WO2012042421A1 - Procédé de traitement de la croissance cellulaire anormale - Google Patents

Procédé de traitement de la croissance cellulaire anormale Download PDF

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WO2012042421A1
WO2012042421A1 PCT/IB2011/054042 IB2011054042W WO2012042421A1 WO 2012042421 A1 WO2012042421 A1 WO 2012042421A1 IB 2011054042 W IB2011054042 W IB 2011054042W WO 2012042421 A1 WO2012042421 A1 WO 2012042421A1
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inhibitor
met
vegf
sunitinib
hgfr
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PCT/IB2011/054042
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English (en)
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James Gail Christensen
Farbod Shojaei
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Pfizer Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the use of c-Met/HGFR and VEGF inhibitors for treating abnormal cell growth in mammals.
  • the invention provides methods of treating mammals suffering from cancer.
  • the invention provides methods of treating mammals suffering from metastatic cancer.
  • the invention provides methods of inhibiting metastatic cancer.
  • VEGF vascular endothelial growth factor
  • RTKIs receptor tyrosine kinase inhibitors
  • sunitinib and sorafenib which target the VEGF pathway
  • sunitinib and sorafenib which target the VEGF pathway
  • sunitinib and sorafenib which target the VEGF pathway
  • sunitinib and sorafenib which target the VEGF pathway
  • sunitinib and sorafenib which target the VEGF pathway
  • Ivy SP et al. An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol 2009; 6 (10): 569-79.
  • tumor cells and stroma non-tumor compartment mainly comprising of fibroblasts, pericytes, myeloid cells and mesenchymal stem cells
  • FGF-2 fibroblast growth factor (Casanovas O, et al. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer cell 2005;8(4):299-309)
  • Bv8 Bosina Variegata (Shojaei F, et al.
  • HGF hepatocytes growth factor/scatter factor
  • c-Met pathway is known to play a significant role in different stages of development and also in tumorigenesis (You WK, et al. The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB reports 2008; 41 (12): 833-9). While HGF is enriched in cells of mesenchymal origin, c-Met is also highly expressed in epithelial cells. c-Met has also been found to express in several other cell types including endothelial cells, neural cells, hematopoietic cells and pericytes.
  • c-Met and HGF have been identified in several cancer types such as bladder, breast, stomach, colon and renal (Peruzzi B, et al. Targeting the c-Met signaling pathway in cancer. Clin Cancer Res 2006; 12(12): 3657-60). It has been suggested that activation of c-Met results in proliferation, survival and increased invasiveness of tumor cells through signaling pathways such as PIK3/Akt, Src, STAT3 and Ras/Mek (Comoglio PM, et al. Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature reviews 2008; 7(6): 504-16; Maulik G, et al. Role of the hepatocyte growth factor receptor, c-Met, in oncogenesis and potential for therapeutic inhibition.
  • c-Met activation has been shown to induce tumor angiogenesis in the vasculature through paracrine HGF mainly by induction of proliferation, migration and survival of endothelial cells (Birchmeier C, et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003;4(12):915-25). It has also been shown that HGF promotes angiogenesis through upregulation of VEGF (a key angiogenic inducer) and also via downregulating thrombospondin-1 expression (a potent angiogenic inhibitor) (Zhang YW, et al.
  • Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation.
  • VEGF inhibitors have provided benefits for cancer patients. Similar to other anti-cancer agents, tumor recurrence has been one of the major challenges in patients treated with angiogenesis inhibitors. Recent reports in preclinical models suggest that activation of alternative angiogenic pathways in anti-VEGF treated tumors is one of the mechanisms of unresponsiveness to the therapy (Bergers G, et al. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 2008; 8(8): 592-603). In addition, two recent independent studies suggested that anti-angiogenic therapy may induce tumor progression and metastasis due to increased invasiveness of tumor cells (Ebos JM, et al.
  • the invention provides a method of treating cancer in a mammal in need of such treatment comprising the step of administering a therapeutically effective amount of a VEGF inhibitor and a therapeutically effective amount of c-Met/HGFR inhibitor.
  • the mammal is a human.
  • the cancer is selected from the group consisting of colon cancer, non-small cell lung cancer, melanoma, renal carcinoma, hepatocellular carcinoma, glioblastoma multiform, and pancreatic neuroendocrine neoplasms.
  • the VEGF inhibitor is selected from the group consisting of sunitinib, SU- 14813, PF-337210, bevacizumab, and axitinib. In some embodiments, the VEGF inhibitor is sunitinib. In some embodiments, the VEGF inhibitor is axitinib. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the VEGF inhibitor is SU-14813. In some embodiments, the VEGF inhibitor is PF-337210. In some embodiments, the c-Met/HGFR inhibitor is crizotinib or PF-04217903. In some embodiments, the c-Met/HGFR inhibitor is crizotinib.
  • the c- Met/HGFR inhibitor is PF-04217903.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is PF-04217903.
  • the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is PF- 04217903.
  • the VEGF inhibitor is bevacizumab and the c- Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is PF- 04217903. In some embodiments, the VEGF inhibitor is PF-337210 and the c- Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is PF- 337210 and the c-Met/HGFR inhibitor is PF-04217903.
  • the present invention provides a pharmaceutical composition comprising a VEGF inhibitor and a c-Met/HGFR inhibitor combined in an amount therapeutically effective for the treatment of cancer in a mammal.
  • the invention provides a method of treating cancer in a mammal in need of such treatment comprising the step of administering a pharmaceutical composition of the invention.
  • the cancer is selected from the group consisting of colon cancer, non-small cell lung cancer, melanoma, renal carcinoma, hepatocellular carcinoma, glioblastoma multiform, and pancreatic neuroendocrine neoplasms.
  • the VEGF inhibitor is selected from the group consisting of sunitinib, SU- 14813, PF-337210, bevacizumab, and axitinib. In some embodiments, the VEGF inhibitor is sunitinib. In some embodiments, the VEGF inhibitor is axitinib. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the VEGF inhibitor is SU-14813. In some embodiments, the VEGF inhibitor is PF-337210. In some embodiments, the c-Met/HGFR inhibitor is crizotinib or PF-04217903. In some embodiments, the c-Met/HGFR inhibitor is crizotinib.
  • the c- Met/HGFR inhibitor is PF-04217903.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is PF-04217903.
  • the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is PF- 04217903.
  • the VEGF inhibitor is bevacizumab and the c- Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is PF- 04217903. In some embodiments, the VEGF inhibitor is PF-337210 and the c- Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is PF- 337210 and the c-Met/HGFR inhibitor is PF-04217903.
  • the invention provides a method of inhibiting angiogenesis in a mammal comprising the step of administering a therapeutically effective amount of a VEGF inhibitor and a c-Met/HGFR inhibitor.
  • the mammal is a human.
  • the cancer is selected from the group consisting of colon cancer, non-small cell lung cancer, melanoma, renal carcinoma, hepatocellular carcinoma, glioblastoma multiform, and pancreatic neuroendocrine neoplasms.
  • the VEGF inhibitor is selected from the group consisting of sunitinib, SU-14813, PF-337210, bevacizumab, and axitinib.
  • the VEGF inhibitor is sunitinib. In some embodiments, the VEGF inhibitor is axitinib. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the VEGF inhibitor is SU-14813. In some embodiments, the VEGF inhibitor is PF-337210. In some embodiments, the c-Met/HGFR inhibitor is crizotinib or PF-04217903. In some embodiments, the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the c-Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is PF- 04217903. In some embodiments, the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is axitinib and the c- Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is PF-04217903.
  • the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is PF-337210 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is PF- 337210 and the c-Met/HGFR inhibitor is PF-04217903.
  • the invention provides a method of inhibiting angiogenesis in a mammal in need of such treatment comprising the step of administering a pharmaceutical composition of the invention.
  • the mammal is a human.
  • the cancer is selected from the group consisting of colon cancer, non-small cell lung cancer, melanoma, renal carcinoma, hepatocellular carcinoma, glioblastoma multiform, and pancreatic neuroendocrine neoplasms.
  • the VEGF inhibitor is selected from the group consisting of sunitinib, SU-14813, PF-337210, bevacizumab, and axitinib. In some embodiments, the VEGF inhibitor is sunitinib.
  • the VEGF inhibitor is axitinib. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the VEGF inhibitor is SU-14813. In some embodiments, the VEGF inhibitor is PF-337210. In some embodiments, the c-Met/HGFR inhibitor is crizotinib or PF-04217903. In some embodiments, the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the c-Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is PF- 04217903. In some embodiments, the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is axitinib and the c- Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is PF-04217903.
  • the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is PF-337210 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is PF- 337210 and the c-Met/HGFR inhibitor is PF-04217903.
  • the invention provides a method of treating metastatic cancer in a mammal in need of such treatment comprising the step of administering a therapeutically effective amount of a VEGF inhibitor and a c-Met/HGFR inhibitor.
  • the mammal is a human.
  • the cancer is selected from the group consisting of colon cancer, non-small cell lung cancer, melanoma, renal carcinoma, hepatocellular carcinoma, glioblastoma multiform, and pancreatic neuroendocrine neoplasms.
  • the VEGF inhibitor is selected from the group consisting of sunitinib, SU-14813, PF-337210, bevacizumab, and axitinib.
  • the VEGF inhibitor is sunitinib. In some embodiments, the VEGF inhibitor is axitinib. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the VEGF inhibitor is SU-14813. In some embodiments, the VEGF inhibitor is PF-337210. In some embodiments, the c- Met/HGFR inhibitor is crizotinib or PF-04217903. In some embodiments, the c- Met/HGFR inhibitor is crizotinib. In some embodiments, the c-Met/HGFR inhibitor is PF- 04217903.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is sunitinib and the c- Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is PF- 04217903. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is SU-14813 and the c- Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is PF- 337210 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is PF-337210 and the c-Met/HGFR inhibitor is PF-04217903.
  • the invention provides a method of inhibiting metastasis in a mammal in need of such treatment comprising the step of administering a therapeutically effective amount of a VEGF inhibitor and a c-Met/HGFR inhibitor.
  • the metastasis is in the lymph nodes.
  • the metastasis is in the colon.
  • the mammal is a human.
  • the cancer is selected from the group consisting of colon cancer, non- small cell lung cancer, melanoma, renal carcinoma, hepatocellular carcinoma, glioblastoma multiform, and pancreatic neuroendocrine neoplasms.
  • the VEGF inhibitor is selected from the group consisting of sunitinib, SU- 14813, PF-337210, bevacizumab, and axitinib. In some embodiments, the VEGF inhibitor is sunitinib. In some embodiments, the VEGF inhibitor is axitinib. In some embodiments, the VEGF inhibitor is bevacizumab. In some embodiments, the VEGF inhibitor is SU-14813. In some embodiments, the VEGF inhibitor is PF-337210. In some embodiments, the c-Met/HGFR inhibitor is crizotinib or PF-04217903. In some embodiments, the c-Met/HGFR inhibitor is crizotinib.
  • the c- Met/HGFR inhibitor is PF-04217903.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is sunitinib and the c-Met/HGFR inhibitor is PF-04217903.
  • the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is crizotinib.
  • the VEGF inhibitor is axitinib and the c-Met/HGFR inhibitor is PF- 04217903.
  • the VEGF inhibitor is bevacizumab and the c- Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is bevacizumab and the c-Met/HGFR inhibitor is PF-04217903. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is SU-14813 and the c-Met/HGFR inhibitor is PF- 04217903. In some embodiments, the VEGF inhibitor is PF-337210 and the c- Met/HGFR inhibitor is crizotinib. In some embodiments, the VEGF inhibitor is PF- 337210 and the c-Met/HGFR inhibitor is PF-04217903. Brief Description of the Drawings
  • Figure 1 Identification of cell lines resistance or sensitive to Sunitinib treatment.
  • FIG. 1A B16F1 (Fig. 1A) and Tib6 (Fig. 1 B) tumors are sensitive to Sunitinib and EL4 (Fig. 1 C) and LLC (Fig. 1 D) tumors were found to be resistant to such therapy.
  • Fig. 1 E & 1 F Inhibition of PDGF-R, CSF-1 R and c-Kit pathways does not provide any advantage in tumor growth inhibition compared to inhibition of VEGF alone.
  • Tumor growth inhibition in EL4 (Fig. 1 E) or LLC (Fig. 1 F) is completely similar between Sunitinib vs. axitinib.
  • Figure 2 Endothelial cells, but not tumor cells, are mainly targeted by HGF/c-Met axis. HGF measurement in the sera (Fig.
  • Fig. 2A and tumors (Fig. 2B) in both vehicle- and Sunitinib- treated tumors. Bars represent mean concentration of HGF in Sunitinib or vehicle treated tumors + SEM.
  • Fig. 2C HGF is mainly expressed in stromal compartment in the tumor mass.
  • Fig. 2D c-Met is mainly expressed in endothelial cells. Images are the representative histograms from each line comparing c-Met expression (red line) vs. isotype control (black line). While tumor cells have minimal expression of c- Met, it is highly enriched in endothelial cells.
  • FIG. 3 Proliferation of endothelial cells, but not tumor cells, is induced by HGF.
  • Tumor cells B16F1 , Tib6, EL4, LLC; Fig. 3A
  • endothelial cells HGF and VEGF.
  • Cells were treated with three different concentrations (10 ng/ml; 100 ng/ml and 200 ng/ml) of HGF and VEGF. After 4 days incubation, cells were counted using a Coulter Counter Machine. Asterisks are indicative of a significant difference in HGF- or VEGF- treated cells vs. PBS.
  • FIG. 5 Inhibition of angiogenesis is one of the mechanisms by which combination treatment affects tumor growth.
  • Vascular quantification in the resistant or sensitive tumors Fig. 5A. Images of CD31 staining were selected from each section (four image from each section and up to twenty four images in total) and vascular density was calculated by dividing the signal intensity of CD31 + pixels to entire area of the image. Bars represent mean vascular density + SEM.
  • Asterisks indicate significant difference (p ⁇ 0.05) when comparing Sunitinib to combination treatment (Fig. 5B & 5C). Endothelial cells, but not tumor cells, are sensitive to combination treatment using Sunitinib and PF-04217903. Data are the representative of one of two independent studies. Asterisks indicate significant differences when comparing Sunitinib alone to the vehicle and ⁇ indicates significant difference when comparing cell number in combination treatment vs. Sunitinib or PF-04217903 at corresponding concentration.
  • Figure 6 Effectiveness of single agent and combination treatment on primary versus metastatic tumor growth in H460 lung orthotopic tumors.
  • GFP-images Fig. 6A
  • Fig. 6B terminal tumor weight
  • Figure 6C Analysis of metastasis in the lung or in the lymph nodes ( Figure 6C) suggested that sunitinib does not inhibit tumor metastasis, however, crizotinib or combination treatment reduced the onset of metastasis.
  • Figure 7 Effectiveness of single agent and combination treatment on primary versus metastatic tumor growth in Colo205 colon orthotopic tumors. GFP images (Fig.
  • abnormal cell growth refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition).
  • treating means reversing, alleviating, or inhibiting the progress of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of treating as “treating” is defined immediately above.
  • angiogenesis inhibitor includes any substance that inhibits the growth of new blood vessels (i.e angiogenesis).
  • An angiogenesis inhibitor can be any substance that acts by binding/inhibiting VEGF, inhibiting bFGF, inhibiting cell proliferation, cell migration and survival of endothelial cells, inducing apoptosis of endothelial cells, activating of the immune system, downregulating angiogenesis stimulators, stimulating angiogenesis inhibitor formation, inhibiting basement membrane degradation, and the like.
  • Metastasis means the spread of a disease, here cancer or abnormal cell growth, from one organ or part to another non-adjacent organ or part.
  • Metastasis can be local metastasis in which some cancer cells originating from the primary tumor acquire the ability to penetrate and infiltrate surrounding normal tissues in the local area, forming a new tumor (sometimes referred to as the "daughter" tumor).
  • Metastasis also can be lymphatic spread in which some cancer cells originating from the primary tumor acquire the ability to penetrate the walls of lymphnodes or the lymphatic vessels, after which they are able to circulate through the bloodstream (sometimes referred to as "circulating tumor cells”) to other sites and tissues in the body.
  • Metastasis as used herein, also can be hematogeneous spread in which some cancer cells originating from the primary tumor acquire the ability to penetrate the walls of blood vessels, after which they are able to circulate through the bloodstream (sometimes referred to as "circulating tumor cells") to other sites and tissues in the body.
  • the metastasis process can be any known process involving the proliferation of cancer cells in another part of the body, another organ or in another tissue. For example, after tumor cells from a primary tumor come to rest at another site, the cell can re-penetrate through the vessel or walls, continue to multiply, and eventually form another clinically detectable tumor.
  • the new tumor is called a secondary or metastatic tumor, and its cells are like those in the original tumor.
  • the secondary tumor is made up of abnormal breast cells, not of abnormal lung cells.
  • the tumor in the lung is then called metastatic breast cancer, not lung cancer.
  • sites for metastases include but are not limited to the lungs, liver, brain, and bones.
  • VEGF inhibitor includes any substance that inhibits or binds to VEGF or VEGF-R.
  • references herein to VEGF inhibitors used in the include references to pharmaceutically acceptable salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of pharmaceutically acceptable salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.
  • one preferred VEGF inhibitor is sunitinib which as used herein refers to sunitinib malate (i.e. Sutent ® ) and also the freebase of sunitinib and any other pharmaceutically acceptable salt of sunitinib.
  • a preferred VEGF inhibitor is sunitinib, 5-(5-fluoro-2-oxo-1 ,2-dihydroindol-(3Z)- ylidenemethyl)-2,4-dimethyl-1 H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide, represented by formula
  • Sunitinib targets multiple receptor tyrosine kinase inhibitors, including PDGFR, KIT and VEGFR, and is a potent and selective anti-angiogenesis agent.
  • Sunitinib or its L-malate salt is also referred to as SU1 1248, SU01 1248, sunitinib malate (USAN/WHO designation) or SUTENTTM (L-malate salt).
  • the term "sunitinib” includes 5-(5-fluoro-2-oxo-1 ,2-dihydroindol-(3Z)-ylidenemethyl)-2,4-dimethyl-1 H-pyrrole-3- carboxylic acid (2-diethylaminoethyl)-annide, its pharmaceutically acceptable salts, including the L-malate salt, and SUTENTTM
  • Sunitinib its synthesis, and particular polymorphs are described in U.S. Patent Nos. 6,573,293, 7,435,832 and 7,125,905; U.S. Patent Publication Nos. 2003-0229229, and 2005-0059824, and in J.M. Manley, M.J. Kalman, B.G. Conway, C.C. Ball, J.L. Havens and R. Vaidyanathan, "Early Amidation Approach to 3-[(4-amido)pyrrol-2-yl]-2- indolinones," J. Org. Chem. 68, 6447-6450 (2003).
  • Preferred formulations of sunitinib and its L-malate salt are described in U.S.
  • Patent Publication 2004-0229930 and in PCT Publication No. WO2004/024127 Preferred dosing regimens are described in U.S. Patent Publication 2005-0182122 and in PCT Publication No. WO 2006/120557. The disclosures of these references are incorporated herein by reference in their entireties.
  • VEGF inhibitors include, but are not limited to, axitinib, 6-[2- (methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole, AG-13676, (Pfizer Inc.) having the structure
  • RTKs receptor tyrosine kinases
  • SU-14813 is an inhibitor of VEGF, PDGFRa and PDGFR , KIT, and FLT3, and is described in U.S. Patent Nos. 6,653,308 and 7,247,627, as well as in some of the references cited for sunitinib, the disclosures of which are incorporated herein in their entireties.
  • PF-337210 N,2-dimethyl-6-(7-(2-morpholinoethoxy)quinoline-4-yloxy)benzofuran-3-carboxamide (Pfizer Inc.) having the structure
  • VEGF inhibitors include, but are not limited to, Avastin (bevacizumab, Genentech), an anti-VEGF monoclonal antibody, and VEGF inhibitors described in, for example, US Patent No. 6,534,524, 5,834,504, 5,883,1 13, 5,886,020, 5,792,783, 6,653,308 and 6,235,764, each of which is incorporated by reference in its entirety for all purposes, and in WO 99/24440, WO 95/21613, WO 99/61422, WO 98/50356, WO 99/10349, WO 97/32856, WO 97/22596, WO 98/54093, WO 98/02438, WO 99/16755, and WO 98/02437, all of which are herein incorporated by reference in their entirety.
  • c-l Met/HGFR inhibitor includes any substance that inhibits or binds to c-Met or its ligand, HGFR. Unless indicated otherwise, all references herein to c-Met/HGFR inhibitors include references to pharmaceutically acceptable salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of pharmaceutically acceptable salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.
  • a particularly preferred c-Met/HGFR inhibitor is crizotinib, (R)-3-(1 -(2,6-dichloro-3- fluorophenyl)ethoxy)-5-(1 -(piperidin-4-yl)-1 H-pyrazol-4-yl)pyridins-2-amine, represented by formula
  • Crizotinib targets protein tyrosine kinases including c-Met/HGFR and ALK. Crizotinib is also referred to as PF-02341066.
  • crizotinib includes (R)-3-(1 -(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1 -(piperidin-4-yl)-1 H-pyrazol-4- yl)pyridin-2-amine, and its pharmaceutically acceptable salts.
  • c-Met/HGFR inhibitor is PF-04217903, 2-(4-(3- (quinolin-6-ylmethyl)-3H-[1 ,2,3]triazolo[4,5-b]pyrazin-5-yl)-1 H-pyrazol-1 -yl)ethanol, represented by formula
  • Crizotinib targets protein tyrosine kinases including c- Met/HGFR and ALK.
  • PF-04217903 includes (R)-3-(1 -(2,6- dichloro-3-fluorophenyl)ethoxy)-5-(1 -(piperidin-4-yl)-1 H-pyrazol-4-yl)pyridin-2-amine, and its pharmaceutically acceptable salts including its phosphate salt.
  • c-Met/HGFR inhibitors useful in the practice of the present invention include but are not limited to AMEP (Bioalliance), EMD-1204831 (Merck KgaA/EMD Serono), INCB-028060 (Incyte/Novartis), ARQ197 (ArQule), AMG102 (Amgen) and RG-3638 (Roche/Genentech), and those described in WO2007/0265272, WO2009/068955, WO2006/086484, WO2005/030140, WO2008/051808, US Patent 4,923,986, US Patent 7,713,969, US Patent 7,579,473, all of which are herein incorporated by reference in their entirety.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/d
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • a pharmaceutically acceptable salt of the inventive compounds can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • the compounds of the invention may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when the solvent is water.
  • Pharmaceutically acceptable solvates in accordance with the invention include hydrates and solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d6-acetone, d6-DMSO.
  • the invention also includes isotopically-labeled compounds, which are identical to the VEGF inhibitors and c-Met inhibitors described herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • An isotopically labeled compound can generally be prepared by carrying out the procedures described for the non-labeled compound, substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts.
  • complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
  • the resulting complexes may be ionized, partially ionized, or non-ionized.
  • VEGF inhibitors used in the include references to pharmaceutically acceptable salts, solvates, hydrates and complexes thereof, and to solvates, hydrates and complexes of pharmaceutically acceptable salts thereof, including polymorphs, stereoisomers, and isotopically labeled versions thereof.
  • PDGFR- ⁇ , CSF-1 R, c-Kit and Flt3 in preclinical models and identified tumors that were resistant/sensitive to the therapy. Analysis of protein lysates in the resistant or sensitive tumors found a greater expression for HGF in the former. Combination treatment using highly selective c-Met inhibitors (PF-04217903 and crizotionib (PF-02341066)) and sunitinib provided additive effect in inhibiting tumor growth compared to either single agent. These results indicated a functional role for HGF/c-Met axis in the sunitinib- resistant tumors.
  • sunitinib which is clinically approved for metastatic RCC (renal cell carcinoma) and imatinib-resistant GIST (gastro-intestinal stromal tumor), and is in several trials for multiple tumor types including lung, colon and breast cancers (Smith JK, et al. Emerging roles of targeted small molecule protein- tyrosine kinase inhibitors in cancer therapy. Oncology research 2004;14(4-5): 175-225; van der Veldt AA, et al. Sunitinib for treatment of advanced renal cell cancer: primary tumor response. Clin Cancer Res 2008;14(8):2431 -6).
  • a c-Met inhibitor can be potentially added to a VEGF inhibitor as part of the therapeutic regimen in any tumor type where sutent treatment results in the activation of c-Met pathway via: i) HGF upregulation and/or; ii) c-Met receptor over expression and/or; iii) c-Met receptor activation.
  • Cancers for which the present invention may find particular application include but are not limited to colon cancer, non-small cell lung cancer, melanoma, renal carcinoma, hepatocellular carcinoma, glioblastoma multiform, and pancreatic neuroendocrine neoplasms.
  • Compounds suitable for use in connection with the present invention may be administered in any manner that provides benefit to the patient.
  • Different combinations of c-Met/HGFR inhibitors and VEGF inhibitors may require variation in administration routes and dosing regimens.
  • Different cancer types may also require variation in administration routes and dosing regimens.
  • the invention contemplates all variations in administration based on any combination of factors, such as, the type of cancer being treated, the c-Met/HGFR inhibitor being administered, the VEGF inhibitor being administered, the preferred dosing regimen of the c-Met/HGFR inhibitor being administered, the preferred dosing regimen of the VEGF inhibitor being administered, or the needs of the patient being treated.
  • Sequential administration can include administering a VEGF inhibitor followed by administering a c-Met/HGFR inhibitor.
  • Sequential administration can include administering a c-Met/HGFR inhibitor followed by administering a VEGF inhibitor.
  • Sequential administration can be based on the preferred dosing regimen of either the c-Met/HGFR inhibitor or the VEGF inhibitor.
  • the sequential administration can readily be adjusted based on any one or more of the cancer being treated, the c-Met/HGFR inhibitor being administered, the VEGF inhibitor being administered, the preferred dosing regimen of the c-Met/HGFR inhibitor being administered, the preferred dosing regimen of the VEGF inhibitor being administered, or the patient's needs.
  • Compounds suitable for use in connection with the present invention may be administered by concomitant administration of a VEGF inhibitor and a c-Met/HGFR inhibitor.
  • Concomitant administration can be in the form of a single pharmaceutical composition containing a combination at least one c-Met/HGFR inhibitor and at least one VEGF inhibitor, or simultaneous dosing of at least one c-Met/HGFR inhibitor and at least one VEGF inhibitor administered by different routes of administration, pharmaceutical compositions, or different dosing vehicles.
  • Routes of administration can include, but are not limited to any of oral administration, parenteral administration, topical administration, inhaled/intranasal administration, rectal/intravaginal administration, ocular administration, or any other route of administration known to one of skill in the art.
  • the route of administration may be the same or different for c-Met/HGFR inhibitors and VEGF inhibitors useful in connection with the invention.
  • Compounds suitable for use in connection with the present invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid- filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films (including muco-adhesive), ovules, sprays and liquid formulations.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be used as fillers in soft or hard capsules and typically include a pharmaceutically acceptable carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents.
  • Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981 -986 by Liang and Chen (2001 ), the disclosure of which is incorporated herein by reference in its entirety.
  • the drug may make up from 1 wt% to 80 wt% of the dosage form, more typically from 5 wt% to 60 wt% of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate.
  • the disintegrant will comprise from 1 wt% to 25 wt%, preferably from 5 wt% to 20 wt% of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation.
  • Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • Tablets may also optionally include surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents are typically in amounts of from 0.2 wt% to 5 wt% of the tablet, and glidants typically from 0.2 wt% to 1 wt% of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally are present in amounts from 0.25 wt% to 10 wt%, preferably from 0.5 wt% to 3 wt% of the tablet.
  • compositions include anti-oxidants, colorants, flavoring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80 wt% drug, from about 10 wt% to about
  • 90 wt% binder from about 0 wt% to about 85 wt% diluent, from about 2 wt% to about 10 wt% disintegrant, and from about 0.25 wt% to about 10 wt% lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tableting.
  • the final formulation may include one or more layers and may be coated or uncoated; or encapsulated.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1 -14 (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298. The disclosures of these references are incorporated herein by reference in their entireties.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including micro needle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of compounds of the invention used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and PGLA microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol .
  • Penetration enhancers may be incorporated; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999).
  • Topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Inhaled/lntranasal Administration
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist), or nebulizer, with or without the use of a suitable propellant, such as 1 ,1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • the powder may include a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as /-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ _ to 10 ⁇ _.
  • a typical formulation includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing a desired mount of the compound of the invention.
  • the overall daily dose may be administered in a single dose or, more usually, as divided doses throughout the day.
  • Compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and nonbiodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-l inked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • Formulations for ocular/aural administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, or programmed release.
  • Compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubilizer. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in PCT Publication Nos. WO 91/1 1 172, WO 94/02518 and WO 98/55148, the disclosures of which are incorporated herein by reference in their entireties.
  • an effective dosage is typically in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.07 to about 7000 mg/day, preferably about 0.7 to about 2500 mg/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be used without causing any harmful side effect, with such larger doses typically divided into several smaller doses for administration throughout the day.
  • kits suitable for coadministration of the compositions may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
  • the kit of the invention includes two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically includes directions for administration and may be provided with a memory aid.
  • Nude mice were purchased from Jackson (ME, USA) or Charles Rivers laboratories (MA, USA) and were maintained under guidelines provided by the Pfizer IACUC (Institutional Animal Care and Use Committee). All the tumor cell lines in the current study were obtained from ATCC (American Tissue Culture Collection; Manassas, VA) and were cultured in RPMI 1640 (Invitrogen, CA) supplemented with glutamine (2 mM) and fetal bovine serum (FBS; 10%). For implantation, tumor cells (1x10 6 cells per mouse) were resuspended in 100 ⁇ media and 100 ⁇ matrigel growth factor reduced (BD Biosciences, CA) and were s.c implanted in one of the flanking areas.
  • ATCC American Tissue Culture Collection; Manassas, VA
  • RPMI 1640 Invitrogen, CA
  • FBS fetal bovine serum
  • tumor cells (1x10 6 cells per mouse) were resuspended in 100 ⁇ media and 100 ⁇ matrigel growth factor reduced (
  • Tumor bearing mice were treated once a day with Sunitinib at 80 mg/kg or PF- 04217903 (45 mg/kg) or the combination of both compounds using oral route of administration. Tumors volumes were assessed using caliper measurement as described (Zou HY, et al. An orally available small-molecule inhibitor of c-Met, PF- 2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer research 2007;67(9):4408-17).
  • HUVECs human umbilical vein endothelial cells
  • C166 cells were purchased from Lonza Inc. (Lonza, CA) and ATCC respectively.
  • HUVECs were grown in EBM2 media supplemented with a cocktail of growth factors provided by the supplier (Lonza Inc, Lonza CA) and C166 were grown in DMEM (Invitrogen, CA) supplemented with FBS (10%).
  • DMEM Invitrogen, CA
  • Tumors samples were snap frozen in liquid nitrogen and were kept at -70°C. Total protein from each sample was extracted and was quantified using BCA protein assay (Pierce, IL). Levels of HGF and total Met in the tumors and serums were measured by ELISA kits (R&D System, CA) using protocols provided by the manufacturer. Similar methodology was applied to measure levels of HGF in the conditioned-media or in the tumor lysates.
  • PBMNCs Peripheral blood mononuclear Cells
  • Both tumor cells and PBMNCs were stained with anti-mouse CD1 1 b-APC (BD Biosciences, CA) and anti-mouse Gr1 -PE (BD Biosciences, CA) for 30 min at 4°C followed by washing twice with PBS-FBS (3%).
  • HGF is differentially expressed in the resistant tumors and mainly targets endothelial cells
  • NIH3T3 cells were found to be highly enriched in HGF in both protein lysates and conditioned media.
  • HGF mainly targets endothelial cells
  • tumor cells B16F1 , Tib6, EL4, LLC
  • endothelial cells HGF and VEGF
  • Neither VEGF nor HGF affected cellular proliferation in the tumor cells (Fig. 3A).
  • both growth factors promoted proliferation of endothelial cells (Fig. 3B).
  • Example 4 Efficacy of combination treatment (sunitinib plus PF-04217903) in sensitive or resistant tumors
  • PF-04217903 monotherapy did not inhibit tumor growth in any of the sensitive tumors indicative of lack of activation of c-Met pathway in these tumors.
  • lack of response to PF- 04217903 monotherapy may also signify a role for the VEGF pathway in tumor growth.
  • growth of both resistant tumors EL4; Fig 4C and LLC; Fig. 4D
  • Example 5 Example 5:
  • vasculature was analyzed in both sensitive and resistant tumors (Fig. 5A). Images of CD31 staining were selected from each section (four image from each section and up to twenty four images in total) and vascular density was calculated by dividing the signal intensity of CD31 + pixels to entire area of the image. In the sensitive tumors, Sunitinib significantly (p ⁇ 0.05) reduced the vascular density, as measured by CD31 positive areas, compared to the vehicle-treated tumors. However, combination treatment did not affect vascular density in sunitinib as single agent vs. the combination regimen.
  • Inhibition of c-Met by PF-04217903 did not significantly alter the vasculature in either sensitive or resistant tumors further signifying role of VEGF in promoting tumor growth and angiogenesis.
  • sunitinib inhibited the vasculature compared to the vehicle-treated tumors.
  • combination therapy significantly reduced vascular surface areas compared to sunitinib alone in the resistant tumors.
  • tumor cells B16F1 , Tib6, EL4, LLC; Fig. 5B
  • endothelial cells HAVECs and C166; Fig. 5C
  • Sunitinib, PF-04217903 or the combination of both compounds were added to each well at three different concentrations including 2 ⁇ , 0.2 ⁇ and 0.02 ⁇ .
  • Cells were incubated in a cell-incubator for 4 days and were counted in Coulter Counter Machine as described. While Sunitinib and the combination significantly inhibited endothelial cells proliferation at pharmacologically relevant concentrations (Fig. 5B), tumor cells were not affected by either agent or the combination (Fig. 5C).
  • Example 6 Combination of Sunitinib and PF-02341066 inhibits metastasis in orthtotopic tumors in H460 NSCLC (non-small cell lung cancer)
  • tumor stocks were generated by subcutaneously implanting nude mice with H460-GFP cells (1 x10 6 cells per mouse). Tumors were harvested from subcutaneous implants at log phase and were maintained in RPMI-1640 medium (Sigma-Alrdrich). Necrotic tumors were removed from the media and viable tissues were cut into pieces of 2-2.5 cm 2 . Recipient mice were anesthetized with isoflurane and the area of surgery was disinfected with iodine and alcohol. Left chest wall of the animals was transversely incised followed by an intercostal incision between the 3 rd and 4 th costal in the left lung.
  • Example 7 Combination of sunitinib and PF-02341066 inhibits metastasis in orthtotopic tumors in COLO205 colorectal tumors
  • Nude mice were subcutaneously implanted with Colo205-GFP cells (5x10 6 cells per mouse) to generate stock tumors. Mice were euthanized when tumor growth reached log phase. Tumor chunks were isolated and maintained in RPMI 1640 medium (Sigma-Aldrich) to remove necrotic tumors and to maintain viable tissues for intracecal implantation. The surgical areas in the recipients were sterilized using iodine and alcohol and mice were anesthetized with a mixture of Ketamine, Acepromazine and Xylazine. For intracecal implantation, the left middle abdomen of nude mice were cut for about 1 cm and the colon serosa was removed to allow implantation of two pieces of tumors (each 2-2.5 cm 2 ). To close the abdominal cavity, abdominal muscles and skin were stiched separately using silk sutures. The entire procedure was carried in the laminar flow hood and under a dissecting microscope.
  • mice Orthotopically-implanted mice were allowed to recover from surgical intervention for about 72 hrs and treatment started when tumors reached 75-100 mm 3 .
  • Mice were divided into 4 groups and were administered with therapeutic compounds including Vehicle, Sunitinib, PF-02341066, and a combination of Sunitinib and PF-02341066.
  • Treated-animals were GFP-imaged every week and the study was terminated 14 weeks after tumor implantation.
  • the FluorVivo imaging system (Indec Biosystems) was used to measure tumor size by calculating perpendicular minor dimension (W, width) and major dimension (L, length).

Abstract

La présente invention concerne l'utilisation d'inhibiteurs de c-Met/HGFR et VEGF pour le traitement de la croissance cellulaire anormale chez les mammifères. L'invention concerne en particulier des procédés de traitement de mammifères souffrant d'un cancer. L'invention concerne en particulier le traitement de mammifères souffrant d'un cancer métastatique. L'invention concerne en particulier des procédés d'inhibition d'un cancer métastatique. L'invention concerne en particulier une polythérapie alliant sunitinib et crizotinib ou PF-04217903.
PCT/IB2011/054042 2010-09-29 2011-09-15 Procédé de traitement de la croissance cellulaire anormale WO2012042421A1 (fr)

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