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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, 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. Oncology, human tumor formation in vivo in nude mice. The antibody, 4:277-296 (1994). Modjtahedi and Dean, Int’l J. Oncology, moreover, appeared to act in Synergy with certain chemo 4:277-296 (1994). In many cases, the increased surface therapeutic agents to eradicate human tumors in vivo in EGFr expression was accompanied by production of TGF or xenograft mouse models. Modjtahedi and Dean, Int’l J. EGF by the tumor cells, Suggesting the involvement of an Oncology, 4:277-296 (1994). ImClone is marketing the autocrine growth control in the progression of these tumors. anti-EGF-r antibody C225 now designated Erbitux (cetux Both epidermal growth factor (EGF) and transforming imab). growth factor-alpha (TGF-C.) have been demonstrated to bind to EGF-r and to lead to cellular proliferation and tumor 0016 Yang et al. describe the effect of a fully human growth. These observations suggested that blocking the monoclonal antibody to EGFr on tumors. Cancer Res., interaction between the growth factors and EGFr could 59:1236-1243 (1999). result in arrest of tumor growth and possibly affect tumor 0017 Combinations of antibodies targeting VEGFR and survival. EGFR for the treatment of colon cancer were described by 0013 Thus, certain groups have proposed that antibodies Shaheen et al., Brit. J. of Cancer, 85:584-589 (2001). A against EGF, TGF-C., and EGF-r may be useful in the combination of a EGFR inhibitor and for the therapy of tumors expressing EGF-r. Mendelsohn, Cancer treatment of pancreatic carcinomas was described by Bruns Cells, 7:359 (1989); Mendelsohn, Cancer Biology, 1:339 et al., Cancer Res., 60:2926-2935 (2000) and Clin. Cancer 344 (1990); Modjtahedi and Dean, Int’l J. Oncology, 4:277 Res., 6:1936-1948 (2000). A combination of Iressa and 296 (1994); Tosi et al., Int’l J. Cancer, 62:643-650 (1995). inhibitors of PKAI for the treatment of colon and breast Indeed, it has been demonstrated that anti-EGF-rantibodies cancer was described by Tortora et al., Clin. Cancer Res., while blocking EGF and TGF-C. binding to the receptor 9:866-871 (2003). A combination of and kressa appear to inhibit tumor cell proliferation. At the same time, for the treatment of a variety of cancers was described by however, anti-EGF-rantibodies have not appeared to inhibit Ciardiello et al., Clin. Cancer Res., 7:1459–1465 (2001). A EGF and TGF-C. independent cell growth. Modjtahedi and combination of paclitaxel and EGFR antibody C225 for the Dean, Int’l J. Oncology, 4:277-296 (1994). See also Cirdi treatment of bladder transitional cell carcinoma was ello et al., Eur. J. Cancer, 39:1348-1354 (2003). described by Inoue et al., Clin. Cancer Res., 6:4874-4884 (2000) and Clin. Cancer Res., 6:2635-2643 (2000). Herbstet 0014 MAbs specific to the human EGFr. capable of al. (J. Clin. Oncol., 23(11):2544-2555 (2005)) describe data neutralizing EGF and TGFC. binding to tumor cells and of on a VEGF antibody and EGFR inhibitor erlotinib in lung inhibiting ligand-mediated cell proliferation in vitro, have cancer. A combination of antibodies targeting VEGFR and been generated from mice and rats. Some of these antibod EGFR for the treatment of gastric cancer were described by ies, such as the mouse 108, 225 and 528 or the rat ICR16, Jung et al., Eur. J. Cancer, 38:1133-1140 (2002). ICR62 and ICR64 MAbs, were evaluated extensively for their ability to affect tumor growth in xenograft mouse 0018. It is now found that some combinations of a VEGF models. Most of the anti-EGFr MAbs were efficacious in pathway inhibitor and an antibody that inhibits the EGFR preventing tumor formation in athymic mice when admin pathway provides better results than one or the other inhibi istered together with the human tumor cells. When injected tor used alone. into mice bearing established human tumor Xenografts, the mouse MAbs 225 and 528 caused partial tumor regression DESCRIPTION OF THE DRAWINGS and required the co-administration of chemotherapeutic agents, such as or , for eradication of 0.019 FIG. 1 shows the combination of VEGFR inhibitor the tumors. A chimeric version of the 225 MAb (C225), in AMG 706 and anti-EGFR antibody panitumumab are most which the mouse antibody variable regions are linked to effective in the treatment of A431 human epidermoid car human constant regions, exhibited an improved in vivo cinoma cells. anti-tumor activity but only at high doses. The rat ICR16, ICR62, and ICR64 antibodies caused regression of estab 0020 FIG. 2 shows the combination of VEGFR inhibitor lished tumors but not their complete eradication. These AMG 706 and anti-EGFR antibody panitumumab are most results established EGFr as a promising target for antibody effective in the treatment of HT29 human colon carcinoma therapy against EGFr-expressing solid tumors and led to cells. human clinical trials with the C225 MAb in multiple human 0021 FIG.3 shows the combination of VEGFR inhibitor solid cancers. Therefore, anti-EGFr antibody therapy can be AMG 706 and anti-EGFR antibody panitumumab are most fully evaluated with the availability of a fully human anti effective in the treatment of HT29 human colon carcinoma EGFr antibody that exhibits therapeutic efficacy on EGFr cells. expressing tumors and that can be administered repeatedly to all appropriate patient populations. 0022 FIG. 4 shows the combination of VEGFR inhibitor AMG 706 and anti-EGFR antibody panitumumab are most 0015. A number of murine and rat monoclonal antibodies effective in the treatment of CALU6 human non-small cell against EGF-r have been developed and tested for their lung cancer cells. ability to inhibit the growth of tumor cells in vitro and in vivo. Modjtahedi and Dean, Int’l J. Oncology, 4:277-296 0023 FIG. 5 shows the combination of VEGFR inhibitor (1994). The murine antibody, designated 225, upon which A and Erbitux are effective in the treatment of CALU6 the C225 antibody is based, was developed by University of human non-Small cell lung cancer cells. US 2006/0216288 A1 Sep. 28, 2006

DETAILED DESCRIPTION OF THE 0028. The invention also relates to combinations with a INVENTION VEGFR inhibitor of the formula 0024. The present invention is generally directed to com positions and methods for reducing tumor growth, and O generally treating tumors in animals. The approach taken by R2 the inventors was to determine whether a combination of X - RN EGFR antibodies, particularly human anti-EGFR antibodies C N N RI with VEGFR inhibiting agents that target the tumor vascu 2 R N N1 lature provides a beneficial effect. The results obtained by H the inventors indicate a Surprising benefit from the combi nation of EGFR antibodies and VEGFR inhibiting agents, and that therapies which involve administration of combi 0029 wherein R is selected from unsubstituted or sub nations of these agents are beneficial in the treatment of stituted 9- or 10-membered fused nitrogen-containing cancer. Taken individually, the surprising benefit between heteroaryl, the individual agents tested provide a number of unforeseen 0030 wherein R is substituted with one or more sub options for the treatment of tumors or cancers. stituents selected from halo, amino, hydroxy, C.- alkyl, C-haloalkyl, C-alkoxy, optionally Substi 0.025 The invention also relates to treatment of neoplasia tuted heterocyclylalkoxy, C-alkylamino-Ca including cancer and metastasis, including, but not limited alkynyl, Co-alkylamino-Cio-alkoxy, C-6- to: carcinoma Such as cancer of the bladder, breast, colon alkylamino-Cio-alkoxy-C-alkoxy, and optionally (including colorectal cancer), kidney, head and neck, liver, Substituted heterocyclyl-C-alkynyl: lung (including non-Small cell lung cancer), esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, pros 0031) wherein R' is selected from unsubstituted or sub tate, and skin (including squamous cell carcinoma); hemato stituted poietic tumors of lymphoid lineage (including leukemia, 0032) aryl, acute lymphocitic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin’s lymphoma, 0033 cycloalkyl, non-Hodgkin’s lymphoma, hairy cell lymphoma and Bur 0034) 5-6 membered heteroaryland kett's lymphoma); hematopoietic tumors of myeloid lineage 0035) 9-10 membered bicyclic and 13-14 membered (including acute and chronic myelogenous leukemias, tricyclic heterocyclyl, myelodysplastic syndrome and promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and 0036) wherein substituted R' is substituted with one or rhabdomyosarcoma, and other sarcomas, e.g. soft tissue and more Substituents selected from halo, C-alkyl, bone); tumors of the central and peripheral nervous system optionally Substituted C-cycloalkyl, optionally Sub stituted phenyl, optionally Substituted phenyl-C-C- (including astrocytoma, neuroblastoma, glioma and Schw alkylenyl, C-haloalkoxy, optionally substituted phe annomas); and other tumors (including melanoma, semi nyloxy, optionally substituted 4-6 membered noma, teratocarcinoma, osteosarcoma, Xenoderoma pigmen heterocyclyl-C-C-alkyl, optionally substituted 4-6 tosum, keratoctanthoma, thyroid follicular cancer and membered heterocyclyl-C-C-alkenyl, optionally Sub Kaposi's sarcoma). stituted 4-6 membered heterocyclyl, optionally substi tuted 4-6 membered heterocyclyloxy, optionally sub 0026. The invention also relates to the treatment of stituted 4-6 membered heterocyclyl-C-alkoxy, neoplasia selected from lung cancer, breast cancer, colon optionally substituted 4-6 membered heterocyclylsul cancer and . fonyl, optionally substituted 4-6 membered heterocy clylamino, optionally substituted 4-6 membered het 0027. The invention also relates to the use of the com erocyclylcarbonyl, optionally substituted 4-6 bination of EGFR antibodies, particularly human anti-EGFR membered heterocyclyl-Ca-alkylcarbonyl, C-ha antibodies with VEGFR inhibiting agents in adjuvant or loalkyl, Ca-aminoalkyl, nitro, amino, hydroxy, cyano, neoadjuvant , with or without radiation, for the aminosulfonyl, C2-alkylsulfonyl, halosulfonyl, Ca treatment of neoplasia. “Adjuvant chemotherapy” is defined alkylcarbonyl, C-alkylamino-C-alkyl, C-alky as the continued treatment after either intensive cycles of lamino-C-alkoxy, C-alkylamino-C-alkoxy-C. chemotherapy and/or radiation, or alternatively after Surgery 3-alkoxy, C-alkoxycarbonyl, C1-4- to remove tumors. Alternatively the term describes the use alkoxycarbonylamino-Ca-alkyl, Ca-hydroxyalkyl, of drugs as additional treatment for patients with cancers that are thought to have spread outside their original sites. Neo-adjuvant therapy is defined as intensive cycles of Re Rf chemotherapy and/or radiation given to reduce the size of R7 tumor before a definitive Surgery. Such adjuvant or neo -X- adjuvant chemotherapy +/- radiation relates to the treatment of neoplasea including, but not limited to: carcinoma of the breast, colon, lung, and head and neck. 0037) and C-alkoxy; US 2006/0216288 A1 Sep. 28, 2006

0038 wherein R is one or more substituents indepen 0050 9-10 membered saturated or partially un-satu dently selected from H. halo, hydroxy, amino, C-alkyl, rated bicyclic heterocyclyl, and Cle-haloalkyl, C-alkoxy, C2-alkylamino, aminosul fonyl, C-cycloalkyl, cyano, C-hydroxyalkyl, nitro, 0051) 13-14 membered saturated or partially un-satu C2-3-alkenyl, C2-s-alkynyl, C-haloalkoxy, Co-car rated tricyclic heterocyclyl, boxyalkyl, 4-6-membered heterocyclyl-C-alkylamino, 0.052 wherein substituted R' is substituted with one or unsubstituted or substituted phenyl and unsubstituted or more Substituents selected from halo, C-alkyl, substituted 4-6 membered heterocyclyl: optionally substituted C-cycloalkyl, optionally sub stituted phenyl, optionally Substituted phenyl-C-C- 0039) wherein R is selected from a direct bond, Ca alkylenyl, C-haloalkoxy, optionally Substituted 4-6 alkyl, and membered heterocyclyl-C-C-alkyl, optionally substi tuted 4-6 membered heterocyclyl-C-C-alkenyl, optionally substituted 4-6 membered heterocyclyl, optionally substituted phenyloxy, optionally substituted ~~1. 4-6 membered heterocyclyloxy, optionally substituted HO 4-6 membered heterocyclyl-C-C-alkoxy, optionally substituted 4-6 membered heterocyclylsulfonyl, optionally substituted 4-6 membered heterocycly 0040 and lamino, optionally substituted 4-6 membered heterocy clylcarbonyl, optionally substituted 5-6 membered het 0041) wherein R and Rare independently selected from erocyclyl-Ca-alkylcarbonyl, C-haloalkyl, Ca H and C-haloalkyl; and aminoalkyl, nitro, amino, hydroxy, Oxo, cyano, 0042 wherein R7 is selected from H, C-alkyl, option aminosulfonyl, C2-alkylsulfonyl, halosulfonyl, Ca ally substituted phenyl, optionally substituted phenyl-C- alkylcarbonyl, C-alkylamino-C-alkyl, C-alky 3-alkyl, 4-6 membered heterocyclyl, optionally substi lamino-C-alkoxy, C-alkylamino-C-alkoxy-C- tuted 4-6 membered heterocyclyl-C-C-alkyl, C 3-alkoxy, C-alkoxycarbonyl, C1-4- alkoxy-C-alkyl and C-alkoxy-C-alkoxy-C- alkoxycarbonylamino-Ca-alkyl, Ca-hydroxyalkyl, alkyl: and pharmaceutically acceptable derivatives thereof. Re Rf 0043. The invention also relates to combinations with a VEGFR inhibitor of the formula

I I 0053) and C-alkoxy; O R2 0054 wherein R is one or more substituents indepen X - RN dently selected from H. halo, hydroxy, amino, C-alkyl, C N N R1 C-haloalkyl, C-alkoxy, C-alkylamino, aminosul 2 R2 fonyl, C-cycloalkyl, cyano, C-2-hydroxyalkyl, nitro, N N1 NR C2-s-alkenyl, C2-s-alkynyl, C-haloalkoxy, C-car boxyalkyl, 5-6-membered heterocyclyl-C-alkylamino, unsubstituted or substituted phenyl and unsubstituted or 0044 wherein R is selected from substituted 5-6 membered heterocyclyl: 0045 a) unsubstituted or substituted 5- or 6-membered 0.055 wherein R is selected from a direct bond, C nitrogen-containing heteroaryl, and alkyl, and 0046 b) unsubstituted or substituted 9- or 10-mem bered fused heteroaryl, 0047 where substituted R is substituted with one or ~~~ more Substituents selected from halo, amino, HO hydroxy, C-alkyl, C-haloalkyl, C-alkoxy, optionally Substituted heterocyclyl-C6-alkoxy, optionally substituted heterocyclyl-C-alkylamino, 0056 wherein R is selected from C2-alkyl, C optionally Substituted heterocyclyl-C-alkyl, C branched alkyl, C-a-branched haloalkyl, amino-Ca alkylamino-Ca-alkynyl, Co-alkylamino-Cio alkyl and C2-alkylamino-C-alkyl; alkoxy, Co-alkylamino-Cio-alkoxy-C6-alkoxy, 0057 wherein R and Rare independently selected from and optionally substituted heterocyclyl-C-alky H and C-haloalkyl, and nyl: 0058 wherein R is selected from H, C-alkyl, option 0048 wherein R' is a ring selected from unsubstituted or ally substituted phenyl, optionally substituted phenyl-C- Substituted 3-alkyl, optionally substituted 4-6 membered heterocy clyl, optionally substituted 4-6 membered heterocyclyl 0049 4-6 membered saturated or partially un-saturated C-C-alkyl, C-alkoxy-C-alkyl and C-alkoxy-C- monocyclic heterocyclyl, 3-alkoxy-C-alkyl; US 2006/0216288 A1 Sep. 28, 2006 and pharmaceutically acceptable isomers and derivatives C-alkoxycarbonyl, C-alkoxycarbonylamino-Ca thereof. alkyl, Ca-hydroxyalkyl, 0059. The invention also relates to combinations with a VEGFR inhibitor of the formula Re Rf -X-Ro1 III 0065 and C-alkoxy; 0066 wherein R and Rare independently selected from H and C-haloalkyl: 0067 wherein R7 is selected from H, C-alkyl, option ally substituted phenyl-C-alkyl, 4-6 membered hetero cyclyl, and optionally substituted 4-6 membered hetero cyclyl-C-C-alkyl; 0068 wherein R is selected from H, C-alkyl, option ally substituted phenyl-C-alkyl, 4-6 membered hetero cyclyl, and optionally substituted 4-6 membered hetero cyclyl-C-C-alkyl, C-alkoxy-C2-alkyl and C 0060) wherein R* is one or more substituents indepen alkoxy-C-alkoxy-C-alkyl; and dently selected from H. halo, hydroxy, amino, C-alkyl, 0069 wherein R is one or more substituents indepen C-haloalkyl, C-alkoxy, C-alkylamino, aminosul dently selected from H. halo, amino, hydroxy, C-alkyl, fonyl, C-cycloalkyl, cyano, oxo, C-2-hydroxyalkyl, Co-haloalkyl, C6-alkoxy, C-haloalkoxy, Co-ami nitro, C2-s-alkenyl, C2-s-alkynyl, C-haloalkoxy, Co noalkyl, C-hydroxyalkyl, optionally substituted phe nyl, optionally substituted heterocyclyl, optionally Sub carboxyalkyl, 5-6-membered heterocyclyl-C-alky stituted heterocyclyl-C-alkoxy, aminosulfonyl, C.- lamino, unsubstituted or substituted phenyl and unsubsti cycloalkyl, C-alkylamino, C-alkylamino-C1-alkyl, tuted or substituted 5-6 membered heterocyclyl; optionally Substituted heterocyclyl-C-alkylamino, optionally substituted heterocyclyl-C-alkyl, C-alky 0061 wherein R'" is selected from unsubstituted or sub lamino-C2-alkynyl, C-alkylamino-Cio-alkoxy, Co stituted alkylamino-C-alkoxy-C-alkoxy, and optionally Sub 0062 phenyl, and stituted heterocyclyl-Ca-alkynyl: and pharmaceutically acceptable isomers and derivatives 0063 9-10 membered bicyclic and 13-14 membered thereof. tricyclic unsaturated or partially unsaturated heterocy 0070 The invention also relates to combinations with a clyl, VEGFR inhibitor of the formula 0064) wherein substituted R'" is optionally substituted with one or more substituents selected from halo, IV Co-alkyl, optionally Substituted C-cycloalkyl, O optionally substituted phenyl, optionally substituted R2 phenyl-C-C-alkyl, C-haloalkoxy, optionally sub Xs-N- stituted phenyloxy, optionally Substituted 4-6 mem bered heterocyclyl-C-C-alkyl, optionally substituted C 2 H 4-6 membered heterocyclyl-C-C-alkenyl, optionally N t substituted 5-6 membered heterocyclyl, optionally sub CHR stituted 4-6 membered heterocyclyloxy, optionally sub stituted 4-6 membered heterocyclyl-C-C-alkoxy, 0071 wherein R is selected from optionally substituted 5-6 membered heterocyclylsul 0072 a) unsubstituted or substituted 5- or 6-membered fonyl, optionally substituted 5-6 membered heterocy rings-selected from 4-pyridyl, 2-pyridyl, 4-pyrimidi clylamino, optionally substituted 5-6 membered het nyl, and tetrahydro-2H-pyran-4-yl, and erocyclylcarbonyl, optionally substituted 5-6 0073 b) unsubstituted or substituted 9- or 10-mem membered heterocyclylcarbonyl-C-alkyl, optionally bered fused rings selected from 4-quinolyl, 6-quinolyl, substituted 5-6 membered heterocyclyl-C-alkylcar 2,3-dihydro-5-benzofuryl, 5-benzoxazolyl, 1 H-pyrrolo bonyl, Ca-haloalkyl, Ca-aminoalkyl, nitro, amino, 2,3-bipyridin-4-yl, and 2,3-dihydro-1H-pyrrolo2,3-b hydroxy, OXO, cyano, aminosulfonyl, C2-alkylsulfo pyridin-4-yl, nyl, halosulfonyl, C-alkylcarbonyl, amino-Ca 0074 where substituted R is substituted with one or alkylcarbonyl, C-alkylamino-Ca-alkylcarbonyl, more substituents selected from methylamino-, C-alkylamino-C-alkyl, Cis-alkylamino-Cis amino, methoxy, methylaminocarbonyl, morpholino, alkoxy, C-3-alkylamino-C-3-alkoxy-Cls-alkoxy, and trifluoromethoxy;

US 2006/0216288 A1 Sep. 28, 2006

0118. The invention also relates to co-therapy with the 0.132. The invention also relates to a kit according to any VEGFR inhibitor AMG706. of the foregoing, further comprising integrally thereto or as one or more separate documents, information pertaining to 0119) The invention also relates to co-therapy with the contents or the kit and the use of the inhibitors. VEGFR inhibitors including Nexavar (Bayer BAY 43-9006), Astra Zeneca AZ 2171, Novartis/Schering PTK/ 0.133 The invention also relates to a kit according to any ZK, PTK787/ZK 222584, Pfizer AG-13736 and Sutent of the foregoing, wherein the compositions are formulated (Pfizer SU11248). for reconstitution in a diluent. The invention also relates to a kit according to any of the foregoing, further comprising 0120). Other VEGFR inhibitors described in the following a container of sterile diluent. patents and patent applications can be used in combination therapy: U.S. Pat. No. 6,258,812, US 2003/0105091, WO 0.134. The invention also relates to a kit according to any 01/37820, U.S. Pat. No. 6,235,764, WO 01/32651, U.S. Pat. of the foregoing, wherein said compositions are disposed in No. 6,630,500, U.S. Pat. No. 6,515,004, U.S. Pat. No. vials under partial vacuum sealed by a septum and Suitable 6,713,485, U.S. Pat. No. 5,521,184, U.S. Pat. No. 5,770,599, for reconstitution to form a formulation effective for parental U.S. Pat. No. 5,747,498, WO 02/68406, WO 02/66470, WO administration. 02/55501, WO 04/05279, WO 04/07481, WO 04/07458, 0.135). As used in relation to the invention, the term WO 04/09784, WO 02/59110, WO 99/45009, WO “treating or “treatment” and the like should be taken 00/59509, WO 99/61422, U.S. Pat. No. 5,990,141, WO broadly. They should not be taken to imply that an animal is OOf 12089 and WO OO/O2871. treated to total recovery. Accordingly, these terms include 0121 The invention also relates to co-therapy with amelioration of the symptoms or severity of a particular VEGFR inhibitors described in US 2003/O125339 which is condition or preventing or otherwise reducing the risk of herein incorporated by reference in its entirety, particularly further development of a particular condition. in parts disclosing VEGF inhibitors. 0.136 The term “comprising is meant to be open ended, including the indicated component but not excluding other 0122) The invention also relates to co-therapy with elements. VEGFR inhibitors described in US 2003/O125339 or US 2003/0225106 each of which is herein incorporated by 0137) The phrase “therapeutically-effective' is intended reference in its entirety, particularly in parts disclosing to qualify the amount of each agent, which will achieve the VEGF inhibitors. goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while 0123 The invention also relates to co-therapy with avoiding adverse side effects typically associated with alter VEGFR inhibitors described in WO 00/42012, WO native therapies. For example, effective neoplastic therapeu 00/41698, US 2005/0038080A1, US 2003/0125359A1, US tic agents prolong the survivability of the patient, inhibit the 2002/0165394A1, US 2001/003447A1, US 2001/ rapidly-proliferating cell growth associated with the neo 0016659A1, and US 2002/013774A1 which are herein plasm, or effect a regression of the . incorporated by reference in their entirety, particularly in parts disclosing the foregoing VEGF inhibitors. 0.138. It should be appreciated that methods of the inven tion may be applicable to various species of Subjects, 0.124. The invention also relates to humanized or fully preferably mammals, more preferably humans. human EGFR antibodies. 0.139. As used herein, the compounds of the present 0125) The invention also relates to EGFR inhibitory invention include the pharmaceutically acceptable deriva agents (e.g., antibodies or antigen binding regions that tives thereof. specifically bind thereto) such as panitumumab, 0140. Where the plural form is used for compounds, salts, ERBITUXTM (Cetuximab), EMD72000, TheraCIM hR3 or and the like, this is taken to mean also a single compound, LICR 806. salt and the like. 0126. Other EGFR antibodies described in U.S. Pat. No. 0.141. A “pharmaceutically-acceptable derivative' 6,235,883 can be used in combination therapy. denotes any salt, ester of a compound of this invention, or 0127. The invention also relates to co-therapy with pani any other compound which upon administration to a patient tumumab. is capable of providing (directly or indirectly) a compound of this invention, or a metabolite or residue thereof. 0128. The invention also relates to a kit comprising, in 0142. The terms "cancer and "cancerous” when used one or more containers, separately or in admixture one or herein refer to or describe the physiological condition in more EGFR antibodies inhibitors and one or more VEGF mammals that is typically characterized by unregulated cell inhibitors in accordance with any of the foregoing. growth. Examples of cancer include but are not limited to, 0129. The invention also relates to a kit, wherein the carcinoma, lymphoma, sarcoma, blastoma and leukemia. inhibitors are comprised in pharmaceutically acceptable More particular examples of Such cancers include squamous formulations. cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon car 0130. The invention also relates to a kit, comprising cinoma, and head and neck cancer. panitumumab and AMG 706. 0.143 AVEGFR inhibitor is defined as a compound with 0131 The invention also relates to a kit, wherein the a molecular weight less than about 1000 that inhibits the inhibitors are disposed in separate containers. receptor as shown with in vitro testing or by other means. US 2006/0216288 A1 Sep. 28, 2006

0144. The following are among specific VEGF inhibitors 0162 SU-5416 (Sugen and Pfizer/Pharmacia) (also that may be used in the invention in this regard: called CAS Registry Number 194413-58-6, semaxanib, 0145 AEE-788 (Novartis) (also called AE-788 and NVP 204005-46-9, among others) and closely related VEGF AEE-788, among others) including formulations for oral inhibitors; administration and closely related VEGF inhibitors; 0.163 SU-6668 (Sugen and Taiho) (also called CAS Reg istry Number 252916-29-3, SU-006668, and TSU-68, 0146 AG-13736 (Pfizer) (also called AG-013736) among others) and closely related VEGF inhibitors as including formulations for oral administration and closely described in, among others, WO 99/48868, WO 99/61422, related VEGF inhibitors; and WO 00/038519, which are hereby incorporated by 0147 AG-028262 (Pfizer) and closely related VEGF reference in their entireties, particularly in parts pertaining to inhibitors; SU-6668 and closely related VEGF inhibitors, their struc tures and properties, and methods for making and using 0148 AVE-8062 (Ajinomoto Co. and Sanofi-aventis) them; (also called AC-7700 and combretastatin A4 analog, among others), and closely related VEGF inhibitors; 0164. Thalidomide (Celgene) (also called CAS Registry Number 50-35-1, Synovir, Thalidomide Pharmion, and Tha 0149 AZD-2171 (AstraZeneca) and closely related lomid, among others) and closely related VEGF inhibitors: VEGF inhibitors; 0.165 XL-647 (Exelixis) (also called EXEL-7647, among 0150. Nexavar RD (Bayer AG and Onyx) (also called others) and closely related VEGF inhibitors; CAS Registry Number 284461-73-0, BAY-43-9006, raf kinase inhibitor, Sorafenib, Sorafenib analogs, and 0166 XL-999 (Exelixis) (also called EXEL-0999, among IDDBCP150446, among others) and closely related VEGF others) and closely related VEGF inhibitors; inhibitors; 0167 XL-880 (Exelixis) (also called EXEL-2880, among 0151. BMS-387032 (Sunesis and Bristol-Myers Squibb) others) and closely related VEGF inhibitors; (also called SNS-032 and CAS Registry Number 345627 0168 ZD-6474 (AstraZeneca) (also called CAS Registry 80-7, among others) and closely related VEGF inhibitors; Number 443913-73-3, Zactima, and AZD-6474, among oth 0152 CEP-7055 (Cephalon and Sanofi-aventis) (also ers) and closely related anilinoquinazoline VEGF inhibitors: called CEP-11981 and SSR-106462, among others) and and closely related VEGF inhibitors: 0169 ZK-304709 (Schering) (also called CDK inhibitors (indirubin derivatives), ZK-CDK, MTGI, and multi-target 0153 CHIR-258 (Chiron) (also called CAS Registry tumor growth inhibitor, among others) and other closely Number 405169-16-6, GFKI, and GFKI-258, among others) related compounds including the indirubin derivative VEGF and closely related VEGF inhibitors; inhibitors described in WO 00/234717, WO 02/074742, WO 0154 CP-547632 (OSI Pharmaceuticals and Pfizer) (also 02/100401, WO 00/244148, WO 02/096888, WO called CAS Registry Number 252003-65-9, among others) 03/029223, WO 02/092079, and WO 02/094814 which are and closely related VEGF inhibitors such as, for instance, hereby incorporated by reference in their entireties particu CP-564959; larly in parts pertinent to these and closely related VEGF inhibitors, their structures and properties, and methods for 0.155) E-7080 (Eisai Co.) (also called CAS Registry making and using them. Number 417716-92-8 and ER-203492-00, among others) and closely related VEGF inhibitors; 0170 Also among VEGF inhibitors in this regard are: Pazopanib, CDP791, Enzastaurin, BIBF 1120, BAY 573952, 0156 78.6034 (GlaxoSmithKline) and closely related BAY 734506, XL 184, IMC-1121B, CEP 701, SU 014813, VEGF inhibitors; SU 10944, SU 12662, OSI-930, and BMS 582664, and 0157 GW-654652 (GlaxoSmithKline) and closely closely related VEGF inhibitors. related indazolylpyrimidine Kdr inhibitors; 0171 In addition to the foregoing inhibitors that act directly on VEGF or VEGFR, the following inhibitors have 0158 KRN-951 (Kirin Brewery Co.) and other closely anti-angiogenic properties and can be used in the invention related quinoline-urea VEGF inhibitors: in much the same way as inhibitors that act directly: 0159) PKC-412 (Novartis) (also called CAS Registry 0172 ZD-6126 (AstraZeneca and Angiogene) (also Number 120685-11-2, benzoylstaurosporine, CGP-41251, called CAS Registry Number 219923-05-4, N-acetylcolchi midostaurin, and STI-412, among others) and closely related nol phosphate, ANG-453, AZD-6126, ZD-6126 derivatives VEGF inhibitors; and ZM-445526, among others) and closely related VEGF 0160 PTK-787 (Novartis and Schering) (also called CAS inhibitors such as other inhibitors in the ANG-400 series; Registry Numbers 212141-54-3 and 212142-18-2, PTK/ZK, 0173 Imatinib (Novartis) (also called CAS Registry PTK-787/ZK-222584, ZK-22584, VEGF-TKI, VEGF-RKI, Numbers 152459-95-5 and 220127-57-1, Glivec, Gleevec, PTK-787A, DE-00268, CGP-79787, CGP-79787D, vata STI-571, and CGP-57148, among others) and closely related lanib, ZK-222584, among others) and closely related anili VEGF inhibitors; nophthalazine derivative VEGF inhibitors; 0.174 RAD-001 (Novartis) (also called CAS Registry 0161 SU11248 (Sugen and Pfizer) (also called Number 159351-69-6, RAD-001, SDZ-RAD, Certican, and SU-11248, SU-01 1248, SU-11248J, Sutent(R), and Sunitinib everolimus, among others) and closely related VEGF inhibi malate, among others) and closely related VEGF inhibitors: tors; and US 2006/0216288 A1 Sep. 28, 2006

0175 BMS-354825 (Bristol-Myers Squibb) (also called 0187 “PTK/ZK,” also known as , is a multi CAS Registry Number 302962-49-8, Src/Abl kinase inhibi VEGF receptor tyrosine kinase inhibitor that is said to block tor, and dasatinib, among others) and closely related VEGF tumor angiogenesis and lymphangiogenesis. Its chemical inhibitors. aC is N-(4-chlorophenyl)-4-(pyridin-4-ylmeth yl)phthalazin-1-amine. It also is known as CAS Registry 0176). Also useful in the invention in this are regard are Numbers 212141-54-3 and 212142-18-2, PTK787, PTK787/ CCI-779, 17-AAG, DMXAA, CI-1040, and CI-1033. ZK, PTK-787/ZK-222584, PTK787/ZK222584, ZK-22584, 0177 Among the VEGF inhibitors preferred in the inven VEGF-TKI, VEGF-RKI, PTK-787A, DE-00268, CGP tion are the following: (a) a compound described in US 79787, CGP-79787D, Vatalanib, and ZK-222584. See Tho 2003/0125339 which is herein incorporated by reference in mas, A., et al., J. of Clin. Oncology, 23(18): 4162-4171 its entirety, particularly in parts disclosing VEGF inhibitors: (2005); US Patent Application 2005/0118600A1, which are (b) a substituted alkylamine derivative described in US herein incorporated by reference in their entirety, particu 2003/O125339 or US 2003/0225106 each of which is herein larly as to the structure, synthesis, properties, and uses of incorporated by reference in its entirety, particularly in parts PTK/ZK and related compounds. disclosing VEGF inhibitors; (c) a substituted omega-car 0188 “Sutent(R’ is a small molecule receptor tyrosine boxyaryl diphenyl urea or derivative thereofas described in kinase inhibitor with the chemical name (5-5-fluoro-2-oxo WO 00/42012, WO 00/41698, US 2005/003.8080A1, US 1,2-dihydroindol-(3Z)-ylidenemethyl-2,4-dimethyl-1H 2003/0125359A1, US 2002/0165394A1, US 2001/ pyrrole-3-carboxylic acid 2-diethylaminoethylamide). 003447A1, US 2001/0016659A1, and US 2002/013774A1 Sutent(R) is also known as Sunitinib malate, SU 11248, which are herein incorporated by reference in their entirety, SU-11248, SU-011248, and SU-11248J, and is reported to particularly in parts disclosing the foregoing VEGF inhibi have anti-angiogenic and anti-tumor activities. See Mendel, tors; (d) an anilinophthalazine or derivative thereof that D., et al., Clinical Cancer Research, 9:327-337 (2003); binds to and inhibits the activity of multiple receptor Schlessinger, J., The Scientist, 19(7):17 (2005), which are tyrosine kinases including binding to the protein kinase herein incorporated by reference in their entirety, particu domain and inhibition of VEGFR1 and VEGFR2; and (e) (5-5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl larly as to the structure, synthesis, properties, and uses of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2-diethylami Sutent(R) and related compounds. noethylamide) or derivative thereof that are VEGF inhibi 0189 “AMG 706” is a multi-kinase inhibitor that inter tOrS. feres with the Kit, Ret, PDGF, and VEGF-signalling path ways, as described in U.S. Pat. No. 6,995,162, which is 0178. In this regard, certain of the very highly particu herein incorporated by reference in its entirety, particularly larly preferred VEGF inhibitors are further described below, in parts pertinent to AMG 706, its structure and properties, 0179 (1) AMG 706 methods for making and using it, and other related com pounds. Its chemical name is N-(2,3-dihydro-3,3-dimethyl 0180 (2) Nexavar 1H-indol-6-yl)-2-(4-pyridinylmethyl) amino-3-pyridin ecarboxamide. AMG 706 is also occasionally referred to as 0181 (3) AZD-2171 VEGF inhibitor B in this application. As used herein the 0182 (4) AG-13736 term AMG 706 includes pharmaceutically acceptable salts, in particular, the diphosphate salt, except as otherwise 0183 (5) PTK/ZK and provided herein. 0184 (6) Sutent. 0190. An EGFR antibody is defined as an antibody, or 0185. Among these AMG 706 is among the most highly fragment thereof, that interferes with the binding between preferred VEGF inhibitors. EGF and EGFR, as shown with in vitro testing or by other means. Cetuximab is also occasionally referred to as EGF 0186 “Nexavar R” (also known as BAY 43-9006, sor inhibitor B in this application. afenib, CAS Registry Number 284461-73-0, raf kinase inhibitor, Sorafenib analogs, and IDDBCP150446, among 0191) “Panitumumab' is a EGFR antibody, as described others) is a Substituted omega carboxy diphenyl urea that in U.S. Pat. No. 6,235,883, WO 03/99205 and US 2005/ inhibits RAF-1 activation, and thereby decreases RAF-1 0241006 which are herein incorporated by reference in its dependent phosphorylation of MEK-1 and ERK-1, as entirety, particularly in parts pertinent to panitumumab. described in US Patent Application No. 2003/0125359A1, Panitumumab is also occasionally referred to as EGF inhibi WO 03/047523A2, and Wilhelmet al., Current Pharmaceu tor A in this application. tical Design, 8:2255-2257 (2002), each of which is herein 0.192 A “pharmaceutically-acceptable derivative' incorporated by reference in its entirety, particularly in parts denotes any salt, ester of a compound of this invention, or pertinent to Nexavar(R), its structure and properties, methods any other compound which upon administration to a patient for making and using it, and other related molecules. Its is capable of providing (directly or indirectly) a compound chemical name is 4-(4-3-4-Chloro-3-(trifluorometh yl)phenylureidophenoxy)-N-methylpyridine-2-carboxam of this invention, or a metabolite or residue thereof. ide. A variety of derivatives have been produced. Among 0193 The term “pharmaceutically-acceptable salts' these are fluorinated derivatives described in US Patent embraces salts commonly used to form alkali metal salts and Application 2005/0038080A1 and WO 2005/009961A2, to form addition salts of free acids or free bases. The nature which are herein incorporated by reference in their entire of the salt is not critical, provided that it is pharmaceutically ties, particularly as to these and other pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addi active diphenyl urea compounds tion salts may be prepared from an inorganic acid or from an US 2006/0216288 A1 Sep. 28, 2006

organic acid. Examples of Such inorganic acids are hydro didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, chloric, hydrobromic, hydroiodic, nitric, carbonic, Sulfuric Merck & Co. EX-015, fazarabine, , and phosphoric acid. Appropriate organic acids may be phosphate, 5-, N-(2-furanidyl)-5-fluorouracil, selected from aliphatic, cycloaliphatic, aromatic, aryla Daiichi Seiyaku FO-152, isopropyl pyrrolizine, Lilly liphatic, heterocyclic, carboxylic and Sulfonic classes of LY-188011, Lilly LY-264618, methobenzaprim, methotrex organic acids, example of which are formic, acetic, adipic, ate, Wellcome MZPES, norspermidine, NCI NSC-127716, butyric, propionic, Succinic, glycolic, gluconic, lactic, malic, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyru Warner-Lambert PALA, , piritrexim, , Vic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hy Asahi Chemical PL-AC, Takeda TAC-788, thioguanine, droxybenzoic, phenylacetic, mandelic, embonic (pamoic), , Erbamont TIF, trimetrexate, tyrosine kinase methanesulfonic, ethanesulfonic, ethanedisulfonic, benze inhibitors, Taiho UFT and uricytin. nesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluene 0.197 A second family of antineoplastic agents which Sulfonic, Sulfanilic, cyclohexylaminosulfonic, camphoric, may be used in combination with compounds of the present camphorsulfonic, digluconic, cyclopentanepropionic, dode invention consists of alkylating-type antineoplastic agents. cylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, Suitable alkylating-type antineoplastic agents may be hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-naphthale selected from but not limited to the group consisting of nesulfonic, oxalic, palmoic, pectinic, persulfuric, 2-phenyl Shionogi 254-S, aldo-phosphamide analogues, , propionic, picric, pivalic propionic, succinic, tartaric, thio anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, cyanic, mesylic, undecanoic, Stearic, algenic, budotitane, Wakunaga CA-102, , , B-hydroxybutyric, Salicylic, galactaric and galacturonic Chinoin-139, Chinoin-153, , cisplatin, cyclo acid. Suitable pharmaceutically-acceptable base addition phosphamide, American Cyanamid CL-286558, Sanofi salts include metallic salts, such as salts made from alumi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP num, calcium, lithium, magnesium, potassium, Sodium and (Myr)2, diphenylspiromustine, diplatinum cytostatic, Erba Zinc, or salts made from organic bases including primary, distamycin derivatives, Chugai DWA-2114R, ITI E09, secondary and tertiary amines, Substituted amines including elmustine, Erbamont FCE-24517, cyclic amines, such as caffeine, arginine, diethylamine, sodium, , Unimed G-6-M, Chinoin GYKI N-ethyl piperidine, aistidine, glucamine, isopropylamine, 17230, hepsul-fam, , iproplatin, , lysine, morpholine, N-ethyl morpholine, piperazine, piperi , mitolactol, Nippon Kayaku NK-121, NCI dine, triethylamine, trimethylamine. All of these salts may NSC-264395, NCI NSC-342215, , Upjohn be prepared by conventional means from the corresponding PCNU, , Proter PTT-119, , semus compound of the invention by reacting, for example, the tine, SmithKline SK&F-101772, Yakult Honsha SN-22, appropriate acid or base with the compound of the invention. spiromus-tine, Tanabe Seiyaku TA-077, tauromustine, temo When a basic group and an acid group are present in the Zolomide, teroxirone, tetraplatin and trimelamol. same molecule, a compound of the invention may also form internal salts. 0.198. A third family of antineoplastic agents which may be used in combination with compounds of the present 0194 Currently, standard treatment of primary tumors invention consists of antibiotic-type antineoplastic agents. consists of Surgical excision followed by either radiation or Suitable antibiotic-type antineoplastic agents may be IV administered chemotherapy. The typical chemotherapy selected from but not limited to the group consisting of regime consists of either DNA alkylating agents, DNA Taiho. 4181-A, , actinomycin D, actinoplanone, intercalating agents, CDK inhibitors, or microtubule poi Erbamont ADR-456, aeroplysinin derivative, Ajinomoto sons. The chemotherapy doses used are just below the AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, maximal tolerated dose and therefore dose limiting toxicities anthracycline, azino-mycin-A, bisucaberin, Bristol-Myers typically include, nausea, vomiting, diarrhea, hair loss, BL-6859, Bristol-Myers BMY-25067, Bristol-Myers BMY neutropenia and the like. 25551, Bristol-Myers BMY-26605, Bristol-Myers BMY 0.195 There are large numbers of antineoplastic agents 27557, Bristol-Myers BMY-28438, sulfate, bry available in commercial use, in clinical evaluation and in ostatin-1, Taiho C-1027, calichemycin, chromoximycin, pre-clinical development, which would be selected for treat , , Kyowa Hakko DC-102, ment of neoplasia by combination drug chemotherapy. Such Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa antineoplastic agents fall into several major categories, Hakko DC89-A1, Kyowa Hakko DC92-B, ditrisarubicin B, namely, antibiotic-type agents, alkylating agents, antime Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, , erbstatin, esorubicin, esperamicin tabolite agents, hormonal agents, immunological agents, A1, esperamicin-Alb, Erbamont FCE-21954, Fujisawa interferon-type agents and a category of miscellaneous FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gre agents. gatin-A, grincamycin, herbimycin, , illudins, 0196. A first family of antineoplastic agents which may kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin be used in combination with compounds of the present Brewery KRN-8602, Kyowa Hakko KT-5432, Kyowa invention consists of antimetabolite-typefthymidilate Syn Hakko KT-5594, Kyowa Hakko KT-6149, American Cyana thase inhibitor antineoplastic agents. Suitable antimetabolite mid LL-D49194, Meiji Seika ME 2303, menogaril, mito antineoplastic agents may be selected from but not limited to mycin, , SmithKline M-TAG, neoenactin, Nip the group consisting of 5-FU, fibrinogen, acanthifolic acid, pon Kayaku NK-313, Nippon Kayaku NKT-01, SRI aminothiadiazole, brequinar Sodium, , Ciba-Geigy International NSC-357704, oxalysine, oxaunomycin, peplo CGP-30694, cyclopentyl cytosine, phosphate mycin, pilatin, , porothramycin, pyrindanycin A, stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow Tobishi RA-I, rapamycin, rhizoxin, rodorubicin, Sibanomi DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, cin, Siwenmycin, Sumitomo SM-5887, Snow Brand US 2006/0216288 A1 Sep. 28, 2006

SN-706, Snow Brand SN-07, Sorangicin-A, sparsomycin, tase, Toyama T-506, Toyama T-680, taxol. Teijin TEI-0303, SS Pharmaceutical SS-21020, SS Pharmaceutical , thaliblastine, Eastman Kodak TJB-29, tocot SS-7313B, SS Pharmaceutical SS-9816B, steflimycin B, rienol, , Topostin, Teijin TT-82, Kyowa Hakko Taiho 4181-2, talisomycin, Takeda TAN-868A, terpentecin, UCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman thrazine, tricrozarin A, Upjohn U-73975, Kyowa Hakko Kodak USB-006, sulfate, , , UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 and vinestramide, , vintriptol, Vinzolidine, withano . lides and Yamanouchi YM-534. 0199 A fourth family of antineoplastic agents which may 0200 Alternatively, the present compounds may also be be used in combination with compounds of the present used in co-therapies with other anti-neoplastic agents. Such invention consists of a miscellaneous family of antineoplas as acemannan, aclarubicin, aldesleukin, alemtuzumab, ali tic agents, including tubulin interacting agents, topoi , altretamine, amifostine, , somerase II inhibitors, topoisomerase I inhibitors and hor , , , anastroZole, ANCER, monal agents, selected from but not limited to the group ancestim, ARGLABIN, , BAM 002 (Nov consisting of C-carotene, C.-difluoromethyl-arginine, acitre elos), , bicalutamide, broXuridine, , tin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide, celmoleukin, cetrorelix, , clotrimazole, cytarabine amphethinile, amsacrine, Angiostat, ankinomycin, anti-neo ocfosfate, DA3030 (Dong-A), daclizumab, denileukin difti plaston A10, antineoplaston A2, antineoplaston A3, antine toX, deslorelin, dexraZOxane, dilaZep, , docosanol, oplaston A5, antineoplaston AS2-1, Henkel APD, aphidi doxercalciferol, doxifluridine, doxorubicin, bromocriptine, colin glycinate, , Avarol, baccharin, batracylin, carmustine, cytarabine, fluorouracil, HIT diclofenac, inter benfluron, benzotript, Ipsen-Beaufour BIM-23015, bisant feron alfa, daunorubicin, doxorubicin, tretinoin, edelfosine, rene, Bristol-Myers BMY-40481, Vestar boron-10, bromo edrecolomab, eflornithine, emitefur, epirubicin, epoetin fosfamide, Wellcome BW-502, Wellcome BW-773, carace beta, phosphate, exemestane, , fadrozole, mide, carmethizole hydrochloride, Ajinomoto CDAF, filgrastim, finasteride, fludarabine phosphate, formestane, chlorsulfaquinoxalone, Chemes CHX-2053, Chemex CHX fotemustine, gallium nitrate, gemcitabine, gemtuzumab 100, Warner-Lambert CI-921, Warner-Lambert CI-937, Zogamicin, gimeracil/oteracil/ combination, glyco Warner-Lambert CI-941, Warner-Lambert CI-958, clan pine, goserelin, heptaplatin, human chorionic gonadotropin, fenur, claviridenone, ICN compound 1259, ICN compound human fetal alpha fetoprotein, ibandronic acid, idarubicin, 4711, Contracan, Yakult Honsha CPT-11, crisinatol, curad (imiduimod, interferon alfa, interferon alfa, natural, inter erm, cytochalasin B, cytarabine, cytocytin, Merz D-609. feron alfa-2, interferon alfa-2a, interferon alfa-2b, interferon DABIS maleate, , datelliptinium, didemnin-B, alfa-N1, interferon alfa-n3, interferon alfacon-1, interferon dihaematoporphyrin ether, dihydrolenperone, dinaline, dis alpha, natural, interferon beta, interferon beta-1a, interferon tamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, beta-1b, interferon gamma, natural interferon gamma-1a, Daiichi Seiyaku DN-9693, docetaxel elliprabin, elliptinium interferon gamma-1b, interleukin-1 beta, iobenguane, irino acetate, Tsumura EPMTC, the epothilones, ergotamine, eto tecan, irsogladine, lanreotide, LC 9018 (Yakult), lefluno poside, etretinate, fenretinide, Fujisawa FR-57704, gallium mide, lenograstim, lentinan Sulfate, letrozole, leukocyte nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, alpha interferon, leuprorelin, levamisole--fluorouracil, liaro grifolan NMF-5N, hexadecylphosphocholine, Green Cross Zole, lobaplatin, , lovastatin, , melar HO-221, homoharringtonine, hydroxyurea, BTG ICRF-187, Soprol, metoclopramide, mifepristone, miltefosine, miri ilmofosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot mostim, mismatched double stranded RNA, , K-477, Otsuak K-76COONa, Kureha Chemical K-AM, mitolactol, mitoxantrone, molgramoStim, nafarelin, nalox MECT Corp KI-8110, American Cyanamid L-623, leuko one-pentazocine, nartograstim, , nilutamide, nos regulin, lonidamine, Lundbeck LU-23-112, Lilly capine, novel erythropoiesis stimulating protein, NSC LY-186641, NCI (US) MAP. marycin, Merrel Dow MDL 631570 octreotide, oprelvekin, osaterone, oxaliplatin, pacli 27048, Medco MEDR-340, merbarone, merocyanline taxel, pamidronic acid, , peginterferon alfa-2b. derivatives, methylanilinoacridine, Molecular Genetics pentosan polysulfate Sodium, pentostatin, picibanil, piraru MGI-136, minactivin, mitonafide, mitoquidone mopidamol. bicin, rabbit antithymocyte polyclonal antibody, polyethyl motretinide, Zenyaku Kogyo MST-16, N-(retinoyl)amino ene glycol interferon alfa-2a, , raloxifene, acids, Nisshin Flour Milling N-021, N-acylated-dehydroala , rasburicase, rhenium Re 186 etidronate, RII nines, nafazatrom, Taisho NCU-190, derivative, retinamide, rituximab, romurtide, samarium (153 Sm) lex Normosang, NCI NSC-145813, NCI NSC-361456, NCI idronam, SargramoStim, sizofiran, Sobuzoxane, Sonermin, NSC-604782, NCI NSC-95580, ocreotide, Ono ONO-112, strontium-89 chloride, Suramin, tasonermin, tazarotene, oquizanocine, Akzo Org-10172, paclitaxel, pancratistatin, tegafur, , , teniposide, tetrachloro pazelliptine, Warner-Lambert PD-111707, Warner-Lambert decaoxide, thalidomide, thymalfasin, thyrotropin alfa, topo PD-115934, Warner-Lambert PD-131141, Pierre Fabre tecan, toremifene, to situmomab-iodine 131, trastuzumab, PE-1001, ICRT peptide D, piroxantrone, polyhaematopor , tretinoin, triloStane, trimetrexate, triptorelin, phyrin, polypreic acid, Efamol porphyrin, probimane, pro tumor necrosis factor alpha, natural, ubenimex, bladder carbazine, proglumide, Invitron protease nexin I, Tobishi cancer vaccine, Maruyama Vaccine, melanoma lysate vac RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, cine, , , vinorelbine, VIRULIZIN, retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone Zinostatin stimalamer, or Zoledronic acid; abarelix; AE 941 Poulenc RP-56976, SmithKline SK&F-104864, Sumitomo (Aetema), ambamustine, antisense oligonucleotide, bcl-2 SM-108, Kuraray SMANCS, SeaPharm SP-10094, spatol, (Genta), APC 8015 (Dendreon), cetuximab, , dex spirocyclopropane derivatives, spirogermanium, Unimed, aminoglutethimide, diaziquone, EL 532 (Elan), EM 800 SS Pharmaceutical SS-554, Strypoldinone, Stypoldione, (Endorecherche), eniluracil, etanidazole, fenretinide, Suntory SUN 0237, Suntory SUN 2071, superoxide dismu filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin US 2006/0216288 A1 Sep. 28, 2006

17 immunogen, HLA-B7 gene therapy (Vical), granulocyte for the treatment intended. The compounds and composi macrophage colony stimulating factor, histamine dihydro tions of the present invention may, for example, be admin chloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran), istered orally, mucosally, topically, rectally, pulmonarily interleukin-2, iproxifene, LDI 200 (Milkhaus), leridistim, Such as by inhalation spray, or parentally including intra lintuzumab, CA 125 MAb (Biomira), cancer MAb (Japan vascularly, intravenously, intraperitoneally, Subcutaneously, Pharmaceutical Development), HER-2 and Fc MAb intramuscularly intrasternally and infusion techniques, in (Medarex), idiotypic 105AD7 MAb (CRC Technology), dosage unit formulations containing conventional pharma idiotypic CEA MAb (Trilex), LYM-1-iodine 131 MAb ceutically acceptable carriers, adjuvants, and vehicles. (Techniclone), polymorphic epithelial mucin-yttrium 90 0207. The pharmaceutically active compounds of this MAb (Antisoma), marimastat, menogaril, mitumomab, invention can be processed in accordance with conventional motexafin gadolinium, MX 6 (Galderma), , nola methods of pharmacy to produce medicinal agents for trexed, P 30 protein, pegvisomant, , porfiromy administration to patients, including humans and other cin, prinomastat, RL 0903 (Shire), , , mammals. sodium phenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathio 0208 For oral administration, the pharmaceutical com molybdate, thaliblastine, thrombopoietin, tin ethyl etiopur position may be in the form of, for example, a tablet, purin, tirapazamine, cancer vaccine (Biomira), melanoma capsule, Suspension or liquid. The pharmaceutical compo vaccine (New York University), melanoma vaccine (Sloan sition is preferably made in the form of a dosage unit Kettering Institute), melanoma oncolysate vaccine (New containing a particular amount of the active ingredient. York Medical College), viral melanoma cell lysates vaccine Examples of Such dosage units are tablets or capsules. For (Royal Newcastle Hospital), or Valspodar. example, these may contain an amount of active ingredient from about 1 to 2000 mg, preferably from about 1 to 500 mg. 0201 Alternatively, the present compounds may also be A Suitable daily dose for a human or other mammal may used with radiation. Alternatively, the present compounds vary widely depending on the condition of the patient and may also be used in conjunction with agents used for other factors, but, once again, can be determined using hormonal therapy, Such as for treatment of breast and routine methods. For example dosages from about 10 mg to prostate cancer. Examples include aromatase inhibitors (e.g. about 150 mg. or about 25 to about 125 mg may be used. The Arimidex (chemical name: anastrozole). Aromasin (chemi therapeutically effective amount of VEGFR inhibitor in the cal name: exemestane), and Femara (chemical name: letro composition can be chosen to be about 25 mg, about 50 mg. Zole)): Serms (selective estrogen-receptor modulators) such about 75 mg, about 100 mg, about 125 mg, or about 150 mg. as tamoxifen, and ERDs (estrogen-receptor downregula The therapeutically effective amount of VEGFR inhibitor in tors), e.g. Faslodex (chemical name: fulvestrant). the composition can be chosen to be about 50 mg dosed 0202 As will be appreciated, the dose of an combination twice a day, or about 75 mg dosed twice a day, or about 100 of the present invention to be administered, the period of mg dosed twice a day, or about 100 mg dosed once a day, or administration, and the general administration regime may about 125 mg dosed once a day. differ between subjects depending on such variables as the 0209 The amount of compounds which are administered severity of symptoms, the type of tumor to be treated, the and the dosage regimen for treating a disease condition with mode of administration chosen, type of composition, size of the compounds and/or compositions of this invention a unit dosage, kind of excipients, the age and/or general depends on a variety of factors, including the age, weight, health of a subject, and other factors well known to those of sex and medical condition of the Subject, the type of disease, ordinary skill in the art. the severity of the disease, the route and frequency of administration, and the particular compound employed. 0203 Administration may include a single daily dose or Thus, the dosage regimen may vary widely, but can be administration of a number of discrete divided doses as may determined routinely using standard methods. A daily dose be appropriate. An administration regime may also include of about 0.01 to 500 mg/kg, preferably between about 0.01 administration of one or more of the active agents, or and about 50 mg/kg, and more preferably about 0.01 and compositions comprising same, as described herein. The about 30 mg/kg body weight may be appropriate. The daily period of administration may be variable. dose can be administered in one to four doses per day. 0204. It may occur for as long a period is desired. 0210 For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more 0205 Administration may include simultaneous admin adjuvants appropriate to the indicated route of administra istration of Suitable agents or compositions or sequential tion. If administered per os, the compounds may be admixed administration of agents or compositions. with lactose. Sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, Stearic acid, Formulations magnesium Stearate, magnesium oxide, sodium and calcium 0206. Also embraced within this invention is a class of salts of phosphoric and Sulfuric acids, gelatin, acacia gum, pharmaceutical compositions comprising the active VEGFR Sodium alginate, polyvinylpyrrolidone, and/or polyvinyl inhibitors in association with one or more non-toxic, phar alcohol, and then tableted or encapsulated for convenient maceutically-acceptable carriers and/or diluents and/or adju administration. Such capsules or tablets may contain a vants (collectively referred to herein as “carrier materials) controlled-release formulation as may be provided in a and, if desired, other active ingredients. The active com dispersion of active compound in hydroxypropylmethyl pounds of the present invention may be administered by any cellulose. suitable route, preferably in the form of a pharmaceutical 0211 Formulations for parenteral administration may be composition adapted to such a route, and in a dose effective in the form of aqueous or non-aqueous isotonic sterile US 2006/0216288 A1 Sep. 28, 2006 injection Solutions or Suspensions. These solutions and Sus the standard delivery technique for the majority of tumors. pensions may be prepared from sterile powders or granules However, in connection with tumors in the peritoneal cavity, using one or more of the carriers or diluents mentioned for Such as tumors of the ovaries, biliary duct, other ducts, and use in the formulations for oral administration or by using the like, intraperitoneal administration may prove favorable other Suitable dispersing or wetting agents and Suspending for obtaining high dose of antibody at the tumor and to agents. The compounds may be dissolved in water, polyeth minimize antibody clearance. In a similar manner certain ylene glycol, propylene glycol, ethanol, corn oil, cottonseed Solid tumors possess vasculature that is appropriate for oil, peanut oil, sesame oil, benzyl alcohol, Sodium chloride, regional perfusion. Regional perfusion will allow the obten tragacanth gum, and/or various buffers. Other adjuvants and tion of a high dose of the antibody at the site of a tumor and modes of administration are well and widely known in the will minimize short-term clearance of the antibody. pharmaceutical art. The active ingredient may also be 0217. The antibody can be formulated in an aqueous administered by injection as a composition with Suitable buffer solution. The formulation may contain sodium chlo carriers including saline, dextrose, or water, or with cyclo ride, Sodium phosphate or Sodium acetate at a physiological dextrin (ie. Captisol), cosolvent solubilization (ie. propylene pH of about 5 to about 7.4. The formulation may or may not glycol) or micellar solubilization (ie. Tween 80). contain preservatives. 0212. The sterile injectable preparation may also be a sterile injectable Solution or Suspension in a non-toxic 0218 Kits parenterally acceptable diluent or solvent, for example as a 0219. The invention also provides kits comprising one or Solution in 1,3-butanediol. Among the acceptable vehicles more EGFR antibody and one or more VEGF inhibitors in and solvents that may be employed are water, Ringer's accordance with the foregoing. The inhibitors may be dis Solution, and isotonic sodium chloride solution. In addition, posed in the kits in one or more containers. Each Such sterile, fixed oils are conventionally employed as a solvent container may contain separately or in admixture one or or Suspending medium. For this purpose any bland fixed oil more EGFR antibody and one or more VEGF inhibitors in may be employed, including synthetic mono- or diglycer accordance with any of the foregoing. Typically, such kits ides. In addition, fatty acids such as oleic acid find use in the are designed for medical use, and the inhibitors are com preparation of injectables. prised in pharmaceutically acceptable formulations. Among very highly preferred kits in this regard are those comprising 0213 For pulmonary administration, the pharmaceutical panitumumab and AMG 706. Also among highly preferred composition may be administered in the form of an aerosol embodiments in this regard are kits wherein the inhibitors or with an inhaler including dry powder aerosol. are disposed in separate containers. 0214) The pharmaceutical compositions may be sub 0220) Further preferred kits are those that comprise inte jected to conventional pharmaceutical operations such as grally thereto or as one or more separate documents, infor sterilization and/or may contain conventional adjuvants, mation pertaining to the contents or the kit and the use of the Such as preservatives, stabilizers, wetting agents, emulsifi inhibitors. Also among further preferred kits are those ers, buffers etc. Tablets and pills can additionally be pre wherein the compositions are formulated for reconstitution pared with enteric coatings. Such compositions may also in a diluent. In this regard, kits further comprising one or comprise adjuvants, such as wetting, Sweetening, flavoring, more containers of sterile diluent are especially preferred. and perfuming agents. Yet further preferred embodiments in this regard include kits 0215. While specific dosing for antibodies in accordance wherein at least one of the inhibitors is disposed in vials with the invention has not yet been determined, antibody can under partial vacuum sealed by a septum and Suitable for be administered with weekly doses in the range of about 0.5 reconstitution to form a formulation effective for parental mg/kg to about 10 mg/kg, preferably about 2 mg/kg to about administration. 3 mg/kg, or about 2 mg/kg. Antibody can be administered 0221 Preferred embodiments of the present invention every two weeks with doses in the range of about 1 mg/kg also include kits that provide single-dose packaging of one to about 15 mg/kg, preferably about 3 mg/kg to about 10 or more of the inhibitors. Preferred kits also include those mg/kg, or about 6 mg/kg. Antibody can be administered that provide single and multi-chambered pre-filled Syringes every three weeks with doses in the range of about 2 mg/kg (e.g., liquid Syringes and lyosyringes) for administering one to about 30 mg/kg, preferably about 5 mg/kg to about 15 mg/kg, or about 9 mg/kg. Some antibodies can be admin or more of the inhibitors. Particularly preferred in this regard istered with doses in the range of 50 to 300 mg/m, where are kits in which the Syringes are preloaded. dosing in mg/m, as opposed to the conventional measure 0222. The invention will now be further described with ment of dose in mg/kg, is a measurement based on Surface reference to the following non-limiting examples. area. The therapeutically effective amount of EGFR anti body in the composition can be chosen from about 1 mg, EXAMPLE 1. about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 0223 A431 epidermoid carcinoma cells (ATCC) were mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about expanded in culture, harvested and injected Subcutaneously 11 mg, about 12 mg, about 13 mg, about 14 mg. or about 15 into 5-8 week old female nude mice (CD1 nu/nu, Charles ng. River Labs) (n=5-15). Administration of VEGFR inhibitor B 0216) Three distinct delivery approaches are expected to by oral gavage (10 mpk/dose) or by injection of anti-EGFR be useful for delivery of the antibodies in accordance with antibody A (20 ug/dose) or by a combination of VEGFR the invention. Conventional intravenous delivery, Such as inhibitor B by oral gavage (10 mpk/dose) and by injection of through a peripheral line or indwelling catheter over the anti-EGFR antibody A (20 ug/dose) began day 18 post tumor length of time specified in the protocol, will presumably be cell challenge. The VEGFR inhibitor was subsequently US 2006/0216288 A1 Sep. 28, 2006 administered on a daily basis by oral gavage (10 mpk/dose) the VEFGFR inhibitor and EGFR antibody, respectively. and the anti-EGFR antibody was administered injection (20 Regression was noted for the combination therapy. See FIG. ug/dose) twice a week for the duration of the experiment. 3. Combination of VEGFR inhibitor B and anti-EGFR Progression of tumor growth was followed by three dimen antibody A are most effective in the treatment of HT29 sional caliper measurements and recorded as a function of cancer cells. time. Initial statistical analysis was done by repeated mea sures analysis of variance (RMANOVA), followed by EXAMPLE 4 Scheffe post hoc testing for multiple comparisons. Vehicle alone (Ora-Plus, pH 2.0) or IgG2 injection (20 ug/dose) 0226 CALU6 human non-small cell lung cancer cells were the negative controls for the VEFGFR inhibitor and (ATCC) were expanded in culture, harvested and injected EGFR antibody, respectively. Substantial regression was subcutaneously into 5-8 week old female nude mice (CD1 nu/nu, Charles River Labs) (n=5-15). Administration of noted for the combination therapy. Body weights were not VEGFR inhibitor B by oral gavage (75 mpk/dose) or by negatively impacted by any treatment. Combination of injection of anti-EGFR antibody A (500 ug/dose) or by a VEGFR inhibitor B and anti-EGFR antibody A are most combination of VEGFR inhibitor B by oral gavage (75 effective in the treatment of A431 cancer cells. See FIG. 1. mpk/dose) and by injection of anti-EGFR antibody A (500 Body weights were not negatively impacted by any treat ug/dose) began day 14 post tumor cell challenge. The ment. VEGFR inhibitor was subsequently administered on a daily basis by oral gavage (75 mpk/dose) and the anti-EGFR EXAMPLE 2 antibody was administered injection (500 ug/dose) twice a 0224 HT29 human colon carcinoma cells (ATCC) were week for the duration of the experiment. Progression of expanded in culture, harvested and injected Subcutaneously tumor growth was followed by three dimensional caliper into 5-8 week old female nude mice (CD1 nu/nu, Charles measurements and recorded as a function of time. Initial River Labs) (n=5-15). Administration of VEGFR inhibitor B statistical analysis was done by repeated measures analysis by oral gavage (75 mpk/dose) or by injection of anti-EGFR of variance (RMANOVA), followed by Scheffe post hoc antibody A (500 ug/dose) or by a combination of VEGFR testing for multiple comparisons. Vehicle alone (Ora-Plus, inhibitor B by oral gavage (75 mpk/dose) and by injection of pH 2.0) or IgG2 injection (500 ug/dose) were the negative anti-EGFR antibody A (500 ug/dose) began day 14 post controls for the VEFGFR inhibitor and EGFR antibody, tumor cell challenge. The VEGFR inhibitor was subse respectively. Regression was noted for the combination quently administered on a daily basis by oral gavage (75 therapy. See FIG. 4. Combination of VEGFR inhibitor B mpk/dose) and the anti-EGFR antibody was administered and anti-EGFR antibody A are most effective in the treat injection (500 ug/dose) twice a week for the duration of the ment of CALU6 cancer cells. experiment. Progression of tumor growth was followed by three dimensional caliper measurements and recorded as a EXAMPLE 5 function of time. Initial statistical analysis was done by 0227 CALU6 human non-small cell lung cancer cells repeated measures analysis of variance (RMANOVA), fol (ATCC) were expanded in culture, harvested and injected lowed by Scheffe post hoc testing for multiple comparisons. subcutaneously into 5-8 week old female nude mice (CD1 Vehicle alone (Ora-Plus, pH 2.0) or IgG2 injection (500 nu/nu, Charles River Labs) (n=5-15). Administration of ug/dose) were the negative controls for the VEFGFR inhibi VEGFR inhibitor A by oral gavage twice daily (50 mpk/ tor and EGFR antibody, respectively. Regression was noted dose) or by injection of EGFR antibody B (500 ug/dose) or for the combination therapy. See FIG. 2. Combination of by a combination of VEGFR inhibitor A by oral gavage VEGFR inhibitor B and anti-EGFR antibody A is effective twice daily (50 mpk/dose) and by injection of EGFR anti in the treatment of HT29 cancer cells. body B (500 ug/dose) began day 14 post tumor cell chal lenge. The VEGFR inhibitor was subsequently administered EXAMPLE 3 on a twice daily basis by oral gavage (50 mpk/dose) and the 0225 HT29 human colon carcinoma cells (ATCC) were anti-EGFR antibody was administered injection (500 expanded in culture, harvested and injected Subcutaneously ug/dose) twice a week for the duration of the experiment. into 5-8 week old female nude mice (CD1 nu/nu, Charles Progression of tumor growth was followed by three dimen River Labs) (n=5-15). Administration of VEGFR inhibitor B sional caliper measurements and recorded as a function of by oral gavage (37.5 mpk/dose) or by injection of anti time. Initial statistical analysis was done by repeated mea EGFR antibody A (500 ug/dose) or by a combination of sures analysis of variance (RMANOVA), followed by VEGFR inhibitor B by oral gavage (37.5 mpk/dose) and by Scheffe post hoc testing for multiple comparisons. Vehicle injection of anti-EGFR antibody A (500 ug/dose) began day alone (Ora-Plus, pH 2.0) or IgG2 injection (500 ug/dose) 14 post tumor cell challenge. The VEGFR inhibitor was were the negative controls for the VEFGFR inhibitor and Subsequently administered on a daily basis by oral gavage EGFR antibody, respectively. Reduction of tumor size was (37.5 mpk/dose) and the anti-EGFR antibody was adminis noted for the combination therapy. See FIG. 5. Combination tered injection (500 ug/dose) twice a week for the duration of VEGFR inhibitor A and EGFR antibody B is effective in of the experiment. Progression of tumor growth was fol the treatment of CALU6 cancer cells. lowed by three dimensional caliper measurements and 0228. The foregoing is merely illustrative of the inven recorded as a function of time. Initial statistical analysis was tion and is not intended to limit the invention to the disclosed done by repeated measures analysis of variance compounds. Variations and changes which are obvious to (RMANOVA), followed by Scheffe post hoc testing for one skilled in the art are intended to be within the scope and multiple comparisons. Vehicle alone (Ora-Plus, pH 2.0) or nature of the invention which are defined in the appended IgG2 injection (500 ug/dose) were the negative controls for claims. US 2006/0216288 A1 Sep. 28, 2006

0229. From the foregoing description, one skilled in the fonyl, halosulfonyl, C-alkylcarbonyl, C-alky art can easily ascertain the essential characteristics of this lamino-Cis-alkyl, C-3-alkylamino-C-3-alkoxy, Cis invention, and without departing from the spirit and scope alkylamino-C-alkoxy-C-alkoxy, C1-4- thereof, can make various changes and modifications of the alkoxycarbonyl, C-alkoxycarbonylamino-Ca invention to adapt it to various usages and conditions. alkyl, Ca-hydroxyalkyl 0230 No unacceptable toxological effects are expected when compounds of the present invention are administered in accordance with the present invention. Re Rf 0231. All mentioned references, patents, applications and -X-Ro1 publications, are hereby incorporated by reference in their entirety, as if here written. What is claimed is: and C1-alkoxy; 1. A method of treating cancer in a subject with an wherein R is one or more substituents independently anti-EGFR antibody in combination with a VEGFR inhibitor Selected from H. halo, hydroxy, amino, C-alkyl, selected from Cle-haloalkyl, C-alkoxy, C2-alkylamino, amino Sulfonyl, C-cycloalkyl, cyano, C-2-hydroxyalkyl, a) compounds of Formula I nitro, C2-s-alkenyl, C2-s-alkynyl, C-haloalkoxy, C-carboxyalkyl, 4-6-membered heterocyclyl-C- alkylamino, unsubstituted or Substituted phenyl and O unsubstituted or substituted 4-6 membered heterocy R2 R clyl; f N N1 NR wherein R is selected from a direct bond, C-alkyl, and 2 R N N1 H ~~~ HO wherein R is selected from unsubstituted or substituted 9 or 10-membered fused nitrogen-containing heteroaryl, wherein R is substituted with one or more substituents and selected from halo, amino, hydroxy, C-alkyl, C haloalkyl, C-alkoxy, optionally Substituted hetero wherein R and Rare independently selected from Hand cyclylalkoxy, Co-alkylamino-C2-alkynyl, Co C-haloalkyl; and alkylamino-Cio-alkoxy, Co-alkylamino-Cio wherein R is selected from H. C-alkyl, optionally alkoxy-C-alkoxy, and optionally substituted Substituted phenyl, optionally substituted phenyl-C- heterocyclyl-Ca-alkynyl: alkyl, 4-6 membered heterocyclyl, optionally substi tuted 4-6 membered heterocyclyl-C-C-alkyl, C wherein R' is selected from unsubstituted or substituted alkoxy-C-alkyl and C-alkoxy-C-alkoxy-C- aryl, alkyl: cycloalkyl, b) inhibitor of Formula II 5-6 membered heteroaryland 9-10 membered bicyclic and 13-14 membered tricyclic II heterocyclyl, O R2 wherein substituted R' is substituted with one or more X -RS Substituents selected from halo, C-alkyl, optionally C N N R1 Substituted C-cycloalkyl, optionally Substituted phe 2 R2 nyl, optionally Substituted phenyl-C-C-alkylenyl, N N1 YR C-haloalkoxy, optionally Substituted phenyloxy, optionally substituted 4-6 membered heterocyclyl-C- C-alkyl, optionally substituted 4-6 membered hetero wherein R is selected from cyclyl-C-C-alkenyl, optionally Substituted 4-6 mem bered heterocyclyl, optionally substituted 4-6 a) unsubstituted or substituted 5- or 6-membered membered heterocyclyloxy, optionally substituted 4-6 nitrogen-containing heteroaryl, and membered heterocyclyl-Ca-alkoxy, optionally Substi b) unsubstituted or substituted 9- or 10-membered tuted 4-6 membered heterocyclylsulfonyl, optionally fused heteroaryl, substituted 4-6 membered heterocyclylamino, option ally substituted 4-6 membered heterocyclylcarbonyl, where substituted R is substituted with one or more optionally substituted 4-6 membered heterocyclyl-C- Substituents selected from halo, amino, hydroxy, 4-alkylcarbonyl, C-haloalkyl, Ca-aminoalkyl, nitro, Co-alkyl, C-haloalkyl, C-alkoxy, optionally amino, hydroxy, cyano, aminosulfonyl, C2-alkylsul Substituted heterocyclyl-C-alkoxy, optionally US 2006/0216288 A1 Sep. 28, 2006 16

Substituted heterocyclyl-C-alkylamino, option wherein R is selected from a direct bond, C-alkyl, and ally substituted heterocyclyl-C-alkyl, C alkylamino-C2-a-alkynyl, C-alkylamino-Cio alkoxy, Co-alkylamino-Cio-alkoxy-Cio alkoxy, and optionally Substituted heterocyclyl ~~~ C-alkynyl: HO wherein R' is a ring selected from unsubstituted or sub stituted wherein R is selected from C-alkyl, Ca-branched alkyl, Ca-branched haloalkyl, amino-Ca-alkyl and 4-6 membered Saturated or partially un-saturated C-alkylamino-C-alkyl: monocyclic heterocyclyl, wherein R and Rare independently selected from Hand 9-10 membered saturated or partially un-saturated C-haloalkyl; and bicyclic heterocyclyl, and wherein R is selected from H. C-alkyl, optionally Substituted phenyl, optionally substituted phenyl-C- 13-14 membered saturated or partially un-saturated alkyl, optionally substituted 4-6 membered heterocy tricyclic heterocyclyl, clyl, optionally substituted 4-6 membered heterocyclyl C-C-alkyl, C-alkoxy-C-alkyl and C-alkoxy wherein substituted R' is substituted with one or more C-3-alkoxy-C-3-alkyl, Substituents selected from halo, C-alkyl, option ally Substituted C-cycloalkyl, optionally Substi c) inhibitor of Formula IV tuted phenyl, optionally Substituted phenyl-C-C- alkylenyl, C-haloalkoxy, optionally substituted IV 4-6 membered heterocyclyl-C-C-alkyl, optionally O substituted 4-6 membered heterocyclyl-C-C-alk R2 enyl, optionally substituted 4-6 membered heterocy X^n-1 n clyl, optionally Substituted phenyloxy, optionally substituted 4-6 membered heterocyclyloxy, option C 2 H ally substituted 4-6 membered heterocyclyl-C-C- N t alkoxy, optionally substituted 4-6 membered hetero CHR cyclylsulfonyl, optionally substituted 4-6 membered heterocyclylamino, optionally Substituted 4-6 mem bered heterocyclylcarbonyl, optionally substituted wherein R is selected from 5-6 membered heterocyclyl-C-alkylcarbonyl, C-haloalkyl, Ca-aminoalkyl, nitro, amino, a) unsubstituted or substituted 5- or 6-membered rings hydroxy, oxo, cyano, aminosulfonyl, C-alkylsul selected from 4-pyridyl, 2-pyridyl, 4-pyrimidinyl, fonyl, halosulfonyl, C-alkylcarbonyl, C-alky and tetrahydro-2H-pyran-4-yl, and lamino-C-alkyl, Cis-alkylamino-Cis-alkoxy, b) unsubstituted or substituted 9- or 10-membered C-alkylamino-C-alkoxy-C-alkoxy, C-4- fused rings selected from 4-quinolyl, 6-quinolyl, alkoxycarbonyl, C-alkoxycarbonylamino-Ca 2,3-dihydro-5-benzofuryl, 5-benzoxazolyl, 1 H-pyr alkyl, Ca-hydroxyalkyl rolo2,3-bipyridin-4-yl, and 2,3-dihydro-1H-pyrrolo 2,3-bipyridin-4-yl, where substituted R is substituted with one or more Substituents selected from methylamino-, amino, methoxy, methylaminocarbonyl, morpholino, and trifluoromethoxy; wherein R' is 4.4-dimethyl-3,4-dihydro-2-oxo-1H quinolinyl; or wherein R' is 4,4-dimethyl-1,2,3,4-tetrahydro-1H and C-alkoxy. quinolinyl; wherein R is one or more substituents independently or wherein R' is 4,4-dimethyl-3,4-dihydro-2-oxo Selected from H. halo, hydroxy, amino, C-alkyl, 1H-1.8naphthyridinyl: Co-haloalkyl, C-alkoxy, C2-alkylamino, amino Sulfonyl, C-cycloalkyl, cyano, C-hydroxyalkyl, or wherein R is 3.3-dimethyl-2,3-dihydro-1H-in dolyl optionally substituted with a substituent nitro, C2-s-alkenyl, C2-s-alkynyl, C-haloalkoxy, selected from pyrrolidin-1-yl-carbonyl, methyl C-carboxyalkyl, 5-6-membered heterocyclyl-C- carbonyl, and methylsulfonyl: alkylamino, unsubstituted or Substituted phenyl and unsubstituted or substituted 5-6 membered heterocy or wherein R' is 4,4-dimethyl-1,2,3,4-tetrahydro clyl; 1H-isoquinolinyl:

US 2006/0216288 A1 Sep. 28, 2006 18

11. The method of claim 1 wherein the VEGFR inhibitor VEGFR inhibitor is selected from AMG 706, Nexavar, AZ is administered in a dose of about 125 mg once a day. 2171, AG-13736, PTK/ZK and Sutent. 12. The method of claim 1, wherein the EGFR antibody 15. Akit comprising, in one or more containers, separately is panitumumab. or in admixture one or more EGFR antibodies inhibitors and 13. The method of claim 1, wherein the EGFR antibody one or more VEGF inhibitors. is Erbitux. 14. A method of treating cancer in a subject with a VEGFR inhibitor and an anti-EGFR antibody, wherein the k . . . .