JP2014513730A - Pharmaceutical compositions and methods for treating cancer - Google Patents

Abstract

The present invention provides pharmaceutical compositions and methods for treating cancer comprising administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor. The present invention relates to pharmaceutical compositions and methods for the treatment of certain cancers, wherein a therapeutically effective amount of 17-alpha hydroxylase is administered to a patient in need thereof without simultaneous or sequential administration of steroids. / C17,20-lyase inhibitor administration. In certain embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor is selective for C17,20-lyase.

Description

  Cancer is characterized by uncontrolled growth of abnormal cells and subsequent invasion of adjacent tissue by these abnormal cells, or lymphatic or blood-derived spread (ie, metastasis) of malignant cells to local lymph nodes and distal sites. It is a disease group. Cancer is thought to be due to both external factors (tobacco, infectious organisms, chemicals, and radiation) and internal factors (mutations caused by inherited mutations, hormones, immune status, and metabolism) . These causative factors may act together or in sequence to initiate or promote carcinogenesis. Notably, currently in the United States, cancer is the second leading cause of death following heart disease, and the number of people diagnosed with cancer has increased significantly and continues to rise at a surprising rate. Individuals diagnosed with prostate cancer (androgen-dependent) and hormone-dependent disorders (eg, androgen-dependent and estrogen-dependent) such as breast cancer, uterine cancer, and ovarian cancer (estrogen-dependent) Of particular concern is the most common and deadly form of cancer and the rapid increase in such diagnoses.

  Prostate cancer is currently the most common non-skin cancer and is the second leading cause of cancer-related death in men after lung cancer. The main course of treatment for patients diagnosed with organ-limited prostate cancer is usually prostatectomy or radiation therapy. Not only are these treatments very invasive and characterized by undesirable and severe side effects, such local treatments are not effective against prostate cancer after metastasis. In addition, surgery may be contraindicated due to the patient's health or may be unacceptable to the patient, and the surgical procedure may not be able to completely remove the cancerous tissue. Radiation therapy is effective only when irradiated neoplastic tissue is more sensitive to radiation than normal tissue. In addition, a large proportion of individuals who receive local treatment such as surgery or radiation therapy will suffer from cancer recurrence and widespread metastasis.

  There are many similarities between prostate cancer and breast cancer, both in the underlying disease biology and therapeutic measures. Similar to the prostate treatment described above, most options for women diagnosed with breast cancer are highly invasive and have significant side effects. Such treatment includes surgery, radiation, and chemotherapy. Like surgery and radiation therapy, the fact that almost all chemotherapeutic agents are toxic, and chemotherapy is prominent, often resulting in dangerous side effects, including severe nausea, bone marrow suppression, and immunosuppression. There are many drawbacks to chemotherapy, including. In addition, many tumor cells are or become resistant to chemotherapeutic agents due to multidrug resistance. In addition, some patients who initially respond to chemotherapy may suffer from cancer recurrence or recurrence.

  Hormone therapy is another treatment option for individuals diagnosed with prostate or breast cancer. Hormone therapy is a form of systemic treatment for prostate cancer or breast cancer, where hormone ablation agents suppress the production of hormones such as estrogens and progesterone that are thought to promote the growth of prostate cancer, or Used to block its action. This therapy is less invasive than surgery and does not have many side effects associated with chemotherapy or radiation. In addition, hormonal therapy can be used alone or in addition to local therapy.

  Hormone therapy is minimally invasive and can be used for more advanced cancers, but some individuals who have undergone current hormone therapy treatment do not respond to such treatment at all or in part There is a case. Current hormonal therapy treatments can lead to temporary remissions of cancers, but these treated cancers can relapse or recur, and at the time of recurrence, these cancers are against hormonal therapy Often becomes tolerant. Because of the typically aggressive nature of these recurrent cancers and their resistance to hormonal therapy, patients with these conditions often have little treatment options.

Other cancers where sex hormones may contribute to cancer progression include uterine cancer, endometrial cancer, non-small cell lung cancer, and colorectal cancer (Non-patent document 1, Non-patent document 2, Non-patent document 3, Non-patent document 4).
Thus, there is a need to find new treatments for cancer, particularly hormone-induced cancers, that will avoid or ameliorate the harsh side effects of currently existing therapies.

Folkerd, E .; J. et al. and Dowsett. M.M. , J .; Clin. Oncol. 2010, 28: 4038-4044 Paggi M.M. G. et al. , Cancer Lett. 2010, 298 (1): 1-8 Fucic A. et al. , Toxicol. Pathol. 2010, 38 (6): 849-55 Gambacciani M. et al. et al. Best Pract Res Clin Endocrinol Metab. 2003 17 (1): 139-47

1. SUMMARY As mentioned above, there is a need to provide alternative therapies for the treatment of cancer, particularly those that avoid or ameliorate the harsh side effects of currently existing therapies. Accordingly, the present invention relates to pharmaceutical compositions and methods for the treatment of certain cancers, wherein therapeutically effective amounts of 17-alpha hydroxy are administered to patients in need thereof without simultaneous or sequential administration of steroids. Administration of a lase / C17,20-lyase inhibitor. In certain embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor is selective for C17,20-lyase. In other embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor is a compound that does not have a steroid skeleton. In another embodiment, the 17-α hydroxylase / C17,20-lyase inhibitor is a compound that is selective for C17,20-lyase and does not have a steroid skeleton.

  In another embodiment, the steroid is administered simultaneously or sequentially, including administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor without simultaneously or sequentially administering the steroid. Without administration of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, as measured by increased progression-free survival or time to metastasis compared to standard therapy. Methods are provided for treating cancer that result in improved clinical outcome.

  In yet another embodiment, a therapeutically effective amount of 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazole is administered without simultaneous or sequential administration of steroids. -7-yl] -N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, and treatment without simultaneous or sequential administration of steroids Administering an effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor improves patient clinical outcome as measured by increased progression-free survival or time to metastasis compared to standard therapy A method of treating cancer that results in is provided.

In another aspect, the present invention provides a safe and efficient dose level, particularly steroids in a patient, that monitors the patient's blood pressure and the serum level of one or more of corticosterone, cortisol, or potassium. Selectively adjusting the dose level to achieve a safe and efficient dose level of 17-α hydroxylase / C17,20-lyase inhibitor that can be administered without simultaneous or sequential administration. A method for treating cancer is provided. Therefore,
(A) measuring one or more levels of one or more serum levels of corticosterone, cortisol, or potassium at a first time point;
(B) administering to the patient a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor;
(C) after administration of a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, one of the patient's blood pressure or corticosterone, cortisol, or potassium Measuring one or more of the above serum levels;
(D) administering to a patient a second dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20 lyase inhibitor, wherein the second dose level exceeds the first dose level; There is provided a method of treating cancer comprising, equal to or less than.

2. Definitions As used herein, the term “cancer” refers to uncontrolled or unregulated cell proliferation, decreased cell differentiation, inappropriate ability to invade surrounding tissue, and / or new growth at a translocation site. Refers to a cellular disorder characterized by the ability to establish. The term “cancer” includes, but is not limited to, solid tumors and blood-derived tumors. The term “cancer” encompasses skin, tissue, organ, bone, cartilage, blood, and vascular diseases. The term “cancer” further encompasses primary and metastatic cancers.

  As used herein, the term “cancer recurrence” refers to a cancer in which the patient has been previously diagnosed with cancer, treated and / or reverted after having previously been diagnosed with no cancer.

  As used herein, the term “cancer relapse” is responsive to anti-cancer treatments once but is no longer responsive to such treatments or is no longer sufficient for such treatments. It refers to cancer that has stopped responding.

  As used herein, the term “refractory cancer” refers to cancer that does not respond to anti-cancer treatment, or cancer that does not respond sufficiently to anti-cancer treatment, including recurrence or relapse of the cancer.

  As used herein and unless otherwise defined, the phrase “hormone refractory cancer” or “cancer refractory to hormone therapy” refers to a cancer that does not respond to hormone therapy, no longer responds to hormone therapy, or It refers to cancer that has progressed with hormone therapy, or that does not respond well to hormone therapy.

  As used herein and unless otherwise defined, the phrase “hormone refractory patient” means a patient having a hormone refractory cancer.

  As used herein and unless otherwise defined, the phrase “chemo-refractory cancer” or “cancer refractory to chemotherapy” refers to a cancer that does not respond to chemotherapy, no longer responds to chemotherapy, or It means cancer that has progressed through chemotherapy or does not respond well to chemotherapy.

  As used herein and unless otherwise defined, the phrase “chemically refractory patient” means a patient having a chemically refractory cancer.

  As used herein and unless otherwise defined, the phrase “gonadectomy-refractory cancer” or “cancer that is refractory to gonadectomy” means a cancer that does not respond to gonadectomy, no longer responds to gonadectomy, Alternatively, it means cancer that has progressed by gonadectomy or that does not respond well to gonadectomy.

  As used herein and unless otherwise defined, the phrase “chemotherapy untreated patient” or “chemotherapy untreated patient” refers to a patient who has never received chemotherapy or a particular cancer Refers to patients who have never received chemotherapy treatment.

  As used herein, and unless otherwise defined, the phrase “hormone naïve patient” or “patient who is naïve to hormone therapy” refers to those who have never received hormone therapy therapy or for a particular cancer Refers to patients who have never received hormonal therapy.

  As used herein and unless otherwise defined, the term “PSA” refers to a prostate-specific antigen, a protein produced by prostate cells.

  As used herein, and unless otherwise defined, the term “PSA gonadectomy level” refers to either one or both of whether the testis has been surgically removed or chemically gonadotomized. Refers to the level of PSA circulating in the patient's blood, meaning that the patient has been administered a specific hormonal drug to temporarily inhibit the hormone that stimulates the testis to produce testosterone.

  As used herein and unless otherwise defined, the term “testosterone gonadectomy level” refers to either one or both of whether the testis has been surgically removed or chemically removed. Refers to the level of testosterone circulating in the patient's blood, meaning that the patient has been administered a specific hormonal drug to temporarily inhibit the hormone that stimulates the testis to produce testosterone.

  As used herein and unless otherwise defined, the phrase “number of circulating tumor cells” refers to the number of cancer cells that have been detached from the primary tumor and circulating in the bloodstream or bone marrow of a cancer patient. .

  As used herein, the term “hormone agent” includes, but is not limited to, “androgen elimination agent”, “estrogen elimination agent”. The term “hormonal agent” may include two or more hormonal agents.

  As used herein, the term “patient” means an animal, preferably a mammal, most preferably a human.

  As used herein, the term “therapeutically effective amount” refers to the amount of a compound, pharmaceutically acceptable salt, or pharmaceutical composition that is effective in treating or preventing a disease or disorder.

  As used herein, the term “steroid” refers to the natural and the hormones secreted by the hypothalamus-anterior pituitary-adrenal cortex (HPA) axis (more commonly referred to as the pituitary). Refers to “corticosteroids”, a group of synthetic analogues. These are glucocorticoids, anti-inflammatory agents with numerous other functions, mineralocorticoids that primarily control salt and water balance by acting on the kidneys, and adrenocortical stimuli that control hormone secretion by the pituitary gland Contains hormones. In certain embodiments, as used herein, the term “steroid” refers to dexamethasone, prednisone, prednisolone, betamethasone, and trimacinolone. In certain other embodiments, the term “steroid” refers to a glucocorticoid.

  As used herein, the term “without simultaneous or sequential administration of steroids” means that a patient can either sequentially or simultaneously receive steroids with a 17-α hydroxylase / C17,20-lyase inhibitor. Refers to a dose cycle not given in In one embodiment, the term is not intended to exclude any previous steroid administration (eg, steroid administration for asthma) or previous therapy received with the steroid for any purpose. In some embodiments, administration refers to the dose given on the same day. In other embodiments, administration is for 1 week, 2 weeks, 3 weeks, 4 weeks, 28 days, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months , 11 months or 12 months lasting 17-α hydroxylase / C17,20-lyase inhibitor dose cycle.

  As used herein, the term “steroid skeleton” refers to a general class of chemicals that are structurally related to each other and share the same chemical skeleton (tetracyclic cyclopenta [a] phenanthrene skeleton).

3. Detailed Description of the Invention As noted above, the present invention relates to pharmaceutical compositions and methods for treating cancer, without the simultaneous or sequential administration of steroids to patients in need thereof. Administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor. As summarized above, there is a need to develop treatments for cancer that minimize and / or avoid long-term steroid exposure and the side effects caused by them, and the present invention does not use steroids as such. Provide a good treatment. In certain other embodiments, the present invention provides a therapeutically effective amount of 17-α hydroxylase / C17,20-lyase inhibition in combination with one or more additional therapeutic agents where the one or more additional therapeutic agents are not steroids. A method of treating cancer comprising administering an agent is provided. In certain other embodiments, the invention provides a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, and one or more additional therapeutic agents where the one or more additional therapeutic agents are not steroids. Pharmaceutical compositions comprising are provided.

  17-α hydroxylase / C17-20 lyase inhibitor

  Exemplary 17-α hydroxylase / C17,20-lyase inhibitors and pharmaceutical compositions thereof are described in International Publication Nos. WO 02/40484 and WO 09/057795, the entire contents of which are incorporated by reference. Incorporated herein.

  Without being bound by any particular theory, an inhibitor that is selective for C17,20-lyase over 17-α hydroxylase is such that incomplete inhibition of 17-hydroxylase maintains cortisol concentrations, Since excessive mineralocorticoids can be prevented, it is considered that there are few side effects. In certain embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor is a selective inhibitor for C17,20-lyase over 17-α hydroxylase. In yet other embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor is about 3 to about 8 times more selective for C17,20-lyase than 17-α hydroxylase. In yet other embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor is about 4 to about 7-fold selective for C17,20-lyase over 17-α hydroxylase. In still other embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor is about 5-fold selective for C17,20-lyase over 17-α hydroxylase.

In certain other embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor does not have a steroid skeleton.

Without being bound by any particular theory, inhibitors that are selective for C17-20 over 17-α hydroxylase and other human CYP family enzymes are also minimal in terms of other CYP drugs that metabolize the enzyme. It is thought that there are not many side effects. In still other embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor is a selective inhibitor for C17,20 over 17-α hydroxylase and other human CYP family enzymes. In some embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value greater than 10 μM for human CYP family enzymes other than C17,20-lyase. In other embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value greater than 20 μM for human CYP family enzymes other than C17,20-lyase. In still other embodiments, the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value greater than 30 μM for human CYP family enzymes other than C17,20-lyase.

  In certain embodiments, the 17,20-lyase inhibitor is 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl] -N. -Methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

  17-alpha hydroxylase / C17-20 lyase inhibitor dosage, combination therapy, and administration thereof

  A therapeutically effective amount or suitable dosage of a 17-α hydroxylase / C17,20-lyase inhibitor is determined by the severity of the condition being treated, the particular inhibitor, the route of administration, and the age of the individual patient, Depends on several factors including weight and response. In certain embodiments, suitable dose levels are those that achieve a therapeutic response as measured by PSA levels, tumor regression, or other standard indicators of disease progression. In other embodiments, a suitable dose level is one that achieves this therapeutic response and minimizes any side effects associated with administration of the therapeutic agent.

  In yet other embodiments, suitable dose levels are those that achieve an improvement in the patient's clinical outcome as measured by increased progression-free survival or time to metastasis compared to standard therapy. In certain embodiments, progression free survival is increased by at least 9 months compared to standard therapy. In other embodiments, progression free survival is increased by at least 12 months compared to standard therapy. In yet other embodiments, progression free survival is increased by at least 15 months compared to standard therapy.

  In yet other embodiments, a suitable dose level is one that results in an improved clinical outcome, further measured by a favorable safety risk / benefit ratio, so that steroids are not administered simultaneously or sequentially. The risk associated with administering a 17-α hydroxylase / C17,20-lyase inhibitor exceeds the benefits associated with avoiding long-term use of steroids. In certain embodiments, the risk associated with administering a 17-α hydroxylase / C17,20-lyase inhibitor without simultaneous or sequential administration of steroids monitors the patient for evidence of mineralocorticoid excess. Is measured. In some embodiments, the patient is monitored for one or more of an ACTH / corticosterone profile, elevated blood pressure, hypokalemia, edema, or cardiovascular symptoms.

  Suitable daily dosages of the 17-α hydroxylase / C17,20-lyase inhibitor generally range from about 400 mg to about 1200 mg per day in single or divided doses or multiple doses. obtain. Other suitable daily dosages of the 17-α hydroxylase / C17,20-lyase inhibitor generally range from about 600 mg to about 1200 mg per day in single or divided doses or multiple doses. It can be. In certain embodiments, a suitable dosage is about 200 mg twice daily to about 600 mg twice daily. In some other embodiments, a suitable dosage is about 300 mg twice daily to about 600 mg twice daily. In other embodiments, a suitable dosage is about 800 mg per day. In certain other embodiments, a suitable dosage is about 400 mg twice a day. In still other embodiments, a suitable dosage is about 600 mg per day. In other embodiments, a suitable dosage is about 300 mg twice daily. In still other embodiments, a suitable dosage is about 200 mg twice daily. In yet other embodiments, a suitable dosage is about 300 mg to about 600 mg once daily. In yet other embodiments, a suitable dosage is about 200 mg to about 600 mg once daily. In still other embodiments, a suitable dosage is about 600 once a day. In yet other embodiments, a suitable dosage is about 600 mg taken once a day in the morning. In still other embodiments, suitable dosages are taken with meals.

  In addition, the frequency with which any of these inhibitors can be administered is about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about About 10 days, about 20 days, about 28 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about every 2 months, about every 3 months, about every 4 months, about every 5 months Every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, every 1 year, every 2 years, every 3 years, every every 4 years It is understood that it may be once or more than once over a period of about every five years.

  Furthermore, the above administration frequency can be carried out continuously or discontinuously over a period of time. For example, a certain amount of 17-α hydroxylase / C17,20-lyase inhibitor can be administered continuously daily for 28 days. The time period during which the frequency of administration can be performed continuously or discontinuously is 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 10 days. About 20 days, about 28 days, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 1 month, about every 2 months, about every 3 months, about every 4 months, about every 5 months, Every 6 months, every 7 months, every 8 months, every 9 months, every 10 months, every 11 months, every 1 year, every 2 years, every 3 years, every 4 years, Or about every 5 years, but not limited to.

  In some embodiments, the therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor is a constant 17-α hydroxylase / C17,20-lyase inhibitor, such as those described above. Administered using a dose cycle or dosing regimen administered at a frequency of The treatment period is then followed by a non-treatment period of a specific time during which the 17-α hydroxylase / C17,20-lyase inhibitor is not administered to the patient, such as the time period described above.

  This non-treatment period may then be followed by a series of subsequent treatment and non-treatment periods of the same or different frequency, or the same or different time length. In some embodiments, the treatment and non-treatment periods are alternated. In other embodiments, the same or different amounts of the same or different 17-α hydroxylase / after the first treatment period in which the first amount of 17-α hydroxylase / C17,20-lyase inhibitor is administered. Another treatment period may be followed in which the C17,20-lyase inhibitor is administered. The second treatment period may be followed by another treatment period. During the treatment and non-treatment periods, one or more additional non-steroidal therapeutic agents may be administered to the patient.

  The 17-α hydroxylase / C17,20-lyase inhibitor can be administered by any method known to those of skill in the art. The 17-α hydroxylase / C17,20-lyase inhibitor can be administered in the form of a composition, in one embodiment, a pharmaceutical composition such as those described herein. Preferably, the pharmaceutical composition is suitable for oral administration. In other embodiments, the pharmaceutical composition is a tablet for oral administration. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

  In some embodiments, the method comprises administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor in combination with an additional therapeutic agent where the additional therapeutic agent is not a steroid. In certain embodiments, the therapeutically effective amount of the 17-α hydroxylase / C17,20-lyase inhibitor is administered without the simultaneous or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone. The In still other embodiments, the therapeutically effective amount of the 17-α hydroxylase / C17,20-lyase inhibitor is administered without administering prednisone simultaneously or sequentially. It is understood that combination therapy includes simultaneous or sequential administration of therapeutic agents. Alternatively, the therapeutic agents are combined into one composition that is administered to the patient.

  In certain embodiments, the additional therapeutic agent is a hormone elimination agent, an antiandrogen / antiandrogen, a differentiating agent, an antineoplastic agent, a kinase inhibitor, an antimetabolite, an alkylating agent, an antibiotic, Immunological agents, interferon-type drugs, DNA damaging agents (for example, insertion agents) growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloprotease inhibitors Agents, anti-resorptive agents, monoclonal antibodies, adhesion molecules, growth factors, apoptosis promoters, antisense agents, vitamin D analogs, RNAi agents, modified peptides, enzyme inhibitors, therapeutic side effects Improving drugs and gene therapy Including but not limited to drugs. Some examples of the above additional therapeutic agent categories are listed below for illustrative purposes, but these examples are not exhaustive and are not intended to be limiting. Many of the following examples can be listed in multiple anticancer drug classes, but are in no way limited to the classes in which they are listed.

  Examples of hormone elimination agents include, but are not limited to, androgen elimination agents and estrogen elimination agents. In some embodiments, hormone elimination agents include, but are not limited to, deslorelin, leuprolide, goserelin, or triptorelin.

  Examples of antiandrogens include, but are not limited to, bicalutamide, flutamide, spironolactone, cyproterone acetate, finasteride, dutasteride, and nilutamide. An example of an anti-estrogen agent includes, but is not limited to tamoxifen.

  Examples of differentiating agents include polyamine inhibitors, vitamin D and analogs thereof (calcitriol, doxel calciferol, ergocalciferol, 22-oxacalcitriol, dihydrotaxitol, paricalcitol, and theo And vitamin A metabolism inhibitors such as RAMBAS (for example, reazolol), vitamin A metabolites such as ATRA, retinoic acid, retinoids, short chain fatty acids, phenylbutyric acid, and non-steroidal anti-inflammatory agents. However, it is not limited to these.

  Examples of anti-neoplastic agents include tubulin interacting agents, topoisomerase inhibitors and drugs, acitretin, alstonine, amonafide, amphetinyl, amsacrine, anquinomycin, antineoplastic agents, aphidicolin glycicin Narate, asparaginase, baccaline, butracicline, benfluron, benzotrips, bromophosamide, caracemide, carmethizol hydrochloride, chlorsulfakinosalone, clanfenur, claviridone, crisnatol, claderm, cytarabine, cytito ), Dacarbazine, dateliptinium, dihematoporphyrin ether, dihydrolenperone ( ihydrolenperone, dinaline, distamycin, docetaxel, eliprabin, eliptinium acetate, epothilone, ergotamine, etoposide, etretinate, fenretinide, hydroxyurea, ilmofosine, gulfosmine, gulfosmine ), Lonidamine, merbarone, merocyanine derivative, methylanilinacridine, minactivin, mitonafide, mitocidone, mitoxantrone, mopidamol tinide), N- (retinoyl) amino acid, N-acylated-dehydroalanine, nafazatrom, nocodazole derivatives, octreotide, oxizanocine, paclitaxel, pancratistatin ti, pazelipistin p (Piroxantrone), polyhaematoporphyrin, polypreic acid, propiman, procarbazine, proglumide, razoxane, literiptine, spatol, spirocyclopropane derivative, r ldinone), superoxide dismutase, teniposide, taliblastine, tocotrienol, topotecan, ukrain, vinblastine sulfate, vincristine, vindesine, vinestramide (vin), vinolol vinol, t Examples include, but are not limited to, witanolide.

  Examples of kinase inhibitors include p38 inhibitors, CDK inhibitors, TNF inhibitors, matrix metalloprotease (MMP) inhibitors, celecoxib, rofecoxib, COX-2 inhibitors including parecoxib, valdecoxib, and etoroxib, and SOD 摸Examples include, but are not limited to, mimics.

  Examples of antimetabolite agents include 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinal sodium, carmofur, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine complex, dezaguanine, dideoxycytidine, Dideoxyguanosine, didox, doxifluridine, fazalabine, floxuridine, fludarabine phosphate, 5-fluorouracil, N- (2′-furanidyl) -5-fluoruracil, an inhibitor of essential amino acids, Isopropylpyrrolidine, methobenzaprim, methotrexate, norspermidine, ornithine decarboxylation inhibitor, pen , Piritrexim (piritrexim), plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinase inhibitors, and uricytin (uricytin) and the like.

  Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (eg, irinotecan, topotecan, camptothecin, and analogs or metabolites thereof, and doxorubicin), topoisomerase II inhibitors (eg, etoposide, teniposide, And daunorubicin), alkylating agents (eg, melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, dacarbazine, methotrexate, mitomycin C, and cyclophosphamide), DNA interference substances (Eg, cisplatin, oxaliplatin, and carboplatin), DNA interference substances (free radical generators such as bleomycin), and nucleosides Mimetics (eg, 5-fluorouracil, capecitabine, gemcitabine, fludarabine, cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea), estrogen receptor antagonists (eg, tamoxifen, fulvestrant), and aromatase Inhibitors such as exemestane, anastrozole, or letrozole.

  Chemotherapeutic agents that interfere with cell proliferation include paclitaxel, docetaxel, and related analogs, vincristine, vinblastine and related analogs, thalidomide, lenalidomide, and related analogs (eg, CC-5013 and CC-4047), protein tyrosine kinases Inhibitors (eg, imatinib mesylate, gefitinib, lapatinib), proteasome inhibitors (eg, bortezomib), NF-κB inhibitors (including inhibitors of IκB kinase), bind to proteins that are overexpressed in cancer, thereby Antibodies that down-regulate cell proliferation (eg, trastuzumab, rituximab, cetuximab, and bevacizumab) and proteins or enzymes known to be upregulated, overexpressed or activated in cancer Other inhibitors) that down-regulate cell proliferation.

  Non-limiting examples of antibiotics include aclarubicin, actinomycin D, actinoplanone, adriamycin, aerolysinin derivatives, amrubicin, anthracycline, azinomycin A, biscaberine, bleomycin sulfate. , Bryostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin, ditrisarubicin B, doxorubicin, doxorubicin-fibrinogen, elsamicin-b ), Esorubicin (esoru) icin), esperamicin-Al, esperamicin-Alb, fostriecin, glidebactin, gregatin-A, grincamycin, herbimycin, idarubicin, irulodin, illudin (Kesarhodins), menogalil, mitomycin, neoenactin, oxalidine, oxaunomycin, peplomycin, pyratin, pirarubicin, porothramincin, pyrindanicin, c Syn, rhodorubicin, sibanomycin, siwenmycin, sorangicin-A, sparsomycin, thalisomycin, terpentecin, thrazine, thrazine, thrazine, thrazine Zorubicin is exemplified.

  Non-limiting examples of enzyme inhibitors include 17-α hydroxylase / C17,20-lyase inhibitors, imidazoles, azoles, or antifungal agents such as ketoconazole.

  Non-limiting examples of monoclonal antibodies include rituximab, trastuzumab, gemtuzumab, ozogamicin, alemtuzumab, ibritumomab, tiuxetane, tositumomab, cetuximab, bevacizumab, panitumumab, and ofatumumab.

  Non-limiting examples of antisense agents include Genasense (Oblimersen), affinitak (ISIS 3521), ISIS 112989 (OGX011), ISIS 23722, AP12009, GEM231, GEM240, IGF-IR / AS ODN, MG98, LErafAON, Ki-67 Sense oligonucleotides, GTI-2040, ISIS 2503, and AP11014.

  Non-limiting examples of peptides and / or modified peptides include vaccines having peptides as inhibitors or modified peptides, ligands, or T cells that respond to eg cancer cells and / or anti-cancer activity Is mentioned.

  Non-limiting examples of drugs that improve the side effects of therapy include diuretics, sedatives, analgesics, anti-inflammatory agents, eplerenone, proton pump inhibitors, H2 receptor antagonists, lipid lowering agents, bone resorption inhibitors Or antipsychotic drugs. In certain embodiments, the one or more additional treatments are selected from radiation, chemotherapy, immunotherapy, non-steroidal hormone ablation therapy, or non-steroid therapy to manage the side effects of the therapy. In certain other embodiments, the one or more additional treatments include cyprouisel T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, Fulvestrant, cisplatin, exemestane, anastrozole, letrozole, trastuzumab, lapatinib, radioisotope, hormone-eliminating agent, hormone blocker treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterin ( (triumpterine). In still other embodiments, the one or more additional treatments include an androgen receptor inhibitor. In certain embodiments, the androgen receptor inhibitor is MDV-3100 (4- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-4-oxo-2-thio). Oxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide or ARN-509 (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo- 6-thioxo-5,7-diazaspiro [3.4] octane-5-yl) -2-fluoro-N-methylbenzamide).

  As mentioned above, the 17-α hydroxylase / C17,20-lyase inhibitor can be present in therapeutic free form or, where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative can directly or indirectly bind a compound or metabolite or residue thereof separately described herein upon administration to a patient in need thereof. Including, but not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives that can be provided.

  As used herein, the term “pharmaceutically acceptable salt” refers to human and lower animal tissues without undue toxicity, irritation, allergic response, etc., within reasonable medical judgment. Refers to those salts that are suitable for use in contact, and that meet a reasonable benefit / risk ratio. “Pharmaceutically acceptable salt” means that when administered to a recipient, the compound of the present invention, or an inhibitory active metabolite thereof, or residue thereof is provided either directly or indirectly. It means a non-toxic salt of a compound of the present invention, or a salt of an ester thereof. As used herein, the term “inhibitory active metabolite or residue” means that the metabolite or residue is also an inhibitor of 17-α hydroxylase / C17,20-lyase. .

Pharmaceutically acceptable salts are well known in the art. For example, S.M. M.M. Berge et al. Describe pharmaceutically acceptable salts in more detail in Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid. A salt of an amino group formed with an organic acid such as acid, succinic acid, or malonic acid, or by other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts are adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, Camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethane sulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, gluconate, hemisulfate Salt, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonic acid Salt, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinic acid , Persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonic acid Salt, undecanoate, valerate, etc. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersible products can be obtained by such quaternization. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and Includes amine cations formed using counterions such as aryl sulfonates.

  As noted above, the pharmaceutically acceptable compositions of the present invention can be used in any and all solvents, diluents, or other as used herein to suit the particular dosage form desired. Pharmaceutically acceptable carriers, adjuvants, including liquid vehicles, dispersions or suspension aids, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc. Or include additional vehicles. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.M. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the formulation of pharmaceutically acceptable compositions and known techniques for their preparation. Any conventional carrier medium produces any undesirable biological effect or otherwise interacts with any other component (s) of the pharmaceutically acceptable composition in a deleterious manner. Except as otherwise incompatible with the compounds of the present invention, such as by acting, its use is contemplated to be within the scope of the present invention. Some examples of materials that can function as pharmaceutically acceptable carriers include ion exchangers, serum proteins such as alumina, aluminum stearate, lecithin, human serum albumin, phosphate, glycine, Buffer substances such as sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salt, or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon, three Electrolytes such as magnesium silicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, sugars such as wool fat, lactose, glucose, and sucrose, starches such as corn starch and potato starch, carboxymethyl cell Celluloses such as sodium acetate, ethylcellulose and cellulose acetate and derivatives thereof, powdered tragacanth, malt, gelatin, talc, cocoa butter and suppository waxes, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and Oils such as soybean oil, glycols such as propylene glycol or polyethylene glycol, esters such as ethyl oleate and ethyl laurate, buffers such as agar, magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free distillation Water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate buffer solutions, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, including but not limited to Size Accordingly, coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition.

  The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals, orally, rectally, parenterally, into the cisterna, intravaginally, depending on the severity of the disease being treated. Alternatively, it can be administered intraperitoneally, topically (by powder, ointment, or drops), as an oral and nasal spray, into the buccal cavity.

  Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may include inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid Benzyl, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and Solubilizers and emulsifiers, such as fatty acid esters of sorbitan, and combinations thereof can be included. In addition to inert diluents, oral compositions can also include adjuvants such as wetting, emulsifying, and suspending agents, sweetening, flavoring, and perfuming agents.

  Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation may also be a sterile injectable solution, suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Or an emulsion. Among the acceptable vehicles and solvents, water, Ringer's solution, U.S.A. S. P. And isotonic sodium chloride solution may be employed. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

  Injectable formulations are reduced, for example, by filtration through a bacteria capture filter or in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. It can be sterilized by incorporating a fungicide.

  In order to sustain the action of the compounds of the invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of poorly soluble crystalline or amorphous material. Thus, the absorption rate of a compound depends at the same time on its dissolution rate, which can depend on the crystal size and crystalline morphology. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polyactide-polyglycoside. Depending on the ratio of polymer to compound and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

  Compositions for rectal or vaginal administration are preferably cocoa butter that is solid at ambient temperature but liquid at body temperature and thus melts in the rectum or vaginal cavity to release the active compound Suppositories that can be prepared by mixing with a suitable non-irritating excipient or carrier such as polyethylene glycol or suppository wax.

  Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound comprises at least one inert, pharmaceutically acceptable excipient or carrier (such as sodium citrate, calcium dihydrogen phosphate, or dicalcium phosphate), and And / or a) fillers or spreaders (such as starch, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, and silicic acid), b) binders (eg, carboxymethylcellulose, hydroxypropylcellulose, alginate, gelatin, Polyvinyl pyrrolidinone, sucrose, and acacia), c) humectants (such as glycerol), d) disintegrators (agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, and sodium carbonate Etc), e) Liquid retarder (such as paraffin), f) absorption enhancer (such as quaternary ammonium compound), g) wetting agent (such as cetyl alcohol and glycerol monostearate), h) absorbent (such as kaolin and bentonite clay), And i) mixed with a lubricant (such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof). In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

  Similar types of solid compositions can also be employed as fillers in soft and hard filled gelatin capsules by using excipients such as lactose or lactose and ultra high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifiers and may be of a composition that releases only the active ingredient (s) preferentially in a particular part of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be employed as fillers in soft and hard filled gelatin capsules by using excipients such as lactose or lactose and ultra-high molecular weight polyethylene glycols.

  The active compound may be in microencapsulated form using one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also include, as a common practice, additional materials other than inert diluents, such as tableting lubricants, and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. They may optionally contain opacifiers and may be of a composition that releases only the active ingredient (s) preferentially in a particular part of the intestine, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

  Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalations, or patches. The active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

  Cancer treated with a 17-α hydroxylase / C17,20-lyase inhibitor or a combination thereof

  As mentioned above, 17-α hydroxylase / C17,20-lyase inhibitors are useful for the treatment of cancer. Cancers that can be treated with the methods and compositions described herein include those cancers that are hormone-dependent, hormone-responsive, or hormone-sensitive (generally “hormone-responsive cancers”). It is not limited to. In particular, cancers that can be treated include, but are not limited to, androgen responsive cancers such as testosterone responsive cancers and estrogen responsive cancers. In addition, in some embodiments, the cancer may be a non-hormone responsive cancer of a cancer that was hormone responsive but later becomes non-hormone responsive. Cancers that can be treated are prostate cancer, breast cancer, testicular cancer, penile cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, fallopian tube cancer, or other reproductive organs Including but not limited to cancer. In other embodiments, the cancer that can be treated is adrenal cancer, cancer of the lymphatic system such as lymph nodes, leukemia, lymphoma, myeloma, Wandenstrom macroglobulinemia, monoclonal immunoglobulin, benign Monoclonal immunoglobulin, heavy chain disease, bone and connective tissue sarcoma, brain tumor, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, Including but not limited to cholangiocarcinoma, lung cancer, oral cancer, skin cancer, kidney cancer, Wilms tumor, and bladder cancer.

  In addition, the methods and compositions described herein can be used to treat various stages of a particular cancer, or a particular form of cancer, such as breast or prostate cancer. In some embodiments, the methods and compositions are pre-cancerous, post-cancerous, advanced cancerous, pre-metastatic, metastatic, ie, cancer that has metastasized from another cancer, such as bone, lymph Can be used to treat nodal, lung metastasized cancer, or non-metastatic cancer. In one embodiment, the patient being treated is newly diagnosed with a cancer, such as prostate cancer. In embodiments related to prostate cancer, prostate cancer may be non-metastatic, may be pre-metastatic, may have metastasized to bone, lung, lymph nodes, or may include advanced adenocarcinoma of the prostate . For example, the prostate cancer can be androgen-independent prostate cancer (AIPC), such as androgen-dependent prostate cancer, which is simply biochemical, positive-scan asymptomatic, or symptomatic in nature, but is not limited thereto Not. Stages of prostate cancer that can be treated by the methods and compositions described herein are stage IA, IIB, II, III, IVA, IVB, and IVC, Gleason grade 1-5 or Gleason sum or score 2-10 cancers, stages A, B, C, or D according to the Newett-Whitmore system, and without limitation, TX, T0, T1a, T1b, T2a, T2b, T3a, T3b, T4, NX, N0 , N1, N2, N3, MX, M0, M1a, M1b, including any combination of TNM scores from the American Joint Committee on Cancer (AJCC) TNM system, including but not limited to Not.

  The methods and compositions described herein can be used for patients with cancer or who have never had cancer before. For example, a patient may be a woman who currently suffers from ovarian cancer, suffers from breast cancer, or suffered from it. A patient can also be one who has been treated for cancer or has not received it before. Such a patient has undergone surgery to treat cancer or another form of cancer, or has not undergone surgery to treat cancer or another form of cancer Also good. For example, a patient may have undergone surgery to remove all or part of a cancerous or non-cancerous tumor. The patient may also have undergone surgery to remove all or part of a body part or organ with cancerous growth, such as prostate, testis, breast, ovary, or uterus. Patients with prostate cancer to be treated can include those who have undergone gonadectomy prior to administration of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, as well as those who have not undergone gonadectomy. In other embodiments, the patient may be gonadectile refractory.

  In some embodiments, the patient has not been treated with chemotherapy, or has not been treated with a particular chemotherapy, such as any of the chemotherapy described herein. In other embodiments, the patient has received, is currently undergoing or intends to receive chemotherapy. Such chemotherapy includes, but is not limited to, administration of paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, and radioisotopes. In certain embodiments, the patient is refractory to particular chemotherapy, including any of those mentioned herein.

  In addition, in some embodiments, the patient is untreated with hormone therapy or has not been treated with a particular hormone therapy, such as any of the hormone therapy described herein. In other embodiments, the patient has received, is currently undergoing or will receive hormone therapy. Such hormone therapies include hormone elimination agents, hormone blocking therapies, antiandrogens, ketoconazole, aromatase inhibitors such as aminoglutethimide, flutamide, cyproterone acetate, goserelin, leuprolein, GnRH agonists, DES, or LHRH-like Including but not limited to body administration. In certain embodiments, the patient is refractory to certain hormonal therapies, including any of those mentioned herein.

  With respect to patients who have previously been treated for prostate cancer, in some embodiments, prostate cancer can include metastatic disease, and in other embodiments, prostate cancer can include non-metastatic disease.

  In some embodiments, the patient will have previously received one or more treatments with abiraterone acetate.

  Further methods for treating cancer

In yet another aspect of the invention, monitoring the patient's blood pressure and serum levels of one or more of corticosterone, cortisol, or potassium may be used to achieve a patient's safe and effective dose level. Methods are provided for treating cancer that allow selective regulation of cancer. Without being bound by any particular theory, ACTH-dependent serum corticosterone and cortisol are believed to represent pharmacokinetic markers of lyase inhibition. Thus, serum corticosterone and cortisol-induced pharmacotherapy with lyase inhibitor molecules is an approach for individual dose adjustment. Therefore,
(A) measuring one or more levels of one or more serum levels of corticosterone, cortisol, or potassium at a first time point;
(B) administering to the patient a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor;
(C) after administration of a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, one of the patient's blood pressure or corticosterone, cortisol, or potassium Measuring one or more of the above serum levels;
(D) administering to a patient a second dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, wherein the second dose level exceeds the first dose level; , Equal to or less than, a method of treating cancer is provided.

  In certain embodiments, the second dose level of step (d) is less than the first dose level. In still other embodiments, the method repeats steps (a)-(d) until the desired dose level of a therapeutically effective amount of 17-α hydroxylase / C17,20-lyase inhibitor is achieved. Further included.

In yet other embodiments, the blood pressure measurement after administration of the first dose level exceeds the blood pressure measurement prior to administration of the first dose level, and (a) the first dose level is administered The subsequent corticosterone level is higher than the corticosterone level before administering the first dose level, or (b) the cortisol level after administering the first dose level is administering the first dose level Lower than the cortisol level prior to administration, or (c) the potassium level after administration of the first dose level is lower than the potassium level prior to administration of the first dose level.

  In other embodiments, the corticosterone level after administration of the first dose level is higher than the corticosterone level prior to administration of the first dose level. In still other embodiments, the cortisol level after administering the first dose level is lower than the cortisol level before administering the first dose level. In yet other embodiments, the potassium level after administration of the first dose level is lower than the potassium level prior to administration of the first dose level.

  In some embodiments, both the first and second dose levels of the 17-α hydroxylase / C17,20-lyase inhibitor are administered without simultaneous or sequential administration of the steroid.

  In still other embodiments, the cancer being treated is a hormone induced cancer. In some embodiments, the cancer is prostate cancer, breast cancer, or ovarian cancer. In other embodiments, the cancer is prostate cancer. In still other embodiments, the prostate cancer is gonadectomy resistant prostate cancer. In yet another embodiment, the prostate cancer is metastatic gonadectomy resistant prostate cancer. In still other embodiments, the prostate cancer is non-metastatic gonadectomy resistant prostate cancer.

  In some embodiments of the above methods, the first dose level is about 200 mg to about 600 mg twice daily. In some other embodiments of the above methods, the first dose level is about 300 mg to about 600 mg twice a day. In yet other embodiments, the first dose is about 400 mg twice daily. In still other embodiments, the first dose is about 300 mg twice daily. In still other embodiments, the first dose is about 200 mg twice daily. In a further embodiment, the first dose level is about 200 mg to about 600 mg once daily. In still further embodiments, the first dose level is about 300 mg to about 600 mg once daily. In yet other embodiments, the first dose is about 600 once a day. In still other embodiments, the first dose is about 600 mg taken once a day in the morning. In some other embodiments, the first dose is taken with a meal. In yet other embodiments, the second dose level is taken with a meal. In still other embodiments, either one or both of the first or second dose levels are taken with a meal. In still other embodiments, the first dose level is about 400 mg twice daily and the second dose level is about 300 mg twice daily. In yet other embodiments, the first dose level is about 300 mg twice daily and the second dose level is about 200 mg twice daily.

  In yet other embodiments, the method comprises simultaneously or sequentially administering one or more additional therapies to the patient along with either the first or second dose or both of the 17-α hydroxylase / C17,20-lyase inhibitor. One or more additional therapies include radiation, chemotherapy, immunotherapy, non-steroid hormone elimination therapy, or non-steroid therapy to manage the side effects of the therapy.

  In still other embodiments, the one or more additional treatments include cyprouisel T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, flu Select from bestland, cisplatin, exemestane, anastrozole, letrozole, trastuzumab, lapatinib, radioisotope, hormone-eliminator, hormone blocker treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterin Is done. In yet other embodiments, the one or more additional treatments are MDV-3100.

  In yet other embodiments, the patient would have previously received one or more treatments with abiraterone acetate.

  Determination of the action of 17-α-hydroxylase / C17,20-lyase inhibitor in vivo

  It is understood that 17-α-hydroxylase / C17,20 inhibitors that inhibit tumor formation in vivo may be indicated. A wide variety of hyperproliferative disorder animal models are known in the art, including tumorigenesis and metastatic spread. In addition, various general animal models that can be applied to many types of cancer have been described.

  For example, a 17-α-hydroxylase / C17,20-lyase inhibitor can be administered to a test animal, preferably a test animal that is prone to develop a tumor, and the test animal can later be tumorigenic compared to a control. Can be tested for a decrease in the incidence of Alternatively, a 17-α-hydroxylase / C17,20-lyase inhibitor can be administered to a test animal having a tumor, which is not subsequently administered with a 17-α-hydroxylase / C17,20-lyase inhibitor. The tumor of the test animal is examined for tumor regression compared to the animal.

  A predictive marker for cancer such as prostate cancer can also assist in measuring the action of a 17-α-hydroxylase / C17,20-lyase inhibitor. Such predictive markers include prostate specific antigen (PSA) concentration, plasma concentration of testosterone, circulating tumor cells (CTC), degree of bone or lymph node metastasis, tumor size or tumor mass, alkaline phosphatase (ALP) ) Plasma concentration, and the degree of pain experienced by the patient.

4). Experimental procedure
Example 1: Testing of alteronel in patients with metastatic gonadectomy resistant prostate cancer

  Trial 17,20- which is 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl] -N-methyl-2-naphthalenecarboxamide The lyase inhibitor alteronel is a selective 17,20-lyase inhibitor that downregulates the production of androgenic steroids in vitro and in vivo.

Methods: Patients received alteronel in a four day cohort of 300 mg BID, 400 mg BID + prednisone 5 mg BID, 600 mg BID + prednisone, and 600 mg QD with a 28-day cycle. Participation criteria were age ≥18 years, receiving androgen block therapy, while histologically or cytologically confirmed prostate with confirmed metastatic (radiographically proven) progressive disease Male patients predicted to continue adenocarcinoma, ECOG functional status of 0-2, prior orchiectomy or luteinizing hormone releasing hormone (LHRH) therapy with testosterone <50 ng / dL and PSA ≧ 5 ng / mL. Exclusion criteria include prior chemotherapy for prostate cancer, aminoglutethimide, ketoconazole, or radiation therapy within 30 days prior to the first dose of study drug, bone or lower back pain unless opiate is mild, opioid required Symptoms, thought to be associated with prostate cancer, such as not showing rapid progressive disease, and uncontrollable blood pressure elevation (> 150/90 mmHg).
1. Evaluation: AEs are graded using NCI-CTCAE v3.0 and serum PSA levels are determined at screening, on days 1 and 15 of cycle 1, day 1 of all subsequent cycles, and test Measured on the last day, PD analysis was performed on the following endocrine panels: testosterone, dehydroepiandrostenedione (DHEA), DHEA-sulfate (DHEA-S), androstenedione, LH, corticotropin (ACTH), Corticosterone and cortisol were evaluated.

  Results: Data shown are for 97 enrolled patients. Baseline patient population statistics and disease characteristics are shown in Table 1.

Table 1: Baseline patient demographics and disease characteristics

  All 97 patients were included in the safety evaluable population. Patients received an average of 6 (range 0-19) treatment cycles. Alteronel's safety profile is summarized in Table 2. The most common adverse events were fatigue, nausea, constipation, diarrhea, headache, and anorexia (Table 3).

Table 2: Alteronel safety profile

Table 3: The most common AE reported in ≧ 20% of patients (any grade)

  Overall, the most common all grades of AEs in the 300 mg BID and 600 mg QD groups were similar to those in the group receiving prednisone. The rate of constipation and anorexia was lower than in patients who received prednisone.

  Constipation: 35 mg / 25% for 300 mg BID and 600 mg QD, respectively, compared to 38% / 50% for 400 and 600 mg BID + prednisone, respectively.

  Anorexia: 22% / 21% for 300 mg BID and 600 mg QD, respectively, compared to 33% / 35% for 400 and 600 mg BID + prednisone, respectively.

  Grade ≧ 3 AEs were also slightly lower than the group without prednisone:

  Compared to 54% in both groups receiving prednisone in combination, the 300 mg BID and 600 mg QD were 48% / 42%, respectively.

  The proportion of SAE was lower in the cohorts that did not receive prednisone, 13% in the 300 mg BID group and 25% in the 600 mg QD group compared to 33% / 31% in the 400 and 600 mg BID + prednisone groups, respectively.

Effectiveness:
PSA response was evaluable in 83 patients (86%) at 12 weeks. The RECIST evaluable population included 49 patients (51%). The PSA response at 12 weeks is shown in FIG. Forty-four patients (53%) had a ≥50% decrease in PSA, of which 21 (25%) had a ≥90% decrease. Of the 56 patients who measured PSA over 24 weeks, 48 (86%) had a decrease in PSA, including 36 (64%) with a PSA drop ≧ 50% and ≧ 90% Including 17 people (30%). Most patients without a PSA response had previously received adrenal therapy (FIG. 1).

Figure 1: Percent change in PSA at 12 weeks with treatment group and prior adrenal therapy

  Testosterone and DHEA-S responses are shown in Table 4. Response was seen as early as day 15 of cycle 1.

Table 4: Effect of alteronel on testosterone and DHEA-S levels

  Table 5 shows that 6 out of 49 evaluable patients (12%) had a partial response (PR) and 25 patients (51%) achieved the best response of stable disease. Mean circulating tumor cell (CTC) numbers were reduced in all groups.

Table 5: Best unconfirmed response by RECIST:

  PSA, hormones, and tumor responses were seen in patients who did not receive prednisone. In the 300 mg BID group, PSA and hormonal responses were seen and PR was achieved in 3 patients. In the 600 mg QD group, PSA and hormonal responses were seen and the best tumor response was seen in 3 patients.

  It is understood that in patients with androgen-independent metastatic CRPC, oral alteronel at a dose of alteronel ≧ 300 mg BID was well tolerated when administered with or without prednisone. Fatigue and nausea were the most common AEs. Alteronol appeared to be active with similar efficacy when given with or without prednisone. A ≥50% decrease in PSA was seen in 53% of all patients and 62% of patients who did not receive prior adrenal therapy. An objective response was seen in 12% of patients. A decrease in testosterone and DHEA-S levels suggests selective 17,20-lyase inhibition in patients with metastatic CRPC.

  Evaluation of circulating tumor cells (CTC) in chemotherapy-naïve patients with metastatic ablation-resistant prostate cancer (mCRPC) who received alteronel

  Background: CTC counts provide information about prognosis in patients with metastatic prostate cancer. In particular, a classification change from ≧ 5 to <5 cells per 7.5 mL whole blood may represent a better prediction of overall survival than a change in prostate specific antigen (PSA) levels. As described above, in a phase 1/2 study of mCRPC (orteloner — 201, NCT00569153) in chemotherapy-naïve patients, the trial 17,20-lyase inhibitor alteronel, ie 6-[(7S) -7-hydroxy. -6,7-dihydro-5H-pyrrolo [l, 2-c] imidazol-7-yl] -N-methyl-2-naphthalenecarboxamide is well tolerated (the most common AE was fatigue) ), Resulting in a significant decrease in circulating concentrations of testosterone and adrenal androgen DHEA-S. A 12-week PSA response rate (≧ 50% reduction) was observed in 52% of patients receiving 400 mg BID + prednisone alternol. Another purpose of the study was to assess the correlation between CTC levels and response to alteronel (PSA changes and clinical response), as well as possible candidate biomarkers (TMPRSS2) detected by fluorescence in situ hybridization (FISH) Assessment of the correlation between the presence or absence of ERG fusion gene product, androgen receptor (AR) mutation, PTEN deletion) and response to alternel and CTC levels.

  Blood samples for evaluation of CTC were taken at baseline, cycles 2 and 4, and thereafter every third cycle on day 1.

Samples were collected in heparinized collection tubes and shipped to the central laboratory within 8 hours. CTCs were counted using a valid Verexex CellSearch® method. ⁸

  CTC analysis was performed in a safety population and a population without prior adrenal indicator therapy (aminoglutethimidin, abiraterone, ketoconazole). CTC levels were evaluated both as dichotomous variables (<5 vs ≧ 5 per 7.5 mL blood) and continuous variables. A CTC level of <5 was considered a predictor of good outcome, and a level of ≧ 5 was considered a predictor of unfavorable outcome. All nominal associations identified between CTC levels and responses were also tested after control of age and prior therapy.

  The overall mean CTC count at baseline was 16.6 (standard deviation: 33.2, Table 3) among 88 evaluable patients. By 12 weeks, the overall average CTC count had dropped to 3.9 (standard deviation: 11.2). The overall mean change in CTC (from baseline to 12 weeks) was -8.9.

Table 6: Summary of CTC values and changes from baseline

  Overall, 48 out of 61 patients (79%) who could assess CTC counts at both baseline and 12 weeks converted to good CTC counts or maintained <5 CTC counts at 12 weeks Was either one of them.

  Overall, 34 of 42 patients (81%) who could assess CTC counts at both baseline and 24 weeks converted to good CTC counts or maintained <5 CTC counts at 24 weeks Was either one of them.

  In patients with baseline CTC counts> 5, 14 (38%) converted to <5 CTC counts at 12 weeks (Table 7).

  In patients with baseline CTC counts <5, 34 (67%) maintained <5 CTC counts at 12 weeks (Table 7).

  The time to disease progression (TTP) for patients with good and unfavorable CTC at baseline is shown in FIG.

Table 7: Change in CTC counts from baseline to 12 and 24 weeks (7.5 mL cells per blood)

Figure 3: TPP in patients with good and unfavorable CTC at baseline:

  (Correlation between baseline CTC and PSA50 response)

  In patients with baseline CTC <5 / 7.5 mL, PSA response rate was 62% (24/39) versus 52% (12/23 patients) with baseline CTC ≧ 5 / 7.5 mL (Table 5).

  There was no significant correlation between CTC count and PSA response in the entire population.

  Among patients who did not receive prior adrenal instruction therapy, among those with a baseline CTC <5 / 7.5 mL, the PSA response rate was 53% (10/19) with a baseline CTC ≧ 5 / 7.5 mL 68% (21 out of 31 patients) (Table 8), and the correlation was not significant.

  Correlation between CTC and clinical response by RECIST

  In patients with baseline CTC <5 / 7.5 mL, the clinical response rate by RECIST at 12 weeks was 25% versus 22% (4 of 18 patients) with baseline CTC ≧ 5 / 7.5 mL (6 of 24 RECIST-evaluable patients) (Table 8).

Table 8: Correlation between baseline CTC and response at 12 and 24 weeks

  Candidate biomarkers by FISH were evaluated as follows.

  TMPRSS2: ERG translocation was detected in 13/48 patients (27.1%). PTEN deletion was detected in 4 out of 50 patients (8.0%). AR amplification was detected in 8/49 patients (16.3%).

  Regarding the PSA response:

  PTEN deletion was associated with a 12 week PSA50 response (p = 0.04, n = 31).

  TMPRSS2: ERG was not statistically significantly associated with the 12 week PSA50 response (p = 0.14, n = 31).

  There is no correlation with AR amplification (n = 32).

  The presence or absence of candidate biomarkers did not significantly correlate with the RECIST response of the entire population.

  TMPRSS2: ERG (n = 22): p = 0.71.

  PTEN (n = 23): p = 0.42.

  AR (n = 23): p = 0.46.

  Similar results were observed when controlled for background covariates and in patients who did not receive prior adrenal instruction therapy.

  The results are consistent with recent data by Danila et al. (1. Danila DC, et al, Eur Urol 60 (2011) 897-904), which indicates that TMPRSS2: ERG status is a significant decrease in PSA or other clinical outcomes It was not a good prediction.

  The presence of TMPRSS2: ERG was significantly correlated with the absolute change in CTC counts at 24 weeks from baseline (n = 19, p = 0.03, corr = −0.50), but as a binary or quantitative variable In any case, no other significant correlation was found between these candidate biomarkers and CTC counts at any time point.

Conclusion In patients with metastatic CRPC, a dose of ≧ 300 mg BID oral oral oral was well tolerated when administered with or without prednisone.

  Alteronol appeared to be active with similar efficacy when given with or without prednisone.

  PSA50 responses at 12 weeks occurred in 53% of all patients and 63% of those who did not receive prior ketoconazole or adrenal instruction therapy.

  An objective clinical response with RECIST was observed.

  The decrease in testosterone and DHEA-S level 9, observed when alteronel was dosed with 600 mg BID without prednisone, PSA50 response, and overall safety profile were high selectivity for 17,20-lyase inhibitors, and This suggests the possibility of steroid-free medication in patients with metastatic CRPC.

  At 12 weeks, 79% of patients had a good CTC count (<5), including 38% of patients who converted to a preferred CTC count with an unfavorable CTC count at baseline (≧ 5) Included.

  TTP was significantly longer in patients with favorable CTC counts at baseline (p <0.001) compared to patients with unfavorable CTC counts.

  PTEN deletion was associated with a 12-week PSA50 response, but candidate biomarkers with FISH were not associated with clinical response with RECIST.

Example 2: Phase 2 study of alteronel in patients with non-metastatic ablation-resistant prostate cancer and elevated prostate-specific antigen

  Androgen signaling is still important in CRPC. Alteronel (orterenol is a selective oral nonsteroidal 17,20-lyase inhibitor that inhibits androgen production and is under development for CRPC. Alteronel limits inhibition of 17α-hydroxylase. Therefore, alteronel 300 mg BID in men with non-metastatic CRPC and elevated PSA was evaluated (NCT01046916).

  Specifically, to evaluate the safety and efficacy of alteronel in patients with gonadectomy-resistant prostate cancer (CRPC), who lacks X-ray evidence of metastasis with elevated prostate-specific antigen (PSA) A phase II trial was conducted.

  [Materials & Methods] Male test subjects had baseline PSA ≧ 2 ng / mL + doubling time ≦ 8 months or PSA ≧ 8 ng / mL + doubling time> 8 months and were surgical or medical gonadectomy with testosterone <50 ng / dL Was in progress. Prior chemotherapy, aminoglutethimide, or ketoconazole, or concurrent corticosteroids were excluded. The starting dose was 300 mg BID, given continuously in a 28-day cycle, and increased to 400 mg BID in men who did not reach ≧ 50% (PSA50) in 3 months of PSA. Alteronel was continued until PSA progressed or metastasized. The initial endpoint is the percentage of men with PSA ≦ 0.2 ng / mL after 3 months. Secondary endpoints included safety, 3 and 6 months PSA30, PSA50, PSA90 rate, progression-free survival, time to PSA progression, time to metastasis, changes in endocrine markers, and circulating tumor cells (CTC) )including.

  Subjects were orally administered 300 mg alteronel twice daily on a continuous schedule without concomitant prednisone. The patient was treated until the disease with PSA progressed or the disease with X-ray progressed. After PSA progression, patients were followed every 3 months until (A) the onset of metastasis, or (B) the end of the scheduled study.

  Patients who do not reach a 50% PSA response after 3 months can receive 400 mg alteronel BID.

The following evaluations were made.
The effect of reducing the PSA level to 0.2 ng / ml or less after 3 months of treatment with 1 alteronel in the patient. PSA levels were measured for each patient and the percentage of patients achieving PSA of 0.2 ng / ml or less was determined at 3 months of treatment (“Cycle 4 Day 1”).
2. PSA response rate (PSA-90, -50, and -30, respectively, at least 90%, 50%, and 30% from baseline at 3 and 6 months of treatment ("Day 7 of Cycle 7) Defined as PSA reduction).
The percentage of patients achieving a PSA of 0.2 ng / ml or less after 3.6 months of alteronel treatment was determined.
4). Time to PSA progression, time to metastasis, and duration of progression-free survival.
5. Monitoring levels of endocrine markers (serum testosterone, DHEA-S, LH, ACTH, corticosterone, and cortisol concentrations).

The PSA response rate was calculated as follows.
1. Denominator: A PSA-evaluable population. Patients with 1 baseline measurement and 1 PSA measurement after initiation.
2. molecule:
i. 3 months: A patient is a responder if the patient has a PSA assessment at 3 months (Day 1 of Cycle 4, Days 77-91) and meets response criteria. Otherwise, the patient is considered a non-responder.
ii. 6 months: A patient is a responder if the patient has a PSA assessment at 6 months (Day 1 of Cycle 7, Days 161-175) and meets response criteria. Otherwise, the patient is considered a non-responder.

result:
Interim data from the study show a decrease in PSA and are well tolerated. In all patients no new or bone lesions were found. FIG. 2 below shows a saddle plot for the percent change in PSA from the start of the study 3 months from baseline.

  Median age is 71 years (range 55-81), ECOG PS0, 1 (84%, 16%), median PSA 12.5 ng / mL (2.6-67.8), testosterone 0.267 nmol / L 38 men with (0.05-0.60) and ACTH 19.5 ng / L (n = 32; 0-47) were tested. The median number of cycles was 5.5 (1-13), with adverse events (AE) reducing the dose for one patient and increasing the dose to 400 mg BID. A predicted dose of 99% was ingested. Gr ≧ 3AE occurs in 16 men (drug-related in 13), the most common (≧ 5%) are dyspnea (11%), elevated blood pressure (8%), fatigue, hypokalemia , Pneumonia (n = 2 respectively). Seven men (18%) had severe AEs, the most common being pneumonia (2 = Gr3, 1 = Gr2). Eight men discontinued ortelinel due to AE (dyspnea, pneumonia, adrenal dysfunction, fatigue, increased blood pressure, diarrhea, abnormal taste). Five men achieved PSA ≦ 0.2 ng / mL (4 in 3 months and 1 in 6 months). The PSA50 rate and PSA90 rate at 3 months were 69% and 34%, respectively. The decrease in median PSA at 3 months was 83% (0.12-50.5) of 1.96 ng / mL and remained at -84% until the last evaluation. The median testosterone decreased to 89% 0.026 nmol / L (0.0-0.28) and the ACTH median increased to 228% 55 ng / L (12-351). Similar results were seen at 6 months, -87% of 2.05 ng / mL (0.10 to 12.3), -86% of 0.033 nmol / L (0.01 to 0.41), respectively. And + 311% of 83.5 ng / L (21-173). The PSA50 rate and PSA90 rate at 6 months were 42% and 17%, respectively. Fourteen (37%) men received> 6 months of treatment. Of the 35 men with baseline CTC / 7.5 mL values, 7 had CTC> 0 and 1 had CTC ≧ 5. At 3 months, 1 of 1 patients converted to CTC <5 and no patient converted to ≧ 5.

  [Conclusion] The current results of these men with non-metastatic CRPC show substantial activity as reflected by the tolerance tolerone given with steroids and the reduction in testosterone and PSA. It shows having.

Claims (266)

  A method of treating cancer comprising administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor without administering steroids simultaneously or sequentially.   The method of claim 1, wherein the 17-α hydroxylase / C17,20-lyase inhibitor is an inhibitor selective for C17,20-lyase over 17-α hydroxylase.   3. The method of claim 2, wherein the 17-α hydroxylase / C17,20-lyase inhibitor is about 3 to about 8 times selective for C17,20-lyase over 17-α hydroxylase.   The method of claim 2, wherein the 17-α hydroxylase / C17,20-lyase inhibitor is about 4 to about 7-fold selective for C17,20-lyase over 17-α hydroxylase.   4. The method of claim 2, wherein the 17-α hydroxylase / C17,20-lyase inhibitor is about 5-fold selective for C17,20-lyase over 17-α hydroxylase.   2. The 17-α hydroxylase / C17,20-lyase inhibitor is a selective inhibitor for C17,20-lyase over 17-α hydroxylase and other human CYP family enzymes. The method described. 7. The method of claim 6, wherein the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value greater than 10 μM for human CYP family enzymes other than C17,20-lyase. 7. The method of claim 6, wherein the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value of greater than 20 μM for human CYP family enzymes other than C17,20-lyase. 7. The method of claim 6, wherein the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value greater than 30 μM for human CYP family enzymes other than C17,20-lyase.   The 17-α hydroxylase / C17,20-lyase inhibitor is 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl]-. The method according to any one of claims 1 to 9, which is N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.   12. The method of claim 1 or 10, wherein the therapeutically effective amount is about 300 to about 600 mg twice a day.   11. The method of claim 1 or 10, wherein the therapeutically effective amount is about 200 to about 600 mg twice a day.   11. The method of claim 1 or 10, wherein the therapeutically effective amount is about 200 mg twice a day.   11. The method of claim 1 or 10, wherein the therapeutically effective amount is about 400 mg twice a day.   11. The method of claim 1 or 10, wherein the therapeutically effective amount is about 300 mg twice a day.   11. The method of claim 1 or 10, wherein the therapeutically effective amount is about 300 to about 600 mg once a day.   11. The method of claim 1 or 10, wherein the therapeutically effective amount is about 600 once a day.   The method of claim 17, wherein the therapeutically effective amount is about 600 mg taken once a day in the morning.   19. A method according to any one of claims 11 to 18, wherein the therapeutically effective amount is taken with a meal.   11. The method of claim 1 or 10, wherein the therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor is administered without the simultaneous or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or triamcinolone. The method described.   21. The method of claim 20, wherein the therapeutically effective amount of a 17-alpha hydroxylase / C17,20-lyase inhibitor is administered without administering prednisone simultaneously or sequentially.   A method of treating cancer comprising administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor without administering steroids simultaneously or sequentially, wherein the steroids are administered simultaneously or sequentially. Administration of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor without administration, as measured by increased progression-free survival compared to standard therapy A method that results in improved outcomes.   23. The method of claim 22, wherein the progression free survival or time to metastasis is increased by at least 9 months.   23. The method of claim 22, wherein the progression free survival or time to metastasis is increased by at least 12 months.   23. The method of claim 22, wherein the progression free survival or time to metastasis is increased by at least 15 months.   The 17-α hydroxylase / C17,20-lyase inhibitor is 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl]-. 23. The method according to claim 22, which is N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.   23. The method of claim 22, wherein the cancer is a hormone induced cancer.   23. The method of claim 22, wherein the cancer is prostate cancer, breast cancer, or ovarian cancer.   24. The method of claim 22, wherein the cancer is prostate cancer.   30. The method of claim 29, wherein the prostate cancer is gonadectomy resistant prostate cancer.   30. The method of claim 29, wherein the prostate cancer is metastatic gonectomy resistant prostate cancer.   30. The method of claim 29, wherein the prostate cancer is non-metastatic gonadectomy resistant prostate cancer.   The improvement in clinical outcome is further measured by a favorable safety risk / benefit ratio, whereby a 17-α hydroxylase / C17,20-lyase inhibitor is administered without simultaneous or sequential administration of steroids 23. The method of claim 22, wherein the risk associated with the risk exceeds the benefit associated with avoiding long-term use of steroids.   The risk associated with administering a 17-α hydroxylase / C17,20-lyase inhibitor without simultaneous or sequential administration of steroids is measured by monitoring the patient for evidence of mineralocorticoid excess 34. The method of claim 33, wherein:   35. The method of claim 34, wherein the patient is monitored for one or more of an ACTH / corticosterone profile, elevated blood pressure, hypokalemia, edema, or cardiovascular symptoms.   24. The method of claim 22, wherein the therapeutically effective amount is about 300 to about 600 mg twice a day.   24. The method of claim 22, wherein the therapeutically effective amount is about 200 to about 600 mg twice a day.   24. The method of claim 22, wherein the therapeutically effective amount is about 200 mg twice a day.   24. The method of claim 22, wherein the therapeutically effective amount is about 400 mg twice a day.   23. The method of claim 22, wherein the therapeutically effective amount is about 300 mg twice a day.   24. The method of claim 22, wherein the therapeutically effective amount is about 300 to about 600 mg once daily.   23. The method of claim 22, wherein the therapeutically effective amount is about 600 once a day.   24. The method of claim 22, wherein the therapeutically effective amount is about 600 mg taken once a day in the morning.   44. The method of any one of claims 36 to 43, wherein the therapeutically effective amount is taken with a meal.   23. The therapeutically effective amount of a 17-alpha hydroxylase / C17,20-lyase inhibitor is administered without simultaneous or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone. The method described in 1.   46. The method of claim 45, wherein the therapeutically effective amount of a 17- [alpha] hydroxylase / C17,20-lyase inhibitor is administered without administering prednisone simultaneously or sequentially.   6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl] -N-methyl- without administering steroids simultaneously or sequentially Treating a cancer comprising administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, which is 2-naphthalenecarboxamide. The method wherein administering the therapeutically effective amount of the 17-α hydroxylase / C17,20-lyase inhibitor without simultaneous or sequential administration of steroids is progression free compared to standard therapy A method that results in improved patient clinical outcome as measured by increased survival.   48. The method of claim 47, wherein the progression free survival or time to metastasis is increased by at least 9 months.   48. The method of claim 47, wherein the progression free survival or time to metastasis is increased by at least 12 months.   48. The method of claim 47, wherein the progression free survival or time to metastasis is increased by at least 15 months.   48. The method of claim 47, wherein the cancer is a hormone-induced cancer.   48. The method of claim 47, wherein the cancer is prostate cancer, breast cancer, or ovarian cancer.   48. The method of claim 47, wherein the cancer is prostate cancer.   54. The method of claim 53, wherein the prostate cancer is gonadectomy resistant prostate cancer.   54. The method of claim 53, wherein the prostate cancer is metastatic gonectomy resistant prostate cancer.   54. The method of claim 53, wherein the prostate cancer is non-metastatic gonadectomy resistant prostate cancer.   The improvement in clinical outcome is further measured by a favorable safety risk / benefit ratio, whereby a 17-α hydroxylase / C17,20-lyase inhibitor is administered without simultaneous or sequential administration of steroids 48. The method of claim 47, wherein the risk associated with the risk exceeds the benefit associated with avoiding long-term use of steroids.   The risk associated with administering a 17-α hydroxylase / C17,20-lyase inhibitor without simultaneous or sequential administration of steroids is measured by monitoring the patient for evidence of mineralocorticoid excess 58. The method of claim 57, wherein:   59. The method of claim 58, wherein the patient is monitored for one or more of an ACTH / corticosterone profile, elevated blood pressure, hypokalemia, edema, or cardiovascular symptoms.   48. The method of claim 47, wherein the therapeutically effective amount is about 300 to about 600 mg twice a day.   48. The method of claim 47, wherein the therapeutically effective amount is about 200 to about 600 mg twice a day.   48. The method of claim 47, wherein the therapeutically effective amount is about 200 mg twice a day.   48. The method of claim 47, wherein the therapeutically effective amount is about 400 mg twice a day.   48. The method of claim 47, wherein the therapeutically effective amount is about 300 mg twice a day.   48. The method of claim 47, wherein the therapeutically effective amount is about 300 to about 600 mg once daily.   48. The method of claim 47, wherein the therapeutically effective amount is about 600 mg once a day.   48. The method of claim 47, wherein the therapeutically effective amount is about 600 mg taken once a day in the morning.   68. The method of any one of claims 60 to 67, wherein the therapeutically effective amount is taken with a meal.   48. The therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor is administered without the simultaneous or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone. The method described in 1.   70. The method of claim 69, wherein the therapeutically effective amount of a 17-alpha hydroxylase / C17,20-lyase inhibitor is administered without administering prednisone simultaneously or sequentially. (A) prior to administration of a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, the blood pressure of said patient, or one of corticosterone, cortisol, or potassium; Measuring one or more of two or more serum levels;
(B) after administering a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, the blood pressure of the patient, or one of corticosterone, cortisol, or potassium. Measuring one or more of the above serum levels;
(C) administering to said patient a second dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, wherein said second dose level is said first dose 48. The method of claim 1, 22, or 47, further comprising: exceeding, equal to, or less than a level.   72. The method of claim 71, further comprising repeating steps (a)-(c) until a desired dose level of a therapeutically effective amount of 17-alpha hydroxylase / C17,20-lyase inhibitor is achieved. . The blood pressure measurement after administering the first dose level exceeds the blood pressure measurement prior to administering the first dose level, and (a) after administering the first dose level. The corticosterone level is higher than the corticosterone level prior to administering the first dose level, or (b) the cortisol level after administering the first dose level is Lower than the cortisol level prior to administering a dose level, or (c) the potassium level after administering the first dose level is lower than the potassium level prior to administering the first dose level, 72. The method of claim 71.   74. The method of claim 73, wherein the corticosterone level after administering the first dose level is higher than the corticosterone level prior to administering the first dose level.   74. The method of claim 73, wherein the cortisol level after administering the first dose level is lower than the cortisol level prior to administering the first dose level.   74. The method of claim 73, wherein the potassium level after administering the first dose level is lower than the potassium level prior to administering the first dose level.   The method of claim 1, wherein the cancer is a hormone-induced cancer.   The method of claim 1, wherein the cancer is prostate cancer, breast cancer, or ovarian cancer.   The method of claim 1, wherein the cancer is prostate cancer.   80. The method of claim 79, wherein the prostate cancer is gonadectomy resistant prostate cancer.   80. The method of claim 79, wherein the prostate cancer is metastatic gonadectomy resistant prostate cancer.   80. The method of claim 79, wherein the prostate cancer is non-metastatic gonadectomy resistant prostate cancer.   72. The method of claim 71, wherein the first dose level is about 400 mg twice a day.   72. The method of claim 71, wherein the second dose level is about 300 mg twice a day.   72. The method of claim 71, wherein the second dose level is about 200 mg twice a day. Further comprising administering one or more additional therapies to the patient simultaneously or sequentially with the 17-α hydroxylase / C17,20-lyase inhibitor, the one or more additional therapies comprising:
a. radiation,
b. chemical treatment,
c. Immunotherapy,
d. Non-steroidal hormone elimination therapy, or e. 48. The method of claim 1, 22, or 47, comprising non-steroidal therapy for managing side effects of therapy.   Said one or more additional therapies are cyproeusel T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane , Anastrozole, letrozole, trastuzumab, lapatinib, radioisotope, hormone ablation agent, hormone blocker treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterine 90. The method of claim 86, wherein the method is selected.   90. The method of claim 86, wherein the one or more additional treatments are androgen receptor inhibitors.   The androgen receptor inhibitor is (4- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide) or (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [ 90. The method of claim 88, wherein the process is 3,4] octane-5-yl) -2-fluoro-N-methylbenzamide A method of treating cancer in a patient comprising
(A) measuring one or more levels of one or more serum levels of corticosterone, cortisol, or potassium at a first time point;
(B) administering to said patient a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor;
(C) after administration of a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, one of the patient's blood pressure or corticosterone, cortisol, or potassium Measuring one or more of the above serum levels;
(D) administering to said patient a second dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, wherein said second dose level is said first dose Exceeding, equal to, or less than a level.   94. The method of claim 90, wherein the second dose level in step (d) is less than the first dose level.   94. The method of claim 90, further comprising repeating steps (a)-(d) until a desired dose level of a therapeutically effective amount of 17- [alpha] hydroxylase / C17,20-lyase inhibitor is achieved. . The blood pressure measurement after administering the first dose level exceeds the blood pressure measurement prior to administering the first dose level, and (a) after administering the first dose level. The corticosterone level is higher than the corticosterone level prior to administering the first dose level, or (b) the cortisol level after administering the first dose level is Lower than the cortisol level prior to administering a dose level, or (c) the potassium level after administering the first dose level is lower than the potassium level prior to administering the first dose level, 92. The method of claim 90.   94. The method of claim 93, wherein the corticosterone level after administering the first dose level is higher than the corticosterone level prior to administering the first dose level.   94. The method of claim 93, wherein the cortisol level after administering the first dose level is lower than the cortisol level prior to administering the first dose level.   94. The method of claim 93, wherein the potassium level after administering the first dose level is lower than the potassium level prior to administering the first dose level.   94. The method of claim 90, wherein the cancer is a hormone induced cancer.   92. The method of claim 90, wherein the cancer is prostate cancer, breast cancer, or ovarian cancer.   94. The method of claim 90, wherein the cancer is prostate cancer.   100. The method of claim 99, wherein the prostate cancer is gonadectomy resistant prostate cancer.   99. The method of claim 99, wherein the prostate cancer is metastatic gonadectomy resistant prostate cancer.   100. The method of claim 99, wherein the prostate cancer is non-metastatic gonadectomy resistant prostate cancer.   94. The method of claim 90, wherein the first dose level is about 300 to about 600 mg twice daily.   94. The method of claim 90, wherein the first dose level is about 200 to about 600 mg twice daily.   92. The method of claim 90, wherein the first dose level is about 400 mg twice daily.   92. The method of claim 90, wherein the first dose level is about 300 mg twice a day.   94. The method of claim 90, wherein the first dose level is about 200 mg twice a day.   94. The method of claim 90, wherein the first dose level is about 300 to about 600 mg once daily.   94. The method of claim 90, wherein the first dose level is about 200 to about 600 mg once daily.   94. The method of claim 90, wherein the first dose level is about 600 mg once a day.   92. The method of claim 90, wherein the first dose is about 600 mg taken once a day in the morning.   112. The method of any one of claims 103-111, wherein the first dose is taken with a meal.   92. The method of claim 90, wherein the first dose level is about 400 mg twice daily.   94. The method of claim 90, wherein the second dose level is about 300 mg twice a day.   94. The method of claim 90, wherein the second dose level is about 200 mg twice a day. Further comprising administering one or more additional therapies to the patient simultaneously or sequentially with the 17-α hydroxylase / C17,20-lyase inhibitor, the one or more additional therapies comprising:
a. radiation,
b. chemical treatment,
c. Immunotherapy,
d. Non-steroidal hormone elimination therapy, or e. 94. The method of claim 90, comprising non-steroidal therapy for managing side effects of therapy.   Said one or more additional therapies are cyproeusel T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane 116, selected from: anastrozole, letrozole, trastuzumab, lapatinib, radioisotope, hormone abolisher, hormone blocker treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterin The method described in 1.   118. The method of claim 117, wherein the one or more additional treatments are androgen receptor inhibitors.   The androgen receptor inhibitor is (4- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide) or (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [ 119] The method of claim 118, which is 3.4] octane-5-yl) -2-fluoro-N-methylbenzamide).     48. The method of claim 1, 22, or 47, wherein the patient has been previously treated with abiraterone acetate one or more times.   A pharmaceutical composition comprising a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor as an active ingredient for the treatment of cancer without simultaneous or sequential administration of steroids.   122. The pharmaceutical composition of claim 121, wherein the pharmaceutical composition provides an improvement in a patient's clinical outcome as measured by increased progression free survival compared to standard therapy.   122. The pharmaceutical composition of claim 121, wherein the progression free survival or time to metastasis is increased by at least 9 months.   122. The pharmaceutical composition of claim 121, wherein the progression free survival or time to metastasis is increased by at least 12 months.   122. The pharmaceutical composition of claim 121, wherein the progression free survival or time to metastasis is increased by at least 15 months.   The 17-α hydroxylase / C17,20-lyase inhibitor is 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl]-. 122. The pharmaceutical composition of claim 121, which is N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt thereof.   122. The pharmaceutical composition of claim 121, wherein the cancer is a hormone-induced cancer.   122. The pharmaceutical composition of claim 121, wherein the cancer is prostate cancer, breast cancer, or ovarian cancer.   122. The pharmaceutical composition of claim 121, wherein the cancer is prostate cancer.   130. The pharmaceutical composition of claim 129, wherein the prostate cancer is gonadectomy resistant prostate cancer.   130. The pharmaceutical composition of claim 129, wherein the prostate cancer is metastatic gonadectomy resistant prostate cancer.   130. The pharmaceutical composition of claim 129, wherein the prostate cancer is non-metastatic ablation resistant prostate cancer.   The improvement in clinical outcome is further measured by a favorable safety risk / benefit ratio, whereby the risk associated with treating the cancer without simultaneous or sequential administration of the steroid is a long-term steroid 122. The pharmaceutical composition of claim 121, wherein the pharmaceutical composition exceeds the benefits associated with avoiding the use of.   134. The pharmaceutical composition of claim 133, wherein the risk associated with treating the cancer without simultaneous or sequential administration of steroids is measured by monitoring the patient for evidence of mineralocorticoid excess. object.   135. The pharmaceutical composition of claim 134, wherein the patient is monitored for one or more of an ACTH / corticosterone profile, elevated blood pressure, hypokalemia, edema, or cardiovascular symptoms.   122. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 300 to about 600 mg twice a day.   122. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 200 to about 600 mg twice a day.   122. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 200 mg twice a day.   122. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 400 mg twice a day.   122. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 300 mg twice a day.   122. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 300 to about 600 mg once daily.   122. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 600 once a day.   122. The pharmaceutical composition of claim 121, wherein the therapeutically effective amount is about 600 mg taken once a day in the morning.   144. The pharmaceutical composition according to any one of claims 136 to 143, wherein the therapeutically effective amount is for use with a meal.   The therapeutically effective amount of the 17-α hydroxylase / C17,20-lyase inhibitor is for treating cancer without simultaneous or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone. 122. The pharmaceutical composition of claim 121.   145. The pharmaceutical composition of claim 145, wherein the therapeutically effective amount of a 17-alpha hydroxylase / C17,20-lyase inhibitor is for treating cancer without administering prednisone simultaneously or sequentially.   Use of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor in the manufacture of a medicament for treating cancer without the simultaneous or sequential administration of steroids.   148. Use according to claim 147, wherein the 17-α hydroxylase / C17,20-lyase inhibitor is a selective inhibitor for C17,20-lyase over 17-α hydroxylase.   149. Use according to claim 148, wherein the 17-α hydroxylase / C17,20-lyase inhibitor is about 3 to about 8 times selective for C17,20-lyase over 17-α hydroxylase.   149. The use of claim 148, wherein the 17-α hydroxylase / C17,20-lyase inhibitor is about 4 to about 7-fold selective for C17,20-lyase over 17-α hydroxylase.   149. Use according to claim 148, wherein the 17-α hydroxylase / C17,20-lyase inhibitor is about 5-fold selective for C17,20-lyase over 17-α hydroxylase.   147. The 147-hydroxylase / C17,20-lyase inhibitor is a selective inhibitor for C17,20-lyase over 17-α hydroxylase and other human CYP family enzymes. Use of description. 153. Use according to claim 152, wherein the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value of greater than 10 μM for human CYP family enzymes other than C17,20-lyase. 153. Use according to claim 152, wherein the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value of greater than 20 μM for human CYP family enzymes other than C17,20-lyase. 153. Use according to claim 152, wherein the 17-α hydroxylase / C17,20-lyase inhibitor has an IC ₅₀ value of greater than 30 μM for human CYP family enzymes other than C17,20-lyase.   The 17-α hydroxylase / C17,20-lyase inhibitor is 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl]-. The use according to any one of claims 147 to 155, which is N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.   157. Use according to claim 147 or 156, wherein the therapeutically effective amount is about 300 to about 600 mg twice a day.   157. Use according to claim 147 or 156, wherein the therapeutically effective amount is about 200 to about 600 mg twice a day.   157. Use according to claim 147 or 156, wherein the therapeutically effective amount is about 200 mg twice a day.   157. Use according to claim 147 or 156, wherein the therapeutically effective amount is about 400 mg twice a day.   157. Use according to claim 147 or 156, wherein the therapeutically effective amount is about 300 mg twice a day.   157. Use according to claim 147 or 156, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.   157. Use according to claim 147 or 156, wherein the therapeutically effective amount is about 600 once a day.   164. Use according to claim 163, wherein the therapeutically effective amount is about 600mg taken once a day in the morning.   164. Use according to any one of claims 157 to 163, wherein the therapeutically effective amount is taken with a meal.   147. The therapeutically effective amount of the 17-α hydroxylase / C17,20-lyase inhibitor is administered without the simultaneous or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone. Or use according to 156.   169. The use of claim 166, wherein the therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor is administered without administering prednisone simultaneously or sequentially.   Use of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor in the manufacture of a formulation for treating cancer without administering steroids simultaneously or sequentially, wherein the steroids are administered simultaneously or sequentially. Without administration, administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor is an indication of the clinical outcome of the patient as measured by increased progression-free survival compared to standard therapy. Use, bring about improvement.   169. Use according to claim 168, wherein the progression free survival or time to metastasis is increased by at least 9 months.   169. Use according to claim 168, wherein the progression free survival or time to metastasis is increased by at least 12 months.   169. Use according to claim 168, wherein the progression free survival or time to metastasis is increased by at least 15 months.   The 17-α hydroxylase / C17,20-lyase inhibitor is 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c] imidazol-7-yl]-. 169. Use according to claim 168, which is N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.   169. Use according to claim 168, wherein the cancer is a hormone-induced cancer.   169. Use according to claim 168, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.   169. Use according to claim 168, wherein the cancer is prostate cancer.   175. Use according to claim 175, wherein the prostate cancer is gonadectomy resistant prostate cancer.   175. Use according to claim 175, wherein the prostate cancer is metastatic gonadectomy resistant prostate cancer.   175. Use according to claim 175, wherein the prostate cancer is non-metastatic gonadectomy resistant prostate cancer.   The improvement in clinical outcome is further measured by a favorable safety risk / benefit ratio, whereby the 17-α hydroxylase / C17,20-lyase inhibitor is administered without the simultaneous or sequential administration of steroids 169. The use of claim 168, wherein the risk associated with doing exceeds the benefit associated with avoiding long-term use of steroids.   The risk associated with administering a 17-α hydroxylase / C17,20-lyase inhibitor without simultaneous or sequential administration of steroids is measured by monitoring the patient for evidence of mineralocorticoid excess 179. The use of claim 179.   181. The use of claim 180, wherein the patient is monitored for one or more of an ACTH / corticosterone profile, elevated blood pressure, hypokalemia, edema, or cardiovascular symptoms.   169. Use according to claim 168, wherein the therapeutically effective amount is about 300 to about 600 mg twice a day.   169. The use of claim 168, wherein the therapeutically effective amount is about 200 to about 600 mg twice a day.   169. Use according to claim 168, wherein the therapeutically effective amount is about 200 mg twice a day.   169. Use according to claim 168, wherein the therapeutically effective amount is about 400 mg twice a day.   169. Use according to claim 168, wherein the therapeutically effective amount is about 300 mg twice a day.   169. Use according to claim 168, wherein the therapeutically effective amount is from about 300 to about 600 mg once daily.   169. Use according to claim 168, wherein the therapeutically effective amount is about 600 once a day.   169. Use according to claim 168, wherein the therapeutically effective amount is about 600 mg taken once a day in the morning.   190. Use according to any one of claims 183 to 189, wherein the therapeutically effective amount is taken with a meal.   168. The therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor is administered without the simultaneous or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone. Use as described in.   191. The use of claim 191, wherein the therapeutically effective amount of a 17-alpha hydroxylase / C17,20-lyase inhibitor is administered without administering prednisone simultaneously or sequentially.   A therapeutically effective amount of 6-[(7S) -7-hydroxy-6,7-dihydro-5H-pyrrolo [1,2-c in the manufacture of a preparation for treating cancer without simultaneous or sequential administration of steroids. ] Use of imidazol-7-yl] -N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or pharmaceutical composition thereof, without simultaneous or sequential administration of steroids, Use wherein administering a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor results in improved clinical outcome of the patient as measured by increased progression-free survival compared to standard therapy .   196. Use according to claim 193, wherein the progression free survival or time to metastasis is increased by at least 9 months.   196. Use according to claim 193, wherein the progression free survival or time to metastasis is increased by at least 12 months.   196. Use according to claim 193, wherein the progression free survival or time to metastasis is increased by at least 15 months.   196. Use according to claim 193, wherein the cancer is a hormone induced cancer.   197. Use according to claim 193, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.   196. Use according to claim 193, wherein the cancer is prostate cancer.   199. Use according to claim 199, wherein the prostate cancer is gonadectomy resistant prostate cancer.   200. Use according to claim 199, wherein the prostate cancer is metastatic ablation-resistant prostate cancer.   200. The use according to claim 199, wherein the prostate cancer is non-metastatic adenectomy resistant prostate cancer.   The improvement in clinical outcome is further measured by a favorable safety risk / benefit ratio, whereby the 17-α hydroxylase / C17,20-lyase inhibitor is administered without the simultaneous or sequential administration of steroids 196. Use according to claim 193, wherein the risk associated with doing exceeds the benefit associated with avoiding long-term use of steroids.   The risk associated with administering a 17-α hydroxylase / C17,20-lyase inhibitor without simultaneous or sequential administration of steroids is measured by monitoring the patient for evidence of mineralocorticoid excess 204. The use according to claim 203.   206. The use of claim 205, wherein the patient is monitored for one or more of an ACTH / corticosterone profile, elevated blood pressure, hypokalemia, edema, or cardiovascular symptoms.   195. The use of claim 193, wherein the therapeutically effective amount is about 300 to about 600 mg twice a day.   196. The use of claim 193, wherein the therapeutically effective amount is about 200 to about 600 mg twice a day.   196. The use of claim 193, wherein the therapeutically effective amount is about 200 mg twice a day.   196. The use of claim 193, wherein the therapeutically effective amount is about 400 mg twice a day.   196. Use according to claim 193, wherein the therapeutically effective amount is about 300 mg twice a day.   196. The use of claim 193, wherein the therapeutically effective amount is about 300 to about 600 mg once daily.   196. Use according to claim 193, wherein the therapeutically effective amount is about 600 once a day.   196. Use according to claim 193, wherein the therapeutically effective amount is about 600 mg taken once a day in the morning.   224. Use according to any one of claims 206 to 213, wherein the therapeutically effective amount is taken with a meal.       193. The therapeutically effective amount of the 17-α hydroxylase / C17,20-lyase inhibitor is administered without simultaneous or sequential administration of dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone. Use as described in.   218. The use of claim 215, wherein the therapeutically effective amount of a 17-alpha hydroxylase / C17,20-lyase inhibitor is administered without administering prednisone simultaneously or sequentially. (A) prior to administration of a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, the blood pressure of said patient, or one of corticosterone, cortisol, or potassium; Measuring one or more of two or more serum levels;
(B) after administering a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, the blood pressure of the patient, or one of corticosterone, cortisol, or potassium. Measuring one or more of the above serum levels;
(C) administering to said patient a second dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, wherein said second dose level is said first dose 194. Use according to claim 147, 168 or 193, further comprising exceeding, equal to or less than a level.   218. The use of claim 217, further comprising repeating steps (a)-(c) until a desired dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor is achieved. . The blood pressure measurement after administering the first dose level exceeds the blood pressure measurement prior to administering the first dose level, and (a) after administering the first dose level. The corticosterone level is higher than the corticosterone level prior to administering the first dose level, or (b) the cortisol level after administering the first dose level is Lower than the cortisol level prior to administering a dose level, or (c) the potassium level after administering the first dose level is lower than the potassium level prior to administering the first dose level, 217. Use according to claim 217.   219. The use of claim 219, wherein the corticosterone level after administering the first dose level is higher than the corticosterone level prior to administering the first dose level.   219. The use of claim 219, wherein the cortisol level after administering the first dose level is lower than the cortisol level prior to administering the first dose level.   219. The use of claim 219, wherein the potassium level after administering the first dose level is lower than the potassium level prior to administering the first dose level.   148. Use according to claim 147, wherein the cancer is a hormone induced cancer.   148. Use according to claim 147, wherein the cancer is prostate cancer, breast cancer or ovarian cancer.   148. Use according to claim 147, wherein the cancer is prostate cancer.   226. Use according to claim 225, wherein the prostate cancer is gonadectomy resistant prostate cancer.   226. The use of claim 225, wherein the prostate cancer is metastatic gonadectomy resistant prostate cancer.   226. The use of claim 225, wherein the prostate cancer is non-metastatic gonadectomy resistant prostate cancer.   169. Use according to claim 168, wherein the first dose level is about 400 mg twice a day.   169. Use according to claim 168, wherein the second dose level is about 300 mg twice a day.   169. Use according to claim 168, wherein the second dose level is about 200 mg twice a day. Further comprising administering one or more additional therapies to the patient simultaneously or sequentially with the 17-α hydroxylase / C17,20-lyase inhibitor, the one or more additional therapies comprising:
a. radiation,
b. chemical treatment,
c. Immunotherapy,
d. Non-steroidal hormone elimination therapy, or e. 194. Use according to claim 147, 168, or 193, comprising non-steroid therapy to manage the side effects of therapy.   Said one or more additional therapies are cyproeusel T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane 232, selected from: anastrozole, letrozole, trastuzumab, lapatinib, radioisotope, hormone elimination agent, hormone blocker treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterin. Use as described in.   235. Use according to claim 232, wherein the one or more additional treatments are androgen receptor inhibitors.   The androgen receptor inhibitor is (4- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide) or (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [ 3,4 Use according to claim 234, which is octan-5-yl) -2-fluoro-N-methylbenzamide). Use of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor in the manufacture of a formulation in the treatment of cancer in a patient comprising
(A) measuring one or more levels of one or more serum levels of corticosterone, cortisol, or potassium at a first time point;
(B) administering to said patient a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor;
(C) after administration of a first dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, one of the patient's blood pressure or corticosterone, cortisol, or potassium Measuring one or more of the above serum levels;
(D) administering to said patient a second dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor, wherein said second dose level is said first dose Use including, exceeding, equal to, or less than a level.   237. Use according to claim 236, wherein the second dose level in step (d) is less than the first dose level.   237. The use of claim 236, further comprising repeating steps (a)-(d) until a desired dose level of a therapeutically effective amount of a 17-α hydroxylase / C17,20-lyase inhibitor is achieved. . The blood pressure measurement after administering the first dose level exceeds the blood pressure measurement prior to administering the first dose level, and (a) after administering the first dose level. The corticosterone level is higher than the corticosterone level prior to administering the first dose level, or (b) the cortisol level after administering the first dose level is Lower than the cortisol level prior to administering a dose level, or (c) the potassium level after administering the first dose level is lower than the potassium level prior to administering the first dose level, 236. Use according to claim 236.   240. The use of claim 239, wherein the corticosterone level after administering the first dose level is higher than the corticosterone level prior to administering the first dose level.   240. The use of claim 239, wherein the cortisol level after administering the first dose level is lower than the cortisol level prior to administering the first dose level.   240. The use of claim 239, wherein the potassium level after administering the first dose level is lower than the potassium level prior to administering the first dose level.   236. The use of claim 236, wherein the cancer is a hormone induced cancer.   236. The use of claim 236, wherein the cancer is prostate cancer, breast cancer, or ovarian cancer.   236. Use according to claim 236, wherein the cancer is prostate cancer.   237. Use according to claim 236, wherein the prostate cancer is gonadectomy resistant prostate cancer.   237. Use according to claim 236, wherein the prostate cancer is metastatic gonadectomy resistant prostate cancer.   237. Use according to claim 236, wherein the prostate cancer is non-metastatic ablation resistant prostate cancer.   237. The use of claim 236, wherein the first dose level is about 300 to about 600 mg twice daily.   237. The use of claim 236, wherein the first dose level is about 200 to about 600 mg twice daily.   238. The use of claim 236, wherein the first dose level is about 400 mg twice a day.   237. The use of claim 236, wherein the first dose level is about 300 mg twice a day.   237. The use of claim 236, wherein the first dose level is about 200 mg twice a day.   238. The use of claim 236, wherein the first dose level is about 300 to about 600 mg once daily.   237. The use of claim 236, wherein the first dose level is about 200 to about 600 mg once daily.   237. The use of claim 236, wherein the first dose level is about 600 mg once a day.   237. The use of claim 236, wherein the first dose is about 600 mg taken once a day in the morning.   258. Use according to any one of claims 249 to 257, wherein the first dose is taken with a meal.   238. The use of claim 236, wherein the first dose level is about 400 mg twice a day.   237. Use according to claim 236, wherein the second dose level is about 300 mg twice a day.   237. The use of claim 236, wherein the second dose level is about 200 mg twice daily. Further comprising administering one or more additional therapies to the patient simultaneously or sequentially with the 17-α hydroxylase / C17,20-lyase inhibitor, the one or more additional therapies comprising:
a. radiation,
b. chemical treatment,
c. Immunotherapy,
d. Non-steroidal hormone elimination therapy, or e. 236. Use according to claim 236, comprising non-steroidal therapy for managing side effects of therapy.   Said one or more additional therapies are cyproeusel T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane 262, selected from anastrozole, letrozole, trastuzumab, lapatinib, radioisotope, hormone-eliminating agent, hormone blocker treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterin Use as described in.   276. Use according to claim 263, wherein the one or more additional treatments are androgen receptor inhibitors.   The androgen receptor inhibitor is (4- (3- (4-cyano-3- (trifluoromethyl) phenyl) -5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl) -2-fluoro-N-methylbenzamide) or (4- (7- (6-cyano-5- (trifluoromethyl) pyridin-3-yl) -8-oxo-6-thioxo-5,7-diazaspiro [ 3.4] Use according to claim 264, which is octane-.5-yl) -2-fluoro-N-methylbenzamide). 194. Use according to claim 147, 168, or 193, wherein the patient has been previously treated with abiraterone acetate one or more times.