EP2709614A1 - Compositions pharmaceutiques et méthodes de traitement du cancer - Google Patents
Compositions pharmaceutiques et méthodes de traitement du cancerInfo
- Publication number
- EP2709614A1 EP2709614A1 EP12785724.1A EP12785724A EP2709614A1 EP 2709614 A1 EP2709614 A1 EP 2709614A1 EP 12785724 A EP12785724 A EP 12785724A EP 2709614 A1 EP2709614 A1 EP 2709614A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- effective amount
- therapeutically effective
- dose level
- cancer
- administration
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- Cancer is a group of diseases characterized by uncontrolled growth of abnormal cells and subsequent invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (i.e., metastasis). Cancer is believed to be caused by both external factors (tobacco, infectious organisms, chemicals, and radiation) and internal factors (inherited mutations, hormones, immune conditions, and mutations that occur from metabolism). These causal factors may act together or in sequence to initiate or promote carcinogensis. Significantly, cancer is currently the second leading cause of death in the United States after heart disease, and the number of people diagnosed with cancer has significantly increased and continues to rise at an alarming rate.
- hormone-dependent disorders e.g., androgen-dependent and estrogen-dependent
- prostate cancer androgen-dependent
- breast, uterine and ovarian cancer estrogen-dependent
- Prostate cancer is currently the most common non-skin cancer and the second leading cause of cancer-related death in men after lung cancer.
- the primary course of treatment for patients disagnosed with organ-confined prostate cancer is usually prostatectomy or radiotherapy. Not only are these treatments highly invasive and characterized by undesirable and serious side effects, such localized treatments are not effective on prostate cancer after it has metastasized.
- surgery can be contraindicated due to the health of the patient or may be unacceptable to the patient, and a surgical procedure may not completely remove cancerous tissue.
- Radiation therapy is effective only when the irradiated neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue.
- a large percent of individuals who receive localized treatments such as surgery or radiotherapy will suffer from recurring cancer and widespread metastases.
- Hormone therapy is a form of systemic treatment for prostate or breast cancer, wherein hormone ablation agents are used to suppress the production or block the effects of hormones, such as estrogen and progesterone, which are believed to promote the growth of prostate cancer.
- hormones such as estrogen and progesterone
- This therapy is less invasive than surgery and does not have many of the side effects associated with chemotherapy or radiation.
- hormone therapy may be used by itself or in addition to localized therapy.
- hormone therapy is less invasive and may be used on more advanced stages of cancer
- some individuals administered current hormone therapy treatments may not respond completely, or even partially, to such treatments.
- Current hormone therapy treatments may offer temporal remission of cancer, but these treated cancers can relapse or recur, and upon recurrence, these cancers often have developed a resistance to hormonal therapy. Due to the typically aggressive nature of these recurrent cancers, and their resistance to hormonal therapy, patients with these conditions are often left with few options for treatment.
- cancers in which sex hormones may play a role in the progression of the cancer include uterine cancer, endometrial cancer, non-small cell lung cancer and colorectal cancer (Folkerd, E.J. and Dowsett M., J. Clin. Oncol 2010, 28: 4038-4044; Paggi 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, Best Tract Res Clin Endocrinol Metab. 2003 17(1): 139-47.
- the present invention relates to pharmaceutical compositions and methods for the treatment of certain cancers comprising administering to a patient in need thereof a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor without the concomitant or sequential administration of a steroid.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor is selective for CI 7, 20-lyase.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a compound that does not have a steroid backbone.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a compound that is selective for CI 7, 20-lyase and also does not have a steroid backbone.
- a method of treating cancer comprising administering a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-Iyase inhibitor without the concomitant or sequential administration of a steroid, wherein the administering of a therapeutically effective amount of a 17-alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid results in an improved clinical outcome for the patient as measured by enhanced progression-free survival or time to metastatis as compared to standard therapy.
- a method of treating cancer comprising administering a therapeutically effective amount of 6-[(7S)-7-hydroxy-6,7-dihydro-5H-pyrrolo[l,2-c]imidazol-7-yl]-N- methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof without the concomitant or sequential administration of a steroid, wherein the administering of a therapeutically effective amount of a 17-alpha hydroxyIase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid results in an improved clinical outcome for the patient as measured by enhanced progression-free survival or time to metastasis as compared to standard therapy.
- the present invention provides a method for treating cancer wherein the monitoring of a patients blood pressure, and serum levels of one or more of corticosterone, Cortisol or potassium enables selectively adjusting dose levels to achieve safe and efficacious dose levels in a patient, particularly safe and efficacious dose levels of a 17-alpha hydroxylase/C17, 20-lyase inhibitor that can be administered without concomitant or sequential administration of a steroid.
- a method of treating cancer comprising:
- cancer refers to a cellular disorder characterized by uncontrolled or disregulated cell proliferation, decreased cellular differentiation, inappropriate ability to invade surrounding tissue, and/or ability to establish new growth at ectopic sites.
- cancer includes, but is not limited to, solid tumors and bloodborne tumors.
- cancer encompasses diseases of skin, tissues, organs, bone, cartilage, blood, and vessels.
- cancer further encompasses primary and metastatic cancers.
- recurring cancer refers to cancer that has returned after a patient has been earlier diagnosed with cancer, has undergone treatment and/or had been previously diagnosed as cancer-free.
- relapse cancer refers to cancer that was at one time responsive to an anti-cancer treatment, but has become no longer responsive to such treatment or is no longer responding sufficiently to such treatment.
- refractory cancer refers to a cancer that is not responding to an anti-cancer treatment or cancer that is not responding sufficiently to an anti-cancer treatment, including recurring or relapsed cancer.
- hormone-refractory cancer or “cancer that is refractory to hormone therapy” mean cancer that is not responding to a hormone therapy, cancer that is no longer responding to or has progressed through a hormone therapy, or cancer that is not responding sufficiently to a hormone therapy.
- hormone-refractory patient means a patient who has hormone-refractory cancer.
- chemo-refractory cancer or “cancer that is refractory to chemotherapy” mean cancer that is not responding to chemotherapy, cancer that is no longer responding to or has progressed through chemotherapy, or cancer that is not responding sufficiently to chemotherapy.
- chemo-refractory patient means a patient who has chemo-refractory cancer.
- the phrases "castration-refractory cancer” or “cancer that is refractory to castration” mean cancer that is not responding to castration, cancer that is no longer responding to or has progressed through castration, or cancer that is not responding sufficiently to castration.
- chemotherapy-naive patient or “patient who is chemotherapy naive” refer to a patient who has never undergone chemotherapy treatment or who has never undergone chemotherapy treatment for a particular cancer.
- hormone therapy-naive patient or “patient who is hormone-therapy naive” refer to a patient who has never undergone hormone therapy treatment or who has never undergone hormone therapy treatment for a particular cancer.
- PSA prostate-specific antigen, which is a protein produced by the cells of the prostate gland.
- the term “castration levels of PSA” refers to the levels of PSA circulating in the blood of a patient who has had either one or both testicles surgically removed or has been chemically castrated, meaning the patient has been administered certain hormonal drugs to temporarily inhibit hormones that stimulate the testicles to produce testosterone.
- the term “castration levels of testosterone” refers to the levels of testosterone circulating in the blood of a patient who has had either one or both testicles surgically removed or has been chemically castrated, meaning the patient has been administered certain hormonal drugs to temporarily inhibit hormones that stimulate the testicles to produce testosterone.
- number of circulating tumor cells refers to the number of cancer cells that have detached from a primary tumor and are circulating in the bloodstream or bone marrow of a cancer patient.
- hormone agent includes, but is not limited to, “androgen ablation agents” and “estrogen ablation agents”. It will be appreciated that the term “hormonal agent” can comprise more than one hormonal agent.
- the term "patient” means an animal, preferably a mammal, and most preferably a human.
- the term "therapeutically effective amount” refers to the amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition that is effective for treating or preventing the disease or disorder.
- steroid refers to "corticosteroids" which are group of natural and synthetic analogues of the hormones secreted by the hypothalamic-anterior pituitary-adrenocortical (HPA) axis, more commonly referred to as the pituitary gland.
- HPA hypothalamic-anterior pituitary-adrenocortical
- glucocorticoids which are anti-inflammatory agents with a large number of other functions
- mineralocorticoids which control salt and water balance primarily through action on the kidneys
- corticotropins which control secretion of hormones by the pituitary gland.
- the term "steroid” refers to dexamethasone, prednisone, prednisolone, betamethasone, and trimacinolone. In certain other embodiments, the term “steroid” refers to glucocorticoids. [002S] As used herein, the term “without the concomitant or sequential administration of a steroid” refers to a dose cycle wherein the patient is not given a steroid with the 17-alpha hydroxylase/C17, 20- lyase inhibitor either sequentially or concomitantly.
- the term is not intended to exclude any previous administration of steroid for any purpose (e.g., steroid administration for asthma), or previous therapies received with steroids.
- the administration refers to a dose given on the same day.
- the administration refers to a dose cycle with the 17-alpha hydroxylase/C17, 20-lyase inhibitor lasting 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.
- steroid backbone refers to a general class of chemical substances that are structurally related to one another and share the same chemical skeleton (a tetracyclic cyclopenta[a]phenanthrene skeleton).
- the present invention relates to pharmaceutical compositions and methods for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor without the concomitant or sequential administration of a steroid.
- a steroid As outlined above, there remains a need to develop treatments for cancer that minimize and/or avoid the prolonged exposure to steroids and their side effects, and the present invention provides such a treatment for cancer without the use of steroids.
- the present invention provides a method of treating cancer comprising administering a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor in combination with one or more additional therapeutic agents, wherein the one or more additional therapeutic agents is not a steroid.
- the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor and one or more additional therapeutic agents, wherein the one or more additional therapeutic agents is not a steroid.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a selective inhibitor of CI 7, 20-lyase over 17-alpha hydroxylase.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor is about 3 to about 8 fold selective for CI 7, 20-lyase over 17-alpha hydroxylase.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor is about 4 to about 7 fold selective for CI 7, 20-lyase over 17-alpha hydroxylase. In still other embodiments, the 17-alpha hydroxylase/C17, 20- lyase inhibitor is about 5 fold selective for CI 7, 20-lyase over 17-alpha hydroxylase.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor does not have a steroid backbone.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor is a selective inhibitor of CI 7, 20 over 17-alpha hydroxylase and other human CYP family enzymes.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC 5 o value for human CYP family enzymes other than CI 7, 20-lyase of greater than 10 ⁇ .
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC 5() value for human CYP family enzymes other than CI 7, 20-lyase of greater than 20 ⁇ . In still other embodiments, the 17-alpha hydroxylase/C17, 20-lyase inhibitor has an IC 50 value for human CYP family enzymes other than CI 7, 20-lyase of greater than 30 ⁇ .
- the 17, 20-lyase inhibitor is 6-[(7S)-7-hydroxy-6,7-dihydro-5H- pyrrolo[l,2-c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide, or a pharmaceutically acceptable salt, or a pharmaceutical composition thereof.
- the therapeutically effective amounts or suitable dosages of the 17-alpha hydroxylase/C17, 20-lyase inhibitor depends upon a number of factors, including the nature of the severity of the condition to be treated, the particular inhibitor, the route of administration and the age, weight, and response of the individual patient.
- the suitable dose level is one that achieves a therapeutic response as measured by PSA levels, tumor regression, or other standard measures of disease progression.
- the suitable dose level is one that achieves this therapeutic response and also minimizes any side effects associated with the administration of the therapeutic agent.
- a suitable dose level is one that achieves an improved clinical outcome for the patient as measured by enhanced progression-free survival or time to metastasis as compared to standard therapy.
- progression-free survivial is enhanced by at least 9 months as compared to standard therapy.
- progression-free survival is enhanced by at least 12 months as compared to standard therapy.
- progression-free survival is enhanced by at least 15 months as compared to standard therapy.
- a suitable dose level is one that results in an improved clinical outcome as measured by a favorable safety risk/benefit ratio, whereby the risk associated with the administering of the 17-alpha hydroxylase/C17,20-Iyase inhibitor without the concomitant or sequential administration of a steroid is outweighed by the benefit associated with avoiding prolonged steroid use.
- the risks associated with the administering of a 17-alpha hydroxylase/C17,20-lyase inhibitor without the concomitant or sequential administration of a steroid is measured by monitoring the patient for evidence of mineralocorticoid excess.
- the patient is monitored for one of more of ACTH corticosterone profile, hypertension, hypokalemia, edema, or cardiovascular symptoms.
- Suitable daily dosages of 17-alpha hydroxylase/C17, 20-lyase inhibitors can generally range, in single or divided or multiple doses, from about 400 mg to about 1200 mg per day.
- Other suitable daily dosages of 17-alpha hydroxylase/C17, 20-lyase inhibitors can generally range, in single or divided or multiple doses, from about 600 mg to about 1200 mg per day.
- the suitable dosages are from about 200 mg twice daily to about 600 mg twice daily.
- the suitable dosages are from about 300 mg twice daily to about 600 mg twice daily.
- suitable dosages are about 800 mg per day.
- suitable dosages are about 400 mg twice daily.
- suitable dosages are about 600 mg per day. In other embodiments, suitable dosages are 300 mg twice daily. In still other embodiments, suitable dosages are 200 mg twice daily. In yet other embodiments, suitable dosages are from about 300 mg to about 600 mg once daily. In yet other embodiments, suitable dosages are from about 200 mg to about 600 mg once daily. In still other embodiments, a suitable dosage is about 600 once daily. In yet other embodiments, a suitable dosage is about 600 mg once daily taken in the morning. In still other embodiments, the suitable dosage amount is taken with a meal.
- the frequency with which any of these inhibitors can be administered can be once or more than once over a period of 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 10 days, about 20 days, about 28 days, about a week, about 2 weeks, about 3 weeks, about 4 weeks, about a month, about every 2 months, about every 3 months, about every 4 months, about every 5 months, about every 6 months, about every 7 months, about every 8 months, about every 9 months, about every 10 months, about every 11 months, about every year, about every 2 years, about every 3 years, about every 4 years, or about every 5 years.
- the above frequencies of administration can occur continuously or non- continuously over certain time periods.
- a certain amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor can be administered daily continuously over 28 days.
- Time periods over which the frequencies of administration can occur continuously or non-continuously include without limitation 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 a week about 2 weeks, about 3 weeks, about 4 weeks, about a month, about every 2 months, about every 3 months, about every 4 months, about evey 5 months, about every 6 months, about every 7 months, about every 8 months, about every 9 months, about every 10 months, about every 11 months, about every year, about every 2 years, about every 3 years, about every 4 years, or about every 5 years.
- the therapeutically effective amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered using dose cycling or a dosing regimen in which the 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered at a certain frequency, such as those described above.
- the treatment period is then followed by a non-treatment period of a particular time duration, such as the time periods described above, in which the 17-alpha hydroxylase/C17, 20-lyase inhibitor is not administered to the patient.
- This non-treatment period can then be followed by a series of subsequent treatment and non- treatment periods of the same or different frequencies or the same or different lengths of time.
- the treatment and non-treatment periods are alternated, hi other embodiments, a first treatment period in which a first amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered can be followed by another treatment period in which a same or different amount of the same or a different 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered.
- the second treatment period can be followed by other treatment periods.
- one or more additional non-steroidal therapeutic agents can be administered to the patient.
- the 17-alpha hydroxyIase/C17, 20-lyase inhibitor can be administered by any method known to one skilled in the art.
- the 17-alpha 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.
- the pharmaceutical composition is suitable for oral administration.
- the pharmaceutical composition is a tablet for oral administration.
- these compositions optionally further comprise one or more additional therapeutic agents.
- the method comprises administration of a therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor in combination with an additional therapeutic agent wherein the additional therapeutic agent is not a steroid.
- the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration dexamethasone, prednisone, prednisolone, betamethasone, or trimacinolone.
- the therapeutically effective amount of a 17-alpha hydroxylase/C17, 20-lyase inhibitor is administered without the concomitant or sequential administration of prednisone.
- combination therapy includes administration of the therapeutic agents concurrently or sequentially.
- the therapeutic agents can be combined into one composition which is administered to the patient.
- the additional therapeutic agent includes, but is not limited to, hormone ablation agents, anti-androgen agents/anti-androgens, differentiating agents, anti-neoplastic agents, kinase inhibitors, anti-metabolite agents, alkylating agents, antibiotic agents, immunological agents, interferon-type agents, DNA-damaging agents (e.g., intercalating agents), growth factor inhibitors, cell-cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, mitotic inhibitors, matrix metalloprotease inhibitoris, anti-resorptives, monoclonal antibodies, adhesion molecules, growth factors, proapoptotic agents, antisense agents, vitamin D analogs, RNAi agents, modified peptides, enzyme inhibitors, agents ameliorating the side effects of therapy, and genetic therapeutics.
- hormone ablation agents e.g., anti-androgen agents/anti-androgens, differentiating agents, anti-neoplastic agents, kinase inhibitors, anti-metabol
- hormonal ablation agents include, but are not limited to, androgen ablation agents and estrogen-ablation agents.
- hormonal ablation agents include, but are not limited to, deslorelin, leuprolide, goserelin or triptorelin.
- anti-androgen agents include, but are not limited to, bicalutamide, flutamide, spironolactone, cyproterone acetate, finasteride, dutasteride, and nilutamide.
- An example of an antiestrogen agent includes, but is not limited to, tamoxifen.
- differentiating agents include, but are not limited to polyamine inhibitors, vitamin D and its analogues, such as calcitriol, doxercalciferol, ergocalciferol, 22-oxacalcitriol, dihydrotachysterol, paricalcitol, and seocalcitol; inhibitors of vitamin A metabolism, such as RAMBAS, e.g., liarozole, metabolites of vitamin A, such as ATRA; retinoic acid; retinoids; short chain fatty acids; phenylbutyrate; and nonsteroidal anti-inflammatory agents.
- polyamine inhibitors such as calcitriol, doxercalciferol, ergocalciferol, 22-oxacalcitriol, dihydrotachysterol, paricalcitol, and seocalcitol
- inhibitors of vitamin A metabolism such as RAMBAS, e.g., liarozole, metabolites of vitamin A, such as ATRA
- anti-neoplastic agents include, but are not limited to tubulin interacting agents, topoisomerase inhibitors and agents, acitretin, alstonine, amonafide, amphethinile, amsacrine, ankinomycin, anti-neoplaston, aphidicolin glycinate, asparaginase, baccharin, batracyclin, benfluron, benzotrips, bromofosamide, caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone, clanfenur, claviridenone, crisnatol, curaderm, cytarabine, cytocytin, dacarbazine, datelliptinium, dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, docetaxel, elliprabin, elliptinium acetate, epoth
- kinase inhibitors include, but are not limited to, p38 inhibitors; CDK inhibitors; TNF inhibitors; matrixmetallo proteinase (MMP) inhibitors; COX-2 inhibitors; including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib; and SOD mimics.
- MMP matrixmetallo proteinase
- anti-metabolite agents include 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, doxifluridine, camrabine, floxuridine, fludarabine phosphate, 5-fIuorouracil, N-(2'-furanidyl)— 5-flurouracil, inhibitors of essential amino acids, isopropyl pyrrolizine, methobenzaprim, methotrexate, norspermidine, ornithine decarboxylantion inhibitors, pentostatin, piritrexim, plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinas
- Non-limiting examples of DNA damaging chemotherapeutic agents include topoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecin and analogs or metabolites thereof, and doxorubicin); topoisomerase II inhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylating agents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide, carmustine, lomustine, semustine, streptozocin, decarbazine, methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators (e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators, free radical generators such as bleomycin; and nucleoside mimetics (e.g., 5-fluorouracil, capec
- Chemotherapeutic agents that disrupt cell replication include: paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, and related analogs; thalidomide, lenalidomide, and related analogs (e.g., CC-5013 and CC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylate, gefitinib, lapatinib); proteasome inhibitors (e.g., bortezomib); NF- ⁇ inhibitors, including inhibitors of IKB kinase; antibodies which bind to proteins overexpressed in cancers and thereby downregulate cell replication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab); and other inhibitors of proteins or enzymes known to be upregulated, over-expressed or activated in cancers, the inhibition of which downregulates cell replication.
- Non-limiting examples of antibiotic agents include aclarubicin, actinomycin D, actinoplanone, adriamycin, aeroplysinin derivative, amrubicin, anthracycline, azinomycin-A, bisucaberine, bleomycin sulfate, bryostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin, ditrisarubicin B, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al, esperamicin-Alb, fostriecin, glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin, kesarirhodins, menogaril, mitomycin,
- Non-limiting examples of enzyme inhibitors include a 17-alpha hydroxylase/C17,20-lyase inhibitor, imidazole, azole, or an antifungal agents, for example, ketoconazole.
- Non-limiting examples of monoclonal antibodies include rituximab, trastuzumab, gentuzumab, ozogamicin, alemtuzumab, ibritumomab, tiuxetan, tositumomab, cetuximab, bevacizumab, panitumumab, and ofatumumab.
- Non-limiting examples of antisense agents include Genasense (oblimersen), affmitak (ISIS3521), ISIS 112989 (OGX 011), ISIS 23722, AP 12009, GEM 231, GEM 240, IGF-IR/AS ODN, MG98, LErafAON, Ki-67 antisense oligonuclotide, GTI-2040, ISIS 2503, and API 1014.
- Non-limiting examples of peptides and/or modified peptides include peptides or modified peptides as inhibitors, ligands or vaccines having for example a T-cell response against cancer cells and/or anti-cancer activity.
- Non-limiting examples of agents ameliorating the side effects of therapy include diuretics, pain relievers, analgesics, anti-inflammatory agents, eplerenone, proton pump inhibitors, H2 receptor antagonists, lipid lowering agents, antiresorptive agents, or antipsychotic agents.
- the one or more additional treatments are selected from radiation, chemotherapy, immunotherapy, a nonsteroidal hormone ablation therapy, or a non-steroidal therapy for the management of the side effects of therapy.
- the one or more additional treaments are selected from sipuleucel- T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane, anastrozole, letrozole, trastuzumab, lapatinib, radioisotopes, hormone ablation agent, hormone deprivation treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or triampterine.
- the one or more additional treatments includes an androgen receptor inhibitor.
- the androgen receptor inhibitor is MDV-3100 (4-(3-(4-cyano- 3-(trifIuoromethyl)phenyl)-5 , 5 -dimemyl-4-oxo-2-thioxoimidazolidin-l-yl)-2-fluoro-N-methylbenzam or ARN-509 (4-(7-(6-cyano-5-(trifluoromemyl)pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5- yl)-2-fluoro-N-methylbenzamide) .
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof.
- a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.
- the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- a “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
- the term “inhibitorily active metabolite or residue thereof means that a metabolite or residue thereof is also an inhibitor of 17-alpha hydroxylase/C17,20-lyase.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et at, describe pharmaceutically acceptable salts in detail in J. 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, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁇ Cnalk l ⁇ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
- the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- a pharmaceutically acceptable carrier, adjuvant, or vehicle which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
- Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions
- any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.
- materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc
- compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the disease being treated.
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adj
- 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.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- a compound of the present invention In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. 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 polylactide-polyglycolide.
- the rate of compound release can be controlled.
- 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 suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, calcium dihydrogen phosphate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose and silicic acid, b) binders such as, for example, carboxymethylcellulose, hydroxypropylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolateand sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as
- Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of 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 opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
- the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- buffering agents 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, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.
- the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
- Such dosage forms can be made by dissolving or dispensing 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.
- the 17-alpha hydroxylase/C17, 20-lyase inhibitor is useful for the treatment of cancer.
- Cancers that can be treated with the methods and compositions described herein include, but are not limited to, those cancers that are hormone-dependent, hormone responsive, or hormone sensitive (collectively "hormone responsive cancers").
- cancers that can be treated include, without limitation, androgen-responsive cancers, such as testosterone-responsive cancers, and estrogen-responsive cancers.
- the cancer can be a non-hormone responsive cancer of a cancer that was hormone responsive but later becomes non-hormone responsive.
- Cancers that can be treated include, without limitation, prostate cancer, breast cancer, testicular cancer, penile cancer, vaginal cancer, vulvar cancer, cervical cancer, uterine cancer, ovarian cancer, endometrial cancer, cancer of the Fallopian tubes or other reproductive organ cancers.
- cancers that may be treated include, without limitation, adrenal cancer, cancer of the lymphatic system, such as the lymph nodes, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, bone and connective tissue sarcoma, brain tumors, thyroid cancer, pancreatic cancer, pituitary cancer, eye cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, lung cancer, oral cancer, skin cancer, kidney cancers, Wilms' tumor, and bladder cancer.
- the lymphatic system such as the lymph nodes, leukemia, lymphoma, myeloma, Waldenstrom's macroglobulinemia, monoclonal gammopathy, benign monoclonal gammopathy, heavy chain disease, bone and connective tissue sarcoma, brain tumors, thyroid cancer, pancreatic cancer
- the methods and compositions described herein can be used to treat various stages of a particular cancer or specific forms of a type of cancer, such as breast or prostate cancer.
- the methods and compositions can be used to treat a pre-cancerous state, a post- cancerous state, an advanced cancerous state, a pre-metastatic cancer, a cancer that is a metastasis, i.e., that has metastasized from another cancer, a cancer that metastasized to, for example, the bones, lymph nodes, lungs, or a non-metastatic cancer.
- the patients treated are newly diagnosed with cancer, such as prostate cancer.
- the prostate cancer may be non-metastatic; may be pre-metastatic; may have metastasized to the bones, lungs, lymph nodes; or may comprise advanced adenocarcinoma of the prostate.
- the prostate cancer can be, without limitation, androgen-dependent prostate cancer; androgen-independent prostate cancer (AIPC) such as those that are biochemical-only in nature, asymptomatic with positive scans or symptomatic.
- AIPC androgen-independent prostate cancer
- stages IA, ⁇ , II, ⁇ , IVA, IVB, and JVC include, without limitation, stages IA, ⁇ , II, ⁇ , IVA, IVB, and JVC; cancers with a Gleason grade of between 1 and 5 or a Gleason sum or score of between 2 and 10; stages A, B, C, or D under the Jewett-Whitmore system; and any combination of TNM scores under the American Joint Committee on Cancer (AJCC) TNM system, including without limitation, TX, TO, Tla, Tib, T2a, T2b, T3a, T3b, T4, NX, NO, Nl, N2, N3, MX, M0, Mia, Mlb, Mlc.
- AJCC American Joint Committee on Cancer
- the methods and compositions described herein can be used for patients who have or had not previously had cancer.
- the patient can be a female who currently has ovarian cancer and who has or had breast cancer.
- the patient can be one who has or has not been previously treated for cancer.
- Such patients may have had surgery to treat the cancer or another form of cancer, or may not have had surgery to treat the cancer or another form of cancer.
- the patient may have had surgery to remove all or a portion of a cancerous or non-cancerous tumor.
- the patient may have had surgery to remove all or a portion of a body part or an organ with a cancerous growth, such as prostate gland, testicle, breast, ovary, or uterus.
- Prostate cancer patients treated can also include those who have been castrated prior to administration of a therapeutically effective amount of a 17-alpha hydroxylase/ CI 7, 20-lyase inhibitor, as well as those who have not been castrated.
- the patient may be castration-refractory.
- the patient is chemotherapy-naive or has not been treated with a particular chemotherapy, such as any of the chemotherapies described herein.
- the patient has or is currently receiving or will receive chemotherapy.
- chemotherapy includes without limitation the administration of paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, and radioisotopes.
- the patient is chemotherapy refractory to a certain chemotherapy, including any of those mentioned herein.
- the patient is hormone therapy-naive or has not been treated with a particular hormone therapy, such as any of the hormone therapies described herein.
- a particular hormone therapy such as any of the hormone therapies described herein.
- the patient has or is currently receiving or will receive hormone therapy.
- hormone therapy includes without limitation the administration of hormone ablation agents, hormone deprivation treatment, antiandrogens, ketoconazole, aromatast inhibitors such as aminoglutethimide, fiutamide, cyproterone acetate, goserelin, leuprorelin, GnRH agonist, DES, or LHRH analogues.
- the patient is refractory to a certain hormone therapy, including any of those mentioned herein.
- the prostate cancers may include metastatic disease, and in other embodiments, the prostate cancers may include non-metastatic disease.
- the patient will have previously received one or more treatments with abiraterone acetate.
- a method for treating cancer wherein the monitoring of a patients blood pressure, and serum levels of one or more of corticosterone, Cortisol or potassium enables selectively adjusting dose levels to achieve safe and efficacious dose levels in a patient.
- ACTH dependent serum corticosterone and Cortisol represent pharmacodynamic markers of lyase inhibition. Accordingly, serum corticosterone and Cortisol guided drug therapy with lyase inhibiting molecules is an approach for individualized dose adjustment. Accordingly, a method of treating cancer is provided comprising:
- step (d) administering to a patient a second dose level of a therapeutically effective amount of the 17- alpha hydroxylase/C17, 20-lyase inhibitor, wherein the second dose level is greater than, equal to, or less than the first dose level.
- the second dose level in step (d) is less than the first dose level.
- the method further comprises repeating steps (a)-(d) until a desired dose level of a therapeutically effective amount of the 17-alpha hydroxylase/C17, 20-lyase inhibitor is achieved.
- the blood pressure measurement after the administration of the first dose level is greater than the blood pressure measurement prior to administration of the first dose level
- the corticosterone level after administration of the first dose level is higher than the corticosterone level prior to the administration of the first dose level.
- the Cortisol level after the administration of the first dose level is lower than the Cortisol level prior to the administration of the first dose level.
- the potassium level after the administration of the first dose level is lower than the potassium level prior to the administration of the first dose level.
- both the first and second dose levels of the 17-alpha hydroxylase/C 17, 20-lyase inhibitor is administered without the concurrent or sequential administration of a steroid.
- the cancer to be treated is a hormonally-driven cancer.
- the cancer is prostate cancer, breast cancer or ovarian cancer.
- the cancer is prostate cancer.
- the prostate cancer is castration resistant prostate cancer.
- the prostate cancer is metastatic castration resistant prostate cancer.
- the prostate cancer is non-metastatic castration resistant prostate cancer.
- the first dose level is from about 200 mg to about 600 mg twice daily. In some other embodiments for the methods described above, the first dose level is from about 300 mg to about 600 mg twice daily. In yet other embodiments, the first dose level is about 400 mg twice daily. In still other embodiments, the first dose level is about 300 mg twice daily. In still other embodiments, the first dose level is about 200 mg twice daily. In further embodiments, the first dose level is from about 200 mg to about 600 mg once daily. In still further embodiments, the first dose level is from about 300 mg to about 600 mg once daily. In yet other embodiments, the first dose level is about 600 once daily. In still other embodiments, the first dose level is about 600 mg once daily. In still other embodiments, the first dose level is about 600 mg once daily taken in the morning.
- the first dose level is taken with a meal.
- the second dose level is taken with a meal.
- either one of or both of the first or second dose level is taken with a meal.
- the first dose level is about 400 mg twice daily and the second dose level is about 300 mg twice daily.
- the first dose level is about 300 mg twice daily and the second dose level is about 200 mg twice daily.
- the method further comprises further comprising administering to the patient one or more additional treatments concurrently with or sequentially with either or both of the first or second dose of the 17-alpha hydroxylase/C17, 20-lyase inhibitor, wherein the one or more additional treatments comprises radiation, chemotherapy, immunotherapy, a non-steroidal hormone ablation therapy, or a non-steroidal therapy for the management of side effects of therapy.
- the one or more additional treaments are selected from sipuleucel- T, paclitaxel, docetaxel, mitoxantrone, estramustine, satraplatin, 5-fluorouracil, cyclophosphamide, doxorubicin, cytarabine, cabazitaxel, tamoxifen, fulvestrant, cisplatin, exemestane, anastrozole, letrozole, trastuzumab, lapatinib, radioisotopes, hormone ablation agent, hormone deprivation treatment, antiandrogen, ketoconazole, aromatase inhibitor, bicalutamide, eplerenone, spironolactone, or tri mpterine.
- the one or more additional treatments is MDV-3100.
- the patient will have previously received one or more treatments with abiraterone acetate.
- 17-alpha-hydroxylase/C17, 20-inhibitors can be demonstrated to inhibit tumor formation in vivo.
- a wide variety of animal models of hyperproliferative disorder, including tumorigenesis and metastatic spread, are known in the art. Additionally, a variety of general animal models applicable to many types of cancer have been described.
- a 17-alpha-hydroxylase/C17, 20-lyase inhibitor can be administered to a test animal, preferably a test animal predisposed to develop a tumor, and the test animal subsequently examined for decreased incidence of tumor formation in comparison with controls.
- a 17- alpha-hydroxylase/C17, 20-lyase inhibitor can be administered to test animals having a tumor and subsequently examine the tumor in the test animals for tumor regression in comparison to control animals not administered the 17-alpha-hydroxylase/C17, 20-lyase inhibitor.
- Predictive markers of cancer can also help measure the effect of the 17-aIpha-hydroxylase/C17, 20-lyase inhibitor.
- Such predictive markers include, but are not limited to the concentration of prostate-specific antigens (PSAs), plasma concentration of testosterone, circulating tumor cells (CTCs), extent of bone metastasis or lymph node metastasis, tumor size or tumor mass, plasma concentration of alkaline phosphatase (ALP), and extent of pain experienced by patient.
- PSAs prostate-specific antigens
- CTCs circulating tumor cells
- ALP alkaline phosphatase
- Example 1 Study of orteronel in Patients with Metastatic Castration-resistant Prostate Cancer:
- the investigational 17,20-lyase inhibitor orteronel which is 6-[(7S)-7-hydroxy-6,7-dihydro- 5H-pyrrolo[l,2-c]imidazol-7-yl]-N-methyl-2-naphthalenecarboxamide is a selective 17,20-lyase inhibitor that downregulates androgenic steroid production in vitro and in vivo.
- Exclusion criteria are: prior chemotherapy for prostate cancer, aminoglutethimide, ketoconazole, or radiation therapy within 30 days prior to first dose of study drug; symptoms considered related to prostate cancer, such as bone or pelvic pain, unless the pain is mile, non-opioid-requiring and not indicative of rapidly progressive disease; and uncontrolled hypertension (> 150/90 mmHg).
- AEs were graded using NCI-CTCAE v3.0; serum PSA levels were measured at screening, days 1 and 15 of cycle 1, day 1 of all subsequent cycles, and at the end of the study;
- DHEA dehydroepiandrostenedione
- DHEA-S DHEA-sulfate
- LH LH
- ACTH adrenocorticotropic hormone
- corticosterone corticosterone
- Results The data shown is for 97 enrolled patients. The baseline patient demographics and disease characteristics are shown in Table 1.
- Table 1 Baseline patient demographics and disease characteristics
- Constipation 35%/25% with 300 mg BID and 600 mg QD, respectively, compared with 38%/50% for 400 and 600 mg BID plus prednisone, respectively.
- 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 Figure 1. 44 patients (53%) had PSA decreases > 50%, of whom 21 (25%) had reductions > 90%. Of 56 patients with a 24- week PSA determination, 48 (86%) had PSA decreases, including 36 (64%) who had a PSA decrease of > 50% and 17 (30%) who had reductions > 90%.
- the majority of patients who did not have a PSA response had received prior adrenal therapy (Figure 1).
- Figure 1 Percent change in PSA at 12 weeks by dose group and prior adrenal therapy
- Testosterone and DUEA-S responses are shown in Table 4. Responses were seen as early as Cycle 1, Day 15.
- Table 5 depicts that partial responses (PR) were seen in 6 (12%) of the 49 evaluable patients; 25 patients (51%) achieved a best response of stable disease.
- Mean circulating tumor cell (CTC) numbers decreased in all groups.
- PSA, hormone and tumor responses were seen in patients not receiving prednisone.
- PSA and hormone responses were seen, and a PR was achieved in 3 patients.
- PSA and hormone responses were seen and a best tumor response was seen in 3 patients.
- CTCs Circulating Tumor Cells
- CTC enumeration provides prognostic information in patients with metastatic prostate cancer.
- the categorical shift from >5 to ⁇ 5 cells per 7.5 mL of whole blood may represent a better predictor of overall survival than changes in prostate-specific antigen (PSA) levels.
- PSA prostate-specific antigen
- Another objective of the trial is the assessment of correlations between CTC levels and response to orteronel (PSA changes and clinical responses) as well as assessment of correlations between the presence or absence of potential candidate biomarkers (TMPRSS2:ERG fusion gene product, androgen receptor (AR) mutations, PTEN deletions) as detected by fluorescence in situ hybridization (FISH) and response to orteronel and CTC levels.
- PSA changes and clinical responses as well as assessment of correlations between the presence or absence of potential candidate biomarkers (TMPRSS2:ERG fusion gene product, androgen receptor (AR) mutations, PTEN deletions) as detected by fluorescence in situ hybridization (FISH) and response to orteronel and CTC levels.
- FISH fluorescence in situ hybridization
- CTC analyses were performed both in the safety population and in the population without prior adrenal directed therapy (aminoglutethimidine, abiraterone, ketoconazole). CTC levels were assessed as both a dichotomous ( ⁇ 5 versus >5 per 7.5 mL of blood) and a continuous variables. A CTC level of ⁇ 5 is considered to be a predictor of favorable outcomes, and a level of >5 a predictor of unfavorable outcomes. All nominal associations identified between CTC levels and response were also tested after controlling for age and prior therapy
- TTP Time to disease progression
- Table 7 Shifts in CTC Count from Baseline to 12 and 24 weekd (cells per 7.5 mL of blood)
- PSA response rate was 62% (24 of 39 patients) versus 52% (12 of 23 patients) in those with baseline CTCs >5/7.5 mL (Table 5).
- TMPRSS2:ERG translocations were detected in 13 of 48 patients (27.1%)
- PTEN deletions were detected in 4 of 50 patients (8.0%).
- AR amplifications were detected in 8 of 49 patients (16.3%).
- TMPRSS2 :ERG was not statistically significantly associated with 12-week PSA50 response
- TTP was significantly longer in patients with a favorable CTC count at baseline compared with patients with an unfavorable CTC count (pO.001).
- Orteronel is an investigational, oral, non-steroidal, selective 17,20-lyase inhibitor that suppresses androgen production and is in development for CRPC.
- Orteronel has limited inhibition of 17a-hydroxylase, and thus, is postulated to have less effect on Cortisol synthesis.
- Orteronel 300mg BID in men with nonmetastatic CRPC and rising PSA was evaluated (NCT01046916).
- the primary endpoint is the percentage of men with PSA ⁇ 0.2ng mL after 3 mo. Secondary endpoints include safety, 3 and 6 mo PSA30, PSA50, PSA90 rates, progression-free survival, time to PSA progression, time to metastases, changes in endocrine markers and circulating tumor cell (CTCs).
- Subjects were orally administered 300 mg of orteronel twice daily on a continuous schedule, without concomitant prednisone. Patients were treated until PSA progression of disease or radiographic progression of disease. After PSA progression, patients were followed every 3 months until (A) development of metastases or (B) the scheduled conclusion of the study.
- PSA response rate PSA-90, -50, and -30, defined as a PSA decline of at least 90%, 50%, and 30%, respectively, from baseline
- PSA response rate at 3 months and 6 months (at "Cycle 7 Day 1"
- Percentage of patients who achieve a PSA of less than or equal to 0.2 ng ml following 6 months of orteronel treatment was determined.
- PSA Response Rate was computed as follows:
- Denominator PSA-evaluable population. Patients who had 1 baseline and 1 post-baseline PSA measurement.
- 6-month Patients are responders if patients have a PSA assessment at 6 months (cycle 7 day 1, between day 161-175) and meet the response criteria. Otherwise patients are considered as non-responders.
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CA2807149C (fr) | 2010-08-04 | 2017-05-02 | Pellficure Pharmaceuticals, Inc. | Nouveau traitement du carcinome de la prostate |
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US20100261689A1 (en) * | 2007-10-29 | 2010-10-14 | Masuo Yamaoka | Pyrrolo [1,2-c] imidazole derivatives for use in the prophylaxis or treatment of cancer which is refractory to known cancer therapies |
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US20100261689A1 (en) * | 2007-10-29 | 2010-10-14 | Masuo Yamaoka | Pyrrolo [1,2-c] imidazole derivatives for use in the prophylaxis or treatment of cancer which is refractory to known cancer therapies |
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