MX2008007986A - Combination of azd2171 and pemetrexed - Google Patents

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 beingtreated with ionising radiation, particularly a method for the treatment of a cancer, particularly a cancer involving a solid tumour, which comprises the administration of AZD2171 in combination with pemetrexed;to a pharmaceutical composition comprising AZD2171 and pemetrexed;to a combination product comprising AZD2171 and pemetrexed for use in a method of treatment of a human or animal body by therapy;to a kit comprising AZD2171 and pemetrexed;to the use of AZD2171 and pemetrexed 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

COMBINATION THERAPY Description of the Invention The present invention relates to a method for the production of a vascular and / or antiegiogenic permeability reducing effect in a warm-blooded animal such as a human, which is optionally being treated with ionizing radiation, particularly, a method for the treatment of a cancer, particularly a cancer involving a solid tumor, which comprises the administration of AZD2171 in combination with pemetrexed; to a pharmaceutical composition comprising AZD2171 and pemetrexed; to a combination product comprising AZD2171 and pemetrexed for use in a method of treating the body of an animal or human by therapy; to a kit comprising AZD2171 and pemetrexed; to the use of AZD2171 and pemetrexed in the manufacture of a medicament for use in the production of a vascular and / or anti-angiogenic permeability reducing effect in a warm-blooded animal such as a human, which is being optionally treated with ionizing radiation . Normal angiogenesis plays an important role in a variety of processes, including embryonic development, wound healing and various components of female reproductive function. Pathological or unwanted angiogenesis has been associated with disease states that include diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma (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 (Cullinan-Bove et al., 1993, Endocrinology 133: 829-837, Senger et al., 1993, Cancer and Metastasis Reviews, 12: 303 -324). Several polypeptides with growth promoter activity in endothelial cells in vitro have been identified, including the growth factors of acidic and basic fibroblasts (aFGF &bFGF) and vascular endothelial growth factor (VEGF). By virtue of the restricted expression of its receptors, the activity of VEGF growth factor, in contrast to that of FGFs, is relatively specific towards endothelial cells.

Recent evidence indicates that VEGF is an important stimulator of 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 of vascular permeability (Connolly et al., 1989, J. Biol. Chem. 264: 20017-20024). Antagonism of the action of VEGF by sequestration of VEGF with antibody can result in the inhibition of tumor growth (Kim et al., 1993, Nature 362: 841-844).

Tyrosine kinase receptors (RTK) are important in the transmission of biochemical signals through the membrane plasma of the 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. The binding of the ligand to the receptor results in the stimulation of tyrosine kinase activity associated with the receptor, which leads to the phosphorylation of the tyrosine residues both in the receptor and in other intracellular molecules. These changes in tyrosine phosphorylation initiate a signaling cascade that leads to a variety of cellular responses. To date, at least nineteen distinct subfamilies of RTK have been identified, defined by amino acid sequence homology. One of these subfamilies is currently comprised by the fms-like tyrosine kinase receptor, Flt-1 (also referred to as VEGFR-1), the receptor containing the insert kinase domain, KDR (also referred to as VEGFR-2 or Flk-1) , and another receptor tyrosine kinase similar to fms, Flt-4 (also referred to as VEGFR-3). Two of these related RTKs, Flt-1 and KDR, have been shown to bind to VEGF with high affinity (De Vries et al., 1992, Science 255: 989-991, Terman et al., 1992, Biochem. Biophys. Res. Comm. 1992 , 187: 1579-1586). The binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the state of tyrosine phosphorylation in cellular proteins and in calcium fluxes.

VEGF is a key stimulus for vasculogenesis and angiogenesis. This cytokine induces a vascular growth phenotype by inducing the proliferation of endothelial cells, the expression and migration of proteases, and the subsequent organization of the cells to form a capillary tube (Keck, PJ, Hauser, SD, Krivi, G., Sanzo, K., Warren, T., Feder, J., and Connolly, DT, Science (Washington DC), 246: 1309-1312, 1989; Lamoreaux, WJ, Fitzgerald, ME, Reiner, A., Hasty, KA , and Charles, ST, Microvasc. Res., 55: 29-42, 1998; Pepper, MS, Montesano, R., Mandroita, SJ, Orci, L. and Vassalli, JD, Enzyme Protein, 49: 138-162, nineteen ninety six.). In addition, VEGF significantly induces vascular permeability (Dvorak, HF, Detmar, M., Claffey, KP, Nagy, JA, van de Water, L., and Senger, DR, (Int. Arch. Allergy Immunol., 107: 233-235, 1995; Bates, DO, Heald, RI, Curry, FE and Williams, BJ Physiol. (Lond.), 533: 263-272, 2001), promoting the formation of an immature hyperpermeable vascular network, which is Characteristic of pathological angiogenesis It has been shown that activation of KDR alone is sufficient to promote all major phenotypic responses to VEGF, including endothelial cell proliferation, migration and survival, and induction of vascular permeability (Meyer et al. , M., Clauss, M., Lepple-Wienhues, A., Waltenberger, J., Augustin, HG, Ziche, M., Lanz, C, Büttner, M., Rziha, H- J., and Dehio, C , EMBO J., 18: 363-374, 1999; Zeng, H., Sanyal, S. and Mukhopadhyay, D., J. Biol. Chem., 276: 32714-32719, 2001; Gille, H., Kowalski, J., Li, B., LeCouter, J., Moffat, B, Zioncheck, TF, Pelletier, N. and Ferrara, N., J. Biol. Chem., 276: 3222-3230 , 2001). Quinazoline derivatives that are inhibitors of the VEGF receptor tyrosine kinase are described in International Patent Application Publication No. WO 00/47212. AZD2171 is described in WO 00/47212 and is Example 240 of that document. AZD2171 is 4- (4-fluoro-2-methyl-1 H-indol-5-yloxy) -6-methoxy-7- (3- (pyrrolidin-1-yl) propoxy) quinazoline: AZD2171 AZD2171 shows excellent in vitro activity in assays of (a) enzyme and (b) HUVEC which are described in WO 00/47212 (pages 80-83). The IC5o values of AZD2171 for the inhibition of the tyrosine kinase activities KDR (VEGFR-2), Flt-1 (VEGFR-1) and Flt-4 (VEGFR-3) isolated in the enzyme assay were < 2 nM and 5 í 2 n and < 3 nM respectively. AZD2171 potently inhibits endothelial cell proliferation stimulated by VEGF (IC50 value of 0.4 ± 0.2 nM in the HUVEC assay), but does not inhibit the basal proliferation of endothelial cells appreciably at a 1250 fold higher concentration (IC50 value is> 500 nM). The growth of a Calu-6 tumor heterograft in the solid tumor model in vivo described in WO 00/47212 (page 83) was inhibited near the 49% **, 69% *** and 91% *** following 28 days of an oral treatment once a day with 1.5, 3 and 6 mg / kg / day of AZD2171 respectively (P ** <0.01, P *** <0.0001; single-tail test). AZD2171 has been shown to induce broad-spectrum antitumor activity in a variety of models following oral administration once a day, (Wedge et al., 2005, Cancer Research 65: 4389-4440). In WO 00/47212 it is stated that the compounds of the invention: "can be applied as a single therapy or can involve, in addition to a compound of the invention, one or more other substances and / or treatments." Such joint treatment can be accomplished by means of the simultaneous, sequential or separate administration of the individual components of the treatment. " WO 00/47212 now goes on to describe examples of such joint treatment, including surgery, radiotherapy and various types of chemotherapeutic agents. Nowhere in WO 00/47212 is it suggested the combination of a compound of the invention and pemetrexed for the treatment of any disease state including cancer. Nowhere in WO 00/47212, the specific combination of AZD2171 and pemetrexed is suggested.

Nowhere in WO 00/47212 is it indicated that the use of any compound of the invention in that regard with other treatments will surprisingly produce beneficial effects.

Unexpectedly and surprisingly we have now found that the particular compound AZD2171 used in combination with a particular selection of combination therapies listed in WO 00/47212, specifically pemetrexed, produces significantly better effects than any one of AZD2171 and pemetrexed used alone. In particular, AZD2171 used in combination with pemetrexed produces significantly better effects on solid tumors than any one of AZD2171 and pemetrexed used alone.

Pemetrexed is commonly used as a disodium of pemetrexed heptahydrate which has the chemical name: L-glutamic acid,? / - [4- [2- (2-amino-4,7-dihydro-4-oxo-1 H -pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -, disodium salt, hepahydrate. The structural formula is as follows: .7H, 0 Na Pemetrexed is also known as ALIMTA ™ (Mark of Lilly) and is an antifolate agent against cancer that breaks down the folate-dependent metabolic processes involved in cell replication. The anti-cancer effects of a method of treatment of the present invention include, but are not limited to, antitumor effects, the rate of response, the time to disease progression and the survival rate. Antitumor effects of a method of treatment of the present invention include, but are not limited to, inhibition of tumor growth, tumor growth retardation, tumor regression, tumor reduction, increased time for renewed growth of the tumor after the interruption of the treatment, the delay of the progression of the disease. It is envisaged that, when a treatment method of the present invention is administered to a warm-blooded animal such as a human, which needs treatment for the cancer, the treatment method will produce an effect, as measured by, for example, one or more of: the extent of the antitumor effect, the rate of response, the time to disease progression and the survival rate. The effects against cancer include prophylactic treatment, as well as the treatment of the existing disease. According to the present invention there is provided a method for the production of a vascular and / or anti-angiogenic permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed. 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 the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof. before, after or simultaneously with an effective amount of pemetrexed. According to a further aspect of the present invention, there is provided a method for the treatment of a cancer that involves a solid tumor in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a salt pharmaceutically acceptable thereof, before, after or simultaneously with an effective amount of pemetrexed. According to a further aspect of the present invention, there is provided a method for the treatment of malignant pleural mesothelioma in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt. of the samebefore, after or simultaneously with an effective amount of pemetrexed. According to a further aspect of the present invention, there is provided a method for the treatment of non-small cell lung cancer (NSCLC) in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed. According to a further aspect of the present invention, there is provided a method for the treatment of small cell lung cancer (SCLC) in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed. According to a further aspect of the present invention, there is provided a method for producing a reducing effect of vascular and / or antiangiogenic permeability in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed; wherein AZD2171 and pemetrexed can each optionally be administered together with a pharmaceutically acceptable carrier or excipient. 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 the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt of the animal. same, before, after or simultaneously with an effective amount of pemetrexed; wherein AZD2171 and pemetrexed can each optionally be administered together with a pharmaceutically acceptable carrier or excipient. According to a further aspect of the present invention, there is provided a method for the treatment of a cancer that involves a solid tumor in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed; where the AZD2171 and the pemetrexed can 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 malignant pleural mesothelioma in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt. of the same, before, after or simultaneously with an effective amount of pemetrexed; wherein AZD2171 and pemetrexed can each optionally be administered together with a pharmaceutically acceptable carrier or excipient.

According to a further aspect of the present invention, there is provided a method for the treatment of non-small cell lung cancer (NSCLC) in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed; wherein AZD2171 and pemetrexed can each optionally be administered together with a pharmaceutically acceptable carrier or excipient. According to a further aspect of the present invention, there is provided a method for the treatment of small cell lung cancer (SCLC) in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed; wherein AZD2171 and pemetrexed can each optionally be administered together with a pharmaceutically acceptable carrier or excipient. According to a further aspect of the invention there is provided a pharmaceutical composition comprising AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in association with a pharmaceutically acceptable carrier or excipient. According to a further aspect of the present invention, there is provided a combination product comprising AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, for use in a method of treating the human or animal body by therapy. According to a further aspect of the present invention, a kit composed of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed is provided. According to a further aspect of the present invention, there is provided a kit comprising: a) AZD2171 or a pharmaceutically acceptable salt thereof in a first unit dosage form; b) pemetrexed in a second unit dosage form; Y c) packaging means containing the first and second dosage forms. According to a further aspect of the present invention, there is provided a kit comprising: a) AZD2171 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient or carrier, in a first unit dosage form; b) pemetrexed together with a pharmaceutically acceptable excipient or carrier, in a second unit dosage form; and c) packaging means containing the first and second dosage forms. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of a vascular permeability reducing effect and / or antiangiogenic in a warm-blooded animal such as a human. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an anticancer effect in a blood animal. hot like a human.

According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an antitumor 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 AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an anticancer effect in a warm-blooded animal. such as a human where the tumor is a malignant pleural mesothelioma. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such as a human where the tumor is a malignant pleural mesothelioma. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an anticancer effect in a warm-blooded animal. just like a human where cancer is lung cancer of cells not small (NSCLC). According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such as a human where the tumor is a non-small cell lung tumor. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an anticancer effect in a warm-blooded animal. just like a human where cancer is small cell lung cancer (SCLC). According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such as a human where the tumor is small cell lung tumor.

According to a further aspect of the present invention, there is provided a combination treatment comprising the administration of an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier or excipient, and the simultaneous, sequential or separate administration of an effective amount of pemetrexed; wherein the pemetrexed can optionally be administered together with a pharmaceutically acceptable carrier or excipient; to a warm-blooded animal such as a human in need of such therapeutic treatment. Such therapeutic treatment includes a vascular and / or anti-angiogenic permeability reducing effect, an anti-cancer effect and an anti-tumor effect. A combination treatment of the present invention, as defined herein, can be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. A combination treatment, as defined herein, may be applied as a single therapy or may involve surgery or radiotherapy or a chemotherapeutic agent in addition to the combination treatment of the invention. Surgery may comprise the step of partial or complete resection of the tumor, before, during or after administration of the combination treatment with AZD2171 described herein. Other chemotherapeutic agents for optional use with a combination treatment of the present invention include those described in WO 00/47212 which are incorporated herein by reference. Such chemotherapy can cover five categories major therapeutic agents: (i) other anti-angiogenic agents including vascular recognition agents; (ii) cytostatic agents; (iii) biological response modifiers (for example interferon); (iv) antibodies (e.g., edrecolomab); and (v) antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology; and other agent categories are: (vi) antisense therapies; (vii) gene therapy strategies; and (viii) immunotherapy strategies. Particular examples of chemotherapeutic agents for use with a combination treatment of the present invention are raltitrexed, etoposide, vinorelbine, paclitaxel, docetaxel, cisplatin, oxaliplatin, carboplatin, gemcitabine, irinotecan (CPT-11), 5-fluorouracil (5-FU, (including capecitabine), doxorubicin, cyclophosphamide, temozolomide and hydroxyurea, such combinations are expected to be particularly useful for the treatment of lung, head and neck cancer, brain, colon, rectum, esophagus, stomach cancer, of cervix, ovaries, skin, breast, bladder, prostate, pancreas and that include malignant hematological neoplasms. Such combinations are expected to be more particularly useful for the treatment of pancreatic cancer, colorectal cancer, malignant pleural mesothelioma, non-small cell lung cancer (NSCLC), breast cancer and bladder cancer. The administration of a triple combination of AZD2171, pemetrexed and ionizing radiation, can produce effects, such as antitumor effects, higher than those achieved with any of AZD2171, pemetrexed and ionizing radiation used alone, greater than those achieved with the combination of AZD2171 and pemetrexed , greater than those achieved with the combination of AZD2171 and ionizing radiation, higher than those achieved with the combination of pemetrexed and ionizing radiation. According to the present invention there is provided a method for the production of a vascular and / or anti-angiogenic permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing 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, the which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation. According to a further aspect of the present invention, there is provided a method for the treatment of a cancer that involves a solid tumor in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation. According to a further aspect of the present invention, there is provided a method for the treatment of malignant pleural mesothelioma in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt. of the same, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation. According to a further aspect of the present invention, there is provided a method for the treatment of Non-small cell lung cancer (NSCLC) in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation. According to a further aspect of the present invention, there is provided a method for the treatment of small cell lung cancer (SCLC) in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation. According to a further aspect of the present invention, there is provided a method for the production of a vascular and / or anti-angiogenic permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to the animal an amount effective of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation, wherein the AZD2171 and the Pemetrexed can each optionally be administered together with a pharmaceutically acceptable carrier or excipient.

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 the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt. thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation, wherein AZD21 71 and pemetrexed can each optionally be administered together with a pharmaceutically acceptable carrier or excipient.

According to a further aspect of the present invention, there is provided a method for the treatment of a cancer that involves a solid tumor in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD21. or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation, where AZD21 71 and pemetrexed can each optionally be administered together with an excipient or pharmaceutically acceptable carrier. According to a further aspect of the present invention, there is provided a method for the treatment of malignant pleural mesothelioma in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation, wherein AZD2171 and pemetrexed may each optionally be administered together with a pharmaceutically acceptable carrier or excipient. According to a further aspect of the present invention, there is provided a method for the treatment of non-small cell lung cancer (NSCLC) in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation, wherein AZD2171 and pemetrexed may each optionally be administered together with an pharmaceutically acceptable carrier or excipient. According to a further aspect of the present invention, there is provided a method for the treatment of small cell lung cancer (SCLC) in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation, wherein the AZD2171 and the pemetrexed can each optionally be administered together with a pharmaceutically excipient or carrier acceptable. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of a vascular permeability reducing effect and / or antiangiogenic in a warm-blooded animal such as a human being being treated with ionizing radiation. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an anticancer effect in a blood animal. hot like a human being being treated with ionizing radiation. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such like a human being being treated with ionizing radiation.

According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an anticancer effect in a blood animal. hot such as a human being being treated with ionizing radiation where cancer is malignant pleural mesothelioma. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such as a human being being treated with ionizing radiation where the tumor is malignant pleural mesothelioma. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an anticancer effect in a blood animal. hot such as a human being being treated with ionizing radiation where the cancer is non-small cell lung cancer (NSCLC). According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such as a human being being treated with ionizing radiation where the tumor is a non-small cell tumor of the lung. According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an anticancer effect in a blood animal. hot such as a human being being treated with ionizing radiation where the cancer is small cell lung cancer (SCLC). According to a further aspect of the present invention, there is provided the use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed, in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such like a human being being treated with ionizing radiation where the tumor is a small cell tumor of the lung. According to a further aspect of the present invention there is provided a therapeutic combination treatment comprising administering an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable carrier or excipient, and administering a quantity effective of pemetrexed, optionally together with a pharmaceutically acceptable excipient or carrier and administration of an effective amount of ionizing radiation, to a warm-blooded animal such as a human in need of such therapeutic treatment, where AZD2171, pemetrexed and ionizing radiation they can be administered simultaneously, sequentially or separately and in any order. A warm-blooded animal such as a human being being treated with ionizing radiation means a warm-blooded animal such as a human which is treated with ionizing radiation before, after or at the same time as the administration of a drug or combination treatment. comprising AZD2171 and pemetrexed. For example, said ionizing radiation can be given to the warm-blooded animal such as a human, within the period from one week before to one week after the administration of a medicament or combination treatment comprising AZD2171 and pemetrexed. This means that AZD2171, pemetrexed and ionizing radiation can be administered separately or sequentially in any order, or they can be administered simultaneously. The warm-blooded animal can simultaneously experience the effect of each of AZD2171, pemetrexed and radiation. According to one aspect of the present invention ionizing radiation is administered before one of AZD2171 and pemetrexed or after one of AZD2171 and pemetrexed. In accordance with one aspect of the present invention ionizing radiation is administered before both AZD2171 and pemetrexed or after both AZD2171 and pemetrexed. According to one aspect of the present invention, AZD2171 is administered to a warm-blooded animal after the animal has been treated with ionizing radiation. According to another aspect of the present invention the effect of a treatment method of the present invention is expected to be at least equivalent to the addition of the effects of each of the treatment components used alone, i.e. each of AZD2171 and pemetrexed used alone or each of AZD2171, pemetrexed and ionizing radiation used alone. According to another aspect of the present invention the effect of a treatment method of the present invention is expected to be greater than the addition of the effects of each of the treatment components used alone, i.e. of each of AZD2171 and pemetrexed used alone or each of AZD2171, pemetrexed and ionizing radiation used alone. According to another aspect of the present invention the effect of a treatment method of the present invention is expected to be a synergistic effect. According to the present invention a combination treatment is defined as providing a synergistic effect, if the effect is therapeutically superior, according to the measurement of, for example, the magnitude of the response, the speed of the response, the time to the progression of the disease or the survival period, which is achievable in the dosing of one or another component 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 AZD2171 or pemetrexed or ionizing radiation alone. Additionally, the effect of the combination treatment is synergistic if a beneficial effect is obtained in a group of patients who do not respond (or respond poorly) to AZD2171 or pemetrexed or ionizing radiation alone. In addition, the effect of the combination treatment is defined as providing a synergistic effect, if one of the components is dosed at its conventional dose and the other component (s) is / are dosed at a dose reduced, and the therapeutic effect, as measured by, for example, the magnitude of the response, the response rate, the time to disease progression or the survival period, is equivalent to that which is achievable in conventional amounts of dosage of the components of the combination treatment. In particular, synergy will be considered present if the conventional dose of AZD2171 or pemetrexed or ionizing radiation can be reduced without detriment to one or more of the magnitude of the response, the response speed, the time up to the progression of the disease and the survival data, in particular without detriment to the duration of the response, but with fewer and / or fewer problematic side effects than those that occur when the conventional doses of each of the components are used. As discussed above, the combination treatments of the present invention as defined herein are of interest for their effects on vascular and / or antiangiogenic permeability. Angiogenesis and / or an increase in vascular permeability is present in a wide range of disease states such as cancer (including leukemia, multiple myeloma and lymphoma), diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, asthma, lymphoedema, endometriosis, dysfunctional uterine bleeding and eye diseases with proliferation of vessels retinal diseases, including senile macular degeneration. The combination treatments of the present invention are expected to be particularly useful in the prophylaxis and treatment of diseases such as cancer and Kaposí's sarcoma. In particular, such combination treatments of the invention are expected to advantageously retard the growth of primary and recurrent solid tumors, for example, of colon, of pancreas, brain, bladder, ovary, breast, prostate, lung and skin. The combination treatments of the present invention are expected to advantageously retard the growth of tumors in pancreatic cancer, bladder cancer, ovarian cancer, breast cancer and lung cancer, including malignant pleural mesothelioma, lung cancer of cells small (SCLC) 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 VEGF including leukemia, multiple myeloma and lymphoma and also, for example, to inhibit the growth of the primary and recurrent solid tumors that are associated with to VEGF, especially those tumors that are significantly dependent on VEGF for their growth and spread, including, for example, certain colon tumors (including the rectum), pancreas, brain, bladder, ovary, breast, prostate, lung, vulva, skin and particularly malignant pleural mesothelioma and NSCLC. More especially, the combination treatments of the present invention are expected to advantageously retard the growth of tumors in malignant pleural mesothelioma. More especially, the combination treatments of the present invention are expected to advantageously retard the growth of non-small cell lung cancer (NSCLC) tumors. In another aspect of the present invention the AZD2171 and the Pemetrexed, optionally with ionizing radiation, are expected to inhibit the growth of primary and recurrent solid tumors that are associated with VEGF, especially those tumors that are significantly dependent on VEGF 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 for administration by inhalation, for example in the form of 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 can be by injection direct in the tumor or by regional application or by local application. In other embodiments of the present invention, AZD2171 of the combination treatment can be applied by endoscopy, intratracheally, intralesionally, percutaneously, intravenously, subcutaneously, intraperitoneally or intratumorally. Preferably AZD2171 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.

AZD2171 will normally be administered to a warm-blooded animal in a unit dose within the range of I-50 mg per square meter of animal body area, for example about 0.03-1.5 mg / kg in a human. A unit dose in the range, for example, of 0.01-1.5mg / kg, preferably 0.03-0.5mg / kg is provided and this is normally a therapeutically effective dose. A unit dosage form such as a tablet or capsule will usually contain, for example I-50mg of active ingredient. Preferably a daily dose in the range of 0.03-0.5mg / kg is employed. Pemetrexed can be administered according to known clinical practice. For example in NSCLC the recommended dose of pemetrexed is 500mg / m2 given in 10 minutes by intravenous infusion administered on the first day of each 21-day cycle. For example, in malignant pleural mesothelioma the recommended dose of pemetrexed is 500mg / m2 given in 10 minutes by intravenous infusion administered on the first day of each 21-day cycle. When this occurs, cisplatin can be administered at 75 mg / m2 on Day 1 as an intravenous infusion in 2 hours approximately 30 minutes after the completion of the administration of pemetrexed. Doses and schedules may vary depending on the particular condition of the disease and the patient's general condition. Doses and schedules may also vary if, in addition to In a combination treatment of the present invention, one or more additional chemotherapeutic agent (s) is / are used. The programming can be determined by the professional who is treating any particular patient. Radiotherapy can be administered in accordance with known practices in clinical radiotherapy. The doses of ionizing radiation will be those known for their use in clinical radiotherapy. The radiation therapy used will include, for example, the use of rays and X-rays, and / or the application of radiation directed from radioisotopes. Other forms of the factors that damage DNA are also included in the present invention, such as microwaves and UV radiation. For example X-rays can be dosed in daily doses of 1.8-2.0Gy, 5 days a week for 5-6 weeks. Normally a total of fractionated doses are in the range of 45-60Gy. Unique higher doses, for example 5-10Gy can be administered as part of a radiotherapy treatment. Unique doses can be administered intraoperatively. The hyperfractionated radiotherapy can be used by means of which small doses of X-rays are administered regularly over a period of time, for example 0.1Gy per hour for several days. The dosage ranges of radioisotopes vary widely and depend on the isotope's half-life, the intensity and type of radiation emitted, and the uptake by the cells.

The size of the dose of each therapy that is required for the prophylactic or therapeutic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the disease being treated. Consequently, the optimal dose can be determined by the professional who is treating any particular patient. For example, it may be necessary or desirable to reduce the aforementioned doses of the components of the combination treatments in order to reduce the toxicity. The present invention relates to the combination of pemetrexed with AZD2171 or with a salt of AZD2171. The salts of AZD2171 for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of AZD2171 and its pharmaceutically acceptable salts. Pharmaceutically acceptable salts may, for example, include acid addition salts. Such acid addition salts include, for example, salts with organic or inorganic acids that provide pharmaceutically acceptable anions such as with hydrogen halides or with sulfuric or phosphoric acid, or with trifluoroacetic, citric or maleic acid. In addition, pharmaceutically acceptable salts can be formed with an organic or inorganic base that provides a pharmaceutically acceptable cation. Such salts with organic or inorganic bases they include for example an alkali metal salt, such as a sodium or potassium salt and an alkaline earth metal salt, such as a calcium or magnesium salt. A preferred salt is the AZD2171 maleate which is described in International Patent Application Publication No. WO 05/061488. AZD2171 can be synthesized according to the processes described in WO 00/47212, particularly those described in Example 240 of WO 00/47212. The maleate salt of AZD2171 can be synthesized according to the processes described in WO 05/061488. Pemetrexed is commercially available. The following tests can be used to demonstrate the activity of AZD2171 in combination with pemetrexed. MX-1 human breast cancer heterograft model Tumor implantation procedures were performed on mice at least 5 weeks old. Heterografts of the human tumor were cultured in athymic female mice (genotype nu / nu, Swiss). Fragments of the MX-1 tumor were implanted in athymic mice and allowed to grow at 0.7-1cm3 to provide donor tumor tissue. The donor tumors were surgically excised and the smaller tumor fragments (20-30 mg) were implanted subcutaneously (s.c.) in the right flanks of the experimental nude mice. When the volume of the main tumor reached 0.1-0.3cm3, a random selection was carried out. The animals were treated with pemetrexed (75mg / kg, intraperitoneally (i.p.) once a day: day 1 -5 and 8-12), or with AZD2171 (1.5mg / kg or 3mg / kg, ) or drug vehicle, which were administered once a day orally (p.o.) during the duration of the study (beginning on day 1). One additional group of animals received a combination of pemetrexed and AZD21 71, using the same doses and schedules that were used for single agent treatment. Tumor volumes were estimated at least twice weekly by bilateral measurements with a vernier vernier caliper. Growth inhibition from the start of treatment was estimated by comparing differences in tumor volume between control and treated groups. The effects of the combination treatment were estimated by comparing the growth of the tumor in the group of animals that received pemetrexed plus AZD21 71 with the growth of the tumor in the groups where the animals received the therapy with a single agent alone. An analogous experiment can be used to observe the combination of AZD21 71 and pemetrexed with ionizing radiation. Example 1 Experiments were conducted in female athymic mice (Swiss genotype nu / nu, = 6 weeks old). Heterografts of the human tumor MX-1 were established in the mice from the implants of tumor cells. The donor tumors were surgically extirpated when they reached a volume of 0.7-1cm3, divided into fragments and frozen until their later use. At the beginning of the experiment, the fragments (approximately 30 mg) were melted and implanted (subcutaneously in the dorsal flank) in the experimental animals. Tumor volumes were estimated at least twice weekly by bilateral measurements with a vernier vernier caliper. Mice were selected randomly in treatment groups when the tumor volume reached 0.1-0.2cm3. Following the random selection on day 14 after tumor implantation, the mice were treated with the drug vehicle (Control) or AZD2171 (1.5mg / kg / day) administered orally (po) once a day until the end of the study, or with pemetrexed (75mg / kg, intraperitoneally (ip) once a day on days 14-18 and 21-25). An additional group of animals received a combination of AZD2171 and pemetrexed, using the same doses and schedules that were used for single agent treatment. The inhibition of tumor growth from the beginning of treatment was estimated by comparing the differences in tumor volume between the control and treated groups. The effects of the combination treatment were estimated by comparing any effect on tumor growth in the group of animals receiving pemetrexed plus AZD2171 with tumor growth in the groups where animals received single agent therapy alone. The data are shown graphically in Figure 1. AZD2171 (1.5mg / kg / day) + pemetrexed (75mg / kg / day from Days 14-18 and Days 21-25) vs AZD2171 (1.5mg / kg / day) : p = 0.04 (2-tailed t tests). AZD2171 (1.5mg / kg / day) + pemetrexed (75mg / kg / day from Days 14-18 and Days 21-25) vs pemetrexed (75mg / kg / day from Days 14-18 and Days 21-25 ): p = 0.03 (2-tailed t tests). The growth of the tumors was significantly inhibited further by the combination of two agents AZD2171 (1.5mg / kg / day) and pemetrexed (75mg / kg / day from Days 14-18 and Days 21-25) than with the agent alone in the same doses. An analogous experiment can be used to observe the combination of AZD2171 and pemetrexed with ionizing radiation.

Claims (11)

REVIVAL NAME IS

1 . Use of AZD21 71 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of a vascular and / or anti-angiogenic permeability reducing effect in a warm-blooded animal such as a human.

2. Use of AZD21 71 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an anticancer effect in a warm-blooded animal such as a human.

3. Use of AZD21 71 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such as a human.

4. Use of AZD21 71 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of a vascular and / or anti-angiogenic permeability reducing effect in a warm-blooded animal such as a human which is being treated with ionizing radiation.

5. Use of AZD21 71 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an anticancer effect in a warm-blooded animal such as a human which is being treated with ionizing radiation.

6. Use of AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed in the manufacture of a medicament for use in the production of an antitumor effect in a warm-blooded animal such as a human being which is being treated with ionizing radiation.

7. Use according to claim 3 or claim 6 wherein the tumor is a malignant pleural mesothelioma or is a non-small cell tumor of the lung or is a small cell tumor of the lung.

8. Use according to claim 2 or claim 5 wherein the cancer is non-small cell lung cancer (NSCLC) or malignant pleural mesothelioma or small cell lung cancer (SCLC).

9. A pharmaceutical composition comprising AZD2171 or a pharmaceutically acceptable salt thereof, and pemetrexed in association with a pharmaceutically acceptable carrier or excipient.

10. A kit comprising AZD2171 or a pharmaceutically acceptable salt thereof and pemetrexed.

11. A method for the production of a vascular and / or anti-angiogenic permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD2171 or a pharmaceutically acceptable salt thereof, before, After or simultaneously with an effective amount of pemetrexed. 1 2. A method for the production of a vascular and / or anti-angiogenic permeability reducing effect in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of AZD21 71 or a pharmaceutically acceptable salt thereof, before, after or simultaneously with an effective amount of pemetrexed and before, after or simultaneously with an effective amount of ionizing radiation.