WO2004071397A2 - Combination therapy of zd6474 with 5-fu or/and cpt-11 - Google Patents
Combination therapy of zd6474 with 5-fu or/and cpt-11 Download PDFInfo
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- WO2004071397A2 WO2004071397A2 PCT/GB2004/000550 GB2004000550W WO2004071397A2 WO 2004071397 A2 WO2004071397 A2 WO 2004071397A2 GB 2004000550 W GB2004000550 W GB 2004000550W WO 2004071397 A2 WO2004071397 A2 WO 2004071397A2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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 animal such as a human, which 5 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 one of: the adrriinistration of ZD6474 in combination with 5-FU; the ad ⁇ iinistration of ZD6474 in combination with CPT-11; and the administration of ZD6474 in combination with 5-FU and CPT-11; to a pharmaceutical composition comprising one of: ZD6474 and 5-FU; ZD6474 and
- Normal angio genesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive
- Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, aposi'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 (Cul inan-Bove et al, 1993, Endocrinology 133:
- VEGF vascular endothelial growth factor
- VEGF 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 VEGF with antibody can result in inhibition of tumour growth (Kim et al, 1993, Nature 362: 841-844).
- Receptor tyro sine kinases are important in the transmission of biochemical signals across the plasma membrane of cells.
- transmembrane molecules characteristically 5 consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyro sine 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.
- RTK subfamilies defined by amino acid sequence homology.
- One of these subfamilies is presently comprised by the fins-like tyrosine kinase receptor, Flt-1, the kinase insert domam-containing receptor, KDR (also referred to as Flk-1), and another fins-like tyrosine kinase receptor, Flt-4.
- Flt-1 and KDR Two of these related RTKs, Flt-1 and KDR, have been shown to bind VEGF with high affinity (De Vries et al, 1992, Science 255:
- VEGF is a key stimulus for vasculogenesis and angiogenesis.
- This cytokine induces a vascular sprouting phenotype by inducing endothelial cell proliferation, protease expression
- VEGF induces significant vascular permeability (Dvorak, H.F., Detmar, M., Claffey, K.P., Nagy, J.A., van de Water, L., and Senger, D.R., (h t. Arch. Allergy Immunol., 107: 233- 235, 1995; Bates, D.O., Heald, R.I., Curry, F.E. and Williams, B. J. Physiol. (Lond.), 533: 263-272, 2001), promoting formation of a hyper-permeable, immature vascular network which is characteristic of pathological angiogenesis.
- WO 98/13354 and WO 01/32651 compounds are described which possess activity against VEGF receptor tyrosine kinase whilst possessing some activity against EGF receptor tyrosine kinase.
- the compound of the present invention, ZD6474 falls within the broad general disclosure of WO 98/13354 and is exemplified in WO 01/32651.
- WO 01/32651 it is stated that compounds of that invention: "may be applied as a sole therapy or may involve, in addition to a compound of the invention, 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 01/32651 then goes on to describe examples of such conjoint treatment including surgery, radiotherapy and many types of chemo therapeutic agent including 5- fluorouracil (5-FU) and irinotecan (CPT-11). Nowhere in WO 01/32651 does it state that use of any compound of the invention therein with other treatments will produce surprisingly beneficial effects.
- 5-FU 5- fluorouracil
- CPT-11 irinotecan
- ZD6474 used in combination with a particular selection of combination therapies namely with one of: 5-FU; CPT-11; and 5-FU and CPT-11, produces significantly better antiangiogenic and/or vascular peraieability reducing effects than any one of: ZD6474; 5-FU; CPT-11; and 5- FU and CPT-11 used alone.
- ZD6474 used in combination with one of: 5-FU; CPT- 11 ; and 5-FU and CPT- 11 produces significantly better anti-cancer effects than any one of: ZD6474; 5-FU; CPT-11; and 5-FU and CPT-11 used alone.
- ZD6474 used in combination with one of: 5-FU; CPT-11; and 5-FU and CPT-11 produces significantly better effects on solid tumours than any one of: ZD6474; 5-FU; CPT-11; and 5-FU and CPT-11 used alone.
- ZD6474 used in combination with one of: 5- FU; CPT-11; and 5-FU and CPT-11 produces significantly better effects in colorectal cancer than any one of: ZD6474; 5-FU; CPT-11; and 5-FU and CPT-11 used alone.
- 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.
- 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, 4-(4-bromo-2- fluoiOanilino)-6-methoxy-7-(l-methylpiperidm-4-ylmethoxy)qu azoline, also known as ZD6474:
- ZD6474 or a pharmaceutically acceptable salt thereof before, after or simultaneously with an effective amount of one of: a) 5-FU; b) CPT-11; and c) 5-FU and CPT-11.
- a method for the treatment of a cancer in a warm-blooded artimal such as a human, which comprises adieriissering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of one of: 5-FU; CPT-11; and 5-FU and CPT-11.
- 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 one of: 5-FU; CPT-11; and 5-FU and CPT-11.
- a method for the treatment of colorectal 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 one of: 5-FU; CPT-11; and 5-FU and CPT-11.
- 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 adixtinistering to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of one of: 5-FU; CPT-11; and 5-FU and CPT-11; wherein ZD6474, 5-FU and CPT-11 may each optionally be administered together with a pharmaceutically acceptable excipient or canier.
- 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 one of: 5-FU; CPT-11; and 5-FU and CPT- 11 ; wherein ZD6474, 5-FU and CPT- 11 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 ariimal 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 one of: 5-FU; CPT- 11 ; and 5-FU and CPT- 11 ; wherein ZD6474, 5-FU and CPT- 11 may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
- a method for the treatment of colorectal 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 one of: 5-FU; CPT-11; and 5-FU and CPT- 11 ; wherein ZD6474, 5-FU and CPT- 11 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 5-FU in association with a pharmaceutically acceptable excipient or carrier.
- a pharmaceutical composition which comprises ZD6474 or a pharmaceutically acceptable salt thereof, and CPT- 11 in association with a pharmaceutically acceptable excipient or carrier.
- a pharmaceutical composition which comprises ZD6474 or a pharmaceutically acceptable salt thereof, and 5-FU and CPT- 11 in association with a pharmaceutically acceptable excipient or carrier.
- a combination product comprising ZD6474 or a pharmaceutically acceptable salt thereof and 5-FU, for use in a method of treatment of a human or animal body by therapy.
- a combination product comprising ZD6474 or a pharmaceutically acceptable salt thereof and CPT- 11 , for use in a method of treatment of a human or animal body by therapy.
- a combination product comprising ZD6474 or a pharmaceutically acceptable salt thereof and 5-FU and CPT- 11 , for use in a method of treatment of a human or animal body by therapy.
- a kit comprising ZD6474 or a pharmaceutically acceptable salt thereof, and 5-FU.
- kits comprising ZD6474 or a pharmaceutically acceptable salt thereof, and CPT-11.
- kits comprising ZD6474 or a pharmaceutically acceptable salt thereof, and 5-FU and CPT-11.
- kits comprising: a) ZD6474 or a pharmaceutically acceptable salt thereof in a first unit dosage form; b) 5-FU 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 in a first unit dosage form; b) CPT-11 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 in a first unit dosage fonn; b) 5-FU in a second unit dosage form; c) CPT-11 in a third unit dosage form; and d) container means for containing said first, second and third dosage forms.
- 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) 5-FU 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.
- 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) CPT-11 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.
- 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) 5-FU together with a pharmaceutically acceptable excipient or carrier, in a second unit dosage form; c) CPT-11 together with a pharmaceutically acceptable excipient or carrier, in a third unit dosage form; and d) container means for containing said first, second and third dosage forms.
- ZD6474 or a pharmaceutically acceptable salt thereof and one of: a) 5-FU; b) CPT-11; and c) 5-FU and CPT-11 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.
- a further aspect of the present invention there is provided the use of
- ZD6474 or a pharmaceutically acceptable salt thereof and one of: a) 5-FU; b) CPT-11; and c) 5-FU and CPT-11 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.
- ZD6474 or a pharmaceutically acceptable salt thereof and one of: a) 5-FU; b) CPT-11; and c) 5-FU and CPT-11 in the manufacture of a medicament for use in the production of an anti-cancer ettect in a warm-blooded animal such as a human wherein the cancer is a colorectal cancer.
- 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 5-FU, optionally together with a pharmaceutically acceptable excipient or carrier, to a warm-blooded animal such as a human in need of such therapeutic treatment wherein the ZD6474 and 5-FU may be administered simultaneously, sequentially or separately and in any order.
- 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 CPT-11, optionally together with a pharmaceutically acceptable excipient or carrier, to a warm-blooded animal such as a human in need of such therapeutic treatment wherein the ZD6474 and CPT- 11 may be administered simultaneously, sequentially or separately and in any order.
- 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 5-FU, optionally together with a pharmaceutically acceptable excipient or carrier, and the administration of an effective amount of CPT-11, optionally together with a pharmaceutically acceptable excipient or carrier, to a warm-blooded animal such as a human in need of such therapeutic treatment wherein the ZD6474, 5-FU and CPT-11 may be adiuinistered simultaneously, sequentially or separately and in any order.
- 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 chemotherapeutic agent in addition to a combination treatment of the invention.
- Surgery may comprise the step of partial or complete tumour resection, prior to, during or after the administration of the combination treatment 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 as stated in WO 01/32651: (i) other antiangiogenic agents including vascular targeting agents;
- biological response modifiers for example interferon
- antibodies for example edrecolomab
- the administration of a multiple combination of ZD6474, 5-FU and ionising radiation or ZD6474, CPT-11 and ionising radiation or ZD6474, 5-FU, CPT-11 and ionising radiation may produce effects, such as anti-tumour effects, greater than those achieved with any of ZD6474, 5-FU, CPT-11 and ionising radiation used alone.
- the administration of a multiple combination of ZD6474, 5-FU and ionising radiation or ZD6474, CPT-11 and ionising radiation or ZD6474, 5-FU, CPT-11 and ionising radiation may produce effects, such as anti- tumour effects, greater than those achieved with the combination of ZD6474 and 5-FU, greater than those achieved with the combination of ZD6474 and CPT-11 and greater than those achieved with the combination of ZD6474, 5-FU and CPT-11.
- the administration of a multiple combination of ZD6474, 5-FU and ionising radiation or ZD6474, CPT-11 and ionising radiation or ZD6474, 5-FU, CPT-11 and ionising radiation may produce effects, such as anti- tumour effects, greater than those achieved with the combination of ZD6474 and ionising radiation, greater than those achieved with the combination of 5-FU and ionising radiation, greater than those achieved with the combination of CPT-11 and ionising radiation, and greater than those achieved with the combination of 5-FU, CPT-11 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 5-FU 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 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 CPT-11 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 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 5-FU, before, after or simultaneously with an effective amount of CPT-11 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 5-FU 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 CPT- 11 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 adieridging to said animal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of 5-FU, before, after or simultaneously with an effective amount of CPT-11 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 ZD 6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of 5-FU 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 CPT-11 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 ar-imal 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 5-FU, before, after or simultaneously with an effective amount of CPT-11 and before, after or simultaneously with an effective amount of ionising radiation.
- a cancer involving a solid tumour is colorectal cancer.
- 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 5-FU and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and 5-FU may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
- 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 CPT- 11 and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and CPT-11 may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
- a method for the production of an antiangiogenic and/or vascular permeability reducing effect in a warmblooded artimal 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 5-FU, before, after or simultaneously with an effective amount of CPT-11 and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474, 5-FU and CPT-11 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 ariimal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of 5-FU and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and 5-FU 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 CPT-11 and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and CPT-11 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 ad ⁇ -istering to said ariimal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of 5-FU, before, after or simultaneously with an effective amount of CPT-11 and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474, 5-FU and CPT-11 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 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 5-FU and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and 5-FU 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 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 CPT-11 and before, after or simultaneously with an effective amount of ionising radiation, wherein ZD6474 and CPT-11 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 comprises administering to said arrimal an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of 5-FU, before, after or simultaneously with an effective amount of CPT-11 and before, after or simultaneously with an effective amount of ionising radiation, wherein
- ZD6474, 5-FU and CPT-11 may each optionally be administered together with a pharmaceutically acceptable excipient or carrier.
- ZD6474 or a pharmaceutically acceptable salt thereof and 5-FU 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 wliich is being treated with ionising radiation.
- ZD6474 or a pharmaceutically acceptable salt thereof and CPT-11 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.
- ZD6474 or a pharmaceutically acceptable salt thereof and 5-FU and CPT-11 in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in a warm-blooded arrimal such as a human which is being treated with ionising radiation.
- ZD6474 or a pharmaceutically acceptable salt thereof and 5-FU in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded ariimal such as a human which is being treated with ionising radiation.
- ZD6474 or a pharmaceutically acceptable salt thereof and CPT-11 in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded arrimal such as a human which is being treated with ionising radiation.
- the warm-blooded animal such as a human has colorectal cancer.
- a therapeutic combination treatment comprising the administration of an effective amount of ZD6474 or a pharmaceutically acceptable salt thereof, optionally together with a phaiinaceutically acceptable excipient or carrier, and the administration of an effective amount of 5-FU, 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 hurnan in need of such therapeutic treatment wherein the ZD6474, 5-FU and ionising radiation may be administered simultaneously, sequentially or separately and in any order.
- 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 CPT-11, 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, CPT-11 and ionising radiation may be administered simultaneously, sequentially or separately and in any order.
- 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 5-FU, optionally together with a pharmaceutically acceptable excipient or carrier, and the administration of an effective amount of CPT- 11 , 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, 5-FU, CPT-11 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 wliich is treated with ionising radiation before, after or at the same time as the administration of a medicament or combination treatment comprising ZD6474 and one of: 5-FU; CPT-11; and 5-FU and CPT-11.
- 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 one of: 5-FU; CPT-11; and 5-FU and CPT-11.
- ZD6474, 5-FU, CPT-11 and ionising radiation may be administered separately or sequentially in any order, or may be administered simultaneously.
- the warm-blooded animal may experience the effect of each of ZD6474, 5-FU, CPT-11 and radiation simultaneously.
- the ionising radiation is administered before one of ZD6474 and one of: 5-FU; CPT-11; and 5-FU and CPT-11, or after one of ZD6474 and one of: 5-FU; CPT-11; and 5-FU and CPT-11.
- the ionising radiation is administered before any of ZD6474 and one of: 5-FU; CPT- 11 ; and 5-FU and CPT- 11 or after all of ZD6474 and one of: 5-FU; CPT-11; and 5-FU and CPT-11.
- ZD6474 is administered to a warmblooded ariimal after the animal has been treated with ionising radiation.
- combination treatments of the present invention that is ZD6474, optionally with ionising radiation, combined with one of: 5-FU; CPT-11; and 5-FU and CPT- 11, as defined herein, are of interest for their antiangiogenic and/or vascular permeability effects.
- Angiogenesis and/or increased 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 resteno sis, autoimmune diseases, acute inflammation, lymphoedema, excessive scar formation and adhesions, 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
- 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.
- combination treatments of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin.
- More particularly such combination treatments of the invention are expected to inhibit any form of cancer associated with VEGF 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 VEGF, especially those tumours which are significantly dependent on VEGF for their growth and spread, including for example, certain tumours of the colon, breast, prostate, lung, vulva and skin.
- such combination treatments of the invention are expected to slow advantageously the growth of primary and secondary (recurrent) tumours in colorectal cancer.
- ZD6474 optionally with ionising radiation, and one of: 5-FU; CPT-11; and 5-FU and CPT-11 are expected to inhibit the growth of those primary and recurrent solid tumours which are associated with VEGF especially those tumours which are significantly dependent on VEGF for their growth and spread.
- ZD6474 optionally with ionising radiation, and one of: 5-FU; CPT-11; and 5-FU and CPT-11 are expected to inhibit the growth of those 5 primary and recurrent solid tumours which are associated with both VEGF and EGF especially those tumours which are significantly dependent on VEGF and EGF for their growth and spread.
- the effect of a method of treatment of the present invention is expected to be at least equivalent to the addition of the 10 effects of each of the components of said treatment used alone, that is, of each of ZD6474, 5- FU, CPT-11 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, 5-FU, CPT- 15 11 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 20 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, 5-FU, CPT-11, 5-FU and CPT-11, or ionising radiation used alone.
- the effect of the combination treatment 25 is synergistic if a beneficial effect is obtained in a group of patients that does not respond (or responds poorly) to ZD6474, 5-FU, CPT-11, 5-FU and CPT-11, or ionising radiation used 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 30 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, 5-FU, CPT- 11 , 5-FU and CPT- 11 , 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.
- 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 endoscopicalfy, intratracheally, intralesionally, percutaneously, intravenously, subcutaneously, intraperitoneally or intratumourally.
- 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 for
- ZD6474 will normally be administered to a warm-blooded ariimal 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.
- CPT-11 is also known as irinotecan. CPT-11 may be administered in accordance with any known route of administration and dosage.
- CPT-11 may be dosed at 350mg/m 2 as an intravenous infusion over a 30 to 90 minute period every 3 weeks.
- CPT-11 is a semi-synthetic derivative of camptothecin and is metabolised in vivo to an active metabolite SN-38.
- 5-FU is 5-fluorouracil.
- 5-FU may be administered according to any known route of adn-inistration and dosage.
- 5-FU may be given as an intravenous daily infusion of 15mg/kg diluted in 500ml of 5% dextrose solution or 500ml 0.9% sodium chloride solution given by intravenous infusion: at the rate of 40 drops per minute over 4 hours; or infused over 30 to 60 minutes; or as a daily continuous infusion over 24 hours.
- the daily dose of 5-FU is recommended not to exceed lg.
- 5-FU is usually given daily in one of these ways until 12-15g has been given and this constitutes one course of 5-FU. It is usual practice to leave 4 to 6 weeks between courses of 5-FU.
- 5-FU may be dosed by intravenous injection at a dose of 12mg/kg on three consecutive days, followed by 6mg/kg on days 5, 7 and 9 ie on the three following alternate days, followed by a maintenance dose of 5-15mg/kg by intravenous injection once a week.
- 5-FU may be given by intravenous injection at a dose of 15mg/kg once a week for the duration of the patient's treatment.
- 5-FU may also be dosed intra-arterially as a regional perfusion at 5-7.5mg/kg by 24 hour continuous infusion.
- 5-FU may also be dosed orally at a dose of 15mg/kg once a week or at a dose of 15mg/kg for six successive days followed by 15mg kg once a week.
- 5-FU is commonly administered with leucovorin.
- the combination treatments of the present invention include the use of 5-FU when given with, or without, leucovorin.
- Leucovorin may be administered according to any known route of administration and dosage.
- leucovorin may be administered orally.
- leucovorin is conveniently administered as calcium leucovorin and given intravenously.
- calcium leucovorin may be given at a dose of 200mg/m 2 by slow intravenous injection, followed immediately by 5-FU at an initial dose of 370mg/m 2 by intravenous injection.
- the injection of leucovorin should not be given more rapidly than over 3-5 minutes because of the calcium content of the solution. This treatment is repeated daily for 5 consecutive days. Subsequent courses may be given after a treatment-free interval of 21-28 days.
- the following regimen may be used: leucovorin 500 mg/m 2 given by 2 hour infusion every week for 6 weeks with 5-FU 500 mg/m 2 given as an iv bolus midway through the 6-week period.
- the following regimen may be used: leucovorin 200 mg/m 2 given by iv 2 hour infusion followed by 5-FU 400 mg/m 2 iv bolus followed by 5-FU 600 mg/m 2 given by iv 22 hour infusion, repeated for 2 consecutive days. The cycle is repeated every 2 weeks.
- 5-FU may be administered orally as capecitabine (XelodaTM), tegafur, or TS-1.
- Capecitabine is a relatively non-cyto toxic fluoropyrimidine carbamate which functions as an orally administered precursor of 5-FU.
- Capecitabine may be administered according to any known dosage. For example a dose of 1250 mg/m 2 may be given orally twice a day, (equivalent to a daily dose of 2500mg/m 2 ), for 14 days followed by a rest period of 7 days.
- Combination treatments of the present invention include the use of 5-FU when given in any form, (including prodrug and precursor forms that are converted to 5-FU systemically or within the tumour), when administered via any route and when given with, or without, leucovorin.
- Combination treatments of the present invention include the use of CPT- 11 or SN-38 when given in any form, (including prodrug and precursor forms that are converted to SN-38 systemically or within the tumour and including liposomal formulations), when administered via any route.
- 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 radioiso topes.
- Other forms of DNA damaging factors are also included in the present invention such as microwaves and UV-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- lOGy 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 radioiso topes 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.
- the combination treatments of the present invention comprise: ZD6474 and 5-FU; ZD6474 and CPT-11; ZD6474, 5-FU and CPT-11; ZD6474, 5-FU and ionising radiation; ZD6474, CPT-11 and ionising radiation; ZD6474, 5-FU, CPT-11 and ionising radiation.
- the agents therein may be administered separately or sequentially in any order, or may be administered simultaneously.
- the present invention comprises combinations of 5-FU or CPT-11 or 5-FU and CPT- 11 with ZD6474 or with a salt of ZD6474.
- Salts 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, dimethylamf ⁇ e, trimethylamine, piperidine, morpholine or tris-(2- hydroxyethyl)amine.
- ZD6474 may be made, for example, according to any of the following processes illustrated by examples (a) -(c) in which, unless otherwise stated:-
- the starting material was prepared as follows: A solution of 7-ber-zyloxy-4-cMoro-6-methoxyquinazoline hydrochloride (8.35g,
- Potassium carbonate (414mg, 3mmol) was added to a suspension of 4-(4-bromo-2- fluoroartilmo)-7-hydroxy-6-methoxyquinazoline (546mg, 1.5mmol) inDMF (5ml). After stirring for 10 minutes at ambient temperature, l-(te7 -butoxycarbony ⁇ )-4-(4- methylphenylsulphonyloxymethyl)piperidine (636mg, 1.72mmol) was added and the mixture was heated at 95°C for 2 hours. After cooling, the mixture was poured onto cooled water (20ml).
- the starting material was prepared as follows: l-(te7t-Butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (40g, 0.1 lmol), (prepared as described for the starting material in process (a) above), was added to a suspension of ethyl 4-hydroxy-3-methoxybenzoate (19.6g, 0. lmol) and potassium carbonate (28g, 0.2mol) in dry DMF (200ml). After stirring at 95°C for 2.5 hours, the mixture was cooled to ambient temperature and partitioned between water and ethyl acetate/ether. The organic layer was washed with water, brine, dried (MgSO ) and evaporated.
- Formaldehyde (12M, 37% in water, 35ml, 420mmol) was added to a solution of ethyl 4-(l-(tert-butoxycarbonyl)piperidin-4-yhnethoxy)-3-methoxybenzoate (35g, 89mmol) in formic acid (35ml). After stirring at 95°C for 3 hours, the volatiles were removed by evaporation. The residue was dissolved in methylene chloride and 3M hydrogen chloride in ether (40ml, 120mmol) was added. After dilution with ether, the mixture was triturated until a sohd was formed.
- 6-methoxy-7-(l-methylpiperidin-4-ylmethoxy)-3,4- dihydiOquinazolin-4-one can be prepared as foUows:
- Triphenylphosphine (1.7g, 6.5mmol) was added under nitrogen to a suspension of 7- hydiOxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydiOquinazolin-4-one (1.53g, 5mmol) in methylene chloride (20ml), foUowed by the addition of l-(tert-butoxycarbonyl)-4- (hydiOxymethyl)piperidine (1.29g, 6mmol), (prepared as described for the starting material in process (a) above), and by a solution of diethyl azodicarboxylate (1.13g, 6.5mmol) in methylene chloride (5ml).
- RPMI RPMI- 1640 medium
- tumours were injected subcutaneously (s.c.) into the flanks of 10 athymic (nu/nu genotype) mice.
- tumours were surgicaUy excised and smaUer tumour fragments thereof (20-30 mg) were implanted s.c. in the right flank of 120 Nude mice.
- tumours reached a volume of 100 to 200 mm 3 (14-16 days after the graft) mice were randomized into groups (13 - 15 per group) and treatment started.
- the control group (Group 1) received a daUy oral (p.o.) administration of ZD6474 vehicle for 14 consecutive days (day 0 - 13) combined with two intravenous (i.v.) injections of saline (the vehicle for 5-FU) on day 0 and 7.
- the treatments consisted of a daily p.o. administration of ZD6474 alone at 25mg/kg/adminstration for 14 consecutive days (day 0 - 13) combined with two i.v. injections of saline (the vehicle for 5-FU) on day 0 and 7.
- ZD6474 was prepared as a suspension in 1% polysorbate 80 (i.e.
- ⁇ Group 3 received two i.v. injections of 5-FU at 75mg/kg/injection, on day 0 and 7, combined with a daUy p.o. administration of ZD6474 vehicle for 14 consecutive days (day 0 - 13).
- ⁇ Group 4 received daUy p.o. administration of ZD6474 at 25irig/Tcg/adminstration for 14 5 consecutive days (day 0 - 13) combined with two i.v. injections of 5-FU at 75mg/kg/injection, on day 0 and 7.
- the administration volume of ZD6474 was 10.0 ml/kg (200 ⁇ l for a 20 g mouse).
- the injection volume of 5-FU was 10.0 ml/kg (200 ⁇ l for a 20 g mouse).
- Tumor volumes were assessed at least twice weekly by bUateral Vernier caliper measurement and, taking length to be the longest diameter across the tumor and width the corresponding perpendicular, calculated using the formula ( ⁇ /6) x (length x width) x the square root of (length x width). Growth inhibition from the start of treatment was assessed by
- the control group (Group 1) received a daUy oral (p.o.) administration of ZD6474 vehicle for 14 consecutive days (day 0 - 13) combined with two intravenous (iv.) injections of sahne (the vehicle for CPT-11) on day 0 and 7. The control group was not continued past this period, as some of the tumour volumes were considered too large ( ⁇ 2 cm 3 ), ⁇
- the treatments consisted of a daUy p.o. administration of ZD6474 alone at 25rr ⁇ g/kg/adminstration for 21 consecutive days (day 0 - 20) combined with three iv. injections of saline (the vehicle for CPT-11) on day 0, 7 and 14.
- ZD6474 was prepared as a suspension in 1% polysorbate 80 (ie. a 1% (v/v) solution of polyoxyethylene (20) sorbitan mono-oleate in deionised water).
- ⁇ Group 3 received three iv. injections of CPT-11 at 20mg/kg/injection, on day 0, 7 and 14, combined with a daUy p.o. administration of ZD6474 vehicle for 21 consecutive days (day 0 - 20).
- ⁇ Group 4 received daUy p.o. administration of ZD6474 at 25mg/kg/ad ⁇ instration for 21 consecutive days (day 0 - 20) combined with three i v. injections of 5-FU at 20mg/kg/injection, on day 0, 7 and 14.
- the administration volume of ZD6474 was 10.0 ml/kg (200 ⁇ l for a 20 g mouse).
- the injection volume of CPT- 11 was 10.0 ml kg (200 ⁇ l for a 20 g mouse).
- Tumor volumes were assessed at least twice weekly by bUateral Vernier caliper 5 measurement and, taking length to be the longest diameter across the tumor and width the corresponding perpendicular, calculated using the formula ( ⁇ /6) x (length x width) x square root of (length x width). Growth inhibition from the start of treatment was assessed by comparison of the differences in tumor volume between control and treated groups. For aU mice, the study was stopped when tumours reached 2,000 mm 3 . For aU mice, the tumours 10 were excised and weights recorded upon tennination of the study.
- mice treated with ZD6474 25mg/kg/day p.o., d 0 - 20), CPT-11 (20 mg/kg iv., d 0, 7 and 14), or the combination thereof, were 475mm 3 , 552mm 3 and 336mm 3 respectively.
- An analogous experiment may be used to look at the combination of ZD6474, 5-FU and CPT- 11 in this animal model.
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Abstract
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Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
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NZ541297A NZ541297A (en) | 2003-02-13 | 2004-02-11 | Combination therapy of ZD6474 with 5-FU or/and CPT-11 |
CA2514227A CA2514227C (en) | 2003-02-13 | 2004-02-11 | Combination therapy of zd6474 with 5-fu or/and cpt-11 |
BR0407301-0A BRPI0407301A (en) | 2003-02-13 | 2004-02-11 | Use of a combination, pharmaceutical composition, kit, and method for treating cancer in a warm-blooded animal such as a human. |
DK04710081.3T DK1592423T3 (en) | 2003-02-13 | 2004-02-11 | Combination therapy of ZD6474 with 5-FU and / or CPT-11 |
EP04710081A EP1592423B1 (en) | 2003-02-13 | 2004-02-11 | Combination therapy of zd6474 with 5-fu and/or cpt-11 |
AU2004212255A AU2004212255B2 (en) | 2003-02-13 | 2004-02-11 | Combination therapy of ZD6474 with 5-FU or/and CPT-11 |
JP2006502268A JP2006517575A (en) | 2003-02-13 | 2004-02-11 | Combination therapy |
SI200431690T SI1592423T1 (en) | 2003-02-13 | 2004-02-11 | Combination therapy of zd6474 with 5-fu and/or cpt-11 |
MXPA05008583A MXPA05008583A (en) | 2003-02-13 | 2004-02-11 | Combination therapy of zd6474 with 5-fu or/and cpt-11. |
US10/543,106 US20060142316A1 (en) | 2003-02-13 | 2004-02-11 | Combination therapy |
DE602004032310T DE602004032310D1 (en) | 2003-02-13 | 2004-02-11 | COMBINATION THERAPY OF ZD6474 WITH 5-FU OR / AND CPT-11 |
AT04710081T ATE506062T1 (en) | 2003-02-13 | 2004-02-11 | COMBINATION THERAPY OF ZD6474 WITH 5-FU OR/AND CPT-11 |
IL169702A IL169702A (en) | 2003-02-13 | 2005-07-17 | Use of zd6474 with 5-fu or/and cpt-11 in the manufacture of medicaments for the treatment of cancer and pharmaceutical compositions and kits comprising the same |
NO20053649A NO331486B1 (en) | 2003-02-13 | 2005-07-27 | Use of 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylmethoxy) quinazoline also known as ZD6474, or a pharmaceutically acceptable salt thereof and ± n of: a) 5- FU; b) CPT-11; and c) 5-FU and CPT-11, in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as a human, as well as a pharmaceutical composition and kits containing the same |
HK06104405.5A HK1084032A1 (en) | 2003-02-13 | 2006-04-11 | Combination therapy of zd6474 with 5-fu and/or cpt-11 |
US12/501,599 US20100130520A1 (en) | 2003-02-13 | 2009-07-13 | Combination therapy |
US12/973,271 US20110086870A1 (en) | 2003-02-13 | 2010-12-20 | Combination Therapy |
US13/282,750 US20120252826A1 (en) | 2003-02-13 | 2011-10-27 | Combination Therapy |
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GB0318311A GB0318311D0 (en) | 2003-08-05 | 2003-08-05 | Combination therapy |
GB0318311.8 | 2003-08-05 |
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US (4) | US20060142316A1 (en) |
EP (1) | EP1592423B1 (en) |
JP (3) | JP2006517575A (en) |
KR (2) | KR20050100683A (en) |
AT (1) | ATE506062T1 (en) |
AU (1) | AU2004212255B2 (en) |
CA (1) | CA2514227C (en) |
CY (1) | CY1111565T1 (en) |
DE (1) | DE602004032310D1 (en) |
DK (1) | DK1592423T3 (en) |
HK (1) | HK1084032A1 (en) |
IL (1) | IL169702A (en) |
MX (1) | MXPA05008583A (en) |
NO (1) | NO331486B1 (en) |
NZ (1) | NZ541297A (en) |
PT (1) | PT1592423E (en) |
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WO2005117980A1 (en) * | 2004-06-04 | 2005-12-15 | Pfizer Products Inc. | Method for treating abnormal cell growth |
US7462623B2 (en) | 2002-11-04 | 2008-12-09 | Astrazeneca Ab | Quinazoline derivatives as Src tyrosine kinase inhibitors |
EP2053048A1 (en) | 2005-09-30 | 2009-04-29 | AstraZeneca AB | Chemical in situ sulphonating process |
JP2009520783A (en) * | 2005-12-22 | 2009-05-28 | アストラゼネカ アクチボラグ | Combination therapy |
US7829573B2 (en) | 2000-04-05 | 2010-11-09 | Astrazeneca Ab | Therapeutic combinations of antihypertensive and antiangiogenics agents |
US10457664B2 (en) | 1999-11-05 | 2019-10-29 | Genzyme Corporation | Quinazoline derivatives as VEGF inhibitors |
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GB0126879D0 (en) * | 2001-11-08 | 2002-01-02 | Astrazeneca Ab | Combination therapy |
GB0218526D0 (en) * | 2002-08-09 | 2002-09-18 | Astrazeneca Ab | Combination therapy |
GB0223380D0 (en) * | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Combination therapy |
DK1592423T3 (en) * | 2003-02-13 | 2011-06-27 | Astrazeneca Ab | Combination therapy of ZD6474 with 5-FU and / or CPT-11 |
GB0310401D0 (en) * | 2003-05-07 | 2003-06-11 | Astrazeneca Ab | Therapeutic agent |
MXPA06000114A (en) * | 2003-07-10 | 2006-04-27 | Astrazeneca Ab | Use of the quinazoline derivative zd6474 combined with platinum compounds and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability. |
BRPI0516052A (en) * | 2004-09-27 | 2008-08-19 | Astrazeneca Ab | use of zd6474 or a pharmaceutically acceptable salt thereof and imatinib, pharmaceutical composition, kit, and method for producing an antiangiogenic effect and / or reducing vascular permeability in a warm-blooded animal |
GB0424339D0 (en) * | 2004-11-03 | 2004-12-08 | Astrazeneca Ab | Combination therapy |
US20100092466A1 (en) * | 2006-09-29 | 2010-04-15 | Anderson Joseph Ryan | Combination of zd6474 and bevacizumab for cancer therapy |
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GB0008269D0 (en) * | 2000-04-05 | 2000-05-24 | Astrazeneca Ab | Combination chemotherapy |
GB0126879D0 (en) * | 2001-11-08 | 2002-01-02 | Astrazeneca Ab | Combination therapy |
KR20050056190A (en) * | 2002-08-09 | 2005-06-14 | 아스트라제네카 아베 | Combination of zd6474, an inhibitor of the vascular endothelial growth factor receptor, with radiotherapy in the treatment of cancer |
GB0218526D0 (en) * | 2002-08-09 | 2002-09-18 | Astrazeneca Ab | Combination therapy |
GB0223380D0 (en) * | 2002-10-09 | 2002-11-13 | Astrazeneca Ab | Combination therapy |
DK1592423T3 (en) * | 2003-02-13 | 2011-06-27 | Astrazeneca Ab | Combination therapy of ZD6474 with 5-FU and / or CPT-11 |
MXPA06000114A (en) * | 2003-07-10 | 2006-04-27 | Astrazeneca Ab | Use of the quinazoline derivative zd6474 combined with platinum compounds and optionally ionising radiation in the treatment of diseases associated with angiogenesis and/or increased vascular permeability. |
BRPI0516052A (en) * | 2004-09-27 | 2008-08-19 | Astrazeneca Ab | use of zd6474 or a pharmaceutically acceptable salt thereof and imatinib, pharmaceutical composition, kit, and method for producing an antiangiogenic effect and / or reducing vascular permeability in a warm-blooded animal |
GB0424339D0 (en) * | 2004-11-03 | 2004-12-08 | Astrazeneca Ab | Combination therapy |
JP4834985B2 (en) * | 2004-12-10 | 2011-12-14 | 日産自動車株式会社 | Battery pack capacity adjustment device |
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US20100092466A1 (en) * | 2006-09-29 | 2010-04-15 | Anderson Joseph Ryan | Combination of zd6474 and bevacizumab for cancer therapy |
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- 2004-02-11 JP JP2006502268A patent/JP2006517575A/en not_active Withdrawn
- 2004-02-11 PT PT04710081T patent/PT1592423E/en unknown
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US10457664B2 (en) | 1999-11-05 | 2019-10-29 | Genzyme Corporation | Quinazoline derivatives as VEGF inhibitors |
US7829573B2 (en) | 2000-04-05 | 2010-11-09 | Astrazeneca Ab | Therapeutic combinations of antihypertensive and antiangiogenics agents |
US7462623B2 (en) | 2002-11-04 | 2008-12-09 | Astrazeneca Ab | Quinazoline derivatives as Src tyrosine kinase inhibitors |
WO2005117980A1 (en) * | 2004-06-04 | 2005-12-15 | Pfizer Products Inc. | Method for treating abnormal cell growth |
EP2053048A1 (en) | 2005-09-30 | 2009-04-29 | AstraZeneca AB | Chemical in situ sulphonating process |
JP2009520783A (en) * | 2005-12-22 | 2009-05-28 | アストラゼネカ アクチボラグ | Combination therapy |
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US20120252826A1 (en) | 2012-10-04 |
PT1592423E (en) | 2011-06-16 |
SI1592423T1 (en) | 2011-07-29 |
MXPA05008583A (en) | 2005-11-04 |
NO331486B1 (en) | 2012-01-16 |
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JP2011016853A (en) | 2011-01-27 |
KR20110006699A (en) | 2011-01-20 |
AU2004212255B2 (en) | 2007-07-05 |
NO20053649L (en) | 2005-09-12 |
CY1111565T1 (en) | 2015-10-07 |
JP2014065750A (en) | 2014-04-17 |
NZ541297A (en) | 2008-03-28 |
JP5563950B2 (en) | 2014-07-30 |
KR20050100683A (en) | 2005-10-19 |
CA2514227C (en) | 2011-08-09 |
AU2004212255A1 (en) | 2004-08-26 |
NO20053649D0 (en) | 2005-07-27 |
IL169702A (en) | 2014-05-28 |
ATE506062T1 (en) | 2011-05-15 |
WO2004071397A3 (en) | 2004-10-14 |
US20100130520A1 (en) | 2010-05-27 |
EP1592423A2 (en) | 2005-11-09 |
HK1084032A1 (en) | 2006-07-21 |
US20060142316A1 (en) | 2006-06-29 |
DE602004032310D1 (en) | 2011-06-01 |
IL169702A0 (en) | 2007-07-04 |
US20110086870A1 (en) | 2011-04-14 |
EP1592423B1 (en) | 2011-04-20 |
CA2514227A1 (en) | 2004-08-26 |
JP2006517575A (en) | 2006-07-27 |
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