`
`(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2015/0005268 A1
`Auerbach et a1.
`(43) Pub. Date: Jan. 1, 2015
`
`
`US 20150005268A1
`
`(54)
`
`(71)
`
`(72)
`
`METHODS AND COMPOSITIONS FOR
`TREATING CANCER
`
`Publication Classification
`
`Applicant: Janssen Oncology, Inc., Los Angeles,
`CA (US)
`
`Inventors: Alan H. Auerbach, Hermosa Beach, CA
`(US); Arie S. Belldegrun, Los Angeles,
`CA (US)
`
`(51)
`
`Int. Cl.
`A61K31/58
`A61K31/573
`(52) U.S.Cl.
`CPC ............. ..A6IK31/58(2013.01);A61K31/573
`(2013.01)
`USPC ........................................................ .. 514/170
`
`(2006.01)
`(2006.01)
`
`(21)
`
`Appl. No.: 14/485,083
`
`(22)
`
`Filed:
`
`Sep. 12, 2014
`
`Related US. Application Data
`
`(63)
`
`Continuation of application No. 14/444,513, filed on
`Jul. 28, 2014, which is a continuation of application
`No. 13/034,340, filed on Feb. 24, 2011, now Pat. No.
`8,822,438, which is a continuation of application No.
`1 1/844,440, filed on Aug. 24, 2007, now abandoned.
`
`(60)
`
`Provisional application No. 60/921,506, filed on Aug.
`25, 2006.
`
`(57)
`
`ABSTRACT
`
`Methods and compositions for treating cancer are described
`herein. More particularly, the methods for treating cancer
`comprise administering a
`1701-hydroxylase/C 17,20-lyase
`inhibitor, such as abiraterone acetate (i.e., 3B-acetoxy-l7-(3-
`pyridyl) androsta-5,16-diene), in combination with at least
`one additional therapeutic agent such as an anti-cancer agent
`or a steroid. Furthermore, disclosed are compositions com-
`prising a 1701-hydroxylase/C1mo-lyase inhibitor, and at least
`one additional therapeutic agent, such as an anti—cancer agent
`or a steroid.
`
`IPR2016-O1582
`
`Wockhardt Bio AG v. Janssen Oncology, Inc.
`
`Amerigen Exhibit 1146
`Amerigen Exhibit 1146
`Amerigen v. Janssen
`Amerigen V. Janssen
`IPR2016-00286
`IPR2016-00286
`
`WCK1117
`
`1
`
`

`

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`
`US 2015/0005268 A1
`
`Jan. 1, 2015
`
`RIETHODS AND COlVIPOSITIONS FOR
`TREATING CANCER
`
`FIELD OF THE INVENTION
`
`[0001] Methods and compositions for treating cancer are
`described herein. More particularly, the methods for treating
`cancer comprise administering a 170t-hydroxylase/C 17,20-
`lyase inhibitor, such as abiraterone acetate (i.e., 3B-acetoxy-
`l7—(3-pyridyl) androsta-5,l6-diene), in combination with at
`least one additional therapeutic agent, such as an anti-cancer
`agcnt or a steroid. Furthcrrnorc, discloscd arc compositions
`comprising a 17ot-hydroxylase/C[mo-lyase inhibitor, and at
`least one additional therapeutic agent such as an anti-cancer
`agent or a steroid. e.g., a corticosteroid or, more specifically,
`a glucocorticoid.
`
`BACKGROUND
`
`[0002] The number of people diagnosed with cancer has
`significantly increased. Of special interest are individuals
`diagnosed with androgen-dependent disorders, such as pros-
`tate cancer, and estrogen-dependent disorders, such as breast
`cancer since such diagnoses are increasing in number at an
`alarming rate.
`[0003] Prostate cancer is currently the most common non-
`skin cancer and the second leading cause of cancer-related
`death in men after lung cancer. The primary course of treat-
`ment for patients diagnosed with organ—confined prostate
`cancer is usually prostatectomy or radiotherapy. Not only are
`these treatments highly invasive and have undesirable side
`effects, such localized treatments are not effective on pro state
`cancer after it has metastasized. Moreover, a large percent of
`individuals who receive localized treatments will suffer from
`recurring cancer.
`[0004] Additionally, breast cancer incidence in women has
`increased from one out of every 20 women in 1960 to one out
`of every eight women in 2005. Moreover, it is the most com-
`mon cancer among white and African-American women.
`Similar to treating prostate cancer, most options for women
`diagnosed with breast cancer are highly invasive and have
`significant side-effects. Such treatments include surgery,
`radiation and chemotherapy.
`[0005] Hormone therapy is another treatment option tir
`individuals diagnosed with prostate or breast cancer. Hor—
`mone therapy is a form of systemic treatment for prostate or
`breast cancer wherein hormone ablation agents are used to
`suppress the production or block the effects of hormones,
`such as estrogen and progesterone in the body, which are
`believed to promote the growth of breast cancer, as well as
`testosterone and dihydrotestosterone, which are believed to
`promote the growth of prostate cancer. Moreover, hormone
`therapy is less invasive than surgery and does not have many
`ofthe side effects associated with chemotherapy or radiation.
`Hormone therapy can also be used by itself or in addition to
`localized therapy and has shown to be effective in individuals
`whose cancer has meta stasized.
`
`[0006] Even though hormone therapy is less invasive and
`can be used on more advanced stages of cancer, some indi-
`viduals administered current honnone therapy treatments
`may not show a significant response or may not show any
`response at all to such treatments.Additionally, some patients
`treated with current honnone therapy treatments may also
`
`suffer from relapsing or recurring cancer. Currently, such
`refractory cancer patients are left with very few treatment
`options.
`[0007] Despite the progress made in the treatment of can-
`cer, there remains a need for more effective ways to treat
`cancer such as, but not limited to, prostate cancer and breast
`cancer. Additionally, there is a need for effective anti-cancer
`treatment options for patients who are not responding to
`current anti—cancer treatments.Also, there is a need for effec—
`tive anti-cancer treatment options for patients whose cancer
`has recurred.
`
`SUMMARY OF THE INVENTION
`
`[0008] Described herein are methods for treating a cancer
`in which a therapeutically effective amount of a l70t-hy-
`droxylase/Clmo-lyase inhibitor, such as abiraterone acetate
`(i.e.
`3B—acetoxy—l7—(3 —pyridyl)androsta—5,l6—diene),
`is
`administered to a patient. e.g., a patient in need thereof, in
`combination with a therapeutically effective amount of at
`least one additional therapeutic agent including, but not liin—
`ited to, an anti-cancer agent or steroid. Such methods can also
`provide an effective treatment for individuals with a refrac-
`tory cancer, including individuals who are currently under-
`going a cancer treatment. Therefore, in certain embodiments,
`the method is directed to treating a refractory cancer in a
`patient, in which a therapeutically effective amount of 170t-
`hydroxylase/C17,2O-lyase inhibitor
`is administered to a
`patient currently receiving an anti-cancer agent.
`[0009] For example, in certain embodiments, the method
`for the treatment of a cancer in a mammal comprises admin-
`istering an amount of about 0.01 mg/kg/day to about 100
`mg/kg/day of abiraterone acetate and an amount of about 0.1
`mg/m2 to about 20 mg/mzof mitoxantrone.
`[0010]
`In another embodiment, the method for the treat-
`ment of a cancer in a mammal comprises administering an
`amount of about 0.01 mg/kg/day to about 100 mg/kg/day of
`abiraterone acetate and an amount of about 1 mg/m2 to about
`175 mg/m2 of docetaxel.
`[0011]
`In still other embodiments, the method for the treat—
`ment of a cancer in a mammal comprises administering an
`amount of about 0.01 mg/kg/day to about 100 mg/kg/day of
`abiraterone acetate and an amount of about 1 mg/m2 to about
`100 mg/m2 of docetaxel.
`[0012] Furthemiore, described herein is a method for the
`treatment of a cancer in a mammal comprising administering
`an amount of about 0.01 mg/kg/day to about 100 mg/kg/day
`of abiraterone acetate; and an amount of about 0.01 mg to
`about 200 mg of leuprolide, wherein the leuprolide is admin-
`istered over a period of about 3 days to about 12 months.
`[0013]
`In other embodiments, the method for the treatment
`of a cancer in a mammal comprises administering an amount
`of about 0.01 mg/kg/day to about 100 mg/kgday of abirater-
`one acetate and an amount ofabout 0.01 mg to about 20 mg of
`goserelin, wherein the go serelin is administered over a period
`of about 28 days to about 3 months.
`[0014] Additionally, in another embodiment, the method
`for the treatment of a cancer in a mammal comprises admin-
`istering an amount of about 0.01 mg/kg/day to about 100
`mg/kg/day ofabiraterone acetate and an amount of about 0.01
`mg to about 20 mg of triptorelin, wherein the triptorelin is
`administered over a period of about 1 month.
`[0015] The method for the treatment of a cancer in a main-
`mal can also comprise administering an amount of about 0.01
`mg/kg/day to about 100 mg/kg/day of abiraterone acetate and
`
`
`
`2
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`US 2015/0005268 A1
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`Jan. 1,2015
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`an amount of about 0.1 ug/day to about 500 [Lg/day of seo-
`calcitol, such as about 100 [Lg/day of seocalcitol.
`[0016] Also, the method for the treatment of a cancer in a
`mammal can comprise administering an amount ofabout 0.01
`mg/kg/day to about 100 mg/kg/day of abiraterone acetate and
`an amount ofabout 1 mg/day to about 300 mg/day ofbicaluta—
`mide.
`
`In yet another embodiment, the method for the treat-
`[0017]
`ment of a cancer in a mammal can comprise administering an
`amount of about 0.01 mg/kg/day to about 100 mg/kg/day of
`abiraterone acetate and an amount of about 1 mg/day to about
`2000 mg/day of flutamide.
`[0018] Moreover, the method for the treatment of a cancer
`in a mammal can comprise administering an amount of about
`50 mg/day to about 2000 rag/day ofabiraterone acetate and an
`amount of about 0.01 mg/day to about 500 mg/day of a
`glucocorticoid including, but not limited to, hydrocortisone,
`arednisone or dexamethasone.
`
`
`
`[0019] Also described herein are compositions for the treat-
`nent of cancer that comprise a combination of a therapeuti-
`cally effective amount of at least one l70t-hydroxylase/Cl7,
`zo-lyase inhibitor and a therapeutically effective amount of at
`east one additional anti-cancer agent, such as, but not limited
`0, mitoxantrone, paclitaxel, docetaxel, leuprolide, goserelin,
`riptorelin, seocalcitol, bicalutamide, flutamide, or a steroid
`'ncluding, but not limited to, hydrocortisone, prednisone, or
`dexamethasone.
`[0020]
`Finally, single unit dosage forms comprising abi—
`‘aterone acetate and a glucocorticoid, optionally with carri-
`ers, diluents or excipients, are contemplated. Also, kits com-
`orising at least one l7a-hydroxylase/C17,20-lyase inhibitor
`and an additional anti cancer agent or steroid are contem-
`olated. For example, the kit may include a vial containing
`abiraterone acetate and another vial containing a glucocorti-
`coid.
`
`DEFINITIONS
`
`some embodiments, the patient is a mule of age about 30
`years to about 85 years. In other embodiments, the patient is
`a female ofage about 30 years to about 85 years. In a particu-
`lar embodiment, the patient has or is susceptible to having
`(e.g., through genetic or environmental factors) cancer. In a
`further embodiment, the patient has or is susceptible to hav—
`ing (e.g., through genetic or environmental factors) a tumor.
`In other embodiments, the patient can be castrated or non-
`castrated.
`
`[0024] The term “l70t-hydroxylase/Clmo-lyase inhibitor”
`as used herein refers to an inhibitor of l7cx-hydroxylase/C17_
`zo—lyase, (which is an enzyme in testosterone synthesis) an
`analog thereof, derivative thereof, metabolite thereof or phar-
`maceutically acceptable salt thereof. Also, unless otherwise
`noted, reference to a particular 170t—hydroxylase/Cl7,20—lyase
`inhibitor can include analogs, derivatives, metabolites or
`pharmaceutically acceptable salts of such particular 170t-
`hydroxylase/C 17,20-lyase inhibitor.
`[0025] The term “anti-cancer agent” as used herein refers to
`any therapeutic agent that directly or indirectly kills cancer
`cells or directly or indirectly prohibits stops or reduces the
`proliferation of cancer cells. It should be noted that even
`though throughout this specification and in the claims the
`phrase “anti-cancer agent” is written as a singular noun, for
`example, “an anti-cancer agent” or “the anti-cancer agent,”
`the phrase “anti-cancer agent” should not be interpreted as
`being limited to the inclusion of a single anti-cancer agent.
`[0026] As used herein, and unless otherwise defined, the
`phrase “therapeutically effective amount” when used in con-
`nection with a l7a-hydroxylase/C17,20-lyase inhibitor or
`therapeutic agent means an amount of the l70t-hydroxylase/
`C 17520-lyase inhibitor or therapeutic agent effective for treat-
`ing a disease or disorder disclosed herein, such as cancer.
`[0027] As used herein and unless otherwise defined the
`phrase “refractory cancer.” means cancer that is not respond-
`ing to an anti-cancer treatment or cancer that is not respond-
`ing sufficiently to an anti-cancer treatment. Refractory cancer
`can also include recurring or relapsing cancer.
`[0028] As used herein and unless otherwise defined the
`phrase “refractory patient,” means a patient who has refrac-
`tory cancer.
`[0029] As used herein and Lmless otherwise defined the
`phrase “relapse cancer.” means cancer that was at one time
`responsive to an anti-cancer treatment but has become no
`longer responsive to such treatment or is no longer respond-
`ing sufficiently to such treatment.
`[0030] As used herein and unless otherwise defined the
`phrase “recurring cancer,” means cancer that has returned
`after a patient has been earlier diagnosed with cancer, under
`gone treatment or had been previously diagnosed as cancer-
`free.
`[0031] As used herein and unless otherwise defined the
`term “derivative” refers to a chemically modified compound
`wherein the chemical modification takes place at one or more
`functional groups ofthe compound. The derivative may retain
`or improve the pharmacological activity of the compound
`from which it is derived.
`
`[0021] As used herein and unless otherwise defined the
`word “cancer,” refers to the growth, division or proliferation
`ofabnormal cells in the body. Cancers that can be treated with
`he methods and the compositions described herein include,
`jut are not limited to, prostate cancer, breast cancer, adrcnal
`cancer, leukemia, lymphoma, myeloma, Waldenstrom’s mac-
`‘oglobulinemia, monoclonal gammopathy, benign mono-
`clonal gammopathy, heavy chain disease, bone and connec—
`ive tissue sarcoma, brain tumors, thyroid cancer, pancreatic
`cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar
`cancer, cervical cancer, uterine cancer, ovarian cancer, esoph-
`ageal cancer, stomach cancer, colon cancer, rectal cancer,
`iver cancer, gallbladder cancer, cholangiocarcinoma, lung
`cancer, testicular cancer, penal cancer, oral cancer, skin can-
`cer, kidney cancers, Wilms’ tumor and bladder cancer.
`[0022] As used herein, and unless otherwise defined, the
`erms “treat,” “treating” and “treatment” include the eradica-
`ion, removal, modification, management or control of a
`umor or primary, regional, or metastatic cancer cells or tissue
`and the minimization or delay of the spread of cancer.
`[0032] As used herein and unless otherwise defined the
`[0023] As used herein, and unless otherwise defined, the
`term “analog” refers to a chemical compound that is structur-
`erm “patient” means an animal, including but not limited to
`ally similar to another but differs slightly in composition (as
`an animal such as a human, monkey, cow, horse, sheep, pig,
`in thc replacement of one atom by an atom of a diffcrcnt
`chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea
`element or in the presence of a particular functional group).
`Jig. In one embodiment, the patient is a mammal and in
`[0033] As used herein and Lmless otherwise defined the
`another embodiment the patient
`is a human. In certain
`
`embodiments, the patient can be an adult male or female. In phrase “pharmaceutically acceptable salt” refers to any salt of
`
`
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`3
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`

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`US 2015/0005268 A1
`
`Jan. 1, 2015
`
`a 17-hydroxylase/C17,2O-lyase inhibitor which retains the
`biological effectiveness of the 17a-hydroxylase/Cl7,20-lyase
`
`inhibitor. Examples of pharmaceutically acceptable salts
`include, but are not limited to, acetates, sulfates, pyro sulfates,
`bisulfates, sulfites, bisulfites, phosphates, monohydrogen—
`phosphates, dihydrogenphosphates, metaphosphates, pyro-
`phosphates, chlorides, bromides,
`iodides, acetates, propi-
`onates,
`decanoates,
`caprylates,
`acrylates,
`formates,
`isobutyrates, caproates, heptanoates, propiolates, oxalates,
`malonates, succinates, suberates, sebacates, fumarates, male-
`ates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates,
`chlorobenzoates,
`methylbenzoates,
`dinitrobenzoates,
`hydroxybenzoates, methoxybenzoates,
`phthalates,
`sul—
`fonates, xylenesulfonates, phylacetates, phenylpropionates,
`phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,
`glycollates,
`tartarates, alkanesulfonates (e.g. methane-sul-
`fonate or mesylate), propanesulfonates, naphthalene-l-sul-
`fonates, naphthalene—2—sulfonates, and mandelates. Several
`of the officially approved salts are listed in Remington: The
`Science and Practice of Pharmacy. Mack Publ. Co., Easton.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`[0034] The methods described herein for treating cancer
`comprise administering to a mammal, preferably a human, a
`l7a-hydroxylase/C 17,20-lyase inhibitor in addition to at least
`one therapeutic agent, such as an anti-cancer agent or steroid,
`particularly a glucocorticoid. The compositions described
`herein comprise a 170t-hydroxylase/C17,20-lyase inhibitor
`and at least one additional therapeutic agent, such as an anti-
`cancer agent or steroid, particularly a corticosteroid or glu-
`cocorticoid. Other anti-cancer treatments such as, adminis-
`tration of yet another anti-cancer agent,
`radiotherapy,
`chemotherapy, photodynamic therapy,
`surgery or other
`immunotherapy, can be used with the methods and composi-
`tions.
`
`l70t-Hydroxylase/C 17,20-Lyase Inhibitors
`
`17(1-hydroxylase/C17,20-lyase inhibitors have been
`[0035]
`shown to be useful in the treatment of cancer, specifically
`hormone-dependent disorders such as, androgen-dependent
`and estrogen-dependent disorders like prostate cancer and
`breast cancer respectively, as described in US. Pat. No.
`5,604,213 to Barrie et al., which is herein incorporated by
`reference in its entirety.
`
`In certain embodiments, the 170L-hydroxylase/C17!
`[0037]
`2o-lyase inhibitor can have the structure of formula (I):
`
`(I)
`
`R>//
`
`\\N
`
`\ R15
`
`R15 R15
`R14
`
`wherein X represents the residue of the A, B and C rings of a
`steroid which can be. without limitation, androstan-30L- or
`38-01;
`androst-5-en-3CL- or 38-01;
`androst-4-en-3-one;
`androst—2—ene; androst—4—ene; androst—5—ene; androsta—5,7—
`dien—30L or 30-01; androsta-l,4-dien-3-one; androsta-3,5-di-
`ene; androsta—3,5-diene-3-ol; estra-1,3,5[10]-triene; estra-1,
`3,5|10|—trien-3-ol; 5a-androstan—3-one; androst-4-ene-3,11-
`dione; 6-fluoroandrost-4-ene-3-one; or androstan-4-ene-3,6-
`dione; each of which, where structurally permissible, can be
`further dcrivatizcd in one or more of the following ways,
`including, but not limited to, to form 3-esters, to have one or
`more carbon or carbon ring double bonds in any of the 5,6-,
`6,7-, 7,8-, 9,11- and 11,12-positions; as 3-oximes; as 3-me-
`thylenes; as 3-carboxylates; as 3-nitriles; as 3-nitros; as
`3—desoxy derivatives; to have one or more hydroxy, halo,
`C 1_4-alkyl, trifluoromethyl, C1_4-alkoxy, C1_4-alkanoyloxy,
`benzoyloxy, oxo, methylene or alkenyl sub stituents in the A,
`B, or C-n'ng; or to be 19-nor;
`[0038] R represents a hydrogen atom or an alkyl group of
`1—4 carbon atoms;
`[0039] R14 represents a hydrogen atom, a halogen atom or
`an alkyl group of 1 to 4 carbon atoms;
`[0040]
`each of the R15 substituents independently repre-
`sents a hydrogen atom or an alkyl or alkoxy group of 1-4
`carbon atoms, a hydroxy group or an alkylcarbonyloxy group
`of 2 to 5 carbon atoms or together represent an oxo or meth-
`ylene group or R14 and one of the R13 groups together repre-
`sent a double bond and the other R 5 group represents a
`hydrogen atom or an alkyl group of 1 to 4 carbon atoms; and
`[0041]
`R1 6 represents a hydrogen atom, halogen atom, or an
`alkyl group of 1 to 4 carbon atoms, in the form of the tree
`bases or pharmaceutically acceptable acid addition salts, but
`excluding
`3 B-acetoxy-17-(3 -pyridyl)androsta-5,14,16-
`triene, 38,15a- and 3B,] 58-diacetoxy-l7-(3-pyridyl)an-
`drosta-5,16-diene
`and 3B-methoxy-17-(3 -pyridyl-50.-an-
`drost-16-ene. Suitable inhibitors also include metabolites,
`derivatives, analogs, or pharmaceutically acceptable salts of
`formula (I).
`[0042]
`In another embodiment, the 170L-hydroxy1ase/C17_
`zo-lyase inhibitor can have the structure of formula (I):
`i
`
`(I)
`
`In certain embodiments, the 170L-hydroxylase/C 17,
`[0036]
`zo-lyase inhibitor can be 17-(3 -pyridyl)androsta-5,16-dien-
`38-01; 17-(3 -pyridyl)andro sta-3, 5,16-triene; 17-(3 -pyridyl)
`androsta-4,16-dien-3 -one, 17-(3-pyridyl)estra-1,3 ,5[10],16-
`tetraen-3-ol; 17-(3 -pyridyl)-50t-androst- l 6-en-30L-ol; 17-(3 -
`pyridyl)-5(x-androst-16-en—3 -one;
`17-(3 -pyridyl) -androsta-
`4,16-diene-3,11-dione;
`17—(3-pyridyl)-androsta-3,5,16-
`trien-3 -ol; 60L- and 6 B-fluoro- l 7-(3 -pyridyl)androsta-4,16-
`dien-3 -ol;
`17-(3-pyridyl)androsta-4,16-dien-3B-dione;
`Sa-trifluoromethyl-17-(3 -pyridyl)androst-1 6-en—3 -01
`or
`their acid addition salts and 3-esters as well as metabolites,
`analogs, derivatives or a pharmaceutically acceptable salt
`thereof.
`
`
`N
`
`/ \
`/
`
`RO
`
`
`
`4
`
`

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`US 2015/0005268 A1
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`Jan. 1,2015
`
`wherein R represents hydrogen or a lower acyl group having
`1 to 4 carbons. Suitable inhibitors also include derivatives,
`analogs, or phamlaceutically acceptable salts of formula
`[0043]
`In still another embodiment, the l70t-hydroxylase/
`(C 17,20-lyase inhibitor can be a 3B-alkanoyloxy-l7—(3-py-
`ridyl) androsta-5,16-diene in which the alkanoyloxy group
`has from 2 to 4 carbon atoms.
`
`In a preferred embodiment, the 170t-hydroxylase
`[0044]
`C [mo-lyase inhibitorcomprises abiraterone acetate or 3 [3-ac-
`etoxy-l7-(3-pyridyl)androsta-5,16-diene which has the fol-
`lowing structural formula:
`
`(11)
`
`N
`
`/ \
`/
`
`AcO
`
`and pharrnaceutically acceptable salts thereof.
`[0045] Preferred salts ofabiraterone acetate and methods of
`making such salts are also disclosed in U.S. Provisional
`Application No. 60/603,559) to Hunt, which is incorporated
`by reference in its entirety. Preferred salts include, but are not
`limited to, acetates, citrates, lactates, alkanesulfonates (e.g.
`methane-sulfonate or mesylate) and tartarates. Of special
`interest is the abiraterone acetate mesylate salt (i.e. 3|5-ac-
`etoxy-17-(3-pyridyl)androsta-5,16-diene mesylate
`salt)
`which has the following structural fonnula:
`
`(111)
`
`
`
`combination with an additional anti-cancer treatment, such as
`an additional anti-cancer agent.
`
`Additional Therapeutic Agents
`
`Suitable compounds that can be used in addition to
`[0048]
`l70t-hydroxylase/C17’20-lyase inhibitors as an anti-cancer
`agent include, but are not limited to, hormone ablation agents,
`anti-androgen agents, differentiating agents, anti-neoplastic
`agents, kinase inhibitors, anti-metabolite agents, alkylating
`agents, antibiotic agents, immunological agents, interferon-
`type agents, intercalating agents, growth factor inhibitors,
`cell cycle inhibitors, enzymes, topoisomerase inhibitors, bio-
`logical response modifiers, mitotic inhibitors, matrix metal-
`loprotease inhibitors, genetic therapeutics, and anti-andro-
`gens. The amount of the additional anti-cancer agent
`administered to a mammal having cancer is an amount that is
`sufficient to treat the cancer whether administered alone or in
`
`combination with a 17a-hydroxylase/C[mo-lyase inhibitor.
`Below are lists of examples of some of the above classes of
`anti—cancer agents. The examples are not all inclusive and are
`for purposes of illustration and not for purposes of limitation.
`Many of the examples below could be listed in multiple
`classes of anti-cancer agents and are not restricted in any way
`to the class in which they are listed in.
`[0049]
`Suitable hormonal ablation agents include, but are
`not limited to, androgen ablation agents and estrogen ablation
`agents. In preferred embodiments, the l70t-hydroxylase/Cl7_
`2o-lyase inhibitor is administered with a hormonal ablation
`agent, such as deslorelin, leuprolide, goserelin or triptorelin.
`Even though throughout this specification and in the claims
`the phrase “hormonal ablation agent” is written as a singular
`noun, for example; “a hormonal ablation agent” or “the hor-
`monal ablation agent,” the phrase “hormonal ablation agent”
`should not be interpreted as being limited to the inclusion of
`a single hormonal ablation agent. The amount of the hor-
`monal ablation agent administered to a mammal having can-
`cer is an amount that is sufficient to treat the cancer whether
`
`administered alone or in combination with a l7a-hydroxy-
`lase/C17azo—lyase inhibitor.
`[0050]
`Suitable anti-androgen agents include but are not
`limited to bicalutamide,
`flutamide and nilutamide. The
`amount ofthe anti-androgen agent administered to a mammal
`having cancer is an amount that is sufficient to treat the cancer
`whether administered alone or in combination with a 170t-
`
`hydroxylase/C 17,2O—lyase inhibitor.
`[0051]
`In another embodiment, the 170t-hydroxylase/C17_
`2o-lyase inhibitor may be administered with a differentiating
`agent. Suitable differentiating agents include, but are not
`limited to, polyamine inhibitors; vitamin D and its analogs,
`such as, calcitriol, doxerealeiferol and seocalcitol; metabo-
`lites of vitamin A, such as, ATRA, retinoic acid, retinoids;
`short-chain fatty acids; phenylbutyrate; and nonsteroidal
`anti-inflammatory agents. The amount of the differentiating
`agent administered to a mammal having cancer is an amount
`that is sufficient to treat the cancer whether administered
`
`[0046] The 170t-hydroxylase/Cl7.20-lyase inhibitors canbe
`made according to any method known to one skilled in the art.
`For example, such inhibitors can be synthesized according to
`the method disclosed in U.S. Pat. Nos. 5,604,213 and 5,618,
`807 to Barrie et al., herein incorporated by reference. Another
`method of making 17ot—hydroxylase/C17,20—lyase inhibitors
`the 17a-hy-
`In another preferred embodiment,
`[0052]
`is disclosed in U.S. provisional application 60/603,558 to
`droxylase/C luc-lyase inhibitor may be administered with an
`Bury, herein incorporated by reference.
`anti-neoplastic agent, including, but not limited to, tubulin
`interacting agents, topoisomerase inhibitors and agents, aci-
`[0047] The
`amount of
`170L-hydroxylase/Cl7,20-lyase
`tretin, alstonine, amonafide, amphethinile, amsacrine, anki-
`inhibitor administered to a mammal having cancer is an
`amotmt that is sufficient to treat the cancer, whether the 170t-
`nomycin, anti-neoplaston, aphidicolin glycinate, asparagi-
`
`
`benfluron,batracylin,baccharin,nase, benzotript,
`
`
`hydroxylase/C l 7,20-lyase inhibitor is administered alone or in
`
`alone or in combination witha 170t-hydroxylase/C1mo-lyase
`inhibitor.
`
`
`
`5
`
`

`

`
`
`US 2015/0005268 A1
`
`Jan. 1, 2015
`
`U‘I
`
`bromofosfamide, caracemide, carmethizole hydrochloride,
`chlorsulfaquinoxalone, clanfenur, claviridenone, crisnatol,
`curaderrn, cytarabine, cytocytin, dacarbazine, datelliptinium,
`dihaematoporphyrin ether, dihydrolenperone, dinaline, dista-
`mycin, docetaxel, elliprabin, elliptinium acetate, epothilones,
`ergotamine, etoposide, etretinate, fenretinide, gallium nitrate,
`genkwadaphnin, hexadecylphosphocholine, homoharringto-
`nine, hydroxyurea,
`ilmofosine,
`isoglutamine,
`isotretinoin,
`leukoregulin, lonidamine, merbarone, merocyanine deriva—
`tives, methylanilinoacridine, minactiVin, mitonafide, mito-
`quidone, mitoxantrone, mopidamol, motretinide, N—(retin-
`oyl)amino acids. N—acylated-dehydroalanines, nafazatrom,
`nocodazole derivative, ocreotide, oquizanocine, paclitaxel,
`pancratistatin, pazelliptine, piroxantrone, polyhaematopor-
`phyrin, polypreic acid, probimane, procarbazine, proglu-
`mide,
`razoxane,
`retelliptine,
`spatol,
`spirocyclopropane
`derivatives, spirogermanium, strypoldinone, superoxide dis-
`mutase,
`teniposide,
`thaliblastine,
`tocotrienol,
`topotecan,
`ukrain, vinblastine sulfate, Vincristine, Vindesine, Vinestra-
`mide, vinorelbine, vintriptol, Vinzolidine, and Withanolides.
`The amount of the anti-neoplastic agent administered to a
`mammal having cancer is an amount that is sufficient to treat
`the cancer Whether administered alone or in combination with
`
`a l70t-hydroxylase/C17220-lyase inhibitor.
`[0053] The 170t-hydroxylase/Cl7,20-lyase inhibitors may
`also be used with a kinase inhibitor including p38 inhibitors
`and CDK inhibitors. TNF inhibitors, metallomatrix proteases
`inhibitors (MMP), COX-2 inhibitors including celecoxib,
`rofecoxib, parecoxib, valdecoxib, and etoricoxib. SOD mim-
`ics or (xv[33 inhibitors. The amount of the kinase inhibitor
`administered to a mammal having cancer is an amount that is
`sufficient to treat the cancer Whether administered alone or in
`
`combination with a l7a-hydroxylase/Clmo-lyase inhibitor,
`[0054]
`In another embodiment, the l70t-hydroxylase/C17,
`zo-lyase inhibitor may be administered With an anti-metabo-
`lite agent. Suitable anti—metabolite agents may be selected
`from, but not limited to, 5-FU-fibrinogen, acanthifolic acid,
`aminothiadiazole, brequinar sodium, carmofur, cyclopentyl
`cytosine, cytarabine phosphate stearate, cytarabine conju—
`gates, dezaguanine, dideoxycytidine, dideoxyguanosine,
`didox, doxifluridine,
`fazarabine,
`floxuridine,
`fludarabine
`phosphate, S-fluorouracil, N-(2'-furanidyl)-5-fluorouracil,
`isopropyl pyrrolizine, methobenzaprim, methotrexate, nor-
`spermidine, pentostatin, piritrexim, plicamycin, thioguanine,
`tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uricy-
`tin. The amount of the anti-metabolite agent administered to
`a mammal having cancer is an amount that is sufficient to treat
`the cancer Whether administered alone or in combination With
`
`a l7ot-hydroxylase/Cl7220-lyase inhibitor.
`[0055]
`In another embodiment, the l70t-hydroxylase/C17,
`zo—lyase inhibitor may be administered With an alkylating
`agent. Suitable alkylating agents may be selected from, but
`not limited to, aldo-phosphamide analogues, altretamine,
`anaxirone, bestrabucil, budotitane, carboplatin, carmustine,
`chlorambucil, cisplatin, cyclophosphamide, cyplatate, diphe-
`nylspiromustine, diplatinum cytostatic, elmustine, estramus-
`tine phosphate sodium, fotemustine, hepsul-fam, ifosfamide,
`iproplatin, lomustine, mafosfamide, mitolactol, oxaliplatin,
`prednimustine, ranimustine, semustine, spiromustine, tauro-
`mustine,
`temozolomide,
`teroxirone,
`tetraplatin and tri-
`melamol. The amount of the alkylating agent administered to
`a mammal having cancer is an amount that is sufficient to treat
`the cancer Whether administered alone or in combination With
`
`the l7a-hy-
`In another preferred embodiment,
`[0056]
`droxylase/C Haze-lyase inhibitor may be administered With an
`antibiotic agent. Suitable antibiotic agents may be selected
`from, but not limited to, aclarubicin, actinomycin D, actino-
`planone, adriamycin, aeroplysinin derivative, amrubicin,
`anthracycline, azino-mycin—A, bisucaberin, bleomycin sul-
`fate, bryostatin—l, calichemycin, chromoximycin, dactino-
`mycin, daunorubicin, ditrisarubicin B, dexamethasone,
`doxorubicin, doxorubicin-fibrinogen, elsamicin—A, epirubi-
`cin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb,
`fostriecin, glidobactin, gregatin-A, grincamycin, herbimycin,
`corticosteroids such its hydrocortisone, idarubicin, illudins,
`kazusamycin, kesarirhodins, menogaril, mitomycin, neoen—
`actin, oxalysine, oxaunomycin, peplomycin, pilatin, piraru-
`bicin, porothramycin, prednisone, prednisolone, pyrindany-
`cin A,
`rapamycin,
`rhizoxin,
`rodorubicin,
`sibanomicin,
`siwenmycin, sorangicin—A, sparsomycin, talisomycin, ter-
`pentecin, thrazine, tricrozarin A, and zorubicin. The amount
`of the antibiotic agent administered to a mammal having
`cancer is an amount that is sufficient to treat the cancer
`Whether administered alone or in combination with a 170.-
`
`hydroxylase/C [mo-lyase inhibitor.
`[0057] Alternatively,
`the
`l7a-hydroxylase/Cnae-lyase
`inhibitors may also be used with other anti-cancer agents,
`including but not
`limited to, acemannan, aclarubicin,
`aldesleukin, alemtuzumab, alitreinoin, altretamine, amifos-
`tine, amsacrine, anagrelide, anastrozole, ancestim, bexaro-
`tene, broxuridine, capecitabine, celmoleukin, cetrorelix,
`cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep,
`docosanol, doxifluridinc, bromocriptinc, carmustine, cytara-
`bine, diclofenac, edelfosine, edrecolomab, eflornithine,
`emitefur, exemestane, exisulind, fadrozole, filgrastim, finas-
`teride, fludarabine phosphate, formestane, fotemustine, gal—
`lium nitrate, geincitabine, glycopine, heptaplatin, ibandronic
`acid, imiquimod iobenguane,
`irinotecan,
`irsogladine,
`lan-
`reotide, leflunomide, lenogiastim, lentinan sulfate, letrozole,
`liarozole, lobaplatin, lonidamine, masoprocol, melarsoprol,
`metoclopramide, mifepristone, miltefosine, minmostim,
`mitoguaz