(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`29 August 2002 (29.08.2002)
`
`(43) International Publication Date
`
`(10) International Publication Number
`WO 02/066019 A2
`
`(51) International Patent Classification’:
`
`AO6IK 31/00
`
`[NZ/CH]; In den Kleematten 18, CH-4105 Bicl-Benken
`(CID.
`(21) International Application Number:©PCT/EP02/01714
`(74) Agent: BECKER, Konrad; Novartis AG, Corporate
`Intellectual Property, Patent & ‘lrademark Department,
`CH-4002 Basel (CH).
`
`(22) International Filing Date: 18 February 2002 (18.02.2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`0104072.4
`0124957.2
`
`19 February 2001 (19.02.2001)
`17 October 2001 (17.10.2001)
`
`GB
`GB
`
`(71) Applicant (for all designated States except AT, US): NO-
`VARTIS AG |CH/CH]; Lichtstrasse 35, CH-4056 Basel
`(CH).
`
`(81) Designated States (national): AB, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FL, GB, GD, GE, GH,
`HR, HU,ID,IL,IN, IS. JP, KE, KG, KP, KR, KZ, LC, LK,
`LT, LU, 1-¥, MA, MD, MK, MN, MX, NO,NZ, OM,PH,
`PL,PT, RO,RU,SE, SG,SI, SK, TJ, TM,TN, TR,TT, UA,
`US, UZ, VN, YU, ZA, ZW.
`
`.
`;
`.
`(84) Designated States (regional): Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, TJ, TM), Europeanpatent (AT, BE,
`CH, CY, DE, Dk, ES, FI, FR, GB, GR, IE, IV, LU, MC,
`NL, PT, SE, TR).
`
`(71) Applicant (for AT only): NOVARTIS-ERFINDUNGEN
`VERWALTUNGSGESELLSCHAFT M.B.H. [AL/AT];
`Published:
`BrunnerStrasse 59, A-1230 Vienna (AT).
`—_without international search report and to be republished
`(72) Inventors; and
`upon receipt ofthat report
`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
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazeite.
`
`O02/066019A2
`
`(54) Title: CANCER ‘TREATMENT
`
`(57) Abstract: Rapamycin derivatives have interesting effects in the treatment of solid tumours, optionally in combination with a
`chemotherapeulic agent.
`
`West-Ward Pharm.
`Exhibit 1055
`Page 001
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`West-Ward Pharm.
`Exhibit 1055
`Page 001
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`WO 02/066019
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`PCT/EP02/01714
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`Cancer Treatment
`
`The presentinvention relates to a new use,in particular a new use for a compound group
`
`comprising rapamycin and derivatives thereof.
`
`Rapamycin is a known macrolide antibiotic produced by Streptomyces
`
`hygroscopicus. Suitable derivatives of rapamycin include e.g. compounds of
`formula |
`
`
`
`wherein
`
`R, is CHor Cz.ealkynyl,
`
`Ro» is H or -CH2-CH2-OH, and
`
`X is =O, (H,H) or (H,OH)
`
`provided that Rz is other than H when X is =O and R, is CH3.
`
`Compounds of formula | are disclosed e.g. in WO 94/09010, WO 95/16691 or WO 96/41807,
`
`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(S)-dihydro-rapamycin, 16~-pent-2-ynyloxy-32(S)-dihydro-40-0-(2-
`hydroxyethyl)-rapamycin and, more preferably, 40-0-(2-hydroxyethyl)-rapamycin (referred
`thereafter as Compound A), disclosed as Example 8 in WO 94/09010.
`
`Compoundsof formula | 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 Compoundsof formula | have potent antiproliferative properties which make them useful
`
`West-Ward Pharm.
`Exhibit 1055
`Page 002
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`West-Ward Pharm.
`Exhibit 1055
`Page 002
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`for cancer chemotherapy, particularly of solid tumors, especially of advancedsolid tumors.
`
`Thereis still the need to expand the armamentarium of cancer treatmentof solid tumors,
`
`especially in cases where treatment with anticancer compoundsis not associated with
`
`disease regressionorstabilization.
`
`In accordancewith the particularfindings 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 therapeutically effective amount of a compoundof
`
`formula I.
`
`1.2 A methodfor inhibiting growth of solid tumors in a subject in need thereof, comprising
`administering to said subject a therapeutically effective amount of a compoundof
`
`formula I.
`
`1.3 A methodfor inducing tumor regression, ¢.g. tumor mass reduction, in a subjectin
`
`need thereof, comprising administering to said subject a therapeutically effective
`
`amount of a compoundof formulaI.
`
`1.4 A methodfor 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.
`1.5 Amethod 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 (whereeverlocated) other than
`
`lymphatic cancer, e.g. brain and other central nervous system tumors (eg. tumors of the
`meninges,brain, spinal cord, cranial nerves and otherparts 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 otherintrathoracic organs, vascular
`
`tumors and tumor-associated vasculartissue); 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 ofbiliary 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 otherparts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform
`
`sinus, hypopharynx, and othersites in the fip, 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
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`West-Ward Pharm.
`Exhibit 1055
`Page 003
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`PCT/EP02/01714
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`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 andlung, e.g. small cell lung cancer or
`non-small cell lung cancer); skeletal system tumors (e.g. bone andarticular cartilage of
`limbs, bonearticular cartilage and othersites); skin tumors (e.g. malignant melanoma of the
`skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamouscell carcinoma of
`skin, mesothelioma, Kaposi’s sarcoma); and tumorsinvolving othertissues 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 of respiratory and digestive systems and
`
`secondary malignant neoplasm of othersites.
`
`Where hereinbefore and subsequently a tumor, a tumor disease, a carcinoma or a canceris
`
`mentioned, also metastasis in the original organ ortissue 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 Amethod 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. CCI779, ABT578 or a
`
`compound of formula I.
`
`1.7 Amethodfor 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. CCI779, ABT578 or a compound of formula I.
`1.8 A method for enhancing the activity of a chemotherapeutic agent or for overcoming
`resistance to a chemotherapeutic agentin a subject in need thereof, comprising
`administering to said subject a therapeutically effective amount of rapamycin or a
`derivative thereof, e.g. CCI779, ABT578 or a compoundof formula I, either
`concomitantly or sequentially with said chemotherapeutic agent.
`1.9 Amethod according to 1.8 wherein the chemotherapeutic agentis an inhibitor of signal
`transduction pathways directed either against host cells or processes involved in tumor
`formation and/or metastases formation or utilised by tumourcells forproliferation,
`survival, differentiation or developmentof drug resistance.
`
`West-Ward Pharm.
`Exhibit 1055
`Page 004
`
`West-Ward Pharm.
`Exhibit 1055
`Page 004
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`-4-
`
`1.10 A method as indicated above, wherein rapamycin or a derivative thereof, e.g. CCI779,
`ABT578 or a compound of formula | is administered intermittently.
`
`CCI779 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 withoutlimitation
`
`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 Acompound of formula | for use in any method as defined under1.1 to 1.5 above.
`
`2.2 Rapamycin or a derivative thereof, e.g. CCI779, ABT578 or a compound of formula |
`
`for use in any method as defined under1.6 to 1.10 above or 7 below.
`3.1 A compound of formula| 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 |
`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. Apharmaceutical composition for use in any method as defined under 1.1 to 1.5 above
`
`comprising a compound of formula | together with one or more pharmaceutically
`
`acceptable diluents or carriers therefor.
`
`4.2 Apharmaceutical 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. CCI779, ABT578
`
`or a compoundof formula |, e.g. Compound A, together with one or more
`
`pharmaceutically acceptable diluents or carriers therefor.
`
`5.1. Apharmaceutical combination comprising a) a first agent which is rapamycin or a
`derivative thereof, e.g. CCI779, 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.
`5.2 Apharmaceutical combination comprising an amountofa)a first agent which is
`rapamycin or a derivative thereof, e.g. CCI779, 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
`
`West-Ward Pharm.
`Exhibit 1055
`Page 005
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`WO 02/066019
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`PCT/EP02/01714
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`the compounds defined under paragraph(iv) or (v) below, to produce a synergistic
`
`therapeutic effect.
`
`6.
`
`Amethod as defined above comprising co-administration, e.g. concomitantly orin
`
`sequence,of a therapeutically effective amount of rapamycin or a derivative thereof,
`
`e.g. CCI779, ABT578 or a compoundof formula I, e.g. Compound A, and a second
`
`drug substance, said second drug substance being a chemotherapeutic agent, e.g. as
`indicated hereinafter.
`
`7. Amethod 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. 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, 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 rapamycinora derivative thereof. It includes butis notlimited to,
`
`i.
`
`ii.
`
`an aromataseinhibitor,
`
`an antiestrogen, an anti-androgen (especially in the case of prostate cancer) or a
`
`gonadorelin agonist,
`
`iii,|a topoisomerase| inhibitor or a topoisomeraseII inhibitor,
`
`iv.
`
`amicrotubule active agent, an alkylating agent, an antineoplastic antimetabolite or a
`
`platin compound,
`
`Vv.
`
`a compound targeting/decreasing a protein orlipid kinase activity or a protein orlipid
`
`phosphatase activity, a further anti-angiogenic compound or a compound which
`induces cell differentiation processes,
`
`vi.
`
`a bradykinin 1 receptor or an angiotensin It antagonist,
`
`West-Ward Pharm.
`Exhibit 1055
`Page 006
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`West-Ward Pharm.
`Exhibit 1055
`Page 006
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`vil,
`
`a cyclooxygenaseinhibitor, a bisphosphonate, a histone deacetylaseinhibitor, a
`heparanaseinhibitor (prevents heparan sulphate degradation), e.g. Pl-88, a biological
`
`vill.
`
`ix.
`
`x.
`
`response modifier, preferably a lymphokineorinterferons, e.g. interferon y, 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 telomeraseinhibitor, e.g. telomestatin,
`
`a protease inhibitor, a matrix metalloproteinaseinhibitor, a methionine aminopeptidase
`inhibitor, e.g. bengamide ora derivative thereof, or a proteosomeinhibitor,e.g.
`PS-341.
`
`The term “aromatase inhibitor” as used herein relates to a compound whichinhibits the
`
`estrogen production,i.e. the conversion of the substrates androstenedione and testosterone
`
`to estrone and estradiol, respectively. The term includes, butis notlimited 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 itis marketed, e.g. under the trademark AROMASIN™.
`
`Formestane can be administered, e.g., in the form asit is marketed, e.g. under the
`
`trademark LENTARON™.Fadrozole can be administered, e.g., in the form asit is marketed,
`
`e.g. under the trademark AFEMA™. Anastrozole 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 asit 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 aromataseinhibitor is particularly useful for the treatment of hormone
`
`receptor positive tumors, e.g. breast tumors.
`
`The term “antiestrogen” as used herein relates to a compound which antagonizes the effect
`
`of estrogens at the estrogen receptorlevel. The term includes,butis notlimited to
`
`tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen can be
`
`administered, e.g., in the form asit is marketed, e.g. under the trademark NOLVADEX™,
`Raloxifene hydrochloride can be administered, e.g., in the form asit is marketed, e.g. under
`the trademark EVISTA™. Fulvestrant can be formulated as disclosed in US 4,659,516 orit
`
`can be administered,e.g., in the form as it is marketed, e.g. under the trademark
`
`West-Ward Pharm.
`Exhibit 1055
`Page 007
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`West-Ward Pharm.
`Exhibit 1055
`Page 007
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`-7-
`
`FASLODEX™, A combination of the invention comprising a chemotherapeutic agent whichis
`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 hormonesandincludes,butis notlimited to,
`
`bicalutamide (CASODEX™), 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 itis marketed, e.g. under the trademark ZOLADEX™,
`
`Abarelix can be formulated, eg. as disclosed in US 5,843,901.
`
`The term “topoisomerase| inhibitor” as used herein includes, but is not limited to topotecan,
`irinotecan, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-
`166148 (compound A1 in WO99/17804). Irinotecan 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 asit is marketed, e.g. under the trademark HYCAMTIN™.
`
`The term “topoisomerase Il inhibitor’ as used herein includes, butis not limited to the
`
`anthracyclines such as doxorubicin (including liposomal formulation, e.g. CAELYX™),
`daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and
`losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide can be
`
`administered, e.g. in the form asit is marketed, e.g. under the trademark ETOPOPHOS™,
`Teniposide can be administered, e.g. in the form as it is marketed, e.g. under the trademark
`VM 26-BRISTOL™ Doxorubicin can be administered,e.g. in the form asit is marketed, e.g.
`under the trademark ADRIBLASTIN™.Epirubicin can be administered,e.g. in the form asit
`is marketed, e.g. under the trademark FARMORUBICIN™.Idarubicin can be administered,
`
`e.g. in the form asit is marketed, e.g. under the trademark ZAVEDOS™.,Mitoxantrone can
`
`be administered, e.g. in the form as it is marketed, e.g. under the trademark
`
`NOVANTRON™,
`
`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 administerede.g. in the form asit is
`
`West-Ward Pharm.
`Exhibit 1055
`Page 008
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`West-Ward Pharm.
`Exhibit 1055
`Page 008
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`-8-
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`marketed, e.g. TAXOL™. Docetaxel can be administered,e.g., in the form asit is marketed,
`
`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 as it is marketed, e.g. under the trademark FARMISTIN™.
`Discodermolide can be obtained, e.g., as disclosed in US 5,010,099.
`
`The term “alkylating agent” as used herein includes, butis not limited to cyclophosphamide,
`ifosfamide, melphalan or nitrosourea (BCNUorGliadel™). 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 asit is marketed, e.g. under the trademark
`
`HOLOXAN™.,
`
`The term “antineoplastic antimetabolite” includes, but is not limited to 5-fluorouracif,
`capecitabine, gemcitabine, methotrexate and edatrexate. Capecitabine can be administered,
`e.g., in the form as it is marketed, e.g. under the trademark XELODA™. Gemcitabine can be
`
`administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR™,
`
`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 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 orlipid 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 tipid kinase inhibitors, e.g. compounds
`
`targeting, decreasing orinhibiting the activity of the epidermal growth factor family of
`
`receptortyrosine 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 (JGF-1R), the Trk receptor tyrosine kinase family, the Axl
`
`receptor tyrosine kinase family, the Ret receptor tyrosine kinase, the Ki/SCFR receptor
`
`tyrosine kinase, members of the c-Abf family and their gene-fusion products (e.g. BCR-Ab!),
`members of the protein kinase C (PKC) and Raffamily of serine/threonine kinases,
`
`members of the MEK, SRC, JAK, FAK, PDK or P1(3) kinase family, or of the PI(3)-kinase-
`
`related kinase family, and/or membersof the cyclin-dependent kinase family (CDK) and anti-
`angiogenic compounds having another mechanismfortheir activity, e.g. unrelated to protein
`orlipid kinase inhibition.
`
`West-Ward Pharm.
`Exhibit 1055
`Page 009
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`West-Ward Pharm.
`Exhibit 1055
`Page 009
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`Compoundswhichtarget, decreaseorinhibit the activity of VEGFR are especially
`
`compounds,proteins or antibodies which inhibit the VEGF receptor tyrosine kinase,inhibit a
`
`VEGF receptoror bind to VEGF,and arein particular those compounds,proteins or
`
`monoclonal antibodies generically and specifically disclosed in WO 98/35958,e.g. 1-(4-
`
`chloroanilino)-4-(4-pyridyimethyl)phthalazine or a pharmaceutically 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,
`
`Dec. 1996, by Z. Zhu et al in Cancer Res, 58, 1998, 3209-3214, and by J. Mordenti et 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'Reilly et 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; SUG668; or anti-VEGF antibodies or anti-VEGF receptor antibodies,e.g.
`RhuMab.
`
`By antibody is meant intact monoclonalantibodies, polyclonal antibodies, multispecific
`
`antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they
`
`exhibit the desired biological activity.
`
`Compounds which target, decreaseor inhibit the activity of the epidermal growth factor
`
`receptor family are especially compounds,proteins or antibodies which inhibit members of
`
`the EGF receptor 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 of ex. 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0
`787 722, EP 0 837 063, US 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®), cetuximab, Iressa, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,
`E2.4, E2.5, E6.2, £6.4, E2.11, E6.3 or E7.6.3.
`
`Compounds which target, decreaseorinhibit the activity of PDGFR are especially
`compoundswhich inhibit the PDGF receptor, e.g. a N-phenyl-2-pyrimidine-amine derivative,
`e.g. imatinib.
`
`West-Ward Pharm.
`Exhibit 1055
`Page 010
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`West-Ward Pharm.
`Exhibit 1055
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`WO 02/066019
`
`PCT/EP02/01714
`
`-10-
`
`Compoundswhich target, decrease orinhibit the activity of c-Ab! family members and their
`
`gene fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib;
`
`PD180970; AG957; or NSC 680410.
`
`Compounds which target, decrease orinhibit the activity of protein kinase C, Raf, MEK,
`
`SRC, JAK, FAK and PDK family members,or PI(3) kinase or PI(3) kinase-related family
`
`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
`
`compoundsinclude e.g. UCN-01, safingoi, 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 which target, decrease orinhibit the activity of a protein orlipid phosphatase are
`
`e.g. inhibitors of phosphatase 1, phosphatase 2A, PTEN or CDC25,e.g. okadaic acid or a
`
`derivative thereof.
`
`Compounds which inducecell differentiation processesare e.g. retinoic acid, a—, y— or 6-
`
`tocopherol or a—, y— or 6-tocotrienol.
`
`The term cyclooxygenaseinhibitor as used herein includes,but is notlimited to, e.g.
`celecoxib (Celebrex"®), rofecoxib (Vioxx®), etoricoxib, valdecoxib or a 5-alkyl-2-
`arylaminophenylacetic acid, e.g. 5-methyl-2-(2’-chloro-6’-fluoroanilino)phenyl acetic acid.
`
`The term “histone deacetylase inhibitor” as used herein includes, butis not limited to MS-27-
`
`275, SAHA, pyroxamide, FR-901228 orvalproic acid.
`
`The term “bisphosphonates” as used herein includes, butis not limited to, etridonic,
`
`clodronic,tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid.
`
`“Etridonic acid” can be administered, e.g., in the form asit is marketed, e.g. under the
`
`trademark DIDRONEL™. “Clodronic acid” can be administered, e.g., in the form asit is
`
`marketed, e.g. under the trademark BONEFOS™.“Tiludronic acid” can be administered,
`
`e.g., in the form asit is marketed, e.g. under the trademark SKELID™, “Pamidronic acid”
`
`can be administered, e.g. in the form as it is marketed, e.g. under the trademark AREDIA™,
`
`“Alendronic acid” can be administered, e.g., in the form asit is marketed, e.g. under the
`trademark FOSAMAX™,“Ibandronic acid” can be administered, e.g., in the form asit is
`marketed, e.g. under the trademark BONDRANAT™.“Risedronic acid” can be administered,
`
`e.g., in the form as it is marketed, e.g. under the trademark ACTONEL™.“Zoledronic acid”
`
`can be administered, e.g. in the form asit is marketed, e.g. under the trademark ZOMETA™
`
`West-Ward Pharm.
`Exhibit 1055
`Page 011
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`West-Ward Pharm.
`Exhibit 1055
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`WO 02/066019
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`PCT/EP02/01714
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`-11-
`
`The term “matrix metalloproteinase inhibitor’ as used herein includes, butis not limited to
`
`collagen peptidomimetic and nonpetidomimetic inhibitors, tetracycline derivatives, e.g.
`
`hydroxamate peptidomimetic inhibitor batimastat andits orally bioavailable analoque
`
`marimastat, prinomastat, BMS-279251, BAY 12-9566, TAA211 or AAJ996.
`
`In each case wherecitations of patent applications or scientific publications are given, the
`
`subject-matterrelating to the compoundsis hereby incorporated into the present application
`
`by reference. Comprised are likewise the pharmaceutically acceptable salts thereof, the
`
`corresponding racemates, diastereoisomers, enantiomers, tautomers as well as the
`
`corresponding crystal modifications of above disclosed compounds wherepresent, e.g.
`
`solvates, hydrates and polymorphs, which are disclosed therein. The compounds used as
`
`active ingredients in the combinations of the invention can be prepared and administered as
`
`described in the cited documents, respectively. Also within the scope of this invention is the
`
`combination of more than two separate active ingredients as set forth above,i.e. a
`
`pharmaceutical combination within the scopeof this invention could include three active
`
`ingredients or more. Further both the first agent and the co-agent are not the identical
`
`ingredient.
`
`Utility of the compoundsof formula | in treating solid tumors as hereinabove specified, may
`
`be demonstrated in animal test methods as well as in clinic, for example in accordance with
`
`the methods hereinafier described.
`
`A.—In Vitro
`
`A.1_ Antiproliferative activity in combination with other agents
`
`A cell line, e.g. the compound A resistant A549line (ICs in low nM range) versus the
`
`comparative CompoundA resistant KB-31 and HCT116 lines (ICsp in the 1M range), is added
`
`to 96-well plates (1,500 cells/well in 100 pl medium) and incubated for 24 hr. Subsequently, a
`two-fold dilution series of each compound (Compoundof formula | or a known
`chemotherapeutic agent) is madein separate tubes(starting at 8 x the ICzo of each
`compound)either aloneorin paired combinations, and the dilutions are added to the wells.
`
`The cells are then re-incubated for 3 days. Methylene biue staining is performed on day 4
`
`and the amount of bound dye (proportional to the numberof surviving cells that bind the dye)
`
`determined. |Csgs are subsequently determined using the Calcusyn program, which provides
`a measureofthe interaction, namely the so-called non-exclusive combination index (Cl),
`where: Cl ~ 1 = the interaction is nearly additive; 0.85 — 0.9 = slight synergism; < 0.85 =
`synergy.In this assay, the compoundsof formula | show interesting antiproliferative activity
`
`West-Ward Pharm.
`Exhibit 1055
`Page 012
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`West-Ward Pharm.
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`WO 02/066019
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`PCT/EP02/01714
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`-12-
`
`in combination with another chemotherapeutic agent. For example the following Cl values
`
`are obtained with a combination of Compound A andcisplatinum, paclitaxel, gemcitabine and
`doxorubicin, showing synergistic effects.
`cl
`
`
`
`Cellline—Cisplatinum Paclitaxel Gemcitabine Doxorubicin
`
`
`
`
`
`KB-31
`
`A549
`
`0.74
`
`0.47
`
`0.9
`
`0.74
`
`0.79
`
`0.76
`
`0.7
`
`0.64
`
`0.52
`0.9
`0.3
`0.47
`HCT116
`
`
`Furthermore, in this assay, Compound A potentiates the loss of A549 cell viability and cell
`death whenit is used in combination with gerncitabine.
`
`A2_ Antiangiogenic activity
`
`In vitro assay of the antiproliferative activity of rapamycin or a derivative thereof, e.g.
`CompoundA, against human umbilical vein endothelial cells (HUVECs) demonstrates ICs,
`
`values of 120 + 22 pM and 841 + 396, and > 10 000 pM for VEGF- and bFGF- and FBS-
`
`stimulated proliferation, respectively. Additionally, no significant effects of Compound A on
`
`bFGF-stimulated normal human dermalfibroblast (NHDF) proliferation are observed over the
`
`same concentration range. These results indicate that CompoundA inhibits the proliferation
`of HUVECs,being particularly potent against the VEGF-inducedproliferation, VEGF being a
`key pro-angiogenic factor.
`
`B.
`
`[In Vivo
`
`In the following assays, antitumoractivity is expressed as T/C% (mean increase in tumor
`volumes of treated animals divided by the meanincrease of tumor volumesof control
`animals multiplied by 100) and % regressions (tumor volume minusinitial tumor volume
`divided by theinitial tumor volume and multiplied by 100).
`
`B.1 Activity in A549 human lung tumor xenografts
`Fragments of A549 tumors (approx. 25 mg; derived from Cell line CCL 185, ATCC,
`
`Rockville MD, USA) are transplanted subcutaneouslyinto the left flank of BALB/c nude mice.
`Treatmentis started on day