I IIIII
`
`1111111111111111111111111111111111111111111111111111111111111
`US008822438B2
`
`c12) United States Patent
`Auerbach et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,822,438 B2
`Sep.2,2014
`
`(54)
`
`METHODS AND COMPOSITIONS FOR
`TREATING CANCER
`
`(75)
`
`Inventors: Alan H. Auerbach, Hermosa Beach, CA
`(US); Arie S. Belldegrum, Los Angeles,
`CA (US)
`
`(73)
`
`Assignee: Janssen Oncology, Inc., Los Angeles,
`CA (US)
`
`( *)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`
`Appl. No.: 13/034,340
`
`(22)
`
`Filed:
`
`Feb.24,2011
`
`(65)
`
`Prior Publication Data
`
`US 2011/0144016Al
`
`Jun. 16, 2011
`
`Related U.S. Application Data
`
`(63)
`
`(60)
`
`Continuation of application No. 11/844,440, filed on
`Aug. 24, 2007, now abandoned.
`
`Provisional application No. 60/921,506, filed on Aug.
`25,2006.
`
`(51)
`
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 31156
`A61K 31158
`(52) U.S. Cl.
`CPC ...................................... A61K 31158 (2013.01)
`USPC ........................................... 514/170; 514/180
`(58) Field of Classification Search
`USPC .................................................. 514/170, 182
`See application file for complete search history.
`
`(56)
`
`References Cited
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`
`(Continued)
`
`Primary Examiner- San-Ming Hui
`
`ABSTRACT
`(57)
`Methods and compositions for treating cancer are described
`herein. More particularly, the methods for treating cancer
`comprise administering a 17a-hydroxylase/C17 20-lyase
`inhibitor, such as abiraterone acetate (i.e., 3~-acetoxy-17 -(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(cid:173)
`prising a 17a-hydroxylase/C17 20-lyase inhibitor, and at least
`one additional therapeutic agent, such as an anti-cancer agent
`or a steroid.
`
`20 Claims, No Drawings
`
`WCK1001
`Page 1
`
`

`
`US 8,822,438 B2
`Page 2
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`
`WCK1001
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`

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`US 8,822,438 B2
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`* cited by examiner
`
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`

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`US 8,822,438 B2
`
`1
`METHODS AND COMPOSITIONS FOR
`TREATING CANCER
`
`FIELD OF THE INVENTION
`
`2
`tionally, there is a need for effective anti-cancer treatment
`options for patients who are not responding to current anti(cid:173)
`cancer treatments. Also, there is a need for effective anti(cid:173)
`cancer treatment options for patients whose cancer has
`recurred.
`
`SUMMARY OF THE INVENTION
`
`Methods and compositions for treating cancer are
`described herein. More particularly, the methods for treating
`cancer comprise administering a 17a-hydroxylase/C17 20-
`lyase inhibitor, such as abiraterone acetate (i.e., 3~-aceto~y-
`17-(3-pyridyl) androsta-5,16-diene), in combination with at 10
`least one additional therapeutic agent, such as an anti-cancer
`agent or a steroid. Furthermore, disclosed are compositions
`comprising a 17a-hydroxylase/C17 20-lyase inhibitor, and at
`least one additional therapeutic ag~nt such as an anti-cancer
`agent or a steroid, e.g., a corticosteroid or, more specifically, 15
`a glucocorticoid.
`
`BACKGROUND
`
`The number of people diagnosed with cancer has signifi(cid:173)
`cantly increased. Of special interest are individuals diagnosed
`with androgen-dependent disorders, such as prostate cancer,
`and estrogen-dependent disorders, such as breast cancer since
`such diagnoses are increasing in number at an alarming rate.
`Prostate cancer is currently the most common non-skin 25
`cancer and the second leading cause of cancer-related death in
`men after lung cancer. The primary course of treatment 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, 30
`such localized treatments are not effective on prostate cancer
`after it has metastasized. Moreover, a large percent of indi(cid:173)
`viduals who receive localized treatments will suffer from
`recurring cancer.
`Additionally, breast cancer incidence in women has 35
`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(cid:173)
`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 40
`significant side-effects. Such treatments include surgery,
`radiation and chemotherapy.
`Hormone therapy is another treatment option for individu-
`als diagnosed with prostate or breast cancer. Hormone
`therapy is a form of systemic treatment for prostate or breast 45
`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 50
`growth of prostate cancer. Moreover, hormone therapy is less
`invasive than surgery and does not have many of the 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 55
`cancer has metastasized.
`Even though hormone therapy is less invasive and can be
`used on more advanced stages of cancer, some individuals
`administered current hormone therapy treatments may not
`show a significant response or may not show any response at 60
`all to such treatments. Additionally, some patients treated
`with current hormone therapy treatments may also suffer
`from relapsing or recurring cancer. Currently, such refractory
`cancer patients are left with very few treatment options.
`Despite the progress made in the treatment of cancer, there 65
`remains a need for more effective ways to treat cancer such as,
`but not limited to, prostate cancer and breast cancer. Addi-
`
`Described herein are methods for treating a cancer in
`which a therapeutically effective amount of a 17a-hydroxy(cid:173)
`lase/C17.20-lyase inhibitor, such as abiraterone acetate (i.e.
`3~-acetoxy-17-(3-pyridyl)androsta-5,16-diene), is adminis(cid:173)
`tered to a patient, e.g., a patient in need thereof, in combina(cid:173)
`tion with a therapeutically effective amount of at least one
`additional therapeutic agent including, but not limited to, an
`anti-cancer agent or steroid. Such methods can also provide
`an effective treatment for individuals with a refractory cancer,
`including individuals who are currently undergoing a cancer
`20 treatment. Therefore, in certain embodiments, the method is
`directed to treating a refractory cancer in a patient, in which a
`therapeutically effective amount of 17a-hydroxylase/C17•20-
`lyase inhibitor is administered to a patient currently receiving
`an anti-cancer agent.
`For example, in certain 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/kg/day
`of abiraterone acetate and an amount of about 0.1 mg/m2 to
`about 20 mg/m2 of mitoxantrone.
`In another embodiment, 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/kg/day of abiraterone
`acetate and an amount of about 1 mg/m2 to about 175 mg/m2
`of paclitaxel.
`In still 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/kg/day of abiraterone
`acetate and an amount of about 1 mg/m2 to about 100 mg/m2
`of docetaxel.
`Furthermore, described herein is a method for the treat(cid:173)
`ment 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 ofleuprolide, wherein the leuprolide is administered
`over a period of about 3 days to about 12 months.
`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/kg/day of abiraterone
`acetate and an amount of about 0.01 mg to about 20 mg of
`goserelin, wherein the goserelin is administered over a period
`of about 28 days to about 3 months.
`Additionally, in another embodiment, 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/kg/day
`of abiraterone acetate and an amount of about 0.01 mg to
`about 20 mg oftriptorelin, wherein the triptorelin is admin-
`istered over a period of about 1 month.
`The method for the treatment of a cancer in a mammal can
`also 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 0.1 flg/day to about 500 flg/day of seocalci-
`tol, such as about 100 flg/day of seocalcitol.
`Also, the method for the treatment 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 300 mg/day ofbicaluta-
`mide.
`
`WCK1001
`Page 4
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`

`
`US 8,822,438 B2
`
`3
`In yet another embodiment, the method for the treatment 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 abirater(cid:173)
`one acetate and an amount of about 1 mg/day to about 2000
`mg/day offlutamide.
`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 mg/day of abiraterone acetate and an
`amount of about 0.01 mg/day to about 500 mg/day of a
`glucocorticoid including, but not limited to, hydrocortisone,
`prednisone or dexamethasone.
`Also described herein are compositions for the treatment of
`cancer that comprise a combination of a therapeutically effec(cid:173)
`tive amount of at least one 17a-hydroxylase/C17 20-lyase
`inhibitor and a therapeutically effective amount of at least one
`additional anti-cancer agent, such as, but not limited to,
`mitoxantrone, paclitaxel, docetaxel, leuprolide, goserelin,
`triptorelin, seocalcitol, bicalutamide, flutamide, or a steroid
`including, but not limited to, hydrocortisone, prednisone, or
`dexamethasone.
`Finally, single unit dosage forms comprising abiraterone
`acetate and a glucocorticoid, optionally with carriers, diluents
`or excipients, are contemplated. Also, kits comprising at least
`one 17 a-hydroxylase/C17 20-lyase inhibitor and an additional
`anti cancer agent or steroid are contemplated. For example,
`the kit may include a vial containing abiraterone acetate and
`another vial containing a glucocorticoid.
`
`DEFINITIONS
`
`As used herein and unless otherwise defined the word
`"cancer," refers to the growth, division or proliferation of
`abnormal cells in the body. Cancers that can be treated with
`the methods and the compositions described herein include,
`but are not limited to, prostate cancer, breast cancer, adrenal
`cancer, leukemia, lymphoma, myeloma, Waldenstriim' s mac(cid:173)
`roglobulinemia, monoclonal gammopathy, benign mono(cid:173)
`clonal gammopathy, heavy chain disease, bone and connec(cid:173)
`tive tissue sarcoma, brain tumors, thyroid cancer, pancreatic
`cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar 40
`cancer, cervical cancer, uterine cancer, ovarian cancer, esoph(cid:173)
`ageal cancer, stomach cancer, colon cancer, rectal cancer,
`liver cancer, gallbladder cancer, cholangiocarcinoma, lung
`cancer, testicular cancer, penal cancer, oral cancer, skin can(cid:173)
`cer, kidney cancers, Wilms' tumor and bladder cancer.
`As used herein, and unless otherwise defined, the terms
`"treat," "treating" and "treatment" include the eradication,
`removal, modification, management or control of a tumor or
`primary, regional, or metastatic cancer cells or tissue and the
`minimization or delay of the spread of cancer.
`As used herein, and unless otherwise defined, the term
`"patient" means an animal, including but not limited to an
`animal such as a human, monkey, cow, horse, sheep, pig,
`chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea
`pig. In one embodiment, the patient is a mammal and in
`another embodiment the patient is a human. In certain
`embodiments, the patient can be an adult male or female. In
`some embodiments, the patient is a male of age about 30 years
`to about 85 years. In other embodiments, the patient is a
`female of age about 30 years to about 85 years. In a particular
`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 having (e.g.,
`through genetic or environmental factors) a tumor. In other
`embodiments, the patient can be castrated or non-castrated.
`The term "17a-hydroxylase/C17 20-lyase inhibitor" as
`used herein refers to an inhibitor of 17a-hydroxylase/C17.20 -
`
`4
`lyase, (which is an enzyme in testosterone synthesis), an
`analog thereof, derivative thereof, metabolite thereof or phar(cid:173)
`maceutically acceptable salt thereof. Also, unless otherwise
`noted, reference to a particular 17a-hydroxylase/C17 20-lyase
`inhibitor can include analogs, derivatives, metab~lites or
`pharmaceutically acceptable salts of such particular 17 a(cid:173)
`hydroxylase/C17 20-lyase inhibitor.
`The term "anti-cancer agent" as used herein refers to any
`therapeutic agent that directly or indirectly kills cancer cells
`10 or directly or indirectly prohibits stops or reduces the prolif(cid:173)
`eration 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
`15 "anti -cancer agent" should not be interpreted as being limited
`to the inclusion of a single anti-cancer agent.
`As used herein, and unless otherwise defined, the phrase
`"therapeutically effective amount" when used in connection
`with a 17a-hydroxylase/C17 20-lyase inhibitor or therapeutic
`20 agent means an amount of the 17a-hydroxylase/C17 20-lyase
`inhibitor or therapeutic agent effective for treating ~ disease
`or disorder disclosed herein, such as cancer.
`As used herein and unless otherwise defined the phrase
`"refractory cancer," means cancer that is not responding to an
`25 anti-cancer treatment or cancer that is not responding suffi(cid:173)
`ciently to an anti -cancer treatment. Refractory cancer can also
`include recurring or relapsing cancer.
`As used herein and unless otherwise defined the phrase
`"refractory patient," means a patient who has refractory can-
`30 cer.
`As used herein and unless otherwise defined the phrase
`"relapse cancer," means cancer that was at one time respon(cid:173)
`sive to an anti -cancer treatment but has become no longer
`responsive to such treatment or is no longer responding suf-
`35 ficiently to such treatment.
`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.
`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 of the compound. The derivative may retain
`or improve the pharmacological activity of the compound
`45 from which it is derived.
`As used herein and unless otherwise defined the term "ana(cid:173)
`log" refers to a chemical compound that is structurally similar
`to another but differs slightly in composition (as in the
`replacement of one atom by an atom of a different element or
`50 in the presence of a particular functional group).
`As used herein and unless otherwise defined the phrase
`"pharmaceutically acceptable salt" refers to any salt of a
`17a-hydroxylase/C17 20-lyase inhibitor which retains the
`biological effectivene~s of the 17a-hydroxylase/C17 20-lyase
`55 inhibitor. Examples of pharmaceutically acceptable salts
`include, but are not limited to, acetates, sulfates, pyrosulfates,
`bisulfates, sulfites, bisulfites, phosphates, monohydrogen(cid:173)
`phosphates, dihydrogenphosphates, metaphosphates, pyro(cid:173)
`phosphates, chlorides, bromides, iodides, acetates, propi-
`60 onates,
`decanoates,
`caprylates,
`acrylates,
`formates,
`isobutyrates, caproates, heptanoates, propiolates, oxalates,
`malonates, succinates, suberates, sebacates, fumarates, male(cid:173)
`ates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates,
`chlorobenzoates,
`methylbenzoates,
`dinitrobenzoates,
`65 hydroxybenzoates, methoxybenzoates, phthalates,
`sul(cid:173)
`fonates, xylenesulfonates, phylacetates, phenylpropionates,
`phenylbutyrates, citrates, lactates, gamma-hydroxybutyrates,
`
`WCK1001
`Page 5
`
`

`
`US 8,822,438 B2
`
`6
`3-desoxy derivatives; to have one or more hydroxy, halo,
`c1-4-alkyl, trifluoro-methyl, c1-4-alkoxy, c1-4-alkanoyloxy,
`benzoyloxy, oxo, methylene or alkenyl substituents in the A,
`B, or C-ring; or to be 19-nor;
`R represents a hydrogen atom or an alkyl group of 1-4
`carbon atoms;
`R 14 represents a hydrogen atom, a halogen atom or an alkyl
`group of 1 to 4 carbon atoms;
`each of the R15 substituents independently represents 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
`methylene group or R14 and one of the R15 groups
`together represent a double bond and the other R 15 group
`represents a hydrogen atom or an alkyl group of 1 to 4
`carbon atoms; and
`R 16 represents a hydrogen atom, halogen atom, or an alkyl
`group of 1 to 4 carbon atoms, in the form of the free bases
`or pharmaceutically acceptable acid addition salts, but
`excluding 3~-acetoxy-17 -(3-pyridyl)androsta-5, 14,16-
`triene, 3~,15a- and 3~,15~-diacetoxy-17-(3-pyridyl)
`androsta-5,16-diene and 3~-methoxy-17-(3-pyridyl-
`5a-androst-16-ene.
`Suitable inhibitors also include metabolites, derivatives,
`analogs, or pharmaceutically acceptable salts of formula (I).
`In another embodiment, the 17a-hydroxylase/C 17 20-lyase
`·
`inhibitor can have the structure of formula (I):
`
`(I)
`
`5
`glycollates, tartarates, alkanesulfonates (e.g. methane-sul(cid:173)
`fonate or mesylate), propanesulfonates, naphthalene-1-sul(cid:173)
`fonates, naphthalene-2-sulfonates, and mandelates. Several
`of the officially approved salts are listed in Remington: The
`Science and Practice of Pharmacy, Mack Pub!. Co., Easton.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The methods described herein for treating cancer comprise
`administering to a mammal, preferably a human, a 17a-hy- 10
`droxylase/C 17 20-lyase inhibitor in addition