(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`"9’W°"“‘“1‘:3駧:';?,i,‘;f‘,;‘$:2;°’g”“””“°“
`
`l||||||||||||||||||||||||||||||IllIll|||||||||||H|||||||||||||||||||||||||||||||||||
`
`(43) International Publication Date
`29 August 2002 (29.03.2002)
`
`(10) International Publication Number
`W0 ()2/066019 A2
`
`(51) International Patent Classiiication7:
`
`A6lK 31/00
`
`[NZ/CH]: In den Klccmattcn 18, CH-4105 Bicl-Bcnkcn
`(C11).
`
`(21) InternationalApplication Number:
`
`PCT/EP02/01714
`
`(22) InternationalFiling Date: 18 February 2002(18,02,2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data,
`01040724
`0124957.2
`
`19 February 2001 (19.02.2001)
`17 October 2001 (17.10.2001)
`‘
`
`GB
`GB
`
`(74) Agent: BECKER, Konrad; Novattis AG, Corporate
`Intellectual Property, Patent & ’l‘mdemaIk Department,
`CH—4002 Basel (CH).
`
`Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA-. BB. BG. BR, BY, BZ, CA. CH. CN. CO. CR, CU.
`CZ, DE, DK, DIVI, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`
`HR, HU, ID, IL, IN, Is, JP, K13, KG, KP, KR, KZ, LC, LK,
`l‘T= ‘U’ ‘M MA= Mu MK MN MX7 N0’ N7'« OM PH’
`PL PT R0: RUv 5E= 5G 5L SK TJ« TM TN« TR« TT« “*7
`Us, UZ, VN. YU, ZA, zw.
`
`(71) Applicant (for all desigr1aledStales except A77 US): NO-
`VARTIS AG [CH/CH]; Lichtstmssc 351 CH_4056 Base]
`(CH)
`
`_
`g
`_
`Designated States (regional): Eurasian patent (AM, AZ,
`BY, KG, K7,, MD, RU, TJ, TM), Eumpean patent (AT, BE,
`CH, CY, DE, DK, ES, Fl, FR, GB, GR, IE, IT, LU, MC,
`
`(71) Applicant (for AT only): NOVARTIS-ERFINDUNGEN
`VERVVALTUNGSGESELLSCHAFT l\l.B.H. [AT/AT]:
`Brunner Strasse 59, A—l230 Vienna (AT).
`
`(72) Inventors; and
`LANE, Heidi
`(75) Inventors/Applicants (for US only:
`[CH/CH]; Lehenmattstr,
`189, CH—4052 Basel
`(CH).
`O’REILLY, Terence
`[CA/CH]; Drahtzugstrasse
`51,
`CH—4057 Basel
`(CH). WOOD, Jeanette, Marjorie
`
`NL’ PT’ SE’ TR)‘
`
`PllbliSl19d1
`— without international search report and to be republished
`
`upon receipt ofthat report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`once Notes on Codes and A ltbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`O02/066019A2
`
`(54) Title: CANCER 'l‘REA'l‘MEN'l‘
`
`(57) Abstract: Raparnycin derivatives have interesting effects in the treatment of solid tumours, optionally in combination with a
`chernolherzipeulic agent.
`
`West-Ward Phar
`Exhibit 10 '
`
`West-Ward Pharm.
`Exhibit 1055
`Page 001
`
`

`

`W0 02/066019
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`PCT/EP02/01714
`
`Cancer Treatment
`
`The present invention relates to a new use, in particular a new use for a compound group
`
`comprising rapamycin and derivatives thereof.
`
`Rapamycin is a known macroiide antibiotic produced by Streptomyces
`
`hygroscopicus. Suitable derivatives of rapamycin include e.g. compounds of
`formula I
`
`wherein
`
`R1 is CH3 or C3,ealkynyl,
`
`R2 is H or -CH2—CH2-OH, and
`
`X is =0, (H,H) or (H,OH)
`
`provided that R2 is other than H when X is =0 and R1 is CH3.
`
`Compounds of formula l are disclosed e.g. in WO 94109010, WO 95/16691 or W0 96l41807,
`
`which are incorporated herein by reference. They may be prepared as diclosed or by
`
`analogy to the procedures described in these references
`
`Preferred compounds are 32-deoxorapamycin, 16-pent-2-ynyloxy-32-deoxorapamycin. 16-
`
`pent-2-ynyloxy-32(8)-dihydro-rapamycin, 16-pent-2-ynyloxy-32(S)-dihydro-40-O-(2-
`
`hydroxyethy|)—rapamycin and, more preferably, 40-0-(2-hydroxyethyl)-rapamycin (referred
`
`thereafter as Compound A), disclosed as Example 8 in WC 94l09010.
`
`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 W0
`
`94/09010, WO 95116691 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 Compounds of formula I have potent antiproliferative properties which make them useful
`
`West-Ward Ph
`Exhibit 1
`Page
`
`West-Ward Pharm.
`Exhibit 1055
`Page 002
`
`

`

`W0 02/066019
`
`PCT/EP02/01714
`
`for cancer chemotherapy, particularly of solid tumors, especially of advanced solid tumors.
`
`There is still the need to expand the armamentarium of cancer treatment of solid 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 method for treating solid tumors in a subject in need thereof, comprising
`
`administering to said subject a therapeutically effective amount of a compound of
`
`formula I.
`
`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.
`
`A method for inducing tumor regression, e.g. tumor mass reduction, in a subject in
`
`need thereof, comprising administering to said subject a therapeutically effective
`
`amount of a compound of formula I.
`
`A method for treating solid tumor invasiveness or symptoms 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.
`
`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 and other parts of central nervous system, e.g.
`
`glioblastomas or medulla blastomas); 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 intrahepatic bile ducts, gall bladder,
`
`other and unspecified parts of biliary tract, pancreas, other and digestive organs); head and
`
`neck; oral cavity (lip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid
`
`gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriforrn
`
`sinus, hypopharynx, and other sites in the lip, oral cavity and pharynx); reproductive system
`
`tumors (e.g. vulva, vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sites
`
`West-Ward Pharm.
`Exhibit 1055
`Page 003
`
`

`

`W0 02/066019
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`PCT/EP02/01714
`
`associated 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. small cell 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 melanoma of the
`
`skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of
`
`skin, mesothelioma, Kaposi’s sarcoma); and tumors involving 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 and related structures, secondary and unspecified malignant neoplasm of
`
`lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and
`
`secondary malignant neoplasm of other sites.
`
`Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or 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 need thereof, comprising administering to said subject a therapeutically
`
`effective amount of rapamycin or a derivative thereof, e.g. CCl779, ABT578 or a
`
`compound of formula I.
`
`A method for inhibiting or controlling deregulated angiogenesis in a subject in need
`
`thereof, comprising administering to said subject a therapeutically effective amount of
`
`rapamycin or a derivative thereof, e.g. CCl779, ABT578 or a compound of formula I.
`
`A method for enhancing the activity of a chemotherapeutic agent or for overcoming
`
`resistance to a chemotherapeutic agent in a subject in need thereof, comprising
`
`administering to said subject a therapeutically effective amount of rapamycin or a
`
`derivative thereof, e.g. CCl779, ABT578 or a compound of formula l, either
`
`concomitantly or sequentially with said chemotherapeutic agent.
`
`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 tumor
`
`formation and/or metastases fonnation or utilised by tumour cells for proliferation,
`
`survival, differentiation or development of drug resistance.
`
`West-Ward Pharm.
`Exhibit 1055
`Page 004
`
`West-Ward Pharm.
`Exhibit 1055
`Page 004
`
`

`

`W0 02/066019
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`PCT/EP02/01714
`
`-4-
`
`1.10 A method as indicated above, wherein rapamycin or a derivative thereof, e.g. CC|779,
`
`ABT578 or a compound of formula l is administered intermittently.
`
`CCl779 is a rapamycin derivative, i.e. 40- [3-hydroxy-2-(hydroxymethyl)-2-methylpropa-
`
`noate]-rapamycin or a pharmaceutically acceptable salt thereof, and is disclosed e.g. in USP
`
`5,362,718. ABT578 is a 40—substituted rapamycin derivative further comprising a diene
`reduction.
`
`Examples of diseases associated with deregulated angiogenesis 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, the present invention also
`
`provides:
`
`2.1 A compound of formula I for use in any method as defined under 1.1 to 1.5 above.
`
`2.2 Rapamycin or a derivative thereof, e.g. CC|779, 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 compound of 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. CC|779, 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.
`
`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.
`
`A pharmaceutical composition for use in any method as defined under 1.6 to 1.10
`
`above or 7 below comprising rapamycin or a derivative thereof, e.g. CC|779, ABT578
`
`or a compound of formula I, e.g. Compound A, together with one or more
`
`pharmaceutically acceptable diluents or carriers therefor.
`
`A pharmaceutical combination ‘comprising a) a first agent which is rapamycin or a
`
`derivative thereof, e.g. CC|779, ABT578 or a compound of formula I, e.g. Compound
`
`A, and b) a co-agent which is a chemotherapeutic agent, e.g. as defined hereinafter.
`
`A pharmaceutical combination comprising an amount of a) a first agent which is
`
`rapamycin or a derivative thereof, e.g. CCl779, ABT578 or a compound of formula I,
`
`e.g. Compound A, and b) a co-agent which is a chemotherapeutic agent selected from
`
`West-Ward Pharm.
`Exhibit 1055
`Page 005
`
`

`

`W0 02/066019
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`PCT/EP02/01714
`
`the compounds defined under paragraph (iv) or (v) below, to produce a synergistic
`
`therapeutic effect.
`
`A method as defined above comprising co-administration, e.g. concomitantly or in
`
`sequence, of a therapeutically effective amount of rapamycin or a derivative thereof,
`
`e.g. CCl779, ABT578 or a compound of formula l, e.g. Compound A, and a second
`
`drug substance, said second drug substance being a chemotherapeutic agent, e.g. as
`indicated hereinafter.
`
`A method for 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—administering to said subject, e.g.
`
`concomitantly or in sequence, of rapamycin or a derivative thereof, e.g. CC|779,
`
`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 “|ymphatic cancer" are meant e.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, haematopoietic and related tissues, for
`
`example diffuse large cell lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma).
`
`By the term “chemotherapeutic agent” is meant especially any chemotherapeutic agent other
`
`than rapamycin or a derivative thereof. it includes but is not limited to,
`
`i.
`
`ii.
`
`an aromatase inhibitor,
`
`an antiestrogen, an anti-androgen (especially in the case of prostate cancer) or a
`
`gonadorelin agonist,
`
`a topoisomerase I inhibitor or a topoisomerase II inhibitor,
`
`a microtubule active agent, an alkylating agent, an antineoplastic antimetabolite or a
`
`platin compound,
`
`a compound targeting/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,
`
`a bradykinin 1 receptor or an angiotensin II antagonist,
`
`West-Ward Ph
`
`West-Ward Pharm.
`Exhibit 1055
`Page 006
`
`

`

`W0 02/066019
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`PCT/EP02/01714
`
`a cyclooxygenase inhibitor, a bisphosphonate, a histone deacetylase inhibitor, a
`
`heparanase inhibitor (prevents heparan sulphate degradation), e.g. Pl-88, a biological
`
`response modifier, preferably a lymphokine or interferons, e.g. interferon 7, an
`
`ubiquitination inhibitor, or an inhibitor which blocks anti—apoptotic pathways,
`
`an inhibitor of Ras oncogenic isoforms, e.g. H-Ras, K—Ras or N-Ras, or a farnesyl
`
`transferase inhibitor, e.g. L-744,832 or DK8G557,
`
`a telomerase inhibitor, e.g. telomestatin,
`
`a protease inhibitor, a matrix metalloproteinase inhibitor, a methionine aminopeptidase
`
`inhibitor, e.g. bengamide or a derivative thereof, or a proteosome inhibitor, 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 testosterone
`
`to estrone and estradiol, respectively. The term includes, but is not limited to steroids,
`
`especially atamestane, exemestane and formestane and, in particular, non-steroids,
`
`especially 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 AROMASINTM.
`
`Formestane can be administered, e.g., in the form as it is marketed, e.g. under the
`
`trademark LENTARONTM. Fadrozole can be administered, e.g., in the form as it is marketed,
`
`e.g. under the trademark AFEMATM. Anastrozole can be administered, e.g., in the fon'n as it
`
`is marketed, e.g. under the trademark ARIMIDEXTM. Letrozole can be administered, e.g., in
`
`the form as it is marketed, e.g. under the trademark FEMARATM or FEMARTM
`
`Aminoglutethimide can be administered, e.g., in the form as it is marketed, e.g. under the
`
`trademark 0RlMETENTM. A combination of the invention comprising a chemotherapeutic
`
`agent which is an aromatase inhibitor is particularly useful for the treatment of hormone
`
`receptor positive tumors, e.g. breast tumors.
`
`The tenn “antiestrogen” as used herein relates to a compound which antagonizes the effect
`
`of estrogens at the estrogen receptor level. The term includes, but is not limited to
`
`tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be
`
`administered, e.g., in the form as it is marketed, e.g. under the trademark NOLVADEXTM.
`
`Raloxifene hydrochloride can be administered, e.g., in the form as it is marketed, e.g. under
`
`the trademark EVISTATM. Fulvestrant can be formulated as disclosed in US 4,659,516 or it
`
`can be administered, e.g., in the form as it is marketed, e.g. under the trademark
`
`West-Ward Pharm.
`Exhibit 1055
`Page 007
`
`

`

`W0 02/066019
`
`PCT/EP02/01714,
`
`-7-
`
`FASLODEXTM. 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 which is capable of
`
`inhibiting the biological effects of androgenic hormones and includes, but is not limited to,
`
`bicalutamide (CASODEXTM), which can be formulated, e.g. as disclosed in US 4,636,505.
`
`The term “gonadorelin agonist” as used herein includes, but is not limited to abarelix,
`
`goserelin and goserelin acetate. Goserelin is disclosed in US 4,100,274 and can be
`
`administered, e.g., in the form as it is marketed, e.g. under the trademark ZOLADEXTM.
`
`Abarelix can be formulated, eg. as disclosed in US 5,843,901.
`
`The term “topoisomerase I inhibitor” as used herein includes, but is not limited to topotecan,
`
`irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-
`
`166148 (compound A1 in W099/17804). lrinotecan can be administered, e.g. in the form as
`
`it is marketed, e.g. under the trademark CAMPTOSARTM. Topotecan can be administered,
`
`e.g., in the form as it is marketed, e.g. under the trademark HYCAMTINTM.
`
`The term “topoisomerase ll inhibitor" as used herein includes, but is not limited to the
`
`anthracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYXTM),
`
`daunorubicin, epirubicin, idarubicin and nemorubicin. the anthraquinones mitoxantrone and
`
`losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide can be
`
`administered, e.g. in the fonn as it is marketed, e.g. under the trademark ETOPOPHOSTM.
`
`Teniposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark
`
`VM 26-BRISTOLTM Doxorubicin can be administered, e.g. in the form as it is marketed, e.g.
`
`under the trademark ADRIBLASTINTM. Epirubicin can be administered, e.g. in the form as it
`
`is marketed, e.g. under the trademark FARMORUBICINTM. ldambicin can be administered,
`
`e.g. in the form as it is marketed, e.g. under the trademark ZAVEDOSTM. Mitoxantrone can
`
`be administered, e.g. in the form as it is marketed, e.g. under the trademark
`
`NOVANTRONTM.
`
`The term "microtubule active agent” relates to microtubule stabilizing and microtubule
`
`destabilizing agents including, but not limited to taxanes, e.g. paclitaxel and docetaxel, vinca
`
`alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine
`
`sulfate. and vinorelbine, discodermolides and epothilones and derivatives thereof, e.g.
`
`epothilone B or a derivative thereof. Paclitaxel may be administered e.g. in the form as it is
`
`West-Ward Pharm.
`Exhibit 1055
`Page 008
`
`

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`W0 02/066019
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`PCT/EP02/01714
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`-3-
`
`marketed, e.g. TAXOLTM. Docetaxel can be administered, e.g., in the form as it is marketed,
`
`e.g. under the trademark TAXOTERETM. Vinblastine sulfate can be administered, e.g., in the
`
`form as it is marketed, e.g. under the trademark VINBLASTIN R.P.TM. Vincristine sulfate can
`be administered, e.g., in the form as it is marketed, e.g. under the trademark FARMISTINTM.
`
`Discodennolide can be obtained, e.g., as disclosed in US 5,010,099.
`
`The term “alkylating agent" as used herein includes, but is not limited to cyclophosphamide,
`
`lfosfamide, melphalan or nitrosourea (BCNU or Gliadelm). Cyclophosphamide can be
`
`administered, e.g., in the form as it is marketed, e.g. under the trademark CYCLOSTINTM.
`
`lfosfamide can be administered, e.g., in the form as it is marketed, e.g. under the trademark
`
`HOLOXANTM.
`
`The term "antineoplastic antimetabolite" includes, but is not limited to 5-fluorouracil,
`
`capecitabine, gemcitabine, methotrexate and edatrexate. Capecitabine can be administered,
`
`e.g., in the form as it is marketed, e.g. under the trademark XELODATM. Gemcitabine can be
`
`administered, e.g., in the form as it is marketed, e.g. under the trademark GEMZARTM.
`
`The term "platin compound" as used herein includes, but is not limited to carboplatin, cis-
`
`platin and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed,
`
`e.g. under the trademark CARBOPLATW. Oxaliplatin can be administered, e.g., in the form
`
`as it is marketed, e.g. under the trademark ELOXATINTM.
`
`The term “compounds targeting/decreasing a protein or lipid kinase activity or further anti-
`
`0
`
`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. compounds
`
`targeting, decreasing or inhibiting the activity of the epidermal growth factor family of
`
`receptor 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 fibroblast 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 Rat receptor tyrosine kinase, the Kit/SCFR receptor
`
`tyrosine kinase, members of the c-Abl family and their gene-fusion products (e.g. BCR-Abl),
`
`members of the protein kinase C (PKC) and Raf family of serine/threonine kinases,
`
`members of the MEK, SRC, JAK, FAK, PDK or Pl(3) kinase family, or of the Pl(3)-kinase-
`
`related kinase family, and/or members of the cyclin-dependent kinase family (CDK) and anti-
`
`angiogenic compounds having another mechanism for their activity, e.g. unrelated to protein
`
`or lipid kinase inhibition.
`
`West-Ward Pharm.
`Exhibit 1055
`Page 009
`
`

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`W0 02/066019
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`PCT/EP02/01714
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`Compounds which target, decrease or inhibit the activity of VEGFR are especially
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`compounds, proteins or antibodies which inhibit the VEGF receptor tyrosine kinase, inhibit a
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`VEGF receptor or bind to VEGF, and are in particular those compounds, proteins or
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`monoclonal antibodies generically and specifically disclosed in W0 98/35958, e.g. 1-(4-
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`chIoroanilino)-4—(4-pyridylmethy|)phthalazine or a pharmaceutically acceptable salt thereof,
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`e.g. the succinate, or in W0 O0/09495, W0 00/27820, W0 00/59509, W0 98l11223, W0
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`O0/27819 and EP 0 769 947; those as described by M. Prewett et al in Cancer Research §_9_
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`(1999) 5209-5218, by F. Yuan et al in Proc. Natl. Acad. Sci. USA, vol. 93, pp. 14765-14770,
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`Dec. 1996, by Z. Zhu et al in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al in
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`Toxicologic Pathology, Vol. 27, no. 1, pp 14-21, 1999; in W0 00I37502 and W0 94/10202;
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`Angiostatinm, described by M. s. 0’Reil|y et al, Cell 79, 1994, 315-328; Endostatinm,
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`described by M. S. 0’ReilIy et al, Cell 88, 1997, 277-285; anthranilic acid amides; ZD4190;
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`ZD6474; SU5416; SU6668; or anti-VEGF antibodies or anti-VEGF receptor antibodies,e.g.
`RhuMab.
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`By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific
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`antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they
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`exhibit the desired biological activity.
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`Compounds which target, decrease or inhibit the activity of the epidermal growth factor
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`receptor family are especially compounds, proteins or antibodies which inhibit members of
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`the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or bind
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`to EGF or EGF related ligands, and are in particular those compounds, proteins or
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`monoclonal antibodies generically and specifically disclosed in WO 97102266, e.g. the
`compound of ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0
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`787 722, EP 0 837 063, US 5,747,498, W0 98/10767, W0 97/30034, WO 97/49688, WO
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`97/38983 and, especially, WO 96/30347 (e.g. compound known as CP 358774), W0
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`96I33980 (e.g. compound ZD 1839) and WO 95/03283 (e.g. compound ZM105180); e.g.
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`trastuzumab (HerpetinR), cetuximab, lressa, 0Sl-774, Cl-1033, EKB-569, GW-2016, E1.1,
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`E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3.
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`Compounds which target, decrease or inhibit the activity of PDGFR are especially
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`compounds which inhibit the PDGF receptor, e.g. a N-phenyl-2-pyrimidine-amine derivative,
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`e.g. imatinib.
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`West-Ward Pharm.
`Exhibit 1055
`Page 010
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`W0 02/066019
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`PCT/EP02/01714
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`Compounds which target, decrease or inhibit the activity of c-Abl family members and their
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`gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib;
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`PD180970; AG957; or NSC 680410.
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`Compounds which target, decrease or inhibit the activity of protein kinase C, Raf, MEK,
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`SRC, JAK, FAK and PDK family members, or Pl(3) kinase or Pl(3) kinase-related family
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`members, and/or members of the cyclin-dependent kinase family (CDK) are especially those
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`staurosporine derivatives disclosed in EP 0 296 110, e.g. midostaurin; examples of further
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`compounds include e.g. UCN—01, safingol, BAY 43-9006, Bryostatin 1, Perifosine;
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`llmofosine; R0 318220 and R0 320432; GO 6976; lsis 3521; or LY333531/LY379196.
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`Further anti-angiogenic compounds are e.g. thalidomide (THALOMID) and TNP-470.
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`Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are
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`e.g. inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25, e.g. okadaic acid or a
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`derivative thereof.
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`Compounds which induce cell differentiation processes are e.g. retinoic acid, ou—, y» or 8-
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`tocopherol or o.—, 7- or 8-tocotrienol.
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`The term cyclooxygenase inhibitor as used herein includes, but is not limited to, e.g.
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`celecoxib (CelebrexR), rofecoxib (VioxxR), etoricoxib, valdecoxib or a 5-alkyl-2-
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`arylaminophenylacetic acid, e.g. 5~methyl-2—(2’-chloro-6’-fluoroanilino)phenyl acetic acid.
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`The term "histone deacetylase inhibitor” as used herein includes, but is not limited to MS-27-
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`275, SAHA, pyroxamide, FR-901228 or valproic acid.
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`The term "bisphosphonates" as used herein includes, but is not limited to, etridonic,
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`clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
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`“Etridonic acid” can be administered, e.g., in the form as it is marketed, e.g. under the
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`trademark DIDRONELTM. "Clodronic acid” can be administered, e.g., in the form as it is
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`marketed, e.g. under the trademark BONEFOSTM. “Tiludronic acid" can be administered,
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`e.g., in the form as it is marketed, e.g. under the trademark SKELIDTM. “Pamidronic acid”
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`can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIATM.
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`“Alendronic acid” can be administered, e.g., in the form as it is marketed, e.g. under the
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`trademark FOSAMAXTM. "|bandronic acid” can be administered, e.g., in the form as it is
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`marketed, e.g. under the trademark BONDRANATTM. “Risedronic acid” can be administered,
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`e.g., in the form as it is marketed, e.g. under the trademark ACTONELTM. “Zoledronic acid”
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`can be administered, e.g. in the form as it is marketed, e.g. under the trademark ZOMETAW
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`West-Ward Pharm.
`Exhibit 1055
`Page 011
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`W0 02/066019
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`PCT/EP02/01714
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`The tenn “matrix metalloproteinase inhibitor” as used herein includes, but is not limited to
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`collagen peptidomimetic and nonpetidomimetic inhibitors, tetracycline derivatives, e.g.
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`hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue
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`marimastat, prinomastat, BMS-279251, BAY 12-9566, TAA211 or AAJ996.
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`in each case where citations of patent applications or scientific publications are given, the
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`subject-matter relating to the compounds is hereby incorporated into the present application
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`by reference. Comprised are likewise the pharmaceutically acceptable salts thereof, the
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`corresponding racemates, diastereoisomers, enantiomers, tautomers as well as the
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`corresponding crystal modifications of above disclosed compounds where present, e.g.
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`solvates, hydrates and polymorphs, which are disclosed therein. The compounds used as
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`active ingredients in the combinations of the invention can be prepared and administered as
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`described in the cited documents, respectively. Also within the scope of this invention is the
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`combination of more than two separate active ingredients as set forth above, i.e. a
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`pharmaceutical combination within the scope of this invention could include three active
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`ingredients or more. Further both the first agent and the co-agent are not the identical
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`ingredient.
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`Utility of the compounds of formula I in treating solid tumors as hereinabove specified, may
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`be demonstrated in animal test methods as well as in clinic, for example in accordance with
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`the methods hereinafter described.
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`A.
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`in Vitro
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`A.1 Antiproliferative activity in combination with other agents
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`A cell line, e.g. the compound A resistant A549 line (lC5o in low nM range) versus the
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`comparative Compound A resistant KB-31 and HCT116 lines (|C5o in the uM range), is added
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`to 96-well plates (1,500 cellslwell in 100 pl medium) and incubated for 24 hr. Subsequently, a
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`two-fold dilution series of each compound (Compound of formula I or a known
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`chemotherapeutic agent) is made in separate tubes (starting at 8 x the |C5o of each
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`compound) either alone or in paired combinations, and the dilutions are added to the wells.
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`The cells are then re-incubated for 3 days. Methylene blue staining is performed on day 4
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`and the amount of bound dye (proportional to the number of surviving cells that bind the dye)
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`determined. 'C5g$ are subsequently determined using the Calcusyn program, which provides
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`a measure of the interaction, namely the so-called non-exclusive combination index (Cl),
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`where: Cl ~ 1 = the interaction is nearly additive; 0.85 — 0.9 = slight synergism; < 0.85 =
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`synergy. In this assay, the compounds of formula l show interesting antiproliferative activity
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`West-Ward Pharm.
`Exhibit 1055
`Page 012
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`W0 02/066019
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`PCT/EP02/01714
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`in combination with another chemotherapeutic agent. For example the following CI values
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`are obtained with a combination of Compound A and cisplatinum, paclitaxel, gemcitabine and
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`doxorubicin, showing synergistic effects.
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`CI
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`Cell line
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`Cisplatinum
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`Paclitaxel
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`Gemcitabine
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`Doxorubicin
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`KB-31
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`A549
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`HCT116
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`0.74
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`0.47
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`0.47
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`0.9
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`.
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`.
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`0.79
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`0.76
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`0.9
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`0.7
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`Furthermore, in this assay, Compound A potentiates the loss of A549 cell viability and cell
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`death when it is used in combination with gemcitabine.
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`A.2 Antiangiogenic activity
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`In vitro assay of the antiproliferative activity of rapamycin or a derivative thereof, e.g.
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`Compound A, against human umbilical vein endothelial cells (HUVECS) demonstrates lC5u
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`values of 120 1: 22 pM and 841 i 396, and > 10 000 pM for VEGF- and bFGF- and FBS-
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`stimulated proliferation. respectively. Additionally, no significant effects of Compound A on
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`bFGF-stimulated normal human dermal fibroblast (NHDF) proliferation are observed over the
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`same concentration range. These results indicate that Compound A inhibits the proliferation
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`of HUVECs, being particularly potent against the VEGF-induced proliferation, VEGF being a
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`key pro-angiogenic factor.
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`B.
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`In Vivo
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`In the following assays, antitumor activity is expressed as T/C% (mean increase in tumor
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`volumes of treated animals divided by the mean increase of tumor volumes of control
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`animals multiplied by 100) and % regressions (tumor volume minus initial tumor volume
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`divided by the initial tumor volume and multiplied by 100).
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`B.1 Activity in A549 human lung tumor xenografts
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`Fragments of A549 tumors (approx. 25 mg; derived from Cell line CCL 185, ATCC,
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`Rockville MD, USA) are transplanted subcutaneously into the left flank of BALB/c nude mice.
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`Treatment is started on day 7 or day 12 follow