WO2015069266A1 - Méthodes d'inhibition de la kinase tie2 utiles dans le traitement du cancer - Google Patents

Méthodes d'inhibition de la kinase tie2 utiles dans le traitement du cancer Download PDF

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WO2015069266A1
WO2015069266A1 PCT/US2013/069005 US2013069005W WO2015069266A1 WO 2015069266 A1 WO2015069266 A1 WO 2015069266A1 US 2013069005 W US2013069005 W US 2013069005W WO 2015069266 A1 WO2015069266 A1 WO 2015069266A1
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formula
composition
combination
methods
agent
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PCT/US2013/069005
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Daniel L. Flynn
Michael D. Kaufman
Bryan Smith
Marc S. RUDOLTZ
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Flynn Daniel L
Kaufman Michael D
Bryan Smith
Rudoltz Marc S
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Priority to CN201810436668.9A priority Critical patent/CN108464981B/zh
Priority to CN201380081931.2A priority patent/CN105873440B/zh
Priority to CA2929715A priority patent/CA2929715A1/fr
Priority to JP2016552405A priority patent/JP6568093B2/ja
Priority to EP13896951.4A priority patent/EP3065549A4/fr
Priority to PCT/US2013/069005 priority patent/WO2015069266A1/fr
Application filed by Flynn Daniel L, Kaufman Michael D, Bryan Smith, Rudoltz Marc S filed Critical Flynn Daniel L
Priority to AU2013404949A priority patent/AU2013404949B2/en
Priority to KR1020217015635A priority patent/KR20210063475A/ko
Priority to KR1020167014649A priority patent/KR20160070188A/ko
Publication of WO2015069266A1 publication Critical patent/WO2015069266A1/fr
Priority to AU2019200261A priority patent/AU2019200261A1/en
Priority to AU2021200113A priority patent/AU2021200113A1/en

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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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to methods of inhibiting TIE2 kinase useful in the treatment of tumor growth, tumor invasiveness, tumor intravasation, tumor dissemination, tumor metastasis, and tumor immunotolerance. Specifically, the invention relates to methods of using compositions of Formula I herein described as potent inhibitors of TIE2 for treating breast cancer growth, invasiveness, intravasation dissemination, metastasis, and immunotolerance.
  • TIE2 Tunica interna endothelial cell kinase-2 (TIE2) is largely restricted to expression in endothelial cells of the vasculature, and in a subset of bone marrow derived TIE2 expressing monocytes (TEMs).
  • TIE2 is the receptor for angiopoietin 1 (ANG1), angiopoietin 2 (ANG2), and angiopoietin 4 (ANG4) and this signaling system plays an important role in both angiogenesis (sprouting of new vessels from existing vessels) and vasculogenesis (de novo new vessel formation).
  • ANG1 angiopoietin 1
  • ANG2 angiopoietin 2
  • ANG4 angiopoietin 4
  • TEMs are a subset of circulating monocytes and tissue macrophages that have proangiogenic and provasculogenic activity in tumor models (De Palma MD et al, Cancer Cell 2005; 8:211-226). TIE2 inhibition decreases the ability of TEMs to associate with blood vessels (Mazzieri R, Cancer Cell 2011 ; 19:512-526) and markedly decreases the proangiogenic activity of this macrophage subset (De Palma M, Clin Cancer Res 201 1; 17(16):5226-5232). [0004] Cytotoxic chemotherapy, radiation therapy, and anti-angiogenic treatments damage the tumor-associated vasculature thus leading to a hypoxic tumor environment.
  • the hypoxic tumor environment leads to rebound tumor vascularization by activating an angiogenic switch from the vascular endothelial growth factor (VEGF)/VEGFR2 pathway to the ANG/TIE2 pathway in vascular endothelial cells.
  • VEGF vascular endothelial growth factor
  • the recruitment of pro-vasculogenic TEMs from the bone marrow to these hypoxic tumor sites facilitates this revascularization by the association of TEMs with endothelial cells within the tumor microenvironment.
  • TEMs and TIE2-expressing endothelial cells are thus believed to play an important role in the revascularization of tumors after these treatments, leading to progression due to the growth of residual tumor cells (De Palma M, et al. Trends Immunol 2007; 28:519-524).
  • TIE2 is also a mediator of osteoclast differentiation, and TIE2 inhibition led to decreased osteolytic bone invasion and decreased tumor growth in the 4T1 mouse breast cancer model (Dales JP, et al. Int J Oncol 2003; 22:391 -397 ). Beyond the physiologic expression of TIE2 on endothelial, monocyte/macrophage, and osteoclast cells of the tumor microenvironment, TIE2 has also been demonstrated to be present on breast cancer cells. Tumor cell expression of TIE2 was associated with an elevated risk of metastatic disease and an independent predictor of prognosis on multivariate analysis (Min Y, et al. Cancer Res 2010; 70:2918-2828).
  • TIE2-expressing tissue macrophages are located within specialized vascular structures known as tumor microenvironment for metastases (TMEMs).
  • TMEMs tumor microenvironment for metastases
  • TIE2-expressing tissue macrophages have recently been demonstrated to play a role in breast cancer immunotolerance.
  • TEMs from breast tumors are able to suppress tumor-specific immune responses.
  • suppressive functions of TEMs are similarly driven by TIE2 and VEGFR kinase activity.
  • TEMs isolated from breast cancer tissue can function as antigen-presenting cells that elicit only a weak proliferation of T cells.
  • Blocking TIE2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells with robust antigen-presentation.
  • Immunosuppressive activity of TEMs is also associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors.
  • TIE2 and VEGFR kinase activities were required to maintain high CD86 surface expression levels and to convert T cells into immunosuppressive regulatory cells (Ibberson M, et al. Clin Cancer Res 2013; 19:3439-3449).
  • the polyoma middle-T antigen (PyMT) syngeneic mouse breast cancer model utilizes the mouse mammary tumor virus (MMTV) promoter, a breast specific promoter, to express PyMT in mouse breast tissue.
  • MMTV mouse mammary tumor virus
  • PyMT breast cancer cells are implanted in the mouse mammary fat pad, and these cancers metastasize and lead to the death of the mouse.
  • the PyMT model utilizes fully immunocompetent mice. Metastasis in this model is known to be modulated by TIE2 expressing macrophages within TMEM vascular structures.
  • Methods of the present invention find utility in the inhibition TIE2 kinase.
  • the present invention is useful in the treatment or prophylaxis against of tumor growth, invasiveness, intravasation, dissemination, metastasis, and tumor immunotolerance.
  • the invention relates to methods of using compositions of Formula I, described below, as potent inhibitors of TIE2 for treating breast cancer growth, invasiveness, intravasation, dissemination, metastasis, and immunotolerance:
  • n is an integer from 0 to 7;
  • X is the basic radical of a pharmaceutically acceptable salt
  • composition of Formula I is the parent free base.
  • HX is absent whereby the structure of Formula I is the parent free base.
  • compositions of Formula I also find utility in other cancers wherein TIE2 expression, either in the tumor cell or in the tumor microenvironment, causes tumor progression by mechanisms mediating primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance.
  • Inhibition of TIE2 kinase by the composition of Formula I therefore finds utility in the treatment of cancer by inhibiting processes including primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance.
  • TIE2 kinase has been shown to be causative of cancer progression in gliomas (Liu et al, Oncotarget (2010) 1 : 700-709; Brunckhorst et al, Cancer Research (2010) 70: 7283-7293), melanomas (Helfrich et al, Clin Cancer Res (2009) 15: 1384-1392 ), ovarian cancer (Karlan et al, J.
  • Figure 1 shows the inhibition of primary PyMT tumor growth using the composition of Formula II , paclitaxel, or a combination thereof.
  • Figure 2 shows the inhibition of PyMT tumor macrophage accumulation using the composition of Formula II, paclitaxel, or a combination thereof.
  • Figure 3 shows the inhibition of PyMT tumor TIE2-expressing cell accumulation using the composition of Formula II, paclitaxel, or a combination thereof.
  • Figure 4 shows the inhibition of lung metastases in the PyMT breast cancer model using the composition of Formula II, paclitaxel, or a combination thereof.
  • Figure 5 shows the inhibition of lung metastases in the PyMT breast cancer model comparing the activities of paclitaxel and the combination of paclitaxel and the composition of Formula II.
  • Figure 6 shows the inhibition of lung metastases in the PyMT breast cancer model using eribulin as a single agent or in combination with the composition of Formula II.
  • Figure 7 shows enzymatic and in vivo activities of eribulin as a single agent or in combination with the composition of Formula II.
  • Formula I include, without limitation, water-soluble and water-insoluble salts, such as substituted or unsubstituted benzenesulfonate , the acetate, amsonate (4,4-diaminostilbene-2, 2 -disulfonate), benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafiuorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laur
  • polygalacturonate propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.
  • specific examples of the basic radicals include para-toluene sulfonate, trifiate, and methanesulfonate .
  • salt refers to pharmaceutically acceptable salts
  • compositions of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base.
  • treating refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.
  • administer refers to either directly administering a composition or pharmaceutically acceptable salt of the compound or a composition to a subject, or administering a prodrug derivative or analog of the composition or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • an "effective amount,” when used in connection with medical uses is an amount that is effective for providing a measurable treatment, prevention, or reduction in the rate of pathogenesis of a disease of interest.
  • the present invention relates to methods of the treatment (blocking) or prophylaxis against tumor growth, invasiveness, intravasation, dissemination, metastasis, and tumor immunotolerance.
  • the method comprises administering to a patient in need of treatment or reduction of prophylactic effects of these conditions an effective amount of a composition of Formula I herein described in a dosing regimen that regulates TIE2 inhibition.
  • compositions described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose.
  • therapeutic agents e.g. compositions of Formulae I or II (and/or additional agents) described herein
  • the therapeutic agents are given at a pharmacologically effective dose.
  • a “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease.
  • An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease.
  • administration of therapeutic agents to a patient suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival.
  • Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
  • the composition of Formula I is l-(3-tert-butyl- 1 -(quinolin-6-yl)- 1 H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea para-toluene sulfonic acid salt of Formula II which is a potent inhibitor of TIE2, the receptor tyrosine kinase for angiopoietin ligands.
  • compositions of Formula I find utility in cancers wherein TIE2 expression, either in the tumor cell or in the tumor microenvironment, causes tumor progression by mechanisms mediating primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance.
  • Inhibition of TIE2 kinase by the composition of Formula I therefore finds utility in the treatment of cancer by inhibiting processes including primary tumor growth, primary tumor invasiveness, tumor intravasation into the blood stream, tumor cell dissemination, tumor metastases to distal tissues, or tumor immunotolerance.
  • compositions of Formula I block cells within the tumor microenvironment known to cause tumor growth, invasion, intravasation, dissemination, metastases, of tumor induced immunotolerance. Such cell types within the tumor
  • microenvironment include TIE2-expressing monocytes, TIE2-expessing macrophages, and TIE2-expressing endothelial cells.
  • Tumors responsive to angiopoietin/TIE2 signaling include but are not limited to breast cancer, ovarian cancer, hepatocellular carcinoma, gliomas, colorectal cancer, and hematological malignancies.
  • composition of Formula I when the HX is absent is the free base compound l -(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea having the structure:
  • composition of Formula I may be administered as a single agent or in combination with other therapeutic agents known to treat cancers.
  • other therapeutic agents include radiation therapy, anti-tubulin agents, DNA alkylating agents, DNA synthesis-inhibiting agents, DNA intercalating agents, anti-estrogen agents, anti-androgens, steroids, anti-EGFR agents, kinase inhibitors, topoisomerase inhibitors, Histone Deacetylase (HDAC) inhibitors, DNA methylation inhibitors, anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, thalidomide, lenalidomide, antibody-drag-conjugates (ADCs), immunomodulating agents, or cancer vaccines.
  • HDAC Histone Deacetylase
  • Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. , for determining the LD50 (the dose lethal to about 50% of the population) and the ED50 (the dose therapeutically effective in about 50% of the population).
  • the dosage can vary depending upon the dosage form employed and the route of administration utilized.
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50.
  • compositions and methods that exhibit large therapeutic indices are preferred.
  • a therapeutically effective dose can be estimated initially from in vitro assays, including, for example, cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture, or in an appropriate animal model.
  • Levels of the described compositions in plasma can be measured, for example, by high performance liquid chromatography.
  • the effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • the prophylactic effect will result in a quantifiable change of at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 70%, or at least about 90%. In some embodiments, the effect will result in a quantifiable change of about 10%, about 20%, about 30%, about 50%, about 70%, or even about 90% or more. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.
  • compositions of Formulae I or II when used in combination with other anticancer agents, the other anti-cancer agent may be dosed independently of the dosing schedule of the composition of Formulae I or II.
  • the other anti-cancer agent may be dosed at its previously established therapeutic dose and dosing schedule, or its dose and dosing schedule may be modified to optimize efficacy, safety or tolerability when used in combination with the compositions of Formulae I or II.
  • any compositions of Formulae I or II (and/or additional agents) described herein can be administered to a subject as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle.
  • Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.
  • Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent described herein is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions of Formula I may be used in combination with other agents including chemotherapeutic agents, targeted therapeutics, biological agents, or radiotherapy.
  • compositions of Formula I may be used in combination with chemotherapeutic agents including but not limited to anti-tubulin agents (paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, docetaxel, ixabepilone, vincristine), vinorelbine, DNA-alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-aza cytadine, gemcitabine and methotrexate.
  • chemotherapeutic agents including but not limited to anti-tubulin agents (paclitaxel, paclitaxel protein-bound particles
  • compositions of Formula I may be used in combination with kinase inhibitors including but not limited to erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEEOl l , PD 0332991 , crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axitinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, idelalisib, and quizartinib.
  • kinase inhibitors including but not limited to erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, LY2835219, LEEOl l , PD 0332991 , crizot
  • compositions of Formula I may be used in combination with anti-estrogen agents including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane.
  • anti-estrogen agents including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane.
  • compositions of Formula I may be used in combination with anti-androgen agents including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate.
  • compositions of Formula I may be used in combination with steroid agents including but not limited to prednisone and dexamethazone.
  • compositions of Formula I may be used in combination with topoisomerase I inhibitors including but not limited to irinotecan, camptothecin, and topotecan.
  • compositions of Formula I may be used in combination with topoisomerase II inhibitors including but not limited to etoposide, etoposide phosphate, and mitoxantrone.
  • compositions of Formula I may be used in combination with Histone Deacetylase (HDAC) inhibitors including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, and belinostat.
  • HDAC Histone Deacetylase
  • compositions of Formula I may be used in combination with DNA methylation inhibitors including but not limited to DZNep and 5-aza-2'-deoxycytidine.
  • compositions of Formula I may be used in combination with proteasome inhibitors including but not limited to bortezomib and carfilzomib.
  • compositions of Formula I may be used in combination with thalidomide, lenalidomide and pomalidomide.
  • compositions of Formula I may be used in combination with biological agents including but not limited to trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, anti-PD-1 agents including labrolizumab and nivolumab, anti-PD-Ll agents including MPDL3280A, anti-angiogenic agents including bevacizumab and aflibercept, and antibody-drag-conjugates (ADCs) including brentuximab vedotin and trastuzumab emtansine.
  • biological agents including but not limited to trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, anti-PD-1 agents including labrolizumab and nivolumab, anti-PD-Ll agents including MPDL3280A
  • compositions of Formula I may be used in combination with radiotherapy.
  • compositions of Formula I may be used in combination with therapeutic vaccines including but not limited to sipuleucel-T.
  • composition of Formula I or Formula II can be used in combination with one or more of the other agents described herein.
  • a first aspect of the invention relates to a method of blocking primary breast tumor growth and invasiveness which comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
  • the dosing regimen of the composition of Formula I is a daily dosing administration.
  • the dosing regimen of the composition of Formula I is a daily dosing administration.
  • the intermittent non-daily dosing regimen may include, without limitation, alternate daily dosing, every third-day dosing, twice weekly dosing, or once weekly dosing.
  • a suitable dosing regimen of the composition of Formula I includes administration twice weekly, once weekly, or alternate weekly.
  • the dosing regimen of the composition of Formula I is twice weekly or once weekly.
  • the dosing regimen of the composition of Formula I is administration twice weekly.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis- inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with docetaxel.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with eribulin.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with ixabepilone.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a compositionof Formula I in combination with 5-fluorouracil.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with methotrexate.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with carboplatin.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering of a compositionof Formula I in combination with epirubicin.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with lapatinib.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with everolimus.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with temsirolimus.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with the CDK4/6 inhibitor LY2835219.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with bevacizumab.
  • Another aspect of the invention relates to a method of blocking primary breast tumor growth and invasiveness which comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered in an intermittent non-daily dosing regimen.
  • the intermittent non-daily dosing regimen includes alternate daily dosing, every third daily dosing, twice weekly dosing, and once weekly dosing.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly, once weekly, or alternate weekly.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly or once weekly.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment wherein the composition of Formula I is administered in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti- angiogenic agent.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with docetaxel.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with eribulin.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with ixabepilone.
  • a method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with methotrexate.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with carboplatin.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering of a composition of Formula I in combination with epirubicin.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
  • the method of blocking primary breast tumor growth and invasiveness comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of blocking primary breast tumor growth and invasiveness comprises the administration of a composition of Formula I in combination with bevacizumab.
  • a method of blocking breast cancer intravasation, dissemination and metastasis comprises administering to patient in need thereof an effective amount of a composition of Formula I sufficient to block TIE2 kinase in the tumor microenvironment.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering to patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
  • the dosing regimen sufficient to block breast cancer intravasation, dissemination and metastasis comprises the daily administration of a composition of Formula I.
  • the dosing regimen of a composition of Formula I is administered in an intermittent non-daily dosing manner, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
  • the dosing regimen of a composition of Formula I is administered twice weekly, once weekly, or alternate weekly.
  • the dosing regimen of a composition of Formula I is twice weekly or once weekly administration.
  • the dosing regimen a composition of Formula I is administered twice weekly.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti- angiogenic agent.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with paclitaxel protein-boundn particles for injectable suspension.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with docetaxel.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with eribulin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises adminstering a composition of Formula I in combination with ixabepilone.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises adminstering a composition of Formula I in combination with vinorelbine.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with capecitabine.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with gemcitabine.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with 5-fluorouracil.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with methotrexate.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with cyclophosphamide.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with cisplatin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with carboplatin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with doxorubicin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with epirubicin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with tamoxifen.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with fulvestrant.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with anastrozole.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with letrozole.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with exemestane.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with trastuzumab.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with ado-trastuzumab emtansine.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with pertuzumab.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with lapatinib.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with everolimus.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with temsirolimus.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with the CDK4/6 inhibitor LY2835219.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with bevacizumab.
  • a method of blocking breast cancer intravasation, dissemination and metastasis comprises administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the dosing regimen of the composition of Formula I is administered as intermittent non-daily dosing.
  • the alternate daily dosing includes every third daily dosing, twice weekly dosing, or once weekly dosing.
  • a method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with the dosing regimen of the composition of Formula I being administered twice weekly, once weekly, or alternate weekly.
  • a method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with the dosing regimen of the composition of Formula I being administered twice weekly or once weekly.
  • a method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with the dosing regimen of the composition of Formula I being administered twice weekly.
  • a method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment administered in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor or an anti-angiogenic agent.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with docetaxel.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with eribulin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with ixabepilone.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with methotrexate.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with carbop latin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering of a composition of Formula I in combination with epirubicin.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with ado -trastuzumab emtansine.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2- expressing macrophages administered in combination with everolimus.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2- expressing macrophages administered in combination with terns irolimus.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2- expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2- expressing macrophages administered in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2- expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of blocking breast cancer intravasation, dissemination and metastasis comprises the administration of a composition of Formula I in combination with bevacizumab.
  • Another aspect of the invention relates to a method of blocking breast cancer immunotolerance.
  • the method comprises administering to a patient in need thereof an effective amount of a composition of Formula I.
  • the dosing regimen of the salt is sufficient to block TIE2 kinase in the tumor microenvironment that mediates immunotolerance.
  • the method of blocking breast cancer immunotolerance comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment that mediates immunotolerance.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I daily.
  • the composition of Formula I is administered in an intermittent non-daily manner.
  • the intermittent non- daily manner includes alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
  • administration of the composition of Formula I is twice weekly, once weekly, or alternate weekly.
  • composition of Formula I is administered twice weekly or once weekly.
  • composition of Formula I is administered twice weekly.
  • the method of blocking breast cancer immunotolerance comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with docetaxel.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with eribulin.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with ixabepilone.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with 5-fiuorouracil.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with 5 -methotrexate.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with carboplatin.
  • the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I in combination with epirubicin.
  • the method of blocking breast cancer immuno tolerance comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with lapatinib.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with everolimus.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with temsirolimus.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with bevacizumab.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with ipilimumab.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-PD- 1 agent.
  • a method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with lambrolizumab.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-PD L-l agent.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with MPDL3280A.
  • a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the dosing regimen of the composition of Formula I is administered in an intermittent non-daily dosing manner, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
  • a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly, once weekly, or alternate weekly.
  • a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly or once weekly.
  • a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein the composition of Formula I is administered twice weekly.
  • a method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment administered in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis- inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with docetaxel.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with eribulin.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with ixabepilone.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with 5-fiuorouracil.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with methotrexate.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with carboplatin.
  • the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of blocking breast cancer immunotolerance comprises administering of a composition of Formula I in combination with epirubicin.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of blocking breast cancer immunotolerance comprises the administration of a a composition of Formula I in combination with ado-trastuzumab emtansine.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of blocking breast cancer immunotolerance comprises the administration of a a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with lapatinib.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with everolimus.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with temsirolimus.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor micro environment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of blocking breast cancer immunotolerance comprises the administration of a composition of Formula I in combination with bevacizumab.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with ipilimumab.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-PD- 1 agent.
  • a method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with lambrolizumab.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with an anti-PD L-l agent.
  • the method of blocking breast cancer immunotolerance comprises administering a composition of Formula I in combination with MPDL3280A.
  • Another aspect of the invention relates to a method of increasing overall survival in breast cancer patients compriseing administering to a patient in need thereof an effective amount of a composition of Formula I.
  • the dosing regimen is sufficient to block TIE2 kinase in the tumor microenvironment .
  • the method of increasing overall survival in breast cancer patients comprises a dosing regimen wherein the composition of Formula I administered daily.
  • the method of increasing overall survival in breast cancer patients comprises a composition of Formula I in a dosing regimen administered in an intermittent non-daily manner, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
  • the method of increasing overall survival in breast cancer patients comprises a composition of Formula I in a dosing regimen administered twice weekly, once weekly, or alternate weekly.
  • the dosing regimen of a composition of Formula I is administered twice weekly or once weekly.
  • the dosing regimen of a composition of Formula I is administered only twice weekly.
  • Another embodiment of this aspect of the invention relates to the method of increasing overall survival in breast cancer patients which comprises administering a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti- estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with docetaxel.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with eribulin.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with ixabepilone.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with methotrexate.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with carboplatin.
  • the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I in combination with epirubicin.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with bevacizumab.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with ipilimumab.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with lambrolizumab.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti- anti-PD L- 1 agent.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with MPDL3280A.
  • a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein a dosing regimen of the composition of Formula I is intermittent non-daily dosing administration, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
  • a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein a dosing regimen of the composition of Formula I is twice weekly, once weekly, or alternate weekly, administration.
  • a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, wherein a dosing regimen of the composition of Formula I is twice weekly or once weekly administration.
  • a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I is twice weekly administration.
  • a method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment administered in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti- HER2 agent, a kinase inhibitor, an anti-angiogenic agent, or an immunomodulating agent.
  • the method of increasing overall survival in breast cancer patients administering a composition of Formula I in combination with paclitaxel.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with docetaxel.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with eribulin.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with ixabepilone.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with methotrexate.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with carboplatin.
  • the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of increasing overall survival in breast cancer patients comprises administering of a composition of Formula I in combination with epirubicin.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of increasing overall survival in breast cancer patients comprises the administration of a composition of Formula I in combination with bevacizumab.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with ipilimumab.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with lambrolizumab.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with an anti- anti-PD L- 1 agent.
  • the method of increasing overall survival in breast cancer patients comprises administering a composition of Formula I in combination with MPDL3280A.
  • Another aspect of the invention relates to a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor, comprising administering to a patient in need thereof and effective amount of a composition of Formula I, a dosing regimen of the composition of Formula I is sufficient to block TIE2 kinase in the tumor microenvironment.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
  • a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I being administered daily.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I administered in an intermittent non-daily manner, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen administered twice weekly, once weekly, or alternate weekly.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I in a dosing regimen administered twice weekly or once weekly.
  • the dosing regimen of a composition of Formula I is administered twice weekly.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I in dosing regimen sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages in combination with one or more agents taken from an anti-tubulin agent, a DNA alkylating agent, a DNA synthesis-inhibiting agent, a DNA intercalating agent, an anti-estrogen agent, an anti-HER2 agent, a kinase inhibitor, an anti- angiogenic agent, or an immunomodulating agent.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with docetaxel.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with eribulin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with ixabepilone.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with methotrexate.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with carboplatin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with epirubicin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with ado -trastuzumab emtansine.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with bevacizumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with ipilimumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with lambrolizumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti- anti-PD L- l agent.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with MPDL3280A.
  • a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor micro environment, with a dosing regimen of the composition of Formula I administered as intermittent non-daily dosing, including alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing.
  • a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I administered twice weekly, once weekly, or alternate weekly.
  • a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I administered twice weekly or once weekly.
  • a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment, with a dosing regimen of the composition of Formula I administered twice weekly.
  • a method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in the tumor microenvironment administered in combination with one or more
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with paclitaxel.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with paclitaxel protein-bound particles for injectable suspension.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with docetaxel.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with eribulin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with ixabepilone.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with vinorelbine.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with capecitabine.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with gemcitabine.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with 5-fluorouracil.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with 5-methotrexate.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with cyclophosphamide.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with cisplatin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with carboplatin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with doxorubicin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with pegylated liposomal doxorubicin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering of a composition of Formula I in combination with epirubicin.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with tamoxifen.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with fulvestrant.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with anastrozole.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with letrozole.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with exemestane.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with trastuzumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with ado-trastuzumab emtansine.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with pertuzumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with lapatinib.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with everolimus.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with temsirolimus.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LY2835219.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor LEE01 1.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I at doses sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages administered in combination with the CDK4/6 inhibitor PD 0332991.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises the administration of a composition of Formula I in combination with bevacizumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti-CTLA-4 agent.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with ipilimumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti-PD-1 agent.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with lambrolizumab.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with an anti- anti-PD L- l agent.
  • the method of treating breast cancer patients in a neoadjuvant setting prior to surgical resection of tumor comprises administering a composition of Formula I in combination with MPDL3280A.
  • Another aspect of the invention relates to a method of treating ovarian cancer as TIE2 pathway signaling has been shown to contribute to ovarian cancer progression (Karlan et al, J. Clinical Oncology (2012) 30: 362-370).
  • the method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
  • a composition of Formula I is administered as a single agent.
  • composition of Formula I is administered in combination with paclitaxel + carboplatin, doxetaxel + carboplatin, paclitaxel + cisplatin, or other taxane + platinum drug regimens.
  • Another aspect of the invention relates to a method of treating hepatocellular carcinoma as TIE2 pathway signaling has been shown to contribute to hepatocellular cancer progression and as a diagnostic marker (Matsubara et al, Hepatology (2013) 57: 1416-1425; Mitsuhashi et al, Hepatology (2003) 37: 1 105-1 1 13; Tanaka et al, J. Clin Invest (1999) 103: 341 - 345).
  • the method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor micro environment .
  • composition of Formula I is administered as a single agent.
  • a composition of Formula I is administered in combination with a kinase inhibitor including sorafenib, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, or axitinib.
  • a kinase inhibitor including sorafenib, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, or axitinib.
  • Another aspect of the invention relates to a method of treating glioma as TIE2 pathway signaling has been shown to contribute to glioma cancer progression (Liu et al, Oncotarget (2010) 1 : 700-709; Brunckhorst et al, Cancer Research (2010) 70: 7283-7293).
  • the method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor micro environment .
  • composition of Formula I is administered as a single agent.
  • composition of Formula I is administered in combination with radiotherapy.
  • composition of Formula I is administered in combination with temozolomide therapy.
  • composition of Formula I is administered in combination with radiotherapy and temozolomide therapy.
  • composition of Formula I is administered in combination with bevacizumab therapy.
  • composition of Formula I is administered in combination with radiotherapy and bevacizumab therapy.
  • composition of Formula I is administered in combination with temozolomide therapy and bevacizumab therapy.
  • Another aspect of the invention relates to a method of treating melanoma as TIE2 pathway signaling has been shown to contribute to melanoma progression (Helfrich et al, Clin Cancer Res (2009) 15: 1384-1392; Peinado et al, Nature Medicine (2012) 18: 883-891).
  • the method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor micro environment .
  • composition of Formula I is administered as a single agent.
  • composition of Formula I is administered in combination with vemurafenib.
  • composition of Formula I is administered in combination with dabrafenib.
  • composition of Formula I is administered in combination with dabrafenib and trametinib.
  • composition of Formula I is administered in combination with temozolomide.
  • composition of Formula I is administered in combination with dacarbazine.
  • a composition of Formula I is administered in combination with ipilimumab.
  • composition of Formula I is administered in combination with labrolizumab or nivolumab.
  • composition of Formula I is administered in combination with MPDL3280A.
  • composition of Formula I is administered in combination with imatinib.
  • Another aspect of the invention relates to a method of treating colorectal cancer as TIE2 pathway signaling has been shown to contribute to colorectal cancer progression (Ahmad et al, Cancer (2001) 92: 1 138-1 143; Hashizume et al, Cancer Research (2010) 70: 2213-2223).
  • the method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor micro environment .
  • composition of Formula I is administered as a single agent.
  • composition of Formula I is administered in combination with mFOLFOX6 therapy (oxaplatin + leucovorin + 5-fluorouracil).
  • composition of Formula I is administered in combination with mFOLFOX6 therapy and bevacizumab.
  • composition of Formula I is administered in combination with mFOLFOX6 therapy and panitumumab.
  • composition of Formula I is administered in combination with mFOLFOX6 therapy and cetuximab.
  • composition of Formula I is administered in combination with capecitabine.
  • composition of Formula I is administered in combination with capecitabine and bevacizumab.
  • composition of Formula I is administered in combination with FOLFIRI therapy (irinotecan + leucovorin + 5-fiuorouracil).
  • composition of Formula I is administered in combination with FOLFIRI therapy and bevacizumab.
  • composition of Formula I is administered in combination with FOLFIRI therapy and aflibercept.
  • composition of Formula I is administered in combination with FOLFIRI therapy and cetuximab.
  • composition of Formula I is administered in combination with FOLFIRI therapy and panitumumab.
  • composition of Formula I is administered in combination with panitumumab.
  • composition of Formula I is administered in combination with panitumumab and irinotecan.
  • composition of Formula I is administered in combination with cetuximab.
  • composition of Formula I is administered in combination with cetuximab and irinotecan.
  • Another aspect of the invention relates to a method of treating acute myeloid leukemia as TIE2 pathway signaling has been shown to contribute to acute myeloid leukemia progression (Muller et al, Leukemia Research (2002) 26: 163-168; Hou et al, Leukemia Research (2008) 32: 904-912).
  • the method comprises administering to a patient in need thereof an effective amount of a composition of Formula I in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment.
  • a composition of Formula I is administered as a single agent.
  • composition of Formula I is administered in combination with daunorubicin and cytarabine.
  • composition of Formula I is administered in combination with idarubicin and cytarabine.
  • composition of Formula I is administered in combination with mitoxantrone and cytarabine.
  • composition of Formula I is administered in combination with cytarabine.
  • composition of Formula I is administered in combination with 5-azacytabine.
  • composition of Formula I is administered in combination with decitabine.
  • composition of Formula I is administered in combination with quizartinib.
  • Another aspect of the invention relates to a method of treating cancer.
  • the method comprises administering an effective amount of a composition of Formula I to a patient in need thereof.
  • the patient overexpresses Tunica interna endothelial cell kinase 2 (TIE2) and the cancer is selected from breast cancer, colorectal cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer, ovarian cancer, gliomas, angiosarcomas, melanomas, or acute myeloid leukemia.
  • TIE2 Tunica interna endothelial cell kinase 2
  • composition of Formula I is administered at a frequency of daily.
  • composition of Formula I is administered at a frequency of non-daily intermittent.
  • composition of Formula I is administered at a frequency of three times weekly.
  • composition of Formula I is administered at a frequency of two times weekly.
  • composition of Formula I is administered at a frequency of one time weekly.
  • composition of Formula I is administered at a frequency of one time every two weeks.
  • the cancer is metastatic, triple negative breast cancer (estrogen receptor negative, progesterone receptor negative, HER2 negative).
  • the cancer is estrogen positive (ER + ) and HER2 receptor kinase negative (HER2 ) breast cancer.
  • the cancer is inflammatory breast cancer.
  • the method comprises the treatment of preventing or reducing one or more of primary tumor growth, tumor invasiveness, cancer intravasation, cancer dissemination, metastasis, and tumor immunotolerance. In certain embodiments the method increases patient survival rates.
  • the present invention includes the described salts of Formulae I and/or II (and/or additional agents) in various formulations.
  • Any composition (and/or additional agents) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the composition is in the form of a capsule (see, e.g., U.S. Patent No. 5,698,155).
  • suitable pharmaceutical excipients are described in Remington 's Pharmaceutical
  • the salts herein described can also include a solubilizing agent.
  • the agents can be delivered with a suitable vehicle or delivery device as known in the art.
  • Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device.
  • Compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.
  • the salts of Formulae I and/or II (and/or additional agents) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration.
  • routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin.
  • the administering is effected orally or by parenteral injection.
  • the mode of administration can be left to the discretion of the practitioner, and depend in-part upon the site of the medical condition. In most instances, administration results in the release of any agent described herein into the bloodstream.
  • compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered compositions can comprise one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving the salt of Formula I or II (and/or additional agents) described herein are also suitable for orally administered compositions.
  • fluid from the environment surrounding the capsule is imbibed by the driving composition, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be useful.
  • Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate.
  • the excipients are of pharmaceutical grade.
  • Suspensions in addition to the active compositions, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, etc., and mixtures thereof.
  • Dosage forms suitable for parenteral administration include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions ⁇ e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.
  • the dosage of the salt of Formulae I and/or II (and/or additional agents) described herein as well as the dosing schedule can depend on various parameters, including, but not limited to, the disease being treated, the subject's general health, and the administering physician's discretion.
  • Any agent described herein can be administered prior to ⁇ e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to ⁇ e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of an additional therapeutic agent, to a subject in need thereof.
  • any agent described herein is administered 1 minute apart, 10 minutes apart, 30 minutes apart, less than 1 hour apart, 1 hour apart, 1 hour to 2 hours apart, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, 10 hours to 1 1 hours apart, or 1 1 hours to 12 hours apart.
  • the dosage of the salt of Formula I or II (and/or additional agents) described herein can depend on several factors including the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the subject to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected.
  • the dosage of any composition of Formula I (and/or additional agents) described herein may be 0.001 mg/kg/day to 100 mg/kg/day, 0.01 mg/kg/day to 50 mg/kg/day, or 0.1 mg/kg/day to 10 mg/kg/day.
  • the dosage of any agent described herein is normally 0.001 mg to 1500 mg per day, 1 mg to 600 mg per day, or 5 mg to 30 mg per day.
  • the dosage of the salt (or agent) ranges from 57 mg to 1200 mg per day. In other embodiments, the dosage of the agents or salt ranges from 100 mg to 200 mg per day.
  • the dosage is normally 0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day. Injections may be given up to four times daily.
  • the dosage of any agent described herein is normally 0.1 mg to 1500 mg per day, or 0.5 mg to 10 mg per day, or 0.5 mg to 5 mg per day. A dosage of up to 3000 mg per day can be administered.
  • Administration of the salts (and/or additional agents) described herein can, independently, be one to four times daily. Specifically, administration of the salt can be once a day at a dosing regimen of the salt is from about 50 mg to 1500 mg. Suitable daily dosage for the prophylactic effects sought is 57-1200 mg/day. If administered twice daily, a suitable dosage is 100 mg to 200mg of the salt. Administration of the salt may also be intermittently non-daily. In particular, administration of the salt may be done one to four times per month or one to six times per year or once every two, three, four or five years. In certain embodiments administration of the salt is done weekly or bi-weekly.
  • a suitable salt dosing regimen ranges from 50-200 mg/ per administration.
  • dosage is 200-400 mg/ per administration.
  • Yet other mode of weekly or bi-weekly administration include 400-500 mg/ per administration, 500-600 mg/ per administration, 600-700 mg/ per administration, 700-800 mg/ per administration, 800-900 mg/ per administration, 900-1000 mg/ per administration, 1000-1 100 mg/ per administration, or 1100-1200 mg/ per administration.
  • Administration can be for the duration of one day or one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject. Chronic, long-term administration will be indicated in many cases.
  • the dosage may be administered as a single dose or divided into multiple doses. In general, the desired dosage should be administered at set intervals for a prolonged period, usually at least over several weeks or months, although longer periods of administration of several months or years or more may be needed.
  • Activity of uTIE2 kinase was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al. Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A34o nm ) was continuously monitored spectrophotometrically.
  • the reaction mixture (100 ⁇ ,) contained TIE2 (SignalChem) (5.6 nM), BSA (0.004% (w/v)), polyEY (1.5 mg/ml), MgCi 2 (15 mM), DTT (0.5 mM), pyruvate kinase (4 units), lactate dehydrogenase (7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and ATP (1.5 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. The inhibition reaction was started by mixing serial diluted test composition with the above reaction mixture.
  • composition l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid salt (compound 1 as described in figures) exhibited an IC 50 value of 3.5 nM.
  • uTIE2 protein sequence used for screening (Seq. ID No. 1)
  • Activity of pTIE2 kinase was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system
  • the reaction mixture (100 ⁇ ) contained TIE2 (Life Technologies) (6 nM), BSA (0.004% (w/v)), polyEY (1.5 mg/ml), MgCi 2 (15 mM), DTT (0.5 mM), pyruvate kinase (4 units), lactate dehydrogenase (7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) and ATP (1.5 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5.
  • the inhibition reaction was started by mixing serial diluted test composition with the above reaction mixture. The absorption at 340 nm was monitored continuously for 6 hours at 30 °C on a plate reader (BioTek). The reaction rate was calculated using the 2 to 3 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test composition). IC 50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.
  • compositions l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2- fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid salt and 1- (3-tert-butyl- 1 -(quinolin-6-yl)- 1 H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea bis-hydrochloric acid salt exhibited >50% inhibition of pTIE2 kinase at ⁇ 0.1 ⁇ concentration.
  • l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid salt exhibited an IC 50 value of 4.2 nM.
  • l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea bis-hydrochloric acid salt exhibited an IC 50 value of 2.2 nM.
  • Example 3 Cellular inhibition of TIE2 in CHO cells by l-(3-tert-butyl-l-(quinolin-6-yl)- lH-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea
  • CHO-K1 Cell Culture [0537] CHO-K1 cells (catalog #CCL-61) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Briefly, cells were grown in F12K medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units/mL penicillin G, 100 ⁇ g/ml streptomycin, and 0.29 mg/mL L-glutamine (Invitrogen, Carlsbad, CA) at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Cells were allowed to expand until reaching 70- 95% confluence at which point they were subcultured or harvested for assay use.
  • ATCC American Type Culture Collection
  • CHO Kl cells (1 x 10 5 cells/well) were added to a 24-well tissue-culture treated plate in 1 mL of RPMI1640 medium supplemented with 10% characterized fetal bovine serum and IX non-essential amino acids (Invitrogen, Carlsbad, CA). Cells were then incubated overnight at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Medium was aspirated, and 0.5 mL of medium was added to each well.
  • Transfection-grade plasmid DNA (TIE2 gene Gateway cloned into pcDNA3.2TM/V5-DEST expression vector, Invitrogen, Carlsbad, CA) was diluted to 5 ⁇ g/mL in room temperature Opti-MEM® I Medium without serum (Invitrogen, Carlsbad, CA). Two ⁇ L ⁇ of Lipofectamine LTX Reagent (Invitrogen, Carlsbad, CA) was added per 0.5 ⁇ g of plasmid DNA. The tube was mixed gently and incubated for 25 minutes at room temperature to allow for DNA- Lipofectamine LTX complex formation. 100 ⁇ L of the DNA-Lipofectamine LTX complex was added directly to each well containing cells and mixed gently.
  • Test composition (l -(3-tert-butyl- l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4- (2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid salt) or DMSO was added to the wells (0.5% final DMSO concentration). The plates were then incubated for 4 hours at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Following the incubation, the media was aspirated and the cells were washed with PBS.
  • the cells were lysed using MPER lysis buffer (Pierce, Rockford, IL) containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford, IL) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4 °C for 10 minutes with shaking. Cleared lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, CA) and then transferred to PVDF (Invitrogen, Carlsbad, CA).
  • the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA).
  • BSA Cruz Biotechnology, Santa Cruz, CA
  • a secondary anti-rabbit antibody conjugated to horseradish peroxidase was used to detect phospho-TIE2.
  • ECL Plus GE Healthcare, Piscataway, NJ
  • Fluorescence was detected using a Storm 840 phosphorimager (GE Healthcare, Piscataway, NJ) in fluorescence mode.
  • the 160 kDa phospho-TIE2 band was quantified using ImageQuant software (GE Healthcare, Piscataway, NJ).
  • composition l-(3-tert-butyl- 1 -(quinolin-6-yl)- 1 H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea para-toluene sulfonic acid salt exhibited an IC 50 value of 2.0 nM.
  • Example 4 Cellular inhibition of TIE2 in CHO cells after inhibitor wash-out by l-(3-tert- butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea
  • CHO-K1 cells (catalog #CCL-61) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Briefly, cells were grown in F12K medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 100 units/mL penicillin G, 100 ⁇ g/ml streptomycin, and 0.29 mg/mL L-glutamine (Invitrogen, Carlsbad, CA) at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Cells were allowed to expand until reaching 70- 95% confluence at which point they were subcultured or harvested for assay use.
  • ATCC American Type Culture Collection
  • CHO Kl cells (1 x 10 5 cells/well) were added to a 24-well tissue-culture treated plate in 1 mL of RPMI1640 medium supplemented with 10% characterized fetal bovine serum and IX non-essential amino acids (Invitrogen, Carlsbad, CA). Cells were then incubated overnight at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Medium was aspirated, and 0.5 mL of medium was added to each well.
  • Transfection-grade plasmid DNA (TIE2 gene Gateway cloned into pcDNA3.2TM/V5-DEST expression vector, Invitrogen, Carlsbad, CA) was diluted to 5 ⁇ g/mL in room temperature Opti-MEM® I Medium without serum (Invitrogen, Carlsbad, CA). Two ⁇ L ⁇ of Lipofectamine LTX Reagent (Invitrogen, Carlsbad, CA) was added per 0.5 ⁇ g of plasmid DNA. The tube was mixed gently and incubated for 25 minutes at room temperature to allow for DNA- Lipofectamine LTX complex formation. 100 ⁇ L of the DNA-Lipofectamine LTX complex was added directly to each well containing cells and mixed gently.
  • Test composition (l -(3-tert-butyl- l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4- (2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea para-toluene sulfonic acid salt) or DMSO was added to the wells (0.5% final DMSO concentration). The plates were then incubated for 2 hours at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Following the incubation, the media was aspirated and the cells were washed three times with 1 mL media to wash out free composition.
  • the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA).
  • BSA Cruz Biotechnology, Santa Cruz, CA
  • a secondary anti-rabbit antibody conjugated to horseradish peroxidase was used to detect phospho-TIE2 ECL Plus (GE Healthcare, Piscataway, NJ), a substrate for horseradish peroxidase that generates a fluorescent product, was added. Fluorescence was detected using a Storm 840 phosphorimager (GE Healthcare, Piscataway, NJ) in fluorescence mode.
  • PVDF membranes were stripped and then re -probed with total TIE2 antibody (Santa Cruz Biotechnology, Inc., Dallas, TX) as above.
  • the 160 kDa phospho-TIE2 and total TIE2 bands were quantified using ImageQuant software (GE Healthcare, Piscataway, NJ). Phospho-TIE2 levels were normalized to total TIE2 levels, and data was plotted using Prism software (GraphPad Software, San Diego, CA).
  • Composition 1 When incubated with TIE2- transfected CHO Kl cells for 2 hours at 0.1 ⁇ - 1 ⁇ prior to being washed out, Composition 1 -(3-tert-butyl- 1 -(quinolin-6-yl)- 1 H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea para-toluene sulfonic acid salt disclosed herein exhibited >50% inhibition of phospho-TIE2 levels for >24 hours.
  • Example 5 Cellular inhibition of TIE2 in HUVEC cells by l-(3-tert-butyl-l-(quinolin-6- yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea
  • HUVEC Human umbilical vein endothelial cells; Catalog #CRL-1730
  • ATCC American Type Culture Collection
  • EGM-2 Longza, Walkersville, MD
  • 95% humidity Cells were allowed to expand until reaching 90-95% saturation at which point they were subcultured or harvested for assay use.
  • HUVEC cells 2.5 x W cells/well were added to a 24-well tissue-culture treated plate in 1 mL of EGM-2 culture medium (Lonza, Walkersville, MD). Cells were then incubated overnight at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Media was then aspirated and 1 mL EBM-2 basal medium (Lonza, Walkersville, MD) supplemented with 2% FBS (Invitrogen, Carlsbad, CA) was added. Test composition or DMSO was added to the wells (0.5% final DMSO concentration). The plates were then incubated for 4 hours at 37 degrees Celsius, 5% C0 2 , and 95% humidity.
  • ANG1 growth factor R&D Systems, Minneapolis, MN
  • ANG1 growth factor R&D Systems, Minneapolis, MN
  • anti-polyhistidine antibody R&D Systems, Minneapolis, MN
  • the cells were lysed using MPER lysis buffer (Pierce, Rockford, IL) containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford, IL) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, MO) at 4 °C for 10 minutes with shaking. Cleared lysates were separated by SDS-PAGE on a 4-12% Novex NuPage Bis-Tris gel (Invitrogen, Carlsbad, CA) and then transferred to PVDF (Invitrogen, Carlsbad, CA).
  • the PVDF membrane was blocked with BSA (Santa Cruz Biotechnology, Santa Cruz, CA) and then probed with an antibody for phospho-TIE2 (Cell Signaling Technology, Beverly, MA).
  • BSA Cruz Biotechnology, Santa Cruz, CA
  • a secondary anti-rabbit antibody conjugated to horseradish peroxidase was used to detect phospho-TIE2.
  • ECL Plus GE Healthcare, Piscataway, NJ
  • Fluorescence was detected using a Storm 840 phosphorimager (GE Healthcare, Piscataway, NJ) in fluorescence mode.
  • the 160 kDa phospho-TIE2 band was quantified using ImageQuant software (GE Healthcare, Piscataway, NJ).
  • composition l-(3-tert-butyl- 1 -(quinolin-6-yl)- 1 H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea para-toluene sulfonic acid salt disclosed herein exhibited an IC 50 value of 0.018 nM.
  • Example 6 Inhibition of angiopoietin 1 (ANG1) or angiopoietin 2 (ANG2) stimulated capillary tube formation by l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4- (2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea
  • ANG1 angiopoietin 1
  • ANG2 angiopoietin 2
  • HMVEC Human microvascular endothelial cells; Catalog #PCS-1 10-010) cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Briefly, cells were grown in EGM-2 MV (Lonza, WalkersviUe, MD) at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Cells were allowed to expand until reaching 90-95% saturation at which point they were subcultured or harvested for assay use.
  • HMVEC cells 1.5 x 10 4 cells/well
  • test composition or DMSO control and the appropriate growth factor (ANG1 or ANG2) or control were added to a 96-well tissue- culture treated plate coated with growth-factor reduced Matrigel in 0.1 mL of EBM-2 basal medium (Lonza, Walkersville, MD). Cells were then incubated for 18 hours at 37 degrees Celsius, 5% C0 2 , and 95% humidity. Media was then gently aspirated and wells were gently washed with 0.1 mL EBM-2 basal medium. Media was again aspirated and 1 ⁇ Calcein AM solution (Invitrogen, Carlsbad, CA) in basal medium was added to each well to fluorescently label live cells.
  • composition l-(3-tert-butyl-l-(quinolin- 6-yl)- 1 H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea para- toluene sulfonic acid salt disclosed herein exhibited an IC 50 value of 6.9 nM for inhibition of ANG1 -stimulated HMVEC capillary tube formation.
  • the composition of Formula I disclosed herein exhibited an IC 50 value of 34 nM for inhibition of ANG2-stimulated HMVEC capillary tube formation.
  • Example 7 Inhibition of in vivo primary tumor growth and invasiveness in the murine PyMT breast cancer model by l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2- fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel PyMT syngeneic breast cancer model primary tumor growth
  • the PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 10 6 cells (dissociated from PyMT tumor fragments) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of 10 mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH).
  • NASH National Institutes of Health
  • Treatment was initiated by oral administration (gavage) of Compound 1 twice daily or vehicle (0.4% hydro xypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg. Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
  • Tumor burden (mg) (L x W 2 )/2, where L and W are the respective orthogonal tumor length and width measurements (mm).
  • L and W are the respective orthogonal tumor length and width measurements (mm).
  • Example 8 Inhibition of in vivo primary tumor macrophage accumulation in the murine PyMT breast cancer model by l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2- fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel
  • the PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 10 6 cells (dissociated from PyMT tumor fragments) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of 10 mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH).
  • NASH National Institutes of Health
  • Treatment was initiated by oral administration (gavage) of Compound 1 twice daily or vehicle (0.4% hydro xypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg. Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
  • Endogenous peroxidase and alkaline phosphatase activity in the tissues was quenched with a Dual Endogenous Enzyme Block solution (Dako, S2003) for 5 minutes. Nonspecific protein binding was blocked with serum free Protein Block (Dako, X0909) for 5 minutes.
  • the rat anti mouse CD31 primary antibody was then incubated on the experimental tissue sections for 30 minutes at an immunogenic concentration of 1 : 100.
  • the primary antibody was then conjugated with a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468).
  • the secondary antibody was then amplified with a goat anti rabbit peroxidase labeled polymer (Dako, K4003) for 30 minutes.
  • Enzymatic staining was developed with substrate-chromogen DAB+ (Dako, K3468) for 5 minutes. Excess rat IgG components were further blocked with Rodent Block Rat (Biocare Medical, RBR962H) for 5 minutes. The rat anti mouse F4/80 primary antibody was incubated on the experimental tissue sections for 30 minutes. The F4/80 was then conjugated with a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468). The secondary antibody was then amplified with a goat anti rabbit alkaline phosphatase labeled polymer, (Biocare RALP525) for 30 minutes. Enzymatic staining was developed with substrate chromogen WARP Red (Biocare WR806).
  • Example 9 Inhibition of in vivo primary tumor TIE2 cell accumulation in the murine PyMT breast cancer model by l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2- fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a single agent and in combination with paclitaxel
  • the PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 10 6 cells (dissociated from PyMT tumor fragments) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice
  • mice were implanted in each group.
  • Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH).
  • Treatment was initiated by oral administration (gavage) of Compound 1 twice daily or vehicle (0.4% hydro xypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg. Animals were dosed for 21 days.
  • Endogenous peroxidase and alkaline phosphatase activity in the tissues was quenched with a Dual Endogenous Enzyme Block solution (Dako, S2003) for 5 minutes. Non-specific protein binding was blocked with serum free Protein Block (Dako, X0909) for 5 minutes.
  • the rat anti mouse CD31 primary antibody was then incubated on the experimental tissue sections for 30 minutes at an immunogenic concentration of 1 : 100.
  • the primary antibody was then conjugated with a rabbit anti rat immunoglobulin secondary antibody (Dako, E0468).
  • the secondary antibody was then amplified with a goat anti rabbit peroxidase labeled polymer (Dako, K4003) for 30 minutes.
  • Enzymatic staining was developed with substrate-chromogen DAB+ (Dako, K3468) for 5 minutes. Excess protein components were further blocked with Protein Block (Dako, X0909) for 5 minutes.
  • the rabbit anti TIE2 primary antibody was incubated on the experimental tissue sections for 30 minutes. The TIE2 antibody was then conjugated with an alkaline phosphatase labeled goat anti rabbit polymer for 30 minutes.
  • Enzymatic staining was developed with substrate chromogen WARP Red (Biocare WR806). The counter staining was performed with automation hematoxylin for 10 minutes. The tissue slides were then air dried and cleared to xylene for glass cover slipping.
  • the PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 10 6 cells (dissociated from PyMT tumor fragments) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of 10 mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH).
  • NASH National Institutes of Health
  • Treatment was initiated by oral administration (gavage) of Compound 1 twice daily or vehicle (0.4% hydro xypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg. Animals were dosed for 21 days. Body weights and tumor measurements were recorded three times weekly.
  • Example 11 Inhibition of in vivo lung metastases in the murine PyMT breast cancer model by l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea dosed intermittently (non-daily) in combination with paclitaxel
  • the PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 10 6 cells (dissociated from PyMT tumor fragments and stored frozen in cell- freezing medium) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of three mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH).
  • NASH National Institutes of Health
  • Treatment was initiated by oral administration (gavage) of Compound 1 twice weekly or vehicle (0.4% hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of paclitaxel every five days or vehicle (10% ethanol, 10% Cremophor EL and 80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 600 mg. Animals were dosed for 12 days. Body weights and tumor measurements were recorded three times weekly.
  • Example 12 Inhibition of in vivo lung metastases in the murine PyMT breast cancer model by l-(3-tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2- (methylcarbamoyl)pyridin-4-yloxy)phenyl)urea dosed intermittently (non-daily) in combination with eribulin PyMT syngeneic breast cancer model lung metastasis evaluation
  • the PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 10 6 cells (dissociated from PyMT tumor fragments and stored frozen in cell- freezing medium) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of three mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH).
  • NASH National Institutes of Health
  • Treatment was initiated by oral administration (gavage) of Compound 1 twice weekly or vehicle (0.4% hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of eribulin three times weekly or vehicle (80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 600 mg. Animals were dosed for 12 days. Body weights and tumor measurements were recorded three times weekly.
  • Example 13 Increase in overall survival in the murine PyMT breast cancer model by l-(3- tert-butyl-l-(quinolin-6-yl)-lH-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4- yloxy)phenyl)urea dosed intermittently (non-daily) in combination with eribulin PyMT syngeneic breast cancer model survival evaluation
  • the PyMT syngeneic breast cancer implant mouse model was used to evaluate in vivo activity of compound 1. Briefly, 1 x 10 6 cells (dissociated from PyMT tumor fragments and stored frozen in cell- freezing medium) in 0.1 mL total volume were implanted into the fourth mammary fat pad on the left side of female mice (FVB/NJ, JAXWEST:RB05 mice from Jackson Labs). A total of ten mice were implanted in each group. Molecular Imaging, Inc.'s Animal Care and Use Committee approved all the experimental protocols and conducted experiments in compliance with all the laws, regulations and guidelines of the National Institutes of Health (NIH).
  • NASH National Institutes of Health
  • Treatment was initiated by oral administration (gavage) of Compound 1 once or twice weekly or vehicle (0.4% hydroxypropylmethylcellulose in water) and/or intravenous administration (IV) of eribulin three times weekly or vehicle (80% saline) according to individual body weight on the day of treatment at 0.2 mL per 20 g when tumor size reached approximately 850 mg. Tumors were then resected three days after treatment began. Animals were then dosed for the duration of the survival experiment. Body weights and tumor measurements were recorded three times weekly. In the PyMT model, eribulin at 0.1 mg/kg evidenced no increase in survival. Compound 1 in combination with eribulin demonstrated significant increases in survival (Figure 7). These data evidence in vivo activity by Compound 1 and show correlation to enzymatic and cell data.

Abstract

L'invention concerne des méthodes d'inhibition de la kinase TIE2 utiles dans le traitement de la croissance tumorale, de l'envahissement tumoral, de l'intravasion, de la dissémination tumorale, des métastases et de l'immunosuppression. L'invention concerne en particulier des méthodes d'utilisation de 1-(3-tert-butyl-1-(quinolin-6-yl)-1Hpyrazol- 5-yl)-3-(2-fluoro-4-(2-(méthylcarbamoyl)pyridin-4-yloxy)phényl)urée et de ses sels de Formule I.
PCT/US2013/069005 2013-11-07 2013-11-07 Méthodes d'inhibition de la kinase tie2 utiles dans le traitement du cancer WO2015069266A1 (fr)

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CA2929715A CA2929715A1 (fr) 2013-11-07 2013-11-07 Methodes d'inhibition de la kinase tie2 utiles dans le traitement du cancer
JP2016552405A JP6568093B2 (ja) 2013-11-07 2013-11-07 ガンの処置に有用なｔｉｅ２キナーゼの阻害方法
EP13896951.4A EP3065549A4 (fr) 2013-11-07 2013-11-07 Méthodes d'inhibition de la kinase tie2 utiles dans le traitement du cancer
PCT/US2013/069005 WO2015069266A1 (fr) 2013-11-07 2013-11-07 Méthodes d'inhibition de la kinase tie2 utiles dans le traitement du cancer
CN201810436668.9A CN108464981B (zh) 2013-11-07 2013-11-07 抑制tie2激酶的组合物在制备治疗癌症的药物中的用途
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KR1020217015635A KR20210063475A (ko) 2013-11-07 2013-11-07 암치료에 유용한 tie2 키나아제의 억제 방법
KR1020167014649A KR20160070188A (ko) 2013-11-07 2013-11-07 암치료에 유용한 tie2 키나아제의 억제 방법
AU2019200261A AU2019200261A1 (en) 2013-11-07 2019-01-15 Methods for inhibiting tie2 kinase useful in the treatment of cancer
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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016191401A1 (fr) * 2015-05-27 2016-12-01 Albert Einstein College Of Medicine, Inc. Test actif tmem et ses utilisations pour le diagnostic, le pronostic et le traitement de tumeurs
CN106822128A (zh) * 2017-02-24 2017-06-13 南华大学附属第医院 酪氨酸激酶抑制剂dcc‑2036的新应用
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10322192B2 (en) 2016-03-02 2019-06-18 Eisai R&D Management Co., Ltd. Eribulin-based antibody-drug conjugates and methods of use
CN110003181A (zh) * 2019-05-22 2019-07-12 北京凯恩梅格医药科技有限公司 一种基于克唑替尼结构的c-Met/HDAC双靶点抑制剂及其合成方法与应用
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10570202B2 (en) 2014-02-04 2020-02-25 Pfizer Inc. Combination of a PD-1 antagonist and a VEGFR inhibitor for treating cancer
US10690673B2 (en) 2016-03-29 2020-06-23 Mayo Foundation For Medical Education And Research Method of treating cancer metastasis by CDK 4/6 inhibitors
US10800846B2 (en) 2015-02-26 2020-10-13 Merck Patent Gmbh PD-1/PD-L1 inhibitors for the treatment of cancer
US10869924B2 (en) 2015-06-16 2020-12-22 Merck Patent Gmbh PD-L1 antagonist combination treatments
US10966966B2 (en) 2019-08-12 2021-04-06 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11040027B2 (en) 2017-01-17 2021-06-22 Heparegenix Gmbh Protein kinase inhibitors for promoting liver regeneration or reducing or preventing hepatocyte death
USRE48731E1 (en) 2012-06-07 2021-09-14 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US11185535B2 (en) 2019-12-30 2021-11-30 Deciphera Pharmaceuticals, Llc Amorphous kinase inhibitor formulations and methods of use thereof
US11266635B2 (en) 2019-08-12 2022-03-08 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors
US11274154B2 (en) 2016-10-06 2022-03-15 Pfizer Inc. Dosing regimen of avelumab for the treatment of cancer
US11395818B2 (en) 2019-12-30 2022-07-26 Deciphera Pharmaceuticals, Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160070188A (ko) * 2013-11-07 2016-06-17 데시페라 파마슈티칼스, 엘엘씨. 암치료에 유용한 tie2 키나아제의 억제 방법
WO2021030404A1 (fr) * 2019-08-12 2021-02-18 Deciphera Pharmaceuticals, Llc Procédés et compositions pour traiter des malformations vasculaires
CN112812109B (zh) * 2019-11-18 2022-06-21 中国科学院微生物研究所 化合物DaP-01及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011123788A1 (fr) * 2010-04-01 2011-10-06 Duke University Compositions et méthodes de traitement du cancer
WO2011150198A1 (fr) * 2010-05-27 2011-12-01 Ambit Biosciences Corporation Composés azolyle urée et leurs procédés d'utilisation
WO2012097021A1 (fr) * 2011-01-11 2012-07-19 Glaxosmithkline Llc Combinaison
WO2013036232A2 (fr) * 2011-09-08 2013-03-14 Deciphera Pharmaceuticals, Llc Méthodes et compositions pouvant être utilisées en vue du traitement de maladies myéloprolifératives et d'autres maladies prolifératives
WO2013043569A1 (fr) * 2011-09-20 2013-03-28 Vical Incorporated Immunothérapie combinée à action antitumorale synergique faisant appel à des alloantigènes
WO2013066440A1 (fr) * 2011-07-29 2013-05-10 Medivation Prostate Therapeutics, Inc. Traitement du cancer du sein

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20160070188A (ko) * 2013-11-07 2016-06-17 데시페라 파마슈티칼스, 엘엘씨. 암치료에 유용한 tie2 키나아제의 억제 방법

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011123788A1 (fr) * 2010-04-01 2011-10-06 Duke University Compositions et méthodes de traitement du cancer
WO2011150198A1 (fr) * 2010-05-27 2011-12-01 Ambit Biosciences Corporation Composés azolyle urée et leurs procédés d'utilisation
WO2012097021A1 (fr) * 2011-01-11 2012-07-19 Glaxosmithkline Llc Combinaison
WO2013066440A1 (fr) * 2011-07-29 2013-05-10 Medivation Prostate Therapeutics, Inc. Traitement du cancer du sein
WO2013036232A2 (fr) * 2011-09-08 2013-03-14 Deciphera Pharmaceuticals, Llc Méthodes et compositions pouvant être utilisées en vue du traitement de maladies myéloprolifératives et d'autres maladies prolifératives
WO2013043569A1 (fr) * 2011-09-20 2013-03-28 Vical Incorporated Immunothérapie combinée à action antitumorale synergique faisant appel à des alloantigènes

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DONG, J.: "Overcoming Resistance To BRAF And MEK Inhibitors By Simultaneous Suppression Of CDK4", INTECH, 30 January 2013 (2013-01-30), XP055292361 *
MAZZIERI, R ET AL.: "Targeting The ANG2/TIE2 Axis Inhibits Tumor Growth And Metastasis By Impairing Angiogenesis And Disabling Rebounds Of Proangiogenic Myeloid Cells", CELL, vol. 19, 12 April 2011 (2011-04-12), pages 512 - 526, XP028202041 *
See also references of EP3065549A4 *

Cited By (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE48731E1 (en) 2012-06-07 2021-09-14 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US10570202B2 (en) 2014-02-04 2020-02-25 Pfizer Inc. Combination of a PD-1 antagonist and a VEGFR inhibitor for treating cancer
US10800846B2 (en) 2015-02-26 2020-10-13 Merck Patent Gmbh PD-1/PD-L1 inhibitors for the treatment of cancer
WO2016191401A1 (fr) * 2015-05-27 2016-12-01 Albert Einstein College Of Medicine, Inc. Test actif tmem et ses utilisations pour le diagnostic, le pronostic et le traitement de tumeurs
US10869924B2 (en) 2015-06-16 2020-12-22 Merck Patent Gmbh PD-L1 antagonist combination treatments
US10322192B2 (en) 2016-03-02 2019-06-18 Eisai R&D Management Co., Ltd. Eribulin-based antibody-drug conjugates and methods of use
US10548986B2 (en) 2016-03-02 2020-02-04 Eisai R&D Management Co., Ltd. Eribulin-based antibody-drug conjugates and methods of use
US10690673B2 (en) 2016-03-29 2020-06-23 Mayo Foundation For Medical Education And Research Method of treating cancer metastasis by CDK 4/6 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
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AU2013404949B2 (en) 2018-10-18
CA2929715A1 (fr) 2015-05-14
EP3065549A4 (fr) 2017-05-24
CN108464981A (zh) 2018-08-31
EP3065549A1 (fr) 2016-09-14
JP2017500371A (ja) 2017-01-05
CN105873440B (zh) 2018-06-01
CN108464981B (zh) 2022-06-24
AU2013404949A1 (en) 2016-05-26

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