US 2011 0171289A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0171289 A1 STEFANC et al. (43) Pub. Date: Jul. 14, 2011 (54) COMBINATIONS FOR THE TREATMENT OF Publication Classification DISEASES INVOLVING CELL (51) Int. Cl. PROLIFERATION, MIGRATION OR A 6LX 9/27 (2006.01) APOPTOSIS OF MYELOMA CELLS, OR A63L/502 (2006.01) ANGIOGENESIS A 6LX 3/5.377 (2006.01) A 6LX 3L/395 (2006.01) Martin Friedrich STEFANIC, A63L/506 (2006.01) (75) Inventors: A63/675 (2006.01) Warthausen-Birkenhard (DE); A633/24 (2006.01) Frank HILBERG, Wien (AT): A63L/7008 (2006.01) Gerd MUNZERT, Ulm (DE): A6II 3/66 (2006.01) Flavio SOLCA, Wien (AT); Anke A63L/704 (2006.01) BAUM, Alland (AT); Jacobus C.A. A63L/7068 (2006.01) van MEEL, Moedling (AT) A 6LX 3L/7076 (2006.01) A638/14 (2006.01) (73) Assignee: BOEHRINGERINGELHEM A638/2 (2006.01) INTERNATIONAL GMBH, A 6LX 3/57 (2006.01) Ingelheim am Rhein (DE) A638/20 (2006.01) A638/16 (2006.01) (21) Appl. No.: 12/912,110 A 6LX 39/395 (2006.01) A6IP35/00 (2006.01) A6IP35/02 (2006.01) (22) Filed: Nov. 9, 2010 (52) U.S. Cl. .................... 424/450; 514/254.09: 514/248: 514/234.5; 424/133.1: 514/252.18; 514/90; Related U.S. Application Data 424/649; 514/62: 514/110: 514/34: 514/33; (60) Division of application No. 12/140,661, filed on Jun. 514/49; 514/46; 514/20.9: 424/94.6; 424/85.6; 17, 2008, now Pat. No. 7,846,936, which is a continu 514/171; 424/85.2: 514/21.2: 424/130.1 ation of application No. 10/830,147, filed on Apr. 22, (57) ABSTRACT 2004, now abandoned. The present invention relates to a pharmaceutical combina tion for the treatment of diseases which involves cell prolif (60) Provisional application No. 60/542,036, filed on Feb. eration, migration or apoptosis of myeloma cells, or angio 5, 2004. genesis. The invention also relates to a method for the treatment of said diseases, comprising co-administration of effective amounts of specific active compounds and/or co (30) Foreign Application Priority Data treatment with radiation therapy, in a ratio which provides an additive and Synergistic effect, and to the combined use of Apr. 29, 2003 (EP) ................................ O3 O09 587.1 these specific compounds and/or radiotherapy for the manu Jan. 13, 2004 (EP) ................................ O4 OOO 508.4 facture of corresponding pharmaceutical combination prepa Jan. 21, 2004 (EP) ................................ O4 OO1 1710 rations. th th th: ; ; sh ei is a sit (a of off off Patent Application Publication Jul. 14, 2011 Sheet 1 of 3 US 2011/0171289 A1 FIGURE t . s t f 24h 32h weGF VEGF off Patent Application Publication Jul. 14, 2011 Sheet 2 of 3 US 2011/0171289 A1 FIGURE 2 1500,0 Patent Application Publication Jul. 14, 2011 Sheet 3 of 3 US 2011/0171289 A1 FIGURE 3 E E. E S. is e O 5 10 5 20 25 30 35 40 45 50 55 60 65 Days US 2011/0171289 A1 Jul. 14, 2011 COMBINATIONS FOR THE TREATMENT OF together with its ligand VEGF and its four sub-types known to DISEASES INVOLVING CELL date (Jung et al., European Journal of Cancer, Vol. 38, pp. PROLIFERATION, MIGRATION OR 1133-1140, 2002). Similar studies reported in previous APOPTOSIS OF MYELOMA CELLS, OR reports show that the overexpression of some of these recep ANGOGENESIS tors is implicated in multiple forms of cancer. For example, studies have provided evidence that the epidermal growth FIELD OF THE INVENTION factor EGF acts as a growth factor in tumours, and that the 0001. This invention relates to a method for the treatment vascular endothelial growth factor VEGF is one of the most of diseases involving cell proliferation, migration or apopto common mediators of tumorangiogenesis, which is essential sis of myeloma cells, or angiogenesis, which method com for the growth and metastasis of solid tumours. Inhibitors of prises co-administration to a person in need of such treatment the receptors have thus been and are still evaluated for cancer and/or co-treatment of a person in need of such treatment with therapy (see for example the article of Cerrington et al. In effective amounts of: Advances in Cancer Research, Academic Press 2000, pp. 0002 (i) a selected protein tyrosine kinase receptor 1-38). antagonist; and 0013 Recent studies have also suggested to combine sev 0003 (ii) at least a further chemotherapeutic or natu eral receptor antagonists together, or in further combination rally occurring, semi-synthetic or synthetic therapeutic with a chemotherapeutic agent or radiation. For example, WO agent; and/or 02/070008 suggests the combination of an antagonist specifi 0004 (iii) radiotherapy or radio-immunotherapy. cally directed against the VEGF receptor with an antagonist 0005. This invention relates also to suitable pharmaceuti specifically directed against the EGF receptor, optionally cal compositions comprising effective amounts of: together with radiation or a chemotherapeutic agent, for the 0006 (i) a selected protein tyrosine kinase receptor inhibition of tumour growth. As example of suitable specific antagonist; and antagonists, WO 02/070008 discloses monoclonal antibodies 0007 (ii) at least a further chemotherapeutic or natu directed against the VEGF receptor and monoclonal antibod rally occurring, semi-synthetic or synthetic therapeutic ies directed against the EGF receptor. agent, 0014 Thus, a large number of protein tyrosine kinase and optionally adapted for a co-treatment with radiotherapy receptor antagonists are currently in clinical development for or radio-immunotherapy, as a combined preparation for the treatment of cancer (see for example the Expert Opinion simultaneous, separate or sequential use in the treatment of Review of Laid & Cherrington in Expert Opin. Invest. Drugs, diseases involving cell proliferation, migration or apoptosis Vol. 12, No. 1, pp. 51-64, 2003). However, proof of efficacy of myeloma cells, orangiogenesis, and especially for inhib for these Substances, used alone or with other cancer thera iting tumour growth, Survival and metastasis. pies, in the treatment of oncological diseases, has so far not 0008. This invention relates also to the combined use of been achieved, either because of a lack of additional benefit effective amounts of: over the standard therapy or because of the discovery of 0009 (i) a selected protein tyrosine kinase receptor unacceptable side-effects. antagonist; and 0015 For example, it has been recently published that an 0010 (ii) at least a further chemotherapeutic or natu angiogenesis inhibitor which has already been clinically rally occurring, semi-synthetic or synthetic therapeutic tested, also in conjunction with chemotherapy, namely the agent, inhibitor with code name SU5416, developed by Pharmacia for the manufacture of a pharmaceutical combined prepara for the treatment of cancer, was associated with disturbing tion for simultaneous, separate or sequential use in the treat side effect, namely thromboembolic events (Ken Garber and ment of diseases involving cell proliferation, migration or Ann Arbor, Nature Biotechnology, Vol. 20, pp. 1067-1068, apoptosis of myeloma cells, or angiogenesis, and especially November 2002). for inhibiting tumour growth, Survival and metastasis, option 0016 For the treatment of diseases of oncological nature, ally in combination with a co-treatment with radiotherapy or a large number of chemotherapeutic agents have already been radio-immunotherapy. Suggested, which can be used as mono-therapy (treatment 0011. This invention relates also to the use of an effective with one agent) or as combination therapy (simultaneous, amount of a selected protein tyrosine kinase receptor antago separate or sequential treatment with more than one agent) nist, for the manufacture of a pharmaceutical composition and/or which may be combined with radiotherapy or radio adapted for a simultaneous, separate or sequential co-treat immunotherapy. In this respect, chemotherapeutic agent ment with radiotherapy or radio-immunotherapy of diseases means a naturally occurring, semi-synthetic or synthetic involving cell proliferation, migration or apoptosis of chemical compound which, alone or via further activation, for myeloma cells, orangiogenesis, and especially for inhibiting example with radiations in the case of radio-immunotherapy, inhibits or kills growing cells, and which can be used or is tumour growth, Survival and metastasis. approved for use in the treatment of diseases of oncological nature, which are commonly also denominated as cancers. In BACKGROUND OF THE INVENTION the literature, these agents are generally classified according 0012. In the last decade, the biological activity of several to their mechanism of action. In this matter, reference can be types and sub-types of the protein tyrosin kinase receptor made, for example, to the classification made in “Cancer family have been characterised Such as, for example, the Chemotherapeutic Agents'. American Chemical Society, epidermal growth factor receptor EGFR and its subtypes 1995, W.O. Foye Ed. ErbB-2 and ErbB-4 (Brignola et al., Journal of Biological 0017 Thus, within the meaning of the present invention, Chemistry, Vol. 277, No. 2, pp. 1576-1585, 2002) or the the following classes of chemotherapeutic agents are espe vascular endothelial growth factor receptors VEGFR 1-3 cially of interest, although not representing a limitation: US 2011/0171289 A1 Jul. 14, 2011 0018 Synthetic small molecule VEGF receptor antago or of non-oncological nature, such as diabetic retinopathy, nists rheumatoid arthritis or psoriasis. 0019 Small molecule growth factor (GF) receptor antagonists SUMMARY OF THE INVENTION (0020 Inhibitors of the EGF receptor and/or VEGF 0042. It has now been found that co-administration to a receptor and/or integrin receptors or any other protein person in need of Such treatment and/or co-treatment of a tyrosine kinase receptors, which are not classified under person in need of such treatment with effective amounts of the synthetic Small-molecules 0.043 (i) a selected protein tyrosine kinase receptor (0021.