, 40 and 100 mg of Compound (I) free base are illustrated in the following table.
  • Titanium dioxide a 5.0 5.0 5.3 5.0
  • Macrogol 300 a 3.0 3.0 3.0 3.0
  • the hypromellose, macrogol 300 and titanium dioxide are included as Opadry White (03B28460), supplied by Colorcon.
  • Purified water is used as the solvent/carrier fluid during film-coating and is removed during the coating process.
  • a suitable manufacturing process is outlined below:
  • Binder solution Polyvidone STAGE 2: WET MIX Purified water i
  • Hypromellose Macrogol 300 STAGE 8 i COATING Titanium dioxide Purified water
  • Compound (I) was compared to that of gefitinib to assess its ability to: a) inhibit the activation (phosphorylation) of EGFR, ErbB2 and ErbB3 in ligand- stimulated cells; and b) inhibit the basal and ligand-stimulated proliferation of MCF-7 cells. a) Comparison of Compound (I) With Gefitinib in Ligand Driven Assays Methods:
  • KB cells and MCF-7 cells were obtained from the American Type Culture Collection (ATCC) and routinely cultured in RPMI 1640 (Phenol red free) + 10% Foetal Bovine Serum + 2mM L-Glutamine.
  • KB cells were seeded at 5000cells/well and MCF-7 cells at 4000cells/well in 96 well plates in RPMI 1640 media containing 10% FBS. Cells were incubated for 72 hours before replacing the media with serum-free RPMI 1640 media for 24 hrs. Cells were then treated with Compound (I) or gefitinib for 90 mins at concentrations ranging from 0- lO ⁇ M. Immediately before cell lysis, MCF-7 and KB cells were incubated for 5 minutes with ligand (heregulin (“HRG”) for the MCF-7 cells and epidermal growth factor (" EGF”) for the KB cells) at concentrations required to increase receptor phosphorylation to 90% of max (ED 90 ) to allow inter-assay comparison.
  • HRG ligand
  • EGF epidermal growth factor
  • the p-EGFR status of KB cells was measured using the Human phospho-EGFR Duoset ELISA kit (R&D systems, DYC 1095).
  • the p-ErbB2 and p-ErbB3 content of MCF- 7 cells were measured using the Human phospho-ErbB2 Duoset ELISA kit (R&D systems, DYC 1768) and Human phospho-ErbB3 Duoset ELISA kit (R&D systems, DYC 1769) respectively.
  • the kits measured whole cell tyrosine phosphorylation of EGFR, ErbB2 or ErbB3. Assays were performed according to the manufacturers instructions, with 50 ⁇ l lysate added per well. Results:
  • Table 1 Compound activity against p-EGFR (in KB cells) and p-ErbB2 and p-ErbB3 (in
  • Table 1 shows that Compound (I) is a statistically significantly more potent inhibitor of phospho-EGFR, phospho-ErbB2 and phospho-ErbB3 in these cells than gefitinib. b) Compound (I) compared to gefitinib in basal or HRG-stimulated MCF-7 cell proliferation assay
  • MCF-7 cells were routinely cultured in DMEM (Phenol red free) + 10% Foetal Bovine Serum + 2mM L-Glutamine.
  • Cells were seeded at 4000 cells per well in 96 well plates in DMEM media containing 1% charcoal/dextran-treated FBS and 2mM glutamine and allowed to settle for 4 hours prior to treatment with Compound (I) or gefitinib at concentrations ranging from 0- 3 ⁇ M and 0-10 ⁇ g/ml respectively. Two hours following treatment, cells were incubated with 10ng/ml HRG, a concentration required to increase MCF-7 cell proliferation to 90% of max (ED90). Basal wells were unstimulated with ligand.
  • MCF-7 basal assays represent a situation where there no increased stimulation or activation of erbB2/erbB3 heterodimerisation.
  • Table 3 shows that even in such conditions Compound (I) is a more potent inhibitor of MCF-7 proliferation than gef ⁇ tinib.
  • the BT-474 tumour cell line (human mammary carcinoma) was obtained from Dr Baselga (at Laboratorio Recerca Oncologica, Paseo VaIl D'Hebron 119- 129, Barcelona 08035, Spain). This cell line was subcloned and a certain population referred herein to as BT474c was obtained Cells were routinely cultured in growth medium containing 10% FBS and 2mM L-
  • Taxol is referred to in this example this was paclitaxel powder ex Sigma.
  • SKBr3 cells were seeded at 4000cells/well, BT-474c cells were seeded at 5000 cells/well in complete growth medium (10%FCS).
  • MCF-7 cells were seeded at 6000cells/well in serum free medium. Following 4/5 -hour incubation, cells were treated with Compound (I), Taxol and combinations of Compound (I) and Taxol at the concentrations described below in the Results.
  • the MCF-7 cells were stimulated with ligand (heregulin (HRG) at 30ng/ml) and all cells were incubated with compound for 96 hours and analysed by the MTS assay described below.
  • MTS cell proliferation assay MTS cell proliferation assay
  • the yellow tetrazolium salt ([3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) is reduced in metabolically active cells to form insoluble purple formazan crystals, which are solubilised by a detergent.
  • the colour can be quantified by spectrophotometer, providing an estimation of cell number.
  • the quantity of formazan product as measured by the amount of absorbance at 490nm is directly proportional to the number of living cells in culture.
  • Figure 1 shows that treatment of the MCF-7 cells with combinations of Compound (I) (0.2 ⁇ M) + Taxol (2OnM and 100OnM) significantly reduces cell viability compared to Taxol monotherapy alone (*P ⁇ 0.05). Results in SKBr3 Cells
  • IC 50 concentration significantly reduced cell viability compared to Taxol monotherapy at its IC 50 concentration (*P ⁇ 0.05).
  • the CI values were generated from the monotherapy and combination data using the method described in Chou and Talalay, 1984;Adv. Enzyme Regul. 22:27-55.
  • Figure 4 shows that in each of the cell lines tested, all have a combination index of less than 2, therefore demonstrating a beneficial effect for the combination of Compound (I) and Taxol in the cell lines tested.
  • the Compound (I) + Taxol combination has an overall benefit compared to either single monotherapy alone. All CI values resided in the 'benefit' range. Proliferation in the heregulin stimulated MCF-7 cells is driven by ErbB2/3 heterodimers. In the SK-Br3 cells proliferation is driven by ErbB2 homodimerisation. In the BT-474c cells proliferation is driven by ErbB2 homodimerisation and EGFR/ErbB2 heterodimerisation.
  • mice Female Swiss (nu/nu) mice. Mice were implanted with 0.36mg 60 day estrogen pellets 24 hours before being implanted sub- cutaneously with 5xlO 6 BT474c cells and 50% matrigel/mouse. The mice used for the study were selected on day 7, with a mean tumour volume of 0.3cm 3 . Body weights were measured for the first 7 days, then twice weekly thereafter. Tumours were measured twice- weekly using callipers. Animals were dosed as detailed below:
  • Control A 1% Polysorbate 80 p.o. twice daily
  • Control B 5% Cremaphor/5% Ethanol/90% PBS i.p. once weekly.
  • Group 2 Compound (I) @ 12.5mg/kg p.o. twice daily.
  • Group 3 Taxol @ 15mg/kg i.p. once weekly (on day 0 and day 7).
  • Group 4 Taxol @ 7.5mg/kg i.p. once weekly (on day 0 and day 7).
  • Group 5 Compound (I) @ 12.5mg/kg p.o. twice daily + Taxol @ 15mg/kg i.p. once weekly (on day 0 and day 7).
  • Group 6 Compound (I) @ 12.5mg/kg po twice daily + Taxol @ 7.5mg/kg i.p. once weekly (on day 0 and day 7).
  • the Mean Tumour Volume in each group in the study is shown in Figure 5.
  • the "tumour inhibition" for each of the treatment groups is shown in Table 4.
  • the tumour inhibition is the % difference between the geometric mean delta volume of the tumours from one of the treatment groups and the geometric mean delta volume of the control group.
  • the geometric delta means are calculated as the log 10 of the final tumour volume - the log 10 of the initial tumour volume using a T-test analysis). Accordingly, the tumour inhibition value is a measure of the relative volume change from the start of the study to the last day of study, compared to the growth of the control tumours using a T test for each of the treatments groups.
  • Table 4 End of study (day 14) percentage changes in geometric mean delta volume (T test analysis).
  • tumour inhibition is shown in Table 5.
  • Table 5 the tumour inhibition is calculated based upon the geometric mean delta volumes of the two groups being compared.
  • the Compound (I) and Taxol combination showed significantly enhanced tumour growth inhibition compared to either Compound (I) or Taxol monotherapy. No apparent antagonism was observed in these in vivo studies when both agents were combined.

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Abstract

L'invention concerne une combinaison comprenant 4-(3-chloro-2-fluoroanilino)-7-méthoxy-6-{[l-(N- méthylcarbamoylméthyl)pipéridine-4-yl ]oxy}quinazoléine, ou un sel de celle-ci pharmaceutiquement acceptable, et un taxane.
PCT/GB2009/051471 2008-11-03 2009-11-02 Traitement therapeutique 555 Ceased WO2010061208A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014135876A1 (fr) 2013-03-06 2014-09-12 Astrazeneca Ab Inhibiteurs quinazoline de l'activation des formes mutantes du récepteur de croissance épidermique (egfr)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6262054B1 (en) * 1996-02-01 2001-07-17 Sloan-Kettering Institute Of Cancer Research Combination therapy method for treating breast cancer using edatrexate
GB0126879D0 (en) * 2001-11-08 2002-01-02 Astrazeneca Ab Combination therapy
ATE352550T1 (de) * 2003-09-19 2007-02-15 Astrazeneca Ab Chinazolinderivate
US8088782B2 (en) * 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014135876A1 (fr) 2013-03-06 2014-09-12 Astrazeneca Ab Inhibiteurs quinazoline de l'activation des formes mutantes du récepteur de croissance épidermique (egfr)
US9066979B2 (en) 2013-03-06 2015-06-30 Astrazeneca Ab Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor
US9375432B2 (en) 2013-03-06 2016-06-28 Astrazeneca Ab Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor
US9718806B2 (en) 2013-03-06 2017-08-01 Astrazeneca Ab Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor
EP3342770A1 (fr) 2013-03-06 2018-07-04 AstraZeneca AB Inhibiteurs de quinazoline pour activer des formes mutantes du récepteur du facteur de croissance épidermique

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