`
`(12) 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. Hennosa 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 ofthis
`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 2011/0l440I6A1
`
`Jun. 16,2011
`
`(63)
`
`(60)
`
`(51)
`
`(52)
`
`(58)
`
`(56)
`
`Related U.S. Application Data
`
`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.
`
`Int. Cl.
`A 61K 31/56
`A6IK 31/58
`U.S. CL
`
`(2006.01)
`(2006.01 )
`
`CPC .................................... .. A6IK 31/58 (2013.01)
`USPC ......................................... .. 514/170; 514/180
`Field of Classification Search
`USPC ................................................ .. 514/170,182
`See application file for complete search history.
`
`References Cited
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`Primary Examiner — San-Ming Hui
`
`(57)
`
`ABSTRACT
`
`Methods and compositions for treating cancer are described
`herein. More particularly, the methods for treating cancer
`comprise administering a 17a-hydroxylase/Cum-lyase
`inhibitor, such as abiraterone acetate (i.e., 3B-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. Furthennore, disclosed are compositions com-
`prising a 170.-hydroxylase/C 1 no-lyase inhibitor, and at least
`one additional therapeutic agent, such as an anti-cancer agent
`or a steroid.
`
`20 Claims, No Drawings
`
`ARGENTUM EX1001
`ARGENTUM EX1001
`
`Page 1
`
`Page 1
`
`
`
`
`
`
`US 8,822,438 B2
`Page 2
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`(56)
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`US 8,822,438 B2
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`Urologists and Medical Oncologists to complete a study in early
`
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`
`Prostate Cancer’?”, Journal ofClinical Oncology (2005), vol. 23, No.
`
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`15, pp. 3304-3307.
`
`
`
`“FoxA1 Specifies Unique Androgen and
`Sahu, B.,
`al,,
`et
`
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`
`
`Glucocorticoid Receptor Binding Events in Prostate Cancer Cells”,
`
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`Cancer Research (2013), vol. 73, pp. 1570-1580.
`
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`
`Storlie, J.A., et al., “Prostate Specific Antigen Levels and Clinical
`
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`
`Response to Low Dose Dexamethasone for Hormone-Refractory
`
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`Metastatic Prostate Carcinoma”, Cancer (1995) vol. 76, No. 1, p.
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`96-100.
`
`Tanagho, E.A., et al., “The Leading Single-Volume Resource in
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`
`
`Urology”, Smith’s General Urology, 16th Edition, (2004), Chapter
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`
`
`19, pp. 321-323; Chapter 22, pp. 380-385.
`
`
`
`
`
`
`
`of High Dose
`Tomic,
`et
`“Hormonal Effects
`R.,
`al,,
`
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`
`
`
`Medroxyprogesterone Acetate Treatment in Males with Renal or
`
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`Prostatic Adenocarcinoma”, (1988), vol. 22 (1), Abstract.
`
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`Venkitaran1an, R., et al., “Efficacy of Low-Dose Dexarnethasone in
`
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`Castration-Refractory Prostate Cancer”, BJU Int (2008), 101, pp.
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`1756-1764.
`
`
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`
`
`Vogelzang, N.J., Curriculum Vitae, 15 pages.
`
`
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`
`
`
`Tumor
`Suppress
`A.,
`et
`“Glucocorticoids
`Yana,
`al.,
`
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`
`
`
`
`Lymphandiogenesis of Prostate Cancer Cells”, Clin Cancer Res
`
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`(2006), vol. 12, pp. 6012-6017.
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`
`
`Declaration by Dr. Jacqueline Anne Warner in the matter of Opposi-
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`tion by Northern Rivers Pty Ltd., 25 pages, 2004.
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`Declaration by Helen Grimes in the matter ofOpposition by Northern
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`Rivers Pty Ltd., 43 pages, 2004.
`
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`
`
`Statement of Opposition, Actavis Group PTC ehf.
`
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`
`
`Statement of Opposition, Alfred E. Tiefenbacher (translated in
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`English).
`
`Statement of Opposition, Arnold Siedsma (Synthon B.V.).
`
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`Statement of Opposition, Cabinet Lavoix.
`
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`
`Statement of Opposition, Galenicum Health, S.L.
`
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`
`Statement of Opposition, Generics Ltd.
`
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`
`Statement of Opposition, Helm AG (translated in English).
`
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`
`Statement of Opposition, Hetero Drugs.
`
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`
`Statement of Opposition, Laboratorios Leon Farma, S.A.
`
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`
`Statement of Opposition, Maiwald Patentanwalts GmbH.
`
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`
`Statement of Opposition, Stada Arzneimittel AG (translated in
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`English).
`
`Statement of Opposition, Teva Pharmaceutical Industries, Ltd.
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`* cited by examiner
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`Page 3
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`Page 3
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`US 8,822,438 B2
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`1
`METHODS AND COMPOSITIONS FOR
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`TREATING CANCER
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`FIELD OF THE INVENTION
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`treating cancer are
`for
`Methods and compositions
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`described herein. More particularly, the methods for treating
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`cancer comprise administering a l70t-hydroxylase/C17,2O-
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`lyase inhibitor, such as abiraterone acetate (i.e., 3[3-acetoxy-
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`l7-(3-pyridyl) androsta-5,16-diene), in combination with at
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`least one additional therapeutic agent, such as an anti-cancer
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`agent or a steroid. Furthermore, disclosed are compositions
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`comprising a l70L-hydroxylase/C17,20-lyase inhibitor, and at
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`least one additional therapeutic agent such as an anti-cancer
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`agent or a steroid, e.g., a corticosteroid or, more specifically,
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`a glucocorticoid.
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`BACKGROUND
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`The number of people diagnosed with cancer has signifi-
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`cantly increased. Of special interest are individuals diagnosed
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`with androgen-dependent disorders, such as prostate cancer,
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`and estrogen-dependent disorders, such as breast cancer since
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`such diagnoses are increasing in number at an alarming rate.
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`Prostate cancer is currently the most common non-skin
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`cancer and the second leading cause ofcancer-related death in
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`men after lung cancer. The primary course of treatment for
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`patients diagnosed with organ-confined prostate cancer is
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`usually prostatectomy or radiotherapy. Not only are these
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`treatments highly invasive and have undesirable side effects,
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`such localized treatments are not effective on prostate cancer
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`after it has metastasized. Moreover, a large percent of indi-
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`viduals who receive localized treatments will suffer from
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`recurring cancer.
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`Additionally, breast cancer incidence in women has
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`increased from one out of every 20 women in 1960 to one out
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`of every eight women in 2005. Moreover, it is the most com-
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`mon cancer among white and African-American women.
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`Similar to treating prostate cancer, most options for women
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`diagnosed with breast cancer are highly invasive and have
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`significant side-effects. Such treatments include surgery,
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`radiation and chemotherapy.
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`Hormone therapy is another treatment option for individu-
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`als diagnosed with prostate or breast cancer. Hormone
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`therapy is a form of systemic treatment for prostate or breast
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`cancer wherein hormone ablation agents are used to suppress
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`the production or block the effects of hormones, such as
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`estrogen and progesterone in the body, which are believed to
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`promote the growth of breast cancer, as well as testosterone
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`and dihydrotestosterone, which are believed to promote the
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`growth of pro state cancer. Moreover, hormone therapy is less
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`invasive than surgery and does not have many of the side
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`effects associated with chemotherapy or radiation. Hormone
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`therapy can also be used by itself or in addition to localized
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`therapy and has shown to be effective in individuals whose
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`cancer has metastasized.
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`Even though hormone therapy is less invasive and can be
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`used on more advanced stages of cancer, some individuals
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`administered current hormone therapy treatments may not
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`show a significant response or may not show any response at
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`all to such treatments. Additionally, some patients treated
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`with current hormone therapy treatments may also suffer
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`from relapsing or recurring cancer. Currently, such refractory
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`cancer patients are left with very few treatment options.
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`Despite the progress made in the treatment of cancer, there
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`remains a need for more effective ways to treat cancer such as,
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`but not limited to, prostate cancer and breast cancer. Addi-
`
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`10
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`15
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`20
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`25
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`30
`
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`35
`
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`40
`
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`45
`
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`
`50
`
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`
`55
`
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`
`60
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`
`65
`
`
`2
`
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`tionally, there is a need for effective anti-cancer treatment
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`options for patients who are not responding to current anti-
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`cancer treatments. Also, there is a need for effective anti-
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`cancer treatment options for patients whose cancer has
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`recurred.
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`SUMMARY OF THE INVENTION
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`Described herein are methods for treating a cancer in
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`which a therapeutically effective amount of a l7ot-hydroxy-
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`lase/C1730-lyase inhibitor, such as abiraterone acetate (i.e.
`3 [3-acetoxy-17-(3 -pyridyl)androsta-5,l6-diene), is adminis-
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`tered to a patient, e.g., a patient in need thereof, in combina-
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`tion with a therapeutically effective amount of at least one
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`additional therapeutic agent including, but not limited to, an
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`anti-cancer agent or steroid. Such methods can also provide
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`an effective treatment for individuals with a refractory cancer,
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`including individuals who are currently undergoing a cancer
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`treatment. Therefore, in certain embodiments, the method is
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`directed to treating a refractory cancer in a patient, in which a
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`therapeutically effective amount of l70t-hydroxylase/C17,2O-
`lyase inhibitor is administered to a patient currently receiving
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`an anti-cancer agent.
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`For example, in certain embodiments, the method for the
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`treatment of a cancer in a mammal comprises administering
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`an amount of about 0.01 mg/kg/day to about 100 mg/kg/day
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`of abiraterone acetate and an amount of about 0.1 mg/m2 to
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`about 20 mg/m2 of mitoxantrone.
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`In another embodiment, the method for the treatment of a
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`cancer in a mammal comprises administering an amount of
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`about 0.01 mg/kg/day to about 100 mg/kg/day of abiraterone
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`acetate and an amount of about 1 mg/m2 to about 175 mg/m2
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`of paclitaxel.
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`In still other embodiments, the method for the treatment of
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`a cancer in a mammal comprises administering an amount of
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`about 0.01 mg/kg/day to about 100 mg/kg/day of abiraterone
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`acetate and an amount of about 1 mg/m2 to about 100 mg/m2
`
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`of docetaxel.
`
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`Furthermore, described herein is a method for the treat-
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`ment of a cancer in a mammal comprising administering an
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`amount of about 0.01 mg/kg/day to about 100 mg/kg/day of
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`abiraterone acetate; and an amount of about 0.01 mg to about
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`200 mg of leuprolide, wherein the leuprolide is administered
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`over a period of about 3 days to about 12 months.
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`In other embodiments, the method for the treatment of a
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`cancer in a mammal comprises administering an amount of
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`about 0.01 mg/kg/day to about 100 mg/kg/day of abiraterone
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`acetate and an amount of about 0.01 mg to about 20 mg of
`
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`goserelin, wherein the goserelin is administered over a period
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`of about 28 days to about 3 months.
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`Additionally, in another embodiment, the method for the
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`treatment of a cancer in a mammal comprises administering
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`an amount of about 0.01 mg/kg/day to about 100 mg/kg/day
`
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`of abiraterone acetate and an amount of about 0.01 mg to
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`about 20 mg of triptorelin, wherein the triptorelin is admin-
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`istered over a period of about 1 month.
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`The method for the treatment of a cancer in a mammal can
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`also comprise administering an amount of about 0.01 mg/kg/
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`day to about 100 mg/kg/day of abiraterone acetate and an
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`amount of about 0.1 ug/day to about 500 ug/day of seocalci-
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`tol, such as about 100 p.g/day of seocalcitol.
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`Also, the method for the treatment of a cancer in a mammal
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`can comprise administering an amount of about 0.01 mg/kg/
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`day to about 100 mg/kg/day of abiraterone acetate and an
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`amount of about 1 mg/day to about 300 mg/day of bicaluta-
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`mide.
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`Page 4
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`Page 4
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`4
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`US 8,822,438 B2
`
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`
`3
`In yet another embodiment, the method for the treatment of
`
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`a cancer in a mammal can comprise administering an amount
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`of about 0.01 mg/kg/day to about 100 mg/kg/day of abirater-
`
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`one acetate and an amount of about 1 mg/day to about 2000
`
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`mg/day of flutamide.
`
`
`Moreover, the method for the treatment of a cancer in a
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`mammal can comprise administering an amount of about 50
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`mg/day to about 2000 mg/day of abiraterone acetate and an
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`
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`amount of about 0.01 mg/day to about 500 mg/day of a
`
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`glucocorticoid including, but not limited to, hydrocortisone,
`
`
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`
`
`
`prednisone or dexarnethasone.
`
`
`
`Also described herein are compositions for the treatment of
`
`
`
`
`
`
`
`
`cancer that comprise a combination ofa therapeutically effec-
`
`
`
`
`
`
`
`
`
`
`
`
`
`tive amount of at least one l701-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, flutarnide, or a steroid
`
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`
`
`
`including, but not limited to, hydrocortisone, prednisone, or
`
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`
`
`
`
`
`dexarnethasone.
`
`Finally, single unit dosage forms comprising abiraterone
`
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`
`
`
`
`acetate and a glucocorticoid, optionally with carriers, diluents
`
`
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`
`
`
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`or excipients, are contemplated. Also, kits comprising at least
`
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`
`
`
`
`
`
`
`
`
`
`
`
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`one 1 70t-hydroxylase/C 17,20-lyase inhibitor and an additional
`
`anti cancer agent or steroid are contemplated. For example,
`
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`
`
`
`the kit may include a vial containing abiraterone acetate and
`
`
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`
`another vial containing a glucocorticoid.
`
`
`
`
`DEFINITIONS
`
`
`
`As used herein and unless otherwise defined the word
`
`
`
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`
`
`
`
`“cancer,” refers to the growth, division or proliferation of
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`abnormal cells in the body. Cancers that can be treated with
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`the methods and the compositions described herein include,
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`but are not limited to, prostate cancer, breast cancer, adrenal
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`cancer, leukemia, lymphoma, myeloma, Waldenstrom’s mac-
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`roglobulinemia, monoclonal gammopathy, benign mono-
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`clonal gammopathy, heavy chain disease, bone and connec-
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`tive tissue sarcoma, brain tumors, thyroid cancer, pancreatic
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`cancer, pituitary cancer, eye cancer, vaginal cancer, vulvar
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`cancer, cervical cancer, uterine cancer, ovarian cancer, esoph-
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`ageal cancer, stomach cancer, colon cancer, rectal cancer,
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`liver cancer, gallbladder cancer, cholangiocarcinoma, lung
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`cancer, testicular cancer, penal cancer, oral cancer, skin can-
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`cer, kidney cancers, Wilms’ tumor and bladder cancer.
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`As used herein, and unless otherwise defined, the terms
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`“treat,” “treating” and “treatment” include the eradication,
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`removal, modification, management or control of a tumor or
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`primary, regional, or metastatic cancer cells or tissue and the
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`minimization or delay of the spread of cancer.
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`As used herein, and unless otherwise defined, the term
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`“patient” means an animal, including but not limited to an
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`animal such as a human, monkey, cow, horse, sheep, pig,
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`chicken, turkey, quail, cat, dog, mouse, rat, rabbit, or guinea
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`pig. In one embodiment, the patient is a mammal and in
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`another embodiment
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`is a human.
`In certain
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`embodiments, the patient can be an adult male or female. In
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`some embodiments, the patient is a male ofage about 30 years
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`to about 85 years. In other embodiments, the patient is a
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`female of age about 30 years to about 85 years. In a particular
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`embodiment, the patient has or is susceptible to having (e.g.,
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`through genetic or environmental factors) cancer. In a further
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`embodiment, the patient has or is susceptible to having (e.g.,
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`through genetic or environmental factors) a tumor. In other
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`embodiments, the patient can be castrated or non-castrated.
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`The term “l70L-hydroxylase/C17,20-lyase inhibitor” as
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`used herein refers to an inhibitor of l70t-hydroxylase/C17,2O-
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`10
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`15
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`20
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`25
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`30
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`35
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`40
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`45
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`50
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`55
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`60
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`65
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`lyase, (which is an enzyme in testosterone synthesis), an
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`analog thereof, derivative thereof, metabolite thereof or phar-
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`maceutically acceptable salt thereof. Also, unless otherwise
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`noted, reference to a particular l701-hydroxylase/C17,20-lyase
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`inhibitor can include analogs, derivatives, metabolites or
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`pharmaceutically acceptable salts of such particular 1701-
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`hydroxylase/C1730-lyase inhibitor.
`The term “anti-cancer agent” as used herein refers to any
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`therapeutic agent that directly or indirectly kills cancer cells
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`or directly or indirectly prohibits stops or reduces the prol