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(12) Patent Application Publication (10) Pub. No.: US 2006/0216288 A1 Chang (43) Pub US 20060216288A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0216288 A1 Chang (43) Pub. Date: Sep. 28, 2006 (54) COMBINATIONS FOR THE TREATMENT OF Publication Classification CANCER (51) Int. Cl. (75) Inventor: David Chang, Calabasas, CA (US) A 6LX 39/395 (2006.01) A6II 3/55 (2006.01) Correspondence Address: A6II 3 L/4545 (2006.01) SESS is 2-C A61K 31/4439 (2006.01) ONE AMGEN CENTERY DRIVE A6II 3/44 (2006.O1 ) THOUSAND OAKS, CA 91320-1799 (US) (52) U.S. Cl. ................... 424/143.1: 514/352: 514/210.2: (73) Assignee: Amgen Inc., Thousand Oaks, CA 514/318: 514/340; 514/217.04 (21) Appl. No.: 11/386,271 (22) Filed: Mar. 21, 2006 (57) ABSTRACT Related U.S. Application Data This invention is in the field of pharmaceutical agents and (60) Provisional application No. 60/664,381, filed on Mar. specifically relates to compounds, compositions, uses and 22, 2005. methods for treating cancer. Patent Application Publication Sep. 28, 2006 Sheet 1 of 5 US 2006/0216288A1 Figure 1 -- Vehicle X Compound B, 10 mpk 1800 -- Antibody A, 20 ug 1600 Compound B, 10 mpk+ 1400 Antibody A, 20 ug 1200 1000 800 600 p = 0.0003 1/10 1110 1/10 p < 0.0001 v v v v v v V 174. 22 27 32 37 42 47 Time (days) V Antibody A injection Patent Application Publication Sep. 28, 2006 Sheet 2 of 5 US 2006/0216288A1 Figure 2 -- Vehicle 1800 X Compound B, 75 mpk 1600 th- Antibody A, 500 u 1400 dy 9 1200 Compound B, 75 mpk+ Antibody A, 500 ug 1000 800 600 V Antibodyy A, ipp injectionin 400 200 p < 0.0001 st 0.9515 V. V V V V v V p 13 18 23 28 33 38 43 48 "Treatment began on day 14 Time (days) Patent Application Publication Sep. 28, 2006 Sheet 3 of 5 US 2006/0216288A1 Figure 3 1800 -- Vehicle 1600 * Compound B, 37.5 mpk 1400 -h- Antibody A, 500 ug 1200 3o 1000 AntibodyCompound A, B, 500 37.5 ug mpk + Gd NO 800 V Antibody A, IP injection O 600 S x : x X x H 400 p < 0.0001 = 0.0013 200 p VVVVVVVVVV 13 18 23 28 33 38 43 48 Treatment began on day 14 Time (days) Patent Application Publication Sep. 28, 2006 Sheet 4 of 5 US 2006/0216288A1 Figure 4 Compound Bt Antibody A 1600 -H- Vehicle 1400 E A Compound B 12OO s -- Antibody A 1000 S5 800 VIP injection 600 Hes 400 p- 0.0001 2OO 13 15 17 19 21 23 25 27 29 31 33 35 37 39 41 43 45 47 49 Time (days) Patent Application Publication Sep. 28, 2006 Sheet 5 of 5 US 2006/0216288A1 Figure 5 -- Vehicle 1600 Compound A, 50 mpk E 1400 1200 -- Antibody B, 500 ug 9. 1000 Compound A, 50 S. 800 K -- mpk+ Antibody B, N5 p = 0.0037 500 ug ho 600 400 H V Antibody B injection, ip, twice/week 200 JY. --V I V- - -V - - V- - -v - - - - - - 14 19 24 29 34 39 Time (days) US 2006/0216288 A1 Sep. 28, 2006 COMBINATIONS FOR THE TREATMENT OF 0007. A large number of human tumors, especially glio CANCER mas and carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that the VEGF FIELD OF THE INVENTION released by tumor cells stimulates the growth of blood 0001. This invention is in the field of pharmaceutical capillaries and the proliferation of tumor endothelium in a agents and specifically relates to compounds, compositions, paracrine manner and through the improved blood Supply, uses and methods for treating cancer. accelerate tumor growth. Increased VEGF expression could explain the occurrence of cerebral edema in patients with BACKGROUND glioma. Direct evidence of the role of VEGF as a tumor angiogenesis factor in vivo is shown in Studies in which 0002 Protein kinases represent a large family of proteins VEGF expression or VEGF activity was inhibited. This was which play a central role in the regulation of a wide variety achieved with anti-VEGF antibodies, with dominant-nega of cellular processes, maintaining control over cellular func tive VEGFR-2 mutants which inhibited signal transduction, tion. A partial list of Such kinases includes abl, Akt, bcr-abl. and with antisense-VEGF RNA techniques. All approaches Blk, Brk, Btk, c-kit, c-Met, c-Src, c-fms, CDK1, CDK2, led to a reduction in the growth of glioma cell lines or other CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, tumor cell lines in vivo as a result of inhibited tumor CDK10, cRaf1, CSF1R, CSK, EGFR, ErbB2, ErbB3, angiogenesis. ErbB4, Erk, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, filt-1, Fps, Frk, Fyn, Hck, IGF-R, INS-R, Jak, 0008 Angiogenesis is regarded as an absolute prerequi KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, site for tumors which grow beyond a diameter of about 1-2 tie, tie2, TRK, Yes, and Zap70. Inhibition of such kinases mm, up to this limit, oxygen and nutrients may be supplied has become an important therapeutic target. to the tumor cells by diffusion. Every tumor, regardless of its origin and its cause, is thus dependent on angiogenesis for 0003 Certain diseases are known to be associated with deregulated angiogenesis, for example ocular neovasculari its growth after it has reached a certain size. sation, such as retinopathies (including diabetic retinopa 0009 Three principal mechanisms play an important part thy), age-related macular degeneration, psoriasis, hemangio in the activity of angiogenesis inhibitors against tumors: 1) blastoma, hemangioma, arteriosclerosis, inflammatory Inhibition of the growth of vessels, especially capillaries, disease, such as a rheumatoid or rheumatic inflammatory into avascular resting tumors, with the result that there is no disease, especially arthritis (including rheumatoid arthritis), net tumor growth owing to the balance that is achieved or other chronic inflammatory disorders, such as chronic between cell death and proliferation; 2) Prevention of the asthma, arterial or post-transplantational atherosclerosis, migration of tumor cells owing to the absence of blood flow endometriosis, and neoplastic diseases, for example so to and from tumors; and 3) Inhibition of endothelial cell called Solid tumors and liquid tumors (such as leukemias). proliferation, thus avoiding the paracrine growth-stimulat 0004 At the center of the network regulating the growth ing effect exerted on the Surrounding tissue by the endot and differentiation of the vascular system and its compo helial cells which normally line the vessels. See R. Connell nents, both during embryonic development and normal and J. Beebe, Exp. Opin. Ther. Patents, 11:77-114 (2001). growth, and in a wide number of pathological anomalies and 0010 VEGFs are unique in that they are the only angio diseases, lies the angiogenic factor known as Vascular genic growth factors known to contribute to vascular hyper Endothelial Growth Factor (VEGF; originally termed Vas permeability and the formation of edema. Indeed, vascular cular Permeability Factor. VPF), along with its cellular hyperpermeability and edema that is associated with the receptors (see G. Breier et al., Trends in Cell Biology, expression or administration of many other growth factors 6:454-456 (1996)). appears to be mediated via VEGF production. 0005 VEGF is a dimeric, disulfide-linked 46-kDa gly 0011 Inflammatory cytokines stimulate VEGF produc coprotein related to “Platelet-Derived Growth Factor” tion. Hypoxia results in a marked upregulation of VEGF in (PDGF); it is produced by normal cell lines and tumor cell numerous tissues, hence situations involving infarct, occlu lines; is an endothelial cell-specific mitogen; shows angio Sion, ischemia, anemia, or circulatory impairment typically genic activity in in vivo test systems (e.g. rabbit cornea); is invoke VEGF/VPF-mediated responses. Vascular hyperper chemotactic for endothelial cells and monocytes; and meability, associated edema, altered transendothelial induces plasminogen activators in endothelial cells, which exchange and macromolecular extravasation, which is often are involved in the proteolytic degradation of extracellular accompanied by diapedesis, can result in excessive matrix matrix during the formation of capillaries. A number of deposition, aberrant stromal proliferation, fibrosis, etc. isoforms of VEGF are known, which show comparable Hence, VEGF-mediated hyperpermeability can significantly biological activity, but differ in the type of cells that secrete contribute to disorders with these etiologic features. As such, them and in their heparin-binding capacity. In addition, there regulators of angiogenesis have become an important thera are other members of the VEGF family, such as “Placenta peutic target. See Hicklin and Ellis, J. Clin Oncology, Growth Factor” (PIGF) and VEGF-C. 23:1011-1027 (2005). 0006) VEGF receptors (VEGFR) are transmembranous 0012 Several observations implicate EGFr in supporting receptor tyrosine kinases. They are characterized by an development and progression of human Solid tumors. Sig extracellular domain with seven immunoglobulin-like nal. 2:2-35 (2001). Expression of EGFr has been shown to domains and an intracellular tyrosine kinase domain. Vari induce transformed properties in recipient cells. EGFr ous types of VEGF receptor are known, e.g. VEGFR-1 (also expression has been found to be up-regulated on many known as filt-1), VEGFR-2 (also known as KDR), and human tumors, including lung, colon, breast, prostate, gas VEGFR-3. tric, brain, head and neck, ovarian and renal carcinoma, and US 2006/0216288 A1 Sep. 28, 2006 the increase in receptor levels has been reported to be California and Rorer. See U.S. Pat. No. 4,943,533 and associated with a poor clinical prognosis. Mendelsohn, European Patent No. 359,282. C225 was demonstrated to Cancer Cells, 7:359 (1989); Mendelsohn, Cancer Biology, inhibit EGF-mediated tumor cell growth in vitro and inhibit 1:339-344 (1990); Modjtahedi and Dean, Int’l J.
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