WO2004032937A1 - Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability - Google Patents

Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability Download PDF

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Publication number
WO2004032937A1
WO2004032937A1 PCT/GB2003/004334 GB0304334W WO2004032937A1 WO 2004032937 A1 WO2004032937 A1 WO 2004032937A1 GB 0304334 W GB0304334 W GB 0304334W WO 2004032937 A1 WO2004032937 A1 WO 2004032937A1
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Prior art keywords
gemcitabine
treatment
pharmaceutically acceptable
effective amount
human
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PCT/GB2003/004334
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French (fr)
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Alan Barge
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority to BR0315088-7A priority Critical patent/BR0315088A/en
Priority to SI200330784T priority patent/SI1551409T1/en
Priority to DE60312715T priority patent/DE60312715T2/en
Priority to AU2003269253A priority patent/AU2003269253B2/en
Priority to CA2501651A priority patent/CA2501651C/en
Priority to NZ538999A priority patent/NZ538999A/en
Priority to JP2004542620A priority patent/JP5416328B2/en
Priority to EP03751032A priority patent/EP1551409B1/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to MXPA05003595A priority patent/MXPA05003595A/en
Priority to US10/530,567 priority patent/US20060009418A1/en
Priority to DK03751032T priority patent/DK1551409T3/en
Publication of WO2004032937A1 publication Critical patent/WO2004032937A1/en
Priority to IL167633A priority patent/IL167633A/en
Priority to NO20051575A priority patent/NO330601B1/en
Priority to HK05110642A priority patent/HK1078771A1/en
Priority to CY20071100670T priority patent/CY1106601T1/en
Priority to US12/541,647 priority patent/US20100120708A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded ariimal such as a human which is optionally being treated with ionising radiation, particularly a method for the treatment of a cancer, particularly a cancer involving a solid tumour, which comprises the administration of ZD6474 in combination with gemcitabine; to a pharmaceutical composition comprising ZD6474 and gemcitabine; to a combination product comprising ZD6474 and gemcitabine for use in a method of treatment of a human or animal body by therapy; to a kit comprising ZD6474 and gemcitabine; to the use of ZD6474 and gemcitabine in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is optionally being treated with ionising radiation.
  • Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function.
  • Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1 : 27-31).
  • vascular permeability is thought to play a role in both normal and pathological physiological processes (CuUinan-Bove et al, 1993, Endocrinology 133: 829-837; Senger et al, 1993, Cancer and Metastasis Reviews, 12: 303-324).
  • Several polypeptides with in vitro endothelial cell growth promoting activity have been identified including, acidic and basic fibroblast growth factors (aFGF & bFGF) and vascular endothelial growth factor (NEGF).
  • aFGF & bFGF acidic and basic fibroblast growth factors
  • NEGF vascular endothelial growth factor
  • NEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36: 139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Che 264: 20017-20024).
  • Antagonism of VEGF action by sequestration of NEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844).
  • Receptor tyrosine kinases are important in the transmission of biochemical signals across the plasma membrane of cells.
  • transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor- associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified.
  • One of these subfamilies is presently comprised by the fins-like tyrosine kinase receptor, Fit- 1 , the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fins-like tyrosine kinase receptor, Flt-4.
  • KDR also referred to as Flk-1
  • Flt-4 fins-like tyrosine kinase receptor
  • Two of these related RTKs, Flt-1 and KDR have been shown to bind NEGF with high affinity (De Nries et al, 1992, Science 255: 989-991; Terma et al, 1992, Biochem. Biophys. Res. Comm 1992, 187: 1579-1586). Binding of NEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
  • WO 01/32651 In WO 98/13354 and WO 01/32651 compounds are described which possess activity against NEGF receptor tyrosine kinase (NEGF RTK) whilst possessing some activity against epidermal growth factor (EGF) receptor tyrosine kinase (EGF RTK).
  • NEGF RTK NEGF receptor tyrosine kinase
  • EGF RTK epidermal growth factor receptor tyrosine kinase
  • ZD6474 is 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4- ylmethoxy)quinazoline:
  • ZD6474 ZD6474 falls within the broad general disclosure of WO 98/13354 and is exemplified in
  • ZD6474 is a potent inhibitor of NEGF RTK and also has some activity against EGF RTK. ZD6474 has been shown to elicit broad- spectrum anti-tumour activity in a range of models following once-daily oral administration (Wedge S.R., Ogilvie D.J., Dukes M. et al, Proc. Am Assoc. Cane. Res. 2001; 42: abstract 3126).
  • WO 98/13354 and WO 01/32651 then go on to describe examples of such conjoint treatment including surgery, radiotherapy and various types of chemotherapeutic agent including inhibitors 10 of growth factor function.
  • Gemcitabine is (I ⁇ ) 2'-deoxy-2',2'-difluorocytidine monohydrochloride ( ⁇ -isomer). Gemcitabine is also known as Gemzar TM (Trademark of Lilly) and it is a cytotoxic agent. It is an anti-metabolite which causes inhibition of DNA synthesis.
  • Anti-cancer effects of a method of treatment of the present invention include, but are not limited to, anti-tumour effects, the response rate, the time to disease progression and the survival rate.
  • Anti-tumour effects of a method of treatment of the present invention include but are not limited to, inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, slowing of disease progression.
  • a method of treatment of the present invention when administered to a warm-blooded animal such as a human, in need of treatment for cancer, with or without a solid tumour, said method of treatment will produce an effect, as measured by, for example, one or more of: the extent of the anti-tumour effect, the response rate, the time to disease progression and the survival rate.
  • a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine.
  • a method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine.
  • a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine.
  • a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warmblooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine; wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
  • a method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine; wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
  • a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine; wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
  • a pharmaceutical composition which comprises ZD6474 or a pharmaceutically acceptable salt thereof, and gemcitabine, in association with a pharmaceutically acceptable excipient or carrier.
  • a combination product comprising ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine, for use in a method of treatment of a human or animal body by therapy.
  • kits comprising ZD6474 or a pharmaceutically acceptable salt thereof, and gemcitabine.
  • kits comprising: a) ZD6474 or a pharmaceutically acceptable salt thereof in a first unit dosage form; b) gemcitabine in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • kits comprising: a) ZD6474 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient or carrier, in a first unit dosage form; b) gemcitabine together with a pharmaceutically acceptable excipient or carrier, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
  • ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as a human.
  • ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-tumour effect in a warm-blooded animal such as a human.
  • a therapeutic combination treatment comprising the administration of an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and the simultaneous, sequential or separate administration of an effective amount of gemcitabine, wherein gemcitabine may optionally be administered together with a pharmaceutically acceptable excipient or carrier, to a warm-blooded animal such as a human in need of such therapeutic treatment.
  • Such therapeutic treatment includes an antiangiogenic and/or vascular permeability effect, an anti-cancer effect and an anti-tumour effect.
  • a combination treatment of the present invention as defined herein may be achieved by way of the simultaneous, sequential or separate administration of the individual components of said treatment.
  • a combination treatment as defined herein may be applied as a sole therapy or may involve surgery or radiotherapy or an additional chemo therapeutic 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 with ZD6474 described herein.
  • Other chemotherapeutic agents for optional use with a combination treatment of the present invention include those described in WO 01/32651 which is incorporated herein by reference. Such chemotherapy may cover five main categories of therapeutic agent:
  • biological response modifiers for example interferon
  • antibodies for example edrecolomab
  • chemotherapeutic agent for use with a combination treatment of the present invention is a platinum anti-cancer agent such as cisplatin; such a combination is expected to be particularly useful for the treatment of lung cancer and bladder cancer.
  • the administration of a triple combination of ZD6474, gemcitabine and ionising radiation may produce effects, such as anti-tumour effects, greater than those achieved with any of ZD6474, gemcitabine and ionising radiation used alone, greater than those achieved with the combination of ZD6474 and gemcitabine, greater than those achieved with the combination of ZD6474 and ionising radiation, greater than those achieved with the combination of gemcitabine and ionising radiation.
  • a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation.
  • a method for the treatment of a cancer in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation.
  • a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation.
  • a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warmblooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
  • a method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
  • a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal such as a human which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
  • ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-cancer effect 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 ZD6474 or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and the administration of an effective amount of gemcitabine, 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 ZD6474, gemcitabine and ionising radiation may be administered simultaneously, sequentially or separately and in any order.
  • 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 ZD6474 and gemcitabine.
  • 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 ZD6474 and gemcitabine.
  • ZD6474, gemcitabine and ionising radiation may be administered separately or sequentially in any order, or may be administered simultaneously.
  • the warmblooded animal may experience the effect of each of ZD6474, gemcitabine and radiation simultaneously.
  • the ionising radiation is administered before one of ZD6474 and gemcitabine or after one of ZD6474 and gemcitabine.
  • the ionising radiation is administered before both ZD6474 and gemcitabine or after both ZD6474 and gemcitabine.
  • ZD6474 is administered to a warm- blooded animal after the animal has been treated with ionising radiation.
  • 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 ZD6474 and gemcitabine used alone or of each of ZD6474, gemcitabine and ionising radiation 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 ZD6474 and gemcitabine used alone or of each of ZD6474, gemcitabine and ionising radiation used alone.
  • the effect of a method of treatment of the present invention is expected to be a synergistic effect.
  • a combination treatment 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 ZD6474 or gemcitabine or ionising radiation 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 ZD6474 or gemcitabine or ionising radiation 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 ZD6474 or gemcitabine or ionising radiation 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.
  • angiogenesis and/or an increase in vascular permeability is present in a wide range of disease states including cancer (including leukaemia, multiple myeloma and lymphoma), diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, lymphoedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation including age-related macular degeneration.
  • cancer including leukaemia, multiple myeloma and lymphoma
  • diabetes including leukaemia, multiple myeloma and lymphoma
  • psoriasis rheumatoid arthritis
  • Kaposi's sarcoma haemangioma
  • haemangioma haemangioma
  • acute and chronic nephropathies atheroma
  • Combination treatments of the present invention are expected to be particularly useful in the prophylaxis and treatment of diseases such as cancer and Kaposi's sarcoma.
  • Such combination treatments of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, pancreas, bladder, breast, prostate, lungs and skin.
  • More especially combination treatments of the present invention are expected to slow advantageously the growth of tumours in pancreatic cancer and lung cancer, for example mesothelioma and non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • combination treatments of the invention are expected to inhibit any form of cancer associated with NEGF including leukaemia, mulitple myeloma and lymphoma and also, for example, to inhibit the growth of those primary and recurrent solid tumours which are associated with NEGF, especially those tumours which are significantly dependent on NEGF for their growth and spread, including for example, certain tumours of the colon, pancreas, bladder, breast, prostate, lung, vulva and skin, particularly ⁇ SCLC.
  • ZD6474 and gemcitabine are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with NEGF especially those tumours which are significantly dependent on NEGF for their growth and spread.
  • ZD6474 and gemcitabine are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with both NEGF and EGF especially those tumours which are significantly dependent on NEGF and EGF for their growth and spread.
  • compositions described herein may be in a form suitable for oral administration, for example as a tablet or capsule, for nasal administration or administration by inhalation, for example as a powder or solution, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream, for rectal administration for example as a suppository or the route of administration may be by direct injection into the tumour or by regional delivery or by local delivery.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • sterile solution for example as a sterile solution, suspension or emulsion
  • topical administration for example as an ointment or cream
  • rectal administration for example as a suppository or the route of administration may be by direct injection into the tumour or by regional delivery or by local delivery.
  • the ZD6474 of the combination treatment may be delivered endoscopically, intratracheaUy, intralesionally, percutaneously, intravenously, subcutaneously, intraperitoneally or intratumourally.
  • ZD6474 is administered orally.
  • the compositions described herein may be prepared in a conventional manner using conventional excipients.
  • the compositions of the present invention are advantageously presented in unit dosage form
  • ZD6474 will normally be administered to a warm-blooded animal at a unit dose within the range 10-500mg per square metre body area of the animal, for example approximately 0.3- 15mg/kg in a human.
  • a unit dosage form such as a tablet or capsule will usually contain, for example 25-500mg of active ingredient.
  • a daily dose in the range of 0.5-5mg/kg is employed.
  • Gemcitabine may be administered according to known clinical practice. For example in NSCLC the recommended dose of gemcitabine is lOOOmg/m 2 given by 30 minute intravenous infusion. This may be repeated once weekly for three weeks, followed by a one week rest period. This four week cycle may then be repeated. Dosage reduction may be necessary if the patient experiences undue toxicity. In pancreatic cancer the recommended dose of gemcitabine is lOOOmg/m 2 given by 30 minute intravenous infusion. This may be repeated once weekly for seven weeks followed by a week of rest. Subsequent cycles may consist of injections once weekly for three consecutive weeks out of every four weeks. Dosage reduction may be necessary if the patient experiences undue toxicity.
  • the dosages and schedules may vary according to the particular disease state and the overall condition of the patient. Dosages and schedules may also vary if, in addition to a combination treatment of the present invention, one or more additional chemotherapeutic agents is/are used. Scheduling can be determined by the practitioner who is treating any particular patient. Radiotherapy may be administered according to the known practices in clinical radiotherapy. The dosages of ionising radiation will be those known for use in clinical radiotherapy. The radiation therapy used will include for example the use of ⁇ -rays, X-rays, and/or the directed delivery of radiation from radioisotopes. Other forms of DNA damaging factors are also included in the present invention such as microwaves and UN-irradiation.
  • X-rays may be dosed in daily doses of 1.8-2.0Gy, 5 days a week for 5-6 weeks. Normally a total fractionated dose will lie in the range 45-60Gy.
  • Single larger doses, for example 5-10Gy may be administered as part of a course of radiotherapy. Single doses may be administered intraoperatively.
  • Hyperfractionated radiotherapy may be used whereby small doses of X-rays are administered regularly over a period of time, for example 0. lGy per hour over a number of days. Dosage ranges for radio isotopes vary widely, and depend on the half- life of the isotope, the strength and type of radiation emitted, and on the uptake by cells.
  • the size of the dose of each therapy which is required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the 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. For example, it may be necessary or desirable to reduce the above-mentioned doses of the components of the combination treatments in order to reduce toxicity.
  • the present invention relates to combinations of gemcitabine with ZD6474 or with a salt ofZD6474.
  • Salts of ZD6474 for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of ZD6474 and its pharmaceutically acceptable salts.
  • Such salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation.
  • Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2- hydroxyethyl)amine.
  • ZD6474 may be synthesised according to any of the known processes for making ZD6474.
  • ZD6474 may be made according to any of the processes described in WO 01/32651; for example those described in Examples 2(a), 2(b) and 2(c) of WO 01/32651.
  • Gemcitabine is commercially available.
  • Group 3 gemcitabine twice weekly (on days 2 and 5 of each treatment week) (lOOmg/kg by intraperitoneal injection (i. ⁇ .)); Group 4 - a single daily dose of ZD6474 (50mg/kg oral gavage) and twice weekly gemcitabine (on days 2 and 5 of each treatment week) (GEM: lOOmg/kg i.p.). The animals were sacrificed 32 days after tumour cell injection.
  • pancreatic tumours The incidence of pancreatic tumours, liver metastases, lymph node metastases and peritoneal carcinosis was evaluated.
  • the primary pancreatic tumour weight was measured. All macro scopically enlarged lymph nodes and liver nodules were confirmed by histopathology (H&E staining).
  • tumours in treated animals reached an average weight of 836mg (gemcitabine) 541mg (ZD6474) and 308mg (gemcitabine + ZD6474).
  • Liver metastases were present in 6/10 control and 4/9 gemcitabine treated animals, but only 1/10 and 0/5 animals on ZD6474 or combination treatment displayed liver metastases, respectively.
  • Lymph node metastases were present in 10/10 control and 9/9 gemcitabine treated animals, but only 3/10 and 1/5 animals on ZD6474 or combination treatment displayed lymph node metastases, respectively.

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Abstract

The present invention relates to a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is optionally being treated with ionising radiation, particularly a method for the treatment of a cancer, particularly a cancer involving a solid tumour, which comprises the administration of ZD6474 in combination with gemcitabine; to a pharmaceutical composition comprising ZD6474 and gemcitabine; to a combination product comprising ZD6474 and gemcitabine for use in a method of treatment of a human or animal body by therapy; to a kit comprising ZD6474 and gemcitabine; to the use of ZD6474 and gemcitabine in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is optionally being treated with ionising radiation.

Description

USE OF THE QUINAZO INE DERIVATIVE ZD6474 COMBINED WITH GEMCITABINE AND
OPTIONALLY IONISING RADIATION IN THE TREATMENT OF DISEASES ASSOCIATED
WITH ANGIOGENESIS AND/OR INCREASED VASCULAR PERMEABILITY
The present invention relates to a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded ariimal such as a human which is optionally being treated with ionising radiation, particularly a method for the treatment of a cancer, particularly a cancer involving a solid tumour, which comprises the administration of ZD6474 in combination with gemcitabine; to a pharmaceutical composition comprising ZD6474 and gemcitabine; to a combination product comprising ZD6474 and gemcitabine for use in a method of treatment of a human or animal body by therapy; to a kit comprising ZD6474 and gemcitabine; to the use of ZD6474 and gemcitabine in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is optionally being treated with ionising radiation.
Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacol. Sci. 16: 57-66; Folkman, 1995, Nature Medicine 1 : 27-31). Alteration of vascular permeability is thought to play a role in both normal and pathological physiological processes (CuUinan-Bove et al, 1993, Endocrinology 133: 829-837; Senger et al, 1993, Cancer and Metastasis Reviews, 12: 303-324). Several polypeptides with in vitro endothelial cell growth promoting activity have been identified including, acidic and basic fibroblast growth factors (aFGF & bFGF) and vascular endothelial growth factor (NEGF). By virtue of the restricted expression of its receptors, the growth factor activity of NEGF, in contrast to that of the FGFs, is relatively specific towards endothelial cells. Recent evidence indicates that NEGF is an important stimulator of both normal and pathological angiogenesis (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36: 139-155) and vascular permeability (Connolly et al, 1989, J. Biol. Che 264: 20017-20024). Antagonism of VEGF action by sequestration of NEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844). Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor- associated tyrosine kinase activity which leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fins-like tyrosine kinase receptor, Fit- 1 , the kinase insert domain-containing receptor, KDR (also referred to as Flk-1), and another fins-like tyrosine kinase receptor, Flt-4. Two of these related RTKs, Flt-1 and KDR, have been shown to bind NEGF with high affinity (De Nries et al, 1992, Science 255: 989-991; Terma et al, 1992, Biochem. Biophys. Res. Comm 1992, 187: 1579-1586). Binding of NEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
Quinazoline derivatives which are inhibitors of NEGF receptor tyrosine kinase are described in International Patent Applications Publication Νos. WO 98/13354 and
WO 01/32651. In WO 98/13354 and WO 01/32651 compounds are described which possess activity against NEGF receptor tyrosine kinase (NEGF RTK) whilst possessing some activity against epidermal growth factor (EGF) receptor tyrosine kinase (EGF RTK). ZD6474 is 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-( 1 -methylpiperidin-4- ylmethoxy)quinazoline:
Figure imgf000003_0001
ZD6474 ZD6474 falls within the broad general disclosure of WO 98/13354 and is exemplified in
WO 01/32651. ZD6474 is a potent inhibitor of NEGF RTK and also has some activity against EGF RTK. ZD6474 has been shown to elicit broad- spectrum anti-tumour activity in a range of models following once-daily oral administration (Wedge S.R., Ogilvie D.J., Dukes M. et al, Proc. Am Assoc. Cane. Res. 2001; 42: abstract 3126).
In WO 98/13354 and WO 01/32651 it is stated that compounds of their inventions: "may be applied as a sole therapy or may involve, in addition to a compound of the invention, 5 one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment."
WO 98/13354 and WO 01/32651 then go on to describe examples of such conjoint treatment including surgery, radiotherapy and various types of chemotherapeutic agent including inhibitors 10 of growth factor function.
Nowhere in WO 98/13354 and WO 01/32651 does it suggest the combination of a compound of the invention and gemcitabine for the treatment of any disease state including cancer.
Nowhere in WO 98/13354 and WO 01/32651 is the specific combination of ZD6474 15 and gemcitabine suggested.
Nowhere in WO 98/13354 and WO 01/32651 does it state that use of any compound of the invention therein with other treatments will produce surprisingly beneficial effects.
A triple combination of a VEGF RTK inhibitor (PTK 787), an EGF RTK inhibitor (PKI 166) and gemcitabine is described in Baker et al, Cancer Research 62, 1996 2003, April 1, 20 2002. The authors concluded that a combination of either PTK 787 with gemcitabine or PKI 166 with gemcitabine was beneficial but that the triple combination did not produce additive therapeutic effects.
A combination of gemcitabine with DC 101, a NEGF receptor-2 antibody (anti-KDR antibody) is described in Bruns et al, International Journal of Cancer vol 102, issue 2, 2002 25 pages 101-108.
Unexpectedly and surprisingly we have now found that the particular compound ZD6474 used in combination with a particular selection from the broad description of combination therapies listed in WO 98/13354 and WO 01/32651, namely with gemcitabine, produces significantly better effects than any one of ZD6474 and gemcitabine used alone. In 30 particular, ZD6474 used in combination with gemcitabine produces significantly better effects on solid tumours than any one of ZD6474 and gemcitabine used alone.
Gemcitabine is (IΝΝ) 2'-deoxy-2',2'-difluorocytidine monohydrochloride (β-isomer). Gemcitabine is also known as Gemzar ™ (Trademark of Lilly) and it is a cytotoxic agent. It is an anti-metabolite which causes inhibition of DNA synthesis.
Anti-cancer effects of a method of treatment of the present invention include, but are not limited to, anti-tumour effects, the response rate, the time to disease progression and the survival rate. Anti-tumour effects of a method of treatment of the present invention include but are not limited to, inhibition of tumour growth, tumour growth delay, regression of tumour, shrinkage of tumour, increased time to regrowth of tumour on cessation of treatment, slowing of disease progression. It is expected that when a method of treatment of the present invention is administered to a warm-blooded animal such as a human, in need of treatment for cancer, with or without a solid tumour, said method of treatment will produce an effect, as measured by, for example, one or more of: the extent of the anti-tumour effect, the response rate, the time to disease progression and the survival rate.
According to the present invention there is provided a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine.
According to a further aspect of the present invention there is provided a method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine.
According to a further aspect of the present invention there is provided a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine.
According to a further aspect of the present invention there is provided a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warmblooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine; wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
According to a further aspect of the present invention there is provided a method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine; wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
According to a further aspect of the present invention there is provided a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine; wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier. According to a further aspect of the invention there is provided a pharmaceutical composition which comprises ZD6474 or a pharmaceutically acceptable salt thereof, and gemcitabine, in association with a pharmaceutically acceptable excipient or carrier.
According to a further aspect of the present invention there is provided a combination product comprising ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine, for use in a method of treatment of a human or animal body by therapy.
According to a further aspect of the present invention there is provided a kit comprising ZD6474 or a pharmaceutically acceptable salt thereof, and gemcitabine.
According to a further aspect of the present invention there is provided a kit comprising: a) ZD6474 or a pharmaceutically acceptable salt thereof in a first unit dosage form; b) gemcitabine in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to a further aspect of the present invention there is provided a kit comprising: a) ZD6474 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient or carrier, in a first unit dosage form; b) gemcitabine together with a pharmaceutically acceptable excipient or carrier, in a second unit dosage form; and c) container means for containing said first and second dosage forms.
According to a further aspect of the present invention there is provided the use of ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human.
According to a further aspect of the present invention there is provided the use of
ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as a human.
According to a further aspect of the present invention there is provided the use of
ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-tumour effect in a warm-blooded animal such as a human.
According to a further aspect of the present invention there is provided a therapeutic combination treatment comprising the administration of an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and the simultaneous, sequential or separate administration of an effective amount of gemcitabine, wherein gemcitabine may optionally be administered together with a pharmaceutically acceptable excipient or carrier, to a warm-blooded animal such as a human in need of such therapeutic treatment.
Such therapeutic treatment includes an antiangiogenic and/or vascular permeability effect, an anti-cancer effect and an anti-tumour effect. A combination treatment of the present invention as defined herein may be achieved by way of the simultaneous, sequential or separate administration of the individual components of said treatment. A combination treatment as defined herein may be applied as a sole therapy or may involve surgery or radiotherapy or an additional chemo therapeutic 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 with ZD6474 described herein. Other chemotherapeutic agents for optional use with a combination treatment of the present invention include those described in WO 01/32651 which is incorporated herein by reference. Such chemotherapy may cover five main categories of therapeutic agent:
(i) other antiangiogenic agents including vascular targeting agents; (ii) cyto static agents;
(iii) biological response modifiers (for example interferon);
(iv) antibodies (for example edrecolomab); and
(v) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology. A particular example of a chemotherapeutic agent for use with a combination treatment of the present invention is a platinum anti-cancer agent such as cisplatin; such a combination is expected to be particularly useful for the treatment of lung cancer and bladder cancer.
The administration of a triple combination of ZD6474, gemcitabine and ionising radiation may produce effects, such as anti-tumour effects, greater than those achieved with any of ZD6474, gemcitabine and ionising radiation used alone, greater than those achieved with the combination of ZD6474 and gemcitabine, greater than those achieved with the combination of ZD6474 and ionising radiation, greater than those achieved with the combination of gemcitabine and ionising radiation.
According to the present invention there is provided a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation. According to a further aspect of the present invention there is provided a method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation. According to a further aspect of the present invention there is provided a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation.
According to a further aspect of the present invention there is provided a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warmblooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier. According to a further aspect of the present invention there is provided a method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
According to a further aspect of the present invention there is provided a method for the treatment of a cancer involving a solid tumour in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and gemcitabine may each optionally be administered together with a pharmaceutically acceptable excipient or carrier. According to a further aspect of the present invention there is provided the use of
ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is being treated with ionising radiation. According to a further aspect of the present invention there is provided the use of
ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as a human which is being treated with ionising radiation.
According to a further aspect of the present invention there is provided the use of ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-tumour effect in a warm-blooded animal such as a human which is being treated with ionising radiation.
According to a further aspect of the present invention there is provided a therapeutic combination treatment comprising the administration of an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient or carrier, and the administration of an effective amount of gemcitabine, 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 ZD6474, gemcitabine and ionising radiation may be administered simultaneously, sequentially or separately and in any order. 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 ZD6474 and gemcitabine. For example 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 ZD6474 and gemcitabine. This means that ZD6474, gemcitabine and ionising radiation may be administered separately or sequentially in any order, or may be administered simultaneously. The warmblooded animal may experience the effect of each of ZD6474, gemcitabine and radiation simultaneously. According to one aspect of the present invention the ionising radiation is administered before one of ZD6474 and gemcitabine or after one of ZD6474 and gemcitabine.
According to one aspect of the present invention the ionising radiation is administered before both ZD6474 and gemcitabine or after both ZD6474 and gemcitabine.
According to one aspect of the present invention ZD6474 is administered to a warm- blooded animal after the animal has been treated with ionising radiation.
According to another aspect of the present invention 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 ZD6474 and gemcitabine used alone or of each of ZD6474, gemcitabine and ionising radiation used alone.
According to another aspect of the present invention 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 ZD6474 and gemcitabine used alone or of each of ZD6474, gemcitabine and ionising radiation used alone.
According to another aspect of the present invention the effect of a method of treatment of the present invention is expected to be a synergistic effect.
According to the present invention a combination treatment 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. For example, the effect of the combination treatment is synergistic if the effect is therapeutically superior to the effect achievable with ZD6474 or gemcitabine or ionising radiation alone. Further, 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 ZD6474 or gemcitabine or ionising radiation alone. In addition, 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. In particular, synergy is deemed to be present if the conventional dose of ZD6474 or gemcitabine or ionising radiation 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.
As stated above the combination treatments of the present invention as defined herein are of interest for their antiangiogenic and/or vascular permeability effects. Angiogenesis and/or an increase in vascular permeability is present in a wide range of disease states including cancer (including leukaemia, multiple myeloma and lymphoma), diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, lymphoedema, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation including age-related macular degeneration. Combination treatments of the present invention are expected to be particularly useful in the prophylaxis and treatment of diseases such as cancer and Kaposi's sarcoma. In particular such combination treatments of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, pancreas, bladder, breast, prostate, lungs and skin. More especially combination treatments of the present invention are expected to slow advantageously the growth of tumours in pancreatic cancer and lung cancer, for example mesothelioma and non-small cell lung cancer (NSCLC). More particularly such combination treatments of the invention are expected to inhibit any form of cancer associated with NEGF including leukaemia, mulitple myeloma and lymphoma and also, for example, to inhibit the growth of those primary and recurrent solid tumours which are associated with NEGF, especially those tumours which are significantly dependent on NEGF for their growth and spread, including for example, certain tumours of the colon, pancreas, bladder, breast, prostate, lung, vulva and skin, particularly ΝSCLC.
In another aspect of the present invention ZD6474 and gemcitabine, optionally with ionising radiation, are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with NEGF especially those tumours which are significantly dependent on NEGF for their growth and spread.
In another aspect of the present invention ZD6474 and gemcitabine, optionally with ionising radiation, are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with both NEGF and EGF especially those tumours which are significantly dependent on NEGF and EGF for their growth and spread. The compositions described herein may be in a form suitable for oral administration, for example as a tablet or capsule, for nasal administration or administration by inhalation, for example as a powder or solution, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream, for rectal administration for example as a suppository or the route of administration may be by direct injection into the tumour or by regional delivery or by local delivery. In other embodiments of the present invention the ZD6474 of the combination treatment may be delivered endoscopically, intratracheaUy, intralesionally, percutaneously, intravenously, subcutaneously, intraperitoneally or intratumourally. Preferably ZD6474 is administered orally. In general the compositions described herein may be prepared in a conventional manner using conventional excipients. The compositions of the present invention are advantageously presented in unit dosage form
ZD6474 will normally be administered to a warm-blooded animal at a unit dose within the range 10-500mg per square metre body area of the animal, for example approximately 0.3- 15mg/kg in a human. A unit dose in the range, for example, 0.3-15mg/kg, preferably 0.5-5mg/kg is envisaged and this is normally a therapeutically-effective dose. A unit dosage form such as a tablet or capsule will usually contain, for example 25-500mg of active ingredient. Preferably a daily dose in the range of 0.5-5mg/kg is employed.
Gemcitabine may be administered according to known clinical practice. For example in NSCLC the recommended dose of gemcitabine is lOOOmg/m2 given by 30 minute intravenous infusion. This may be repeated once weekly for three weeks, followed by a one week rest period. This four week cycle may then be repeated. Dosage reduction may be necessary if the patient experiences undue toxicity. In pancreatic cancer the recommended dose of gemcitabine is lOOOmg/m2 given by 30 minute intravenous infusion. This may be repeated once weekly for seven weeks followed by a week of rest. Subsequent cycles may consist of injections once weekly for three consecutive weeks out of every four weeks. Dosage reduction may be necessary if the patient experiences undue toxicity.
The dosages and schedules may vary according to the particular disease state and the overall condition of the patient. Dosages and schedules may also vary if, in addition to a combination treatment of the present invention, one or more additional chemotherapeutic agents is/are used. Scheduling can be determined by the practitioner who is treating any particular patient. Radiotherapy may be administered according to the known practices in clinical radiotherapy. The dosages of ionising radiation will be those known for use in clinical radiotherapy. The radiation therapy used will include for example the use of γ-rays, X-rays, and/or the directed delivery of radiation from radioisotopes. Other forms of DNA damaging factors are also included in the present invention such as microwaves and UN-irradiation. For example X-rays may be dosed in daily doses of 1.8-2.0Gy, 5 days a week for 5-6 weeks. Normally a total fractionated dose will lie in the range 45-60Gy. Single larger doses, for example 5-10Gy may be administered as part of a course of radiotherapy. Single doses may be administered intraoperatively. Hyperfractionated radiotherapy may be used whereby small doses of X-rays are administered regularly over a period of time, for example 0. lGy per hour over a number of days. Dosage ranges for radio isotopes vary widely, and depend on the half- life of the isotope, the strength and type of radiation emitted, and on the uptake by cells. As stated above the size of the dose of each therapy which is required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the 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. For example, it may be necessary or desirable to reduce the above-mentioned doses of the components of the combination treatments in order to reduce toxicity.
The present invention relates to combinations of gemcitabine with ZD6474 or with a salt ofZD6474.
Salts of ZD6474 for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of ZD6474 and its pharmaceutically acceptable salts. Such salts may be formed with an inorganic or organic base which affords a pharmaceutically acceptable cation. Such salts with inorganic or organic bases include for example an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an ammonium salt or for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2- hydroxyethyl)amine.
ZD6474 may be synthesised according to any of the known processes for making ZD6474. For example ZD6474 may be made according to any of the processes described in WO 01/32651; for example those described in Examples 2(a), 2(b) and 2(c) of WO 01/32651. Gemcitabine is commercially available.
The following tests may be used to demonstrate the activity of ZD6474 in combination with gemcitabine.
Model to investigate effects of ZD6474 and gemcitabine therapy on primary pancreatic tumour growth and metastases growing orthotopically in nude mice Nude mice (n=10 per group) were injected with lxlO6 L3.6pl human pancreatic cancer cells into the pancreas. The mice received one of the following treatment regimes 8 days post- tumour injection: Group 1 - control group received saline by daily oral application; Group 2 - a single daily dose of ZD6474 (50mg/kg oral gavage);
Group 3 - gemcitabine twice weekly (on days 2 and 5 of each treatment week) (lOOmg/kg by intraperitoneal injection (i.ρ.)); Group 4 - a single daily dose of ZD6474 (50mg/kg oral gavage) and twice weekly gemcitabine (on days 2 and 5 of each treatment week) (GEM: lOOmg/kg i.p.). The animals were sacrificed 32 days after tumour cell injection.
The incidence of pancreatic tumours, liver metastases, lymph node metastases and peritoneal carcinosis was evaluated. The primary pancreatic tumour weight was measured. All macro scopically enlarged lymph nodes and liver nodules were confirmed by histopathology (H&E staining).
The results are shown in Table 1 Table 1
Figure imgf000015_0001
Compared with the average weight of control tumours (1231mg), tumours in treated animals reached an average weight of 836mg (gemcitabine) 541mg (ZD6474) and 308mg (gemcitabine + ZD6474). Liver metastases were present in 6/10 control and 4/9 gemcitabine treated animals, but only 1/10 and 0/5 animals on ZD6474 or combination treatment displayed liver metastases, respectively. Lymph node metastases were present in 10/10 control and 9/9 gemcitabine treated animals, but only 3/10 and 1/5 animals on ZD6474 or combination treatment displayed lymph node metastases, respectively.

Claims

1. A method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine.
2. A method for the treatment of a cancer in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine.
3. A method according to claim 2 for the treatment of a cancer involving a solid tumour.
4. A pharmaceutical composition which comprises ZD6474 or a pharmaceutically acceptable salt thereof, and gemcitabine, in association with a pharmaceutically acceptable excipient or carrier.
5. A kit comprising ZD6474 or a pharmaceutically acceptable salt thereof, and gemcitabine.
6. Use of ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human.
7. Use of ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as a human.
8. Use according to claim 7 wherein the anti-cancer effect comprises an anti- tumour effect.
9. A method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation.
10. A method for the treatment of a cancer in a warm-blooded -mimal such as a human, which comprises administering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of gemcitabine and before, after or simultaneously with an effective amount of ionising radiation.
11. A method according to claim 10 for the treatment of a cancer involving a solid tumour.
12. Use of ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded animal such as a human which is being treated with ionising radiation.
13. Use of ZD6474 or a pharmaceutically acceptable salt thereof and gemcitabine in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as a human which is being treated with ionising radiation.
14. Use according to claim 13 wherein the anti-cancer effect comprises an anti- tumour effect.
PCT/GB2003/004334 2002-10-09 2003-10-06 Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability WO2004032937A1 (en)

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MXPA05003595A MXPA05003595A (en) 2002-10-09 2003-10-06 Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability.
SI200330784T SI1551409T1 (en) 2002-10-09 2003-10-06 Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of cancer
US10/530,567 US20060009418A1 (en) 2002-10-09 2003-10-06 Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability
CA2501651A CA2501651C (en) 2002-10-09 2003-10-06 Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability
NZ538999A NZ538999A (en) 2002-10-09 2003-10-06 Use of the quinazoline derivative ZD6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability
JP2004542620A JP5416328B2 (en) 2002-10-09 2003-10-06 Use of quinazoline derivative ZD6474 in combination with gemcitabine and optionally in combination with ionizing radiation in the treatment of diseases associated with angiogenesis and / or increased vascular permeability
EP03751032A EP1551409B1 (en) 2002-10-09 2003-10-06 Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiation in the treatment of cancer
BR0315088-7A BR0315088A (en) 2002-10-09 2003-10-06 Methods for producing an antiangiogenic and / or vascular permeability reducing effect in a warm-blooded animal and for treating cancer in a warm-blooded animal, pharmaceutical composition, kit, and use of zd6474 or an acceptable pharmaceutically acceptable salt thereof and gemcitabine
DE60312715T DE60312715T2 (en) 2002-10-09 2003-10-06 USE OF THE QUINAZOLINE DERIVATOR ZD6474 COMBINED WITH GEMCITABIN AND, IF APPLICABLE, IONIZING RADIATION FOR THE TREATMENT OF CANCER
AU2003269253A AU2003269253B2 (en) 2002-10-09 2003-10-06 Use of the quinazoline derivative ZD6474 combined with gemcitabine and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability
DK03751032T DK1551409T3 (en) 2002-10-09 2003-10-06 Use of the quinazoline derivative ZD6474 in combination with gemcitabine and possibly ionizing radiation in the treatment of cancer
IL167633A IL167633A (en) 2002-10-09 2005-03-24 Use of zd6474 combined with gemcitabine in the preparation of medicaments and as medicaments for the production of an angiogenic and/or vascular permeability reducing effect and pharmaceutical compositions and kits comprising such combination
NO20051575A NO330601B1 (en) 2002-10-09 2005-03-29 A pharmaceutical composition comprising the quinazoline derivative ZD6474 combined with gemcitabine, seen comprising the same and their use in the manufacture of a medicament for the treatment of disease.
HK05110642A HK1078771A1 (en) 2002-10-09 2005-11-24 Use of the quinazoline derivative zd6474 combined with gemcitabine and optionally ionising radiationin the treatment of cancer
CY20071100670T CY1106601T1 (en) 2002-10-09 2007-05-17 USE OF THE QUINAZOLINE DERIVATIVE ZD6474 COMBINED WITH GEMCITABINE AND OPTIONALLY IONIZING RADIATION IN THE TREATMENT OF CANCER
US12/541,647 US20100120708A1 (en) 2002-10-09 2009-08-14 Combination therapy comprising ZD6474 and gemcitabine for anti-cancer therapy

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US8372981B2 (en) 2000-10-20 2013-02-12 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US7973160B2 (en) 2000-10-20 2011-07-05 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US7462623B2 (en) 2002-11-04 2008-12-09 Astrazeneca Ab Quinazoline derivatives as Src tyrosine kinase inhibitors
US7994159B2 (en) 2003-03-10 2011-08-09 Eisai R&D Management Co., Ltd. c-Kit kinase inhibitor
US8058474B2 (en) 2003-11-11 2011-11-15 Eisai R&D Management Co., Ltd. Urea derivative and process for preparing the same
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US8969379B2 (en) 2004-09-17 2015-03-03 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7=methoxy-6-quinolinecarboxide
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WO2007014335A2 (en) * 2005-07-27 2007-02-01 The University Of Texas System Combinations comprising gemcitabine and tyrosine kinase inhibitors for the treatment of pancreatic cancer
US8969344B2 (en) 2005-08-02 2015-03-03 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
US9006240B2 (en) 2005-08-02 2015-04-14 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
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US9006256B2 (en) 2006-05-18 2015-04-14 Eisai R&D Management Co., Ltd. Antitumor agent for thyroid cancer
US8865737B2 (en) 2006-08-28 2014-10-21 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
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US8962655B2 (en) 2007-01-29 2015-02-24 Eisai R&D Management Co., Ltd. Composition for treatment of undifferentiated gastric cancer
US8952035B2 (en) 2007-11-09 2015-02-10 Eisai R&D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
US9012458B2 (en) 2010-06-25 2015-04-21 Eisai R&D Management Co., Ltd. Antitumor agent using compounds having kinase inhibitory effect in combination
US8962650B2 (en) 2011-04-18 2015-02-24 Eisai R&D Management Co., Ltd. Therapeutic agent for tumor
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
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US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10822307B2 (en) 2014-08-28 2020-11-03 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
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US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor

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EP1551409A1 (en) 2005-07-13
JP2006504723A (en) 2006-02-09
DE60312715T2 (en) 2007-12-06
IL167633A (en) 2013-03-24
NZ538999A (en) 2008-02-29
HK1078771A1 (en) 2006-03-24
JP2011088921A (en) 2011-05-06
CA2501651A1 (en) 2004-04-22
PT1551409E (en) 2007-05-31
CA2501651C (en) 2011-02-15
JP5416328B2 (en) 2014-02-12
US20100120708A1 (en) 2010-05-13
MXPA05003595A (en) 2005-06-03
US20060009418A1 (en) 2006-01-12
CY1106601T1 (en) 2012-01-25
ZA200502753B (en) 2006-03-29
DE60312715D1 (en) 2007-05-03
KR20050055070A (en) 2005-06-10
KR101098061B1 (en) 2011-12-26
NO330601B1 (en) 2011-05-23
AU2003269253B2 (en) 2007-04-05
CN1703223A (en) 2005-11-30
DK1551409T3 (en) 2007-06-11
NO20051575L (en) 2005-04-25
ES2282656T3 (en) 2007-10-16
AU2003269253A1 (en) 2004-05-04
BR0315088A (en) 2005-08-16
GB0223380D0 (en) 2002-11-13
CN100363004C (en) 2008-01-23
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ATE357236T1 (en) 2007-04-15

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