`(10) Patent No.:
`a2) United States Patent
`Laneetal.
`(45) Date of Patent:
`Apr. 2, 2013
`
`
`US008410131B2
`
`(54) CANCER TREATMENT
`(75)
`Inventors: Heidi Lane, Basel (CH); Terence
`O’Reilly, Basel (CH); Jeanette
`Marjorie Wood, Biel-Benken (CH)
`
`(73) Assignee: Novartis Pharmaceuticals
`Corporation, East Hanover, NJ (US)
`
`(*) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 1189 days.
`
`(21) Appl. No.:
`
`10/468,520
`
`(22)
`
`PCTFiled:
`
`Feb. 18, 2002
`
`(86) PCT No.:
`
`PCT/EP02/01714
`
`7/2002 Bates etal. vcs 427/2.1
`2002/0098278 Al
`
`5/2003 Segaletal.
`oo 604/509
`2003/0100886 Al
`5/2003 Scott et ab. essen 604/509
`2003/0100887 Al
`FOREIGN PATENT DOCUMENTS
`520722
`12/1992
`EP
`566226
`10/1993
`EP
`787722
`8/1997
`EP
`837063
`4/1998
`EP
`1074263
`2/2001
`EP
`1074263
`11/2006
`EP
`94/09010
`4/1994
`WO
`9410202 Al
`5/1994
`WO
`9503283 Al
`2/1995
`WO
`94/1669 1
`6/1995
`WO
`95/28406
`10/1995
`WO
`9630347 Al
`10/1996
`WO
`9633980 Al
`10/1996
`WO
`9641807
`12/1996
`WO
`9702266 Al
`1/1997
`WO
`9730034 Al
`8/1997
`WO
`9735575 Al
`10/1997
`WO
`9738983 Al
`10/1997
`WO
`§ 371 ()Q),
`9747317
`12/1997
`WO
`
`WO 9749688 Al=12/1997
`(2), (4) Date:
`Jan. 27, 2004
`WO
`98/09970
`3/1998
`WO
`9810767 A2
`3/1998
`WO
`9811223 Al
`3/1998
`WO
`9811908
`3/1998
`WO
`9835958 Al
`8/1998
`WO
`9917804 Al
`4/1999
`WO
`99038654 Al
`8/1999
`WO
`0009495
`2/2000
`WO
`0027820
`5/2000
`WO
`0037502
`6/2000
`WO
`0059509
`10/2000
`WO
`01/51049
`7/2001
`WO
`0149338
`7/2001
`WO
`0187372
`11/2001
`WO
`0197809
`12/2001
`
`(87) PCT Pub. No.: WO02/066019
`
`PCT Pub. Date: Aug. 29, 2002
`
`(65)
`
`Prior Publication Data
`
`US 2004/0147541 Al
`
`Jul. 29, 2004
`
`(30)
`
`Foreign Application Priority Data
`
`Feb. 19, 2001
`Oct. 17,2001
`
`(GB) we ecceceseneeectenenes 0104072.4
`(GB) wee ceseneeeeeneeenee 0124957.2
`
`(51)
`
`Int. Cl.
`(2006.01)
`AGIK 31/436
`(2006.01)
`AGIP 35/00
`(52) US. Cd. ccc ceecctenecenteneeecessesensnecassenees 514/291
`(58) Field of Classification Search «0.0.0.0... None
`See application file for complete search history.
`
`(56)
`
`References Cited
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`(Continued)
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`OTHER PUBLICATIONS
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`et al. (eds). 2008; pp. 131-150.*
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`Zhuet al. (“Inhibition of tumor growth and metastasis by targeting
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`Shi et al. (‘Rapamycin enhances apoptosis and increasessensitivy to
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`
`(Continued)
`
`Primary Examiner — Kortney L Klinkel
`(74) Attorney, Agent, or Firm — Ann R. Pokalsky, Esq.;
`Dilworth & Barrese, LLP
`
`(57)
`
`ABSTRACT
`
`Rapamycin derivatives have interesting effects in the treat-
`mentof solid tumors, optionally in combination with a che-
`motherapeutic agent.
`
`9 Claims, No Drawings
`
`West-Ward Pharm.
`Exhibit 1050
`Page 001
`
`West-Ward Pharm.
`Exhibit 1050
`Page 001
`
`
`
`US 8,410,131 B2
`Page 2
`
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`02/05791
`1/2002
`0213802
`2/2002
`0240000
`5/2002
`02/080975
`10/2002
`02080975
`10/2002
`02/0984 16
`12/2002
`
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`Shi et al., “Rapamycin Enhances Apoptosis and Increases Sensitivity
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`Geoergeret al., “Antitumor Activity of the Rapamycin Analog CCI-
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`Zhong et al., “Modulation of Hypoxia-inductible Factor 1-alpha
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`Zhong et al. “Modulation of Hypoxia-Inducible Factor 1-alpha
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`
`Geoergeret al. “Antitumor Activity of the Rapamycin Analog CCI-
`779 in Human Primitive Neuroectodermal Tumor/Medulloblastoma
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`Res 2001, 61(¢ 4): 1527-1532.
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`Antiangiogenesis”, Chirurgisches Forum Fuer Experimentelle and.
`Klinische Forschung, 2001, 37-39.
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`by Blocking Both Mitogen-activated Protein Kinase and p70 S6
`Kinase Pathways”; Cancer Research 2000, 60: 2104-2107.
`Hallenslebenetal., “Identification of a New Metabolite of Macrolide
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`MassSpectrometry”; J Am Soc Mass Spectrom 2000, 11: 516-525.
`Majewski et al., The immunosuppressive macrolide RAD inhibits
`growth of human Ebstein-Barr virus-transformed B lymphocytesin
`vitro and in vivo: A potential approact to prevention and treatment of
`posttransplant lymphoproliferative disorders; PNAS 2000, 97(8):
`4285-4290.
`Mordenti et al., “Efficacy and Concentration-Response of Murine
`Anti-VEGF Monoclonal Antibody in Tumor-Bearing Mice and.
`Extrapolation to Humans”; Toxicologic Pathology 1999, 27(1):
`14-21.
`O’Reilly et al., “Angiostatin: A Novel Angiogenesis Inhibitor That
`Mediates the Suppression of Metastases by a Lewis Lung Carci-
`noma”; Cell 1994, 79: 315-328.
`Inhibitor of
`O’Reilly et
`al.,
`“Endostatin: An Endogeneous
`Angiogenesis and Tumor Growth”; Cell 1997, 88: 277-285.
`Prewett et al., “Antivascular Endothelial Growth Factor Receptor
`(Fetal Liver Kinase 1) Monocolnal Antibody Inhibits Tumor
`Angiogenesis and Growth of Several Mouse and Human Tumors”;
`Cancer Research 1999, 59: 5209-5218.
`Yuan et al. “Time-dependent vascular regression and permeability
`changesin established human tumor xenografts induced by an anti-
`vascular endothelial growth factor/vascular permeability factor anti-
`body”; Proc. Natl. Acad. Sci. 1996, 93: 14765-14770.
`Zhu et al., “Inhibition of Vascular Endothelial Growth Factor-in-
`duced Receptor Activation with Anti-Kinase Insert Domain-contain-
`ing Receptor Single-Chain Antibodies from a Phage Display
`Library”; Cancer Research 1998, 58: 3209-3214.
`Zhaoyou, Modern Oncology 2000, Ist press. (English summary pro-
`vided) English summary only considered.
`
`* cited by examiner
`
`West-Ward Pharm.
`Exhibit 1050
`Page 002
`
`West-Ward Pharm.
`Exhibit 1050
`Page 002
`
`
`
`US 8,410,131 B2
`
`1
`CANCER TREATMENT
`
`The present invention relates to a new use, in particular a
`new use for a compound group comprising rapamycin and
`derivatives thereof.
`
`5
`
`Rapamycin is a known macrolide antibiotic produced by
`Streptomyces hygroscopicus. Suitable derivatives of rapamy-
`cin include e.g. compounds of formula I
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`
`
`wherein
`
`R, is CH; or C_,alkynyl,
`R, is H or —CH,—CH,OH,and
`X is —O,(H,H) or (H,OH)
`provided that R, is other than H when X is —O and R,is CH.
`Compoundsofformula I are disclosed e.g. in U.S. Pat. Nos.
`5,665,772; 6,440,990; 5,985,890; and 6,200,985, which are
`incorporated herein by reference. They may be prepared as
`disclosed or by analogy to the procedures described in these
`references.
`
`Preferred compoundsare 32-deoxorapamycin, 16-pent-2-
`ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S)-di-
`hydro-rapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-40-O-
`(2-hydroxyethyl)-rapamycin and, more preferably, 40-O-(2-
`hydroxyethyl)-rapamycin (referred thereafter as Compound
`A), disclosed as Example 8 in U.S. Pat. Nos. 5,665,772 and
`6,440,990.
`Compounds of formula I have, on the basis of observed
`activity, e.g. binding to macrophilin-12 (also known as
`FK-506 binding protein or FKBP-12), e.g. as described in
`WO 94/09010, WO 95/16691 or WO 96/41807, been found to
`be useful e.g. as immunosuppressant, e.g. in the treatment of
`acute allograft rejection. It has now been found that Com-
`pounds of formula I have potent antiproliferative properties
`which make them useful for cancer chemotherapy, particu-
`larly of solid tumors, especially of advanced solid tumors.
`Thereis still the need to expand the armamentarium of cancer
`treatmentofsolid tumors, especially in cases where treatment
`with anticancer compounds is not associated with disease
`regression or stabilization.
`In accordance with the particular findings of the present
`invention, there is provided:
`1.1 A methodfor treating solid tumors in a subject in need
`thereof, comprising administering to said subject a thera-
`peutically effective amount of a compound of formula I.
`
`2
`1.2 A method for inhibiting growth of solid tumors in a
`subject in need thereof, comprising administering to said
`subject a therapeutically effective amount of a compound
`of formula I.
`
`1.3 A methodfor inducing tumorregression, e.g. tumor mass
`reduction, in a subject in need thereof, comprising admin-
`istering to said subject a therapeutically effective amount
`of a compound of formula I.
`1.4 A methodfor treating solid tumorinvasiveness or symp-
`toms associated with such tumor growth in a subject in
`need thereof, comprising administering to said subject a
`therapeutically effective amount of a compound of formula
`I.
`
`1.5 A method for preventing metastatic spread of tumours or
`for preventing or inhibiting growth of micrometastasis in a
`subject in need thereof, comprising administering to said
`subject a therapeutically effective amount of a compound
`of formula I.
`
`By “solid tumors” are meant tumors and/or metastasis
`(whereever located) other than lymphatic cancer, e.g. brain
`and other central nervous system tumors (eg. tumors of the
`meninges, brain, spinal cord, cranial nerves andotherparts of
`central nervous system, e.g. glioblastomas or medulla blas-
`tomas); head and/or neck cancer; breast tumors; circulatory
`system tumors(e.g. heart, mediastinum and pleura, and other
`intrathoracic organs, vascular tumors and tumor-associated
`vascular tissue); excretory system tumors(e.g. kidney, renal
`pelvis, ureter, bladder, other and unspecified urinary organs);
`gastrointestinal tract tumors(e.g. oesophagus, stomach, small
`intestine, colon, colorectal, rectosigmoid junction, rectum,
`anus and anal canal), tumors involving the liver and intrahe-
`patic bile ducts, gall bladder, other and unspecified parts of
`binary tract, pancreas, other and digestive organs); head and
`neck;oral cavity (lip, tongue, gum,floor ofmouth,palate, and
`other parts of mouth, parotid gland, and other parts of the
`salivary glands, tonsil, oropharynx, nasopharynx, pyriform
`sinus, hypopharynx, and othersites in the lip, oral cavity and
`pharynx); reproductive system tumors (e.g. vulva, vagina,
`Cervix uteri, Corpusuteri, uterus, ovary, and othersites asso-
`ciated with female genital organs, placenta, penis, prostate,
`testis, and other sites associated with male genital organs);
`respiratory tract tumors (e.g. nasal cavity and middle ear,
`accessory sinuses, larynx, trachea, bronchus and lung,e.g.
`smallcell lung cancer or non-small cell lung cancer); skeletal
`system tumors (e.g. bone and articular cartilage of limbs,
`bone articular cartilage and other sites); skin tumors(e.g.
`malignant melanomaofthe skin, non-melanomaskin cancer,
`basal cell carcinoma of skin, squamous cell carcinoma of
`skin, mesothelioma, Kaposi’s sarcoma); and tumors involv-
`ing other tissues incluing peripheral nerves and autonomic
`nervous system, connective and soft tissue, retroperitoneum
`and peritoneum, eye and adnexa, thyroid, adrenal gland and
`other endocrine glands andrelated structures, secondary and
`unspecified malignant neoplasm of lymph nodes, secondary
`malignant neoplasm ofrespiratory and digestive systems and
`secondary malignant neoplasm ofothersites.
`Where hereinbefore and subsequently a tumor, a tumor
`disease, a carcinomaor a cancer is mentioned, also metastasis
`in the original organ or tissue and/or in any other location are
`implied alternatively or in addition, whatever the location of
`the tumor and/or metastasis is.
`In a series of further specific or alternative embodiments,
`the present invention also provides
`1.6 A method for the treatment of a disease associated with
`deregulated angiogenesis in a subject in needthereof, com-
`prising administering to said subject a therapeutically
`West-Ward Pharm.
`Exhibit 1050
`Page 003
`
`West-Ward Pharm.
`Exhibit 1050
`Page 003
`
`
`
`US 8,410,131 B2
`
`10
`
`15
`
`3
`effective amount of rapamycinora derivative thereof, e.g.
`CC1779, ABT578 or a compoundof formulaI.
`1.7A methodfor inhibiting or controlling deregulated anglo-
`genesis in a subject in need thereof, comprising adminis-
`tering to said subjecta therapeutically effective amount of 5
`rapamycin ora derivative thereof, e.g. CCI779, ABT578 or
`a compound of formulaI.
`1.8 A method for enhancing the activity of a chemotherapeu-
`tic agent or for overcomingresistance to a chemotherapeu-
`tic agent in a subject in need thereof, comprising adminis-
`tering to said subject a therapeutically effective amount of
`rapamycin ora derivative thereof, e.g. CCI779, ABT578 or
`a compoundof formulaI, either concomitantly or sequen-
`tially with said chemotherapeutic agent.
`1.9 A method according to 1.8 wherein the chemotherapeutic
`agent
`is an inhibitor of signal
`transduction pathways
`directed either against host cells or processes involved in
`tumorformation and/or metastases formationor utilised by
`tumourcells for proliferation, survival, differentiation or
`developmentof drug resistance.
`1.10 A method as indicated above, wherein rapamycin or a
`derivative thereof, e.g. CCI779, ABT578 or a compound of
`formula I is administered intermittently.
`CCI1779 is a rapamycin derivative, 1.e. 40-[3-hydroxy-2-
`(hydroxymethyl)-2-methylpropanoate]|-rapamycin or a phar-
`maceutically acceptable salt thereof, and is disclosed e.g. in
`USS. Pat. No. 5,362,718. ABT578 is a 40-substituted rapamy-
`cin derivative further comprising a diene reduction.
`Examples of diseases associated with deregulated angio- 30
`genesis include without limitation e.g. neoplastic diseases,
`e.g. solid tumors. Angiogenesis is regarded as a prerequisite
`for those tumors which grow beyond a certain diameter, e.g.
`about 1-2 mm.
`In a series of further specific or alternative embodiments, 35
`the present invention also provides:
`2.1 A compound of formula I for use in any methodas defined
`under 1.1 to 1.5 above.
`
`20
`
`25
`
`2.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578
`or a compound of formula I for use in any method as
`defined under 1.6 to 1.10 above or 7 below.
`3.1 A compoundof formula I for use in the preparation of a
`pharmaceutical composition for use in any method as
`defined under 1.1 to 1.5 above.
`3.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578
`or a compound of formula I for use in the preparation of a
`pharmaceutical composition for use in any method as
`defined under 1.6 to 1.10 above or 7 below.
`4.1 A pharmaceutical composition for use in any method as
`defined under 1.1 to 1.5 above comprising a compound of
`formula I together with one or more pharmaceutically
`acceptable diluents or carriers therefor.
`4.2 A pharmaceutical composition for use in any method as
`defined under 1.6 to 1.10 above or 7 below comprising
`rapamycin ora derivative thereof, e.g. CCI779, ABT578 or
`a compoundof formula I, e.g. Compound A, together with
`one or more pharmaceutically acceptable diluents or car-
`riers therefor.
`5.1 A pharmaceutical combination comprising a) a first agent
`which is rapamycin or a derivative thereof, e.g. CCI779,
`ABT578 or a compoundof formula I, e.g. Compound A,
`and b) a co-agent which is a chemotherapeutic agent, e.g.
`as defined hereinafter.
`
`5.2 A pharmaceutical combination comprising an amountof
`a) a first agent which is rapamycin or a derivative thereof,
`e.g. CCI779, ABT578 or a compound of formulaI, e.g.
`Compound A, and b) a co-agent which is a chemothera-
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`peutic agent selected from the compoundsdefined under
`paragraph(iv) or (v) below, to produce a synergistic thera-
`peutic effect.
`6. A methodas defined above comprising co-administration,
`é.g. concomitantly or in sequence, of a therapeutically
`effective amount of rapamycin or a derivative thereof, e.g.
`CCI779, ABT578 or a compound of formula I, e.g. Com-
`pound A, and a second drug substance, said second drug
`substance being a chemotherapeutic agent, e.g. as indi-
`cated hereinafter.
`
`7. A methodfor treating post-transplant lymphoproliferative
`disorders or a lymphatic cancer, e.g. for treating tumor
`invasiveness or symptoms associated with such tumor
`growth in a subject in need thereof, comprising co-admin-
`istering to said subject, e.g. concomitantly or in sequence,
`ofrapamycin or a derivative thereof, e.g. CCI779, ABT578
`or a compound of formula I, e.g. Compound A, and a
`second drug substance, said second drug substance being a
`chemotherapeutic agent, e.g. as indicated hereinafter.
`By“lymphatic cancer” are meante.g. tumors of blood and
`lymphatic system (e.g. Hodgkin’s disease, Non-Hodgkin’s
`lymphoma, Burkitt’s lymphoma, AIDS-related lymphomas,
`malignant immunoproliferative diseases, multiple myeloma
`and malignant plasma cell neoplasms, lymphoid leukemia,
`myeloid leukemia, acute or chronic lymphocytic leukemia,
`monocytic leukemia, other leukemias of specified cell type,
`leukemia of unspecified cell type, other and unspecified
`malignant neoplasms of lymphoid, haematopoletic and
`related tissues, for example diffuse large cell lymphoma,
`T-cell lymphomaor cutaneous T-cell lymphoma).
`Bythe term “chemotherapeutic agent”is meant especially
`any chemotherapeutic agent other than rapamycinor a deriva-
`tive thereof. It includes but is not limited to,
`i. an aromatase inhibitor,
`il. an antiestrogen, an anti-androgen (especially in the case of
`prostate cancer) or a gonadorelin agonist,
`ili. a topoisomerase | inhibitor or a topoisomeraseIJ inhibitor,
`iv. a microtubule active agent, an alkylating agent, an antine-
`oplastic antimetabolite or a platin compound,
`v. a compoundtargeting/decreasing a protein or lipid kinase
`activity or a protein or lipid phosphatase activity, a further
`anti-angiogenic compound or a compound which induces
`cell differentiation processes,
`vi. a bradykinin I receptor or an angiotensin IJ antagonist,
`vii. a cyclooxygenase inhibitor, a bisphosphonate, a histone
`deacetylase inhibitor, a heparanase inhibitor (prevents
`heparan sulphate degradation), e.g. PI-88, a biological
`response modifier, preferably a lymphokineorinterferons,
`e.g. interferon y, an ubiquitination inhibitor, or an inhibitor
`which blocks anti-apoptotic pathways,
`viii. an inhibitor of Ras oncogenic isoforms, e.g. H-Ras,
`K-Ras or N-Ras, or a famesyl transferase inhibitor, e.g.
`L-744,832 or DK8G557,
`ix. a telomerase inhibitor, e.g. telomestatin,
`xX. a protease inhibitor, a matrix metalloprotelnase inhibitor, a
`methionine aminopeptidase inhibitor, e.g. bengamide or a
`derivative thereof, or a proteosomeinhibitor, e.g. PS-341.
`The term “aromatase inhibitor” as used herein relates to a
`compound which inhibits the estrogen production, i.e. the
`conversion of the substrates androstenedione and testoster-
`one to estrone and estradiol, respectively. The term includes,
`butis not limited to steroids, especially atamestane, exemes-
`tane and formestane and, in particular, non-steroids, espe-
`cially aminoglutethimide, roglethimide, pyridoglutethimide,
`trilostane, testolactone, ketokonazole, vorozole, fadrozole,
`anastrozole and letrozole. Exemestane can be administered,
`e.g., in the form as it is marketed, e.g. under the trademark
`West-Ward Pharm.
`Exhibit 1050
`Page 004
`
`West-Ward Pharm.
`Exhibit 1050
`Page 004
`
`
`
`US 8,410,131 B2
`
`5
`AROMASIN™. Formestane can be administered, e.g., in the
`form as it
`is marketed, e.g. under the trademark LEN-
`TARON™. Fadrozole can be administered, e.g., in the form
`as it is marketed, e.g. under the trademark AFEMA™.Anas-
`trozole can be administered, e.g., in the form asit is marketed,
`e.g. under the trademark ARIMIDEX™.,Letrozole can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark FEMARA™ or FEMAR™ Aminoglutethimide
`can be administered, e.g., in the form as it is marketed, e.g.
`under the trademark ORIMETEN™. A combination of the
`
`invention comprising a chemotherapeutic agent which is an
`aromatase inhibitor is particularly useful for the treatment of
`hormonereceptorpositive tumors, e.g. breast tumors.
`The term “antiestrogen” as used herein relates to a com-
`pound which antagonizes the effect of estrogensat the estro-
`gen receptor level. The term includes, but is not limited to
`tamoxifen, fulvestrant, raloxifene and raloxifene hydrochlo-
`ride. Tamoxifen can be administered, e.g., in the form as it is
`marketed, e.g. under the trademark NOLVADEX™. Ralox-
`ifene hydrochloride can be administered, e.g., in the form as
`it is marketed, e.g. under the trademark EVISTA™. Fulves-
`trant can be formulated as disclosed in U.S. Pat. No. 4,659,
`516 or it can be administered, e.g., in the form as it is mar-
`keted, e.g. under the trademark FASLODE™.A combination
`of the invention comprising a chemotherapeutic agent which
`is an antiestrogen is particularly useful for the treatment of
`estrogen receptor positive tumors, e.g. breast tumors.
`The term “anti-androgen” as used herein relates to any
`substance whichis capable ofinhibiting the biological effects
`of androgenic hormones and includes, but is not limited to,
`bicalutamide (CASODEX™), which can be formulated, e.g.
`as disclosed in U.S. Pat. No. 4,636,505.
`The term “gonadorelin agonist” as used herein includes,
`butis notlimited to abarelix, goserelin and goserelin acetate.
`Goserelin is disclosed in U.S. Pat. No. 4,100,274 and can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark ZOLADEX™. Abarelix can be formulated,e.g. as
`disclosed in U.S. Pat. No. 5,843,901.
`The term “topoisomerase I
`inhibitor” as used herein
`includes, but is not limited to topotecan, irinotecan, 9-nitro-
`camptothecin and the macromolecular camptothecin conju-
`gate PNU-166148 (compound Al in WO99/17804). Irinote-
`can can be administered, e.g. in the form as it is marketed, e.g.
`under the trademark CAMPTOSAR™. Topotecan can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark HYCAMTIN™.
`inhibitor’ as used herein
`The term “topoisomerase II
`includes, but is not limited to the anthracyclines such as
`doxorubicin (including liposomal formulation, e.g. CAE-
`LYX™), daunorubicin, epirubicin, idarubicin and nemorubi-
`cin, the anthraquinones mitoxantrone and losoxantrone, and
`the podophillotoxines etoposide and teniposide. Etoposide
`can be administered, e.g. in the form as it is marketed, e.g.
`under the trademark ETOPOPHOS™. Teniposide can be
`administered, e.g. in the form asit is marketed, e.g. under the
`trademark VM 26-BRISTOL™Doxorubicin can be admin-
`
`istered, e.g. in the form as it is marketed, e.g. under the
`trademark ADRIBLASTIN™. Epirubicin can be adminis-
`tered, e.g. in the form as it is marketed, e.g. under the trade-
`mark FARMORUBICIN™. Idarubicin can be administered,
`e.g. in the form as it is marketed, e.g. under the trademark
`ZAVEDOS™.Mitoxantrone can be administered, e.g. in the
`form as
`it
`is marketed, eg. under
`the
`trademark
`NOVANTRON™.
`
`The term “microtubule active agent” relates to microtubule
`stabilizing and microtubule destabilizing agents including,
`but not limitedto taxanes, e.g. paclitaxel and docetaxel, vinca
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`alkaloids,e.g., vinblastine, especially vinblastine sulfate, vin-
`cristine especially vincristine sulfate, and vinorelbine, disco-
`dermolides and epothilones and derivatives thereof, e.g.
`epothilone B ora derivative thereof. Paclitaxel may be admin-
`istered e.g. in the form as it is marketed, e.g. TAXOL™.
`Docetaxel can be administered, e.g., in the form as it is mar-
`keted, e.g. under the trademark TAXOTERE™.Vinblastine
`sulfate can be administered,e.g., in the form asit is marketed,
`e.g. under the trademark VINBLASTIN R.P.™. Vincristine
`sulfate can be administered,e.g., in the form asit is marketed,
`e.g. under the trademark FARMISTIN™. Discodermolide
`can be obtained, e.g., as disclosed in U.S. Pat. No. 5,010,099.
`The term “alkylating agent”as used herein includes, butis
`not limited to cyclophosphamide, ifosfamide, melphalan or
`nitrosourea (BCNU or Gliadel™). Cyclophosphamide can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark CYCLOSTIN™. Ifosfamide can be administered,
`e.g., in the form as it is marketed, e.g. under the trademark
`HOLOXAN™,
`
`The term “antineoplastic antimetabolite” includes, butis
`not
`limited to 5-fluorouracil, capecitabine, gemcitabine,
`methotrexate and edatrexate. Capecitabine can be adminis-
`tered, e.g., in the form as it is marketed, e.g. underthe trade-
`mark XELODA™. Gemcitabine can be administered, e.g., in
`the form as
`it
`is marketed, e.g. under the trademark
`GEMZAR™,
`
`The term “platin compound”as used herein includes, butis
`not limited to carboplatin, cis-platin and oxaliplatin. Carbo-
`platin can be administered, e.g., in the form asit is marketed,
`e.g. under the trademark CARBOPLAT™.Oxaliplatin can be
`administered, e.g., in the form as it is marketed, e.g. under the
`trademark ELOXATIN™.
`The term “compoundstargeting/decreasing a protein or
`lipid kinase activity or further anti-angiogenic compounds”
`as used herein includes, but is not limited to protein tyrosine
`kinase and/or serine and/or threonine kinase inhibitors or
`
`lipid kinase inhibitors, e.g. compoundstargeting, decreasing
`or inhibiting the activity of the epidermal growth factor fam-
`ily ofreceptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4
`as homo- or heterodimers), the vascular endothelial growth
`factor family of receptor tyrosine kinases (VEGFR), the
`platelet-derived growth factor-receptors (PDGFR), the fibro-
`blast growth factor-receptors (FGFR),the insulin-like growth
`factor receptor 1 (IGF-1R), the Trk receptor tyrosine kinase
`family, the Axl receptor tyrosine kinase family, the Ret recep-
`tor tyrosine kinase, the Kit/SCFR receptor tyrosine kinase,
`membersof the c-Abl family and their gene-fusion products
`(e.g. BCR-Abl), membersof the protein kinase C (PKC) and
`Raffamily of serine/threonine kinases, members ofthe MEK,
`SRC, JAK, FAK, PDKor PI(3) kinase family, or of the PI(3)-
`kinase-related kinase family, and/or members of the cyclin-
`dependent kinase family (CDK) and anti-anglogenic com-
`pounds having another mechanism for their activity, e.g.
`unrelated to protein or lipid kinase inhibition.
`Compounds whichtarget, decreaseor inhibit the activity of
`VEGERare especially compounds, proteins or antibodies
`which inhibit the VEGF receptor tyrosine kinase, inhibit a
`VEGFreceptor or bind to VEGF,andare in particular those
`compounds, proteins or monoclonal antibodies generically
`and specifically disclosed in WO 98/35958, e.g. 1-(4-chlo-
`roanilino)-4-(4-pyridylmethy])phthalazine or a pharmaceuti-
`cally acceptable salt thereof, e.g. the succinate, or in WO
`00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO
`00/27819 and EP 0 769 947; those as described by M. Prewett
`et al in Cancer Research 59 (1999) 5209-5218, by F. Yuan et
`al in Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770,
`December 1996, by Z. Zhu et al in Cancer Res. 58, 1998,
`West-Ward Pharm.
`Exhibit 1050
`Page 005
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`West-Ward Pharm.
`Exhibit 1050
`Page 005
`
`
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`US 8,410,131 B2
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`7
`3209-3214, and by J. Mordentiet al in Toxicologic Pathology,
`Vol. 27, no. 1, pp 14-21, 1999; in WO 00/37502 and WO
`94/10202; Angiostatin™, described by M.S. O’Reillyet al,
`Cell 79, 1994, 315-328; Endostatin™, described by M.S.
`O’Reilly et al, Cell 88, 1997, 277-285; anthranilic acid
`amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF
`antibodies or anti-VEGFreceptor antibodies, e.g. RhuMab.
`By antibody is meant intact monoclonalantibodies, poly-
`clonal antibodies, multispecific antibodies formed from at
`least 2 intact antibodies, and antibodies fragments so long as
`they exhibit the desired biologicalactivity.
`Compounds whichtarget, decreaseor inhibit the activity of
`the epidermal growth factor receptor family are especially
`compounds, proteins or antibodies which inhibit members of
`the EGFreceptor tyrosine kinase family, e.g. EGF receptor,
`ErbB2, ErbB3 and ErbB4 or bind to EGF or EGFrelated
`ligands, and are in particular those compounds, proteins or
`monoclonal antibodies generically and specifically disclosed
`in WO 97/02266, e.g. the compound ofex. 39, or in EP 0564
`409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722,
`EP 0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO
`97/30034, WO 97/49688, WO 97/38983 and, especially, WO
`96/30347 (e.g. compound known as CP 358774), WO
`96/33980 (e.g. compound ZD 1839) and WO 95/03283(e.g.
`compound ZM105180); e.g. trastuzumab (Herpetin®), cetux-
`imab, Iressa, OSI-774, CI-1033, EKB-569, GW-2016, E1.1,
`E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3.
`Compounds whichtarget, decreaseor inhibit the activity of
`PDGERare especially compounds which inhibit the PDGF
`receptor, e.g. a N-phenyl-2-pyrimidine-aminederivative,e.g.
`imatinib.
`
`Compounds whichtarget, decreaseor inhibit the activity of
`c-Abl family membersandtheir gene fusion products, e.g. a
`N-phenyl-2-pyrimidine-amine derivative,
`e.g.
`imatinib;
`PD180970; AG957; or NSC 680410.
`Compounds whichtarget, decreaseor inhibit the activity of
`protein kinase C, Raf, MEK, SRC, JAK, FAK and PDK
`family members, or PI(3) kinase or PI(3) kinase-related fam-
`ily members, and/or membersof the cyclin-dependent kinase
`family (CDK)are especially those staurosporine derivatives
`disclosed in EP 0 296 110, e.g. midostaurin; examples of
`further compounds include e.g. UCN-01, safingol, BAY
`43-9006, Bryostatin 1, Perifosine; IImofosine; RO 318220
`and RO 320432; GO 6976;
`Isis 3521; or LY333531/
`LY379196.
`
`Further anti-angiogenic compoundsare e.g. thalidomide
`(THALOMID)and TNP-470.
`Compounds whichtarget, decreaseor inhibit the activity of
`a protein or lipid phosphatase are e.g. inhibitors of phos-
`phatase 1, phosphatase 2A, PTEN or CDC25, e.g. okadaic
`acid or a derivative thereof.
`Compounds which induce cell differentiation processes
`are e.g. retinoic acid, a-, y- or 6-tocopherol or a-, y- or
`6-tocotrienol.
`
`The term cyclooxygenase inhibitoras used herein includes,
`but is not limited to, e.g. celecoxib (Celebrex”), rofecoxib
`(Vioxx*), etoricoxib, valdecoxib or a 5-alkyl-2-arylami-
`nophenyl