WO2016172517A1 - Méthodes de traitement du cancer de la prostate - Google Patents

Méthodes de traitement du cancer de la prostate Download PDF

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Publication number
WO2016172517A1
WO2016172517A1 PCT/US2016/028898 US2016028898W WO2016172517A1 WO 2016172517 A1 WO2016172517 A1 WO 2016172517A1 US 2016028898 W US2016028898 W US 2016028898W WO 2016172517 A1 WO2016172517 A1 WO 2016172517A1
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Prior art keywords
galeterone
therapy
dose
patients
patient population
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PCT/US2016/028898
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English (en)
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Karen J. Ferrante
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Tokai Pharmaceuticals, Inc.
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Publication of WO2016172517A1 publication Critical patent/WO2016172517A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed

Definitions

  • Cancer represents a significant burden on human health, accounting for an estimated 13% of all deaths each year.
  • Several common cancers and diseases are associated with androgen signaling, such as, for example, prostate cancer, breast cancer, ovarian cancer, bladder cancer, pancreatic cancer and polycystic ovary disease.
  • prostate cancer is the second most common cancer in men. The majority of prostate cancer deaths are due to the development of metastatic disease that is unresponsive to conventional androgen deprivation. This stage of prostate cancer is termed "castration resistant prostate cancer" or CRPC.
  • Androgen receptor (AR) signaling remains a primary target of therapy for the treatment of prostate cancer.
  • Identifying treatment strategies for prostate cancer remains a challenge.
  • the present invention provides compositions and/or methods relating to treatment of cancer, e.g. , prostate cancer, and particularly provides therapeutic regimens and/or modalities that utilize galeterone.
  • cancer e.g. , prostate cancer
  • therapeutic regimens and/or modalities that utilize galeterone.
  • the present disclosure describes particular galeterone therapy regimens, for example, as applied in particular patient populations and/or under particular conditions, and furthermore defines relevant characteristics (e.g.,
  • a method comprising a step of administering a galeterone therapy regimen to a population of prostate cancer patients, wherein the administering is performed without regard to food intake by the patients, and wherein the galeterone therapy regimen comprises administration of at least one dose of a galeterone composition that, when administered to the population, achieves an average AUC of about 500 h ⁇ ng/mL to about 8,000 h ⁇ ng/mL.
  • Administration As used herein, the term “administration” refers to the
  • a composition to a subject or system (e.g. , to a cell, organ, tissue, organism, or relevant component or set of components thereof).
  • route of administration may vary depending, for example, on the subject or system to which the composition is being administered, the nature of the composition, the purpose of the administration, etc.
  • administration to an animal subject may be bronchial (including by bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by intratracheal instillation), transdermal, vaginal and/or vitreal.
  • administration may involve intermittent dosing.
  • administration may involve continuous dosing (e.g., perfusion) for at least a selected period of time.
  • administration may be of a single dose.
  • administration may involve a plurality of doses (e.g., separated from one another in time).
  • adult refers to a human eighteen years of age or older. In some embodiments, a human adult has a weight within the range of about 90 pounds to about 250 pounds.
  • agent may refer to a compound or entity of any chemical class including, for example, polypeptides, nucleic acids, saccharides, lipids, small molecules, metals, or combinations thereof.
  • an agent is or comprises a natural product in that it is found in and/or is obtained from nature.
  • an agent is or comprises one or more entities that is man-made in that it is designed, engineered, and/or produced through action of the hand of man and/or is not found in nature.
  • an agent may be utilized in isolated or pure form; in some embodiments, an agent may be utilized in crude form.
  • agents are provided as collections or libraries, for example that may be screened to identify or characterize active agents within them.
  • agents that may be utilized in accordance with the present invention include small molecules, antibodies, antibody fragments, aptamers, nucleic acids (e.g. , siRNAs, shRNAs, DNA/RNA hybrids, antisense oligonucleotides, ribozymes), peptides, peptide mimetics, etc.
  • an agent is or comprises a polymer.
  • an agent is not a polymer and/or is substantially free of any polymer.
  • an agent contains at least one polymeric moiety.
  • an agent lacks or is substantially free of any polymeric moiety.
  • an analog refers to a substance that shares one or more particular structural features, elements, components, or moieties with a reference substance. Typically, an “analog” shows significant structural similarity with the reference substance, for example sharing a core or consensus structure, but also differs in certain discrete ways.
  • an analog is a substance that can be generated from the reference substance, e.g. , by chemical manipulation of the reference substance.
  • an analog is a substance that can be generated through performance of a synthetic process substantially similar to (e.g. , sharing a plurality of steps with) one that generates the reference substance.
  • an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance.
  • Two events or entities are "associated" with one another, as that term is used herein, if the presence, level and/or form of one is correlated with that of the other.
  • a particular entity e.g., polypeptide, genetic signature, metabolite, etc.
  • two or more entities are physically "associated” with one another if they interact, directly or indirectly, so that they are and/or remain in physical proximity with one another.
  • two or more entities that are physically associated with one another are covalently linked to one another; in some embodiments, two or more entities that are physically associated with one another are not covalently linked to one another but are non-covalently associated, for example by means of hydrogen bonds, van der Waals interaction, hydrophobic interactions, magnetism, and combinations thereof.
  • Binding typically refers to a non-covalent association between or among two or more entities. "Direct” binding involves physical contact between entities or moieties; indirect binding involves physical interaction by way of physical contact with one or more intermediate entities. Binding between two or more entities can typically be assessed in any of a variety of contexts - including where interacting entities or moieties are studied in isolation or in the context of more complex systems (e.g. , while covalently or otherwise associated with a carrier entity and/or in a biological system or cell).
  • Combination therapy refers to those situations in which a subject is simultaneously exposed to two or more therapeutic regimens (e.g. , two or more therapeutic agents).
  • two or more agents or may be administered simultaneously; in some embodiments, such agents may be administered sequentially; in some embodiments, such agents are administered in overlapping dosing regimens.
  • Comparable is used herein to describe two (or more) sets of conditions, circumstances, individuals, or populations that are sufficiently similar to one another to permit comparison of results obtained or phenomena observed.
  • comparable sets of conditions, circumstances, individuals, or populations are characterized by a plurality of substantially identical features and one or a small number of varied features.
  • sets of circumstances, individuals, or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances, individuals, or populations are caused by or indicative of the variation in those features that are varied.
  • relative language used herein e.g. , enhanced, activated, reduced, inhibited, etc. will typically refer to comparisons made under comparable conditions.
  • determining involves manipulation of a physical sample.
  • determining involves consideration and/or manipulation of data or information, for example utilizing a computer or other processing unit adapted to perform a relevant analysis.
  • determining involves receiving relevant information and/or materials from a source.
  • determining involves comparing one or more features of a sample or entity to a comparable reference.
  • Diagnostic information is information that is useful in determining whether a patient has a disease, disorder or condition and/or in classifying a disease, disorder or condition into a phenotypic category or any category having significance with regard to prognosis of a disease, disorder or condition, or likely response to treatment (either treatment in general or any particular treatment) of a disease, disorder or condition.
  • diagnostic refers to providing any type of diagnostic information, including, but not limited to, whether a subject is likely to have or develop a disease, disorder or condition, state, staging or characteristic of a disease, disorder or condition as manifested in the subject, information related to the nature or classification of a tumor, information related to prognosis and/or information useful in selecting an appropriate treatment.
  • Selection of treatment may include the choice of a particular therapeutic agent or other treatment modality such as surgery, radiation, etc., a choice about whether to withhold or deliver therapy, a choice relating to dosing regimen (e.g., frequency or level of one or more doses of a particular therapeutic agent or combination of therapeutic agents), etc.
  • Dosage form and "unit dosage form", as used herein, the term “dosage form” refers to physically discrete unit of a therapeutic agent for a subject (e.g., a human patient) to be treated. Each unit contains a predetermined quantity of active material calculated or
  • such quantity is a unit dosage amount (or a whole fraction thereof) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population (i.e. , with a therapeutic dosing regimen). It will be understood, however, that the total dosage administered to any particular patient will be selected by a medical professional (e.g., a medical doctor) within the scope of sound medical judgment.
  • Dosing regimen is a set of unit doses (typically more than one) that are administered individually to a subject, typically separated by periods of time.
  • a given therapeutic agent has a recommended dosing regimen, which may involve one or more doses.
  • a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses.
  • the therapeutic agent is administered continuously (e.g., by infusion) over a predetermined period.
  • a therapeutic agent is administered once a day (QD) or twice a day (BID).
  • a dosing regimen comprises a plurality of doses each of which are separated from one another by a time period of the same length; in some embodiments, a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses. In some embodiments, all doses within a dosing regimen are of the same unit dose amount. In some embodiments, different doses within a dosing regimen are of different amounts. In some embodiments, a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount different from the first dose amount.
  • a dosing regimen comprises a first dose in a first dose amount, followed by one or more additional doses in a second dose amount same as the first dose amount
  • a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population (i.e. , is a therapeutic dosing regimen).
  • Excipient refers to a non-therapeutic agent that may be included in a pharmaceutical composition, for example to provide or contribute to a desired consistency or stabilizing effect.
  • suitable pharmaceutical excipients include, for example, starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol
  • a marker refers to an entity or moiety whose presence or level is a characteristic of a particular state or event.
  • presence or level of a particular marker may be characteristic of presence or stage of a disease, disorder, or condition.
  • the term refers to a gene expression product that is characteristic of a particular tumor, tumor subclass, stage of tumor, etc.
  • a presence or level of a particular marker correlates with activity (or activity level) of a particular signaling pathway, for example that may be
  • a marker characteristic of a particular class of tumors.
  • the statistical significance of the presence or absence of a marker may vary depending upon the particular marker.
  • detection of a marker is highly specific in that it reflects a high probability that the tumor is of a particular subclass. Such specificity may come at the cost of sensitivity (i.e., a negative result may occur even if the tumor is a tumor that would be expected to express the marker).
  • markers with a high degree of sensitivity may be less specific that those with lower sensitivity. According to the present invention a useful marker need not distinguish tumors of a particular subclass with 100% accuracy.
  • composition As used herein, the term "pharmaceutical
  • composition refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers.
  • active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity;
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue
  • parenteral administration for example
  • intravaginally or intrarectally for example, as a pessary, cream, or foam; sublingually; ocularly; trans dermally; or nasally, pulmonary, and/or to other mucosal surfaces.
  • compositions that, within the scope of sound medical judgment, are suitable for use in contact with tissues of human beings and/or animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • compositions or vehicles such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;
  • compositions 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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 + (Ci_ 4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • 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.
  • prevention refers to a delay of onset, and/or reduction in frequency and/or severity of one or more symptoms of a particular disease, disorder or condition. In some embodiments, prevention is assessed on a population basis such that an agent is considered to "prevent” a particular disease, disorder or condition if a statistically significant decrease in the development, frequency, and/or intensity of one or more symptoms of the disease, disorder or condition is observed in a population susceptible to the disease, disorder, or condition. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.
  • Prognostic and predictive information are used to refer to any information that may be used to indicate any aspect of the course of a disease or condition either in the absence or presence of treatment. Such information may include, but is not limited to, the average life expectancy of a patient, the likelihood that a patient will survive for a given amount of time (e.g., 6 months, 1 year, 5 years, etc.), the likelihood that a patient will be cured of a disease, the likelihood that a patient's disease will respond to a particular therapy (wherein response may be defined in any of a variety of ways). Prognostic and predictive information are included within the broad category of diagnostic information.
  • Reference describes a standard or control relative to which a comparison is performed.
  • an agent, animal, individual, population, sample, sequence or value of interest is compared with a reference or control agent, animal, individual, population, sample, sequence or value.
  • a reference or control is tested and/or determined substantially simultaneously with the testing or determination of interest.
  • a reference or control is a historical reference or control, optionally embodied in a tangible medium.
  • a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment.
  • Refractory refers to any subject or condition that does not respond with an expected clinical efficacy following the administration of provided compositions as normally observed by practicing medical personnel.
  • sample typically refers to a biological sample obtained or derived from a source of interest, as described herein.
  • a source of interest comprises an organism, such as an animal or human.
  • a biological sample is or comprises biological tissue or fluid.
  • a biological sample may be or comprise bone marrow; blood; blood cells; ascites; tissue or fine needle biopsy samples; cell-containing body fluids; free floating nucleic acids; sputum; saliva; urine;
  • a biological sample is or comprises cells obtained from an individual.
  • obtained cells are or include cells from an individual from whom the sample is obtained.
  • a sample is a "primary sample" obtained directly from a source of interest by any appropriate means.
  • a primary biological sample is obtained by methods selected from the group consisting of biopsy (e.g. , fine needle aspiration or tissue biopsy), surgery, collection of body fluid (e.g., blood, lymph, feces etc.), etc.
  • body fluid e.g., blood, lymph, feces etc.
  • sample refers to a preparation that is obtained by processing (e.g., by removing one or more components of and/or by adding one or more agents to) a primary sample. For example, filtering using a semi-permeable membrane.
  • Such a "processed sample” may comprise, for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to techniques such as amplification or reverse transcription of mRNA, isolation and/or purification of certain components, etc.
  • Solid form As is known in the art, many chemical entities (in particular many organic molecules and/or many small molecules) can adopt a variety of different solid forms such as, for example, amorphous forms and/or crystalline forms (e.g., polymorphs, hydrates, solvates, etc.). In some embodiments, such entities may be utilized in any form, including in any solid form. In some embodiments, such entities are utilized in a particular form, for example in a particular solid form.
  • amorphous forms and/or crystalline forms e.g., polymorphs, hydrates, solvates, etc.
  • Stage of cancer refers to a qualitative or quantitative assessment of the level of advancement of a cancer. Criteria used to determine the stage of a cancer include, but are not limited to, the size of the tumor and the extent of metastases (e.g. , localized or distant).
  • the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • the term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.
  • a "therapeutic regimen”, as that term is used herein, refers to a dosing regimen whose administration across a relevant population may be correlated with a desired or beneficial therapeutic outcome.
  • Therapeutically effective amount is meant an amount that produces the desired effect for which it is administered. In some embodiments, the term refers to an amount that is sufficient, when administered to a population suffering from or susceptible to a disease, disorder, and/or condition in accordance with a therapeutic dosing regimen, to treat the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is one that reduces the incidence and/or severity of, and/or delays onset of, one or more symptoms of the disease, disorder, and/or condition. Those of ordinary skill in the art will appreciate that the term "therapeutically effective amount" does not in fact require successful treatment be achieved in a particular individual.
  • a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to patients in need of such treatment.
  • reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues (e.g. , a tissue affected by the disease, disorder or condition) or fluids (e.g. , blood, saliva, serum, sweat, tears, urine, etc.).
  • tissue e.g. a tissue affected by the disease, disorder or condition
  • fluids e.g. , blood, saliva, serum, sweat, tears, urine, etc.
  • a therapeutically effective amount of a particular agent or therapy may be formulated and/or administered in a single dose.
  • a therapeutically effective agent may be formulated and/or administered in a plurality of doses, for example, as part of a dosing regimen.
  • treatment refers to any administration of a substance (e.g. , provided compositions) that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • a substance e.g. , provided compositions
  • such treatment may be administered to a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition.
  • treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
  • Unit dose refers to an amount administered as a single dose and/or in a physically discrete unit of a pharmaceutical composition.
  • a unit dose contains a predetermined quantity of an active agent.
  • a unit dose contains an entire single dose of the agent.
  • more than one unit dose is administered to achieve a total single dose.
  • administration of multiple unit doses is required, or expected to be required, in order to achieve an intended effect.
  • a unit dose may be, for example, a volume of liquid (e.g., an acceptable carrier) containing a predetermined quantity of one or more therapeutic agents, a predetermined amount of one or more therapeutic agents in solid form, a sustained release formulation or drug delivery device containing a predetermined amount of one or more therapeutic agents, etc. It will be appreciated that a unit dose may be present in a formulation that includes any of a variety of components in addition to the therapeutic agent(s). For example, acceptable carriers (e.g., pharmaceutically acceptable carriers), diluents, stabilizers, buffers, preservatives, etc., may be included as described infra.
  • acceptable carriers e.g., pharmaceutically acceptable carriers
  • diluents e.g., diluents, stabilizers, buffers, preservatives, etc.
  • a total appropriate daily dosage of a particular therapeutic agent may comprise a portion, or a plurality, of unit doses, and may be decided, for example, by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular subject or organism may depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of specific active compound employed; specific composition employed; age, body weight, general health, sex and diet of the subject; time of administration, and rate of excretion of the specific active compound employed; duration of the treatment; drugs and/or additional therapies used in combination or coincidental with specific compound(s) employed, and like factors well known in the medical arts.
  • administering ... with regard to food intake refers to an administration, e.g., of a therapy regimen to a subject or population of patients, where the subject or population of patients is known to have consumed, or not consumed, some amount of food before, during or after the administration.
  • the terms "before administration” and “after administration” with respect to food intake may refer to a period of time of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24, 30, 42, or 72 hours, or longer, before or after the administration.
  • food intake includes high fat foods or a high fat diet.
  • the term “administering ... with regard to food intake” implies that the subject or population of patients consumes food before the administration. In some embodiments, the term “administering ... with regard to food intake” implies that the subject or population of patients consumes food after the administration. In some embodiments, the term “administering ... with regard to food intake” implies that the subject or population of patients consumes food during the administration. Alternatively, in some embodiments, the term “administering ... with regard to food intake” means the subject or population of patients is in a fasted state during administration.
  • administering ... without regard to food intake refers to an administration, e.g., of a therapy regimen to a subject or population of patients, regardless of whether the subject or population of patients has consumed, or not consumed, some amount of food before, during or after the administration.
  • prostate cancer remains the second most common cancer-related mortality in men in the United States (1).
  • CRPC castration-resistant prostate cancer
  • the development of a new generation of therapies targeting the androgen axis has been based on an expanded understanding of the molecular mechanisms of CRPC. It is now understood that in the clinical setting of castrate levels of serum testosterone, prostate tumors adapt by upregulating tissue androgens and androgen receptors (ARs) in order to maintain proliferation. Tumor androgen levels remain sufficiently elevated to stimulate ARs as a result of tumor conversion of circulating adrenal androgens and de novo androgen synthesis (2-5).
  • prostate cancer adapts to androgen deprivation therapy (ADT) by AR gene amplification, upregulation of AR transcripts, or protein expression (6, 7).
  • ADT androgen deprivation therapy
  • a major component of resistance to second generation AR targeting agents may be mediated by AR splice variants, such as AR-V7, which are produced in tumor cells as a result of aberrant RNA splicing of the wild type AR transcript.
  • the resultant truncated AR protein lacks the C-terminal domain to which androgen binds and is the primary site of action of nonsteroidal antiandrogens such as enzalutamide. Furthermore, splice variants have been shown to be constitutively active transcription factors, leading to the activation of androgen-responsive genes even at castrate levels of androgens (15, 16). Mutations in the AR may also contribute to resistance in CRPC and AR point mutations allow activation of the receptor by nonphysiologic ligands (e.g. , Cortisol, progesterone, flutamide, bicalutamide (17, 18).
  • nonphysiologic ligands e.g. , Cortisol, progesterone, flutamide, bicalutamide (17, 18).
  • Galeterone is a selective, multitargeted agent that disrupts androgen signaling at multiple points in the pathway. Gal as set forth in the formula:
  • a "galeterone composition” includes galeterone in the form of a pharmaceutically acceptable salt and/or prodrug of the compound depicted in this formula (i.e., of galeterone).
  • the prodrug of galeterone is an acetate prodrug of galeterone of formula:
  • the pharmaceutically acceptable salt of galeterone, or of the acetate prodrug of galeterone is the hydrochloride salt or acetic acid salt.
  • galeterone is a selective potent CYP17 inhibitor and a potent AR antagonist, but unlike other available agents that target androgen signaling, galeterone reduces AR expression in prostate cancer cells by causing an increase in AR protein degradation (19-24).
  • Preclinical in vitro and in vivo data have shown that galeterone treatment in prostate cancer models resulted in a significant reduction in both full-length AR and AR-V7 splice variant levels, and that it has activity against AR point mutations T878A, and F876L (20- 26).
  • ARMOR1 Androgen Receptor Modulation Optimized for Response
  • ARM0R2 part 1 The dose escalation component of ARM0R2 was conducted to determine the phase 2 and phase 3 dose of a galeterone spray dry dispersion (SDD) tablet.
  • SDD galeterone spray dry dispersion
  • This formulation was developed after a healthy volunteer study confirmed a significant food effect with the capsule formulation that was used in ARMORl (see Appendix). Results of this study also demonstrated equivalent serum concentrations using either 1,700 mg of the SDD tablet or 2,600 mg of the capsule, which was the highest dose studied in ARMORl .
  • Dose escalation portion of ARM0R2 was conducted to evaluate the safety and tolerability of escalating doses of the SDD formulation and determine the recommended dose for ARMOR2 part 2 and ARMOR3.
  • Prostate cancer is an androgen-dependent disease. Prostate cancer is commonly treated with one or more of hormone therapy, androgen deprivation therapy (ADT) and androgen suppression therapy, having an overall goal of reducing the levels of androgens in the body or to prevent them from reaching the prostate cancer cells (chemical castration).
  • ADT androgen deprivation therapy
  • androgen suppression therapy having an overall goal of reducing the levels of androgens in the body or to prevent them from reaching the prostate cancer cells (chemical castration).
  • Hormone therapy typically utilizes one or more of LHRH agonists (Lupron, eligard, goserelin, tripterelin, histrelin) and/or LHRH antagonists (firmagon). Hormone therapy may be used in conjunction with surgical resection of the tumor, orchietomy (surgical castration), or radiation therapy or radiopharmaceutical (Radium 223 Dichloride, Xofigo (Radium 223 Dichloride).
  • LHRH agonists Liupron, eligard, goserelin, tripterelin, histrelin
  • LHRH antagonists firmagon
  • Hormone therapy may be used in conjunction with surgical resection of the tumor, orchietomy (surgical castration), or radiation therapy or radiopharmaceutical (Radium 223 Dichloride, Xofigo (Radium 223 Dichloride).
  • Treatment aimed at reducing the production of androgens include abiraterone (a CYP17 inhibitor).
  • Anti-androgen therapy aims at inhibiting the androgen receptor and examples include flutamide, bicalutamide, nilutamide, ARN-509 and enzalutamide.
  • Anti-androgen treatment may be combined with orchiectomy or LHRH analogs as first-line hormone therapy. Such an approach is often referred to as combined androgen blockade (CAB).
  • Other androgen suppressing drugs include estrogens and ketoconazole.
  • targeting the androgen receptor signaling pathway has been a drug development staple, and agents utilized in such strategies include certain CYP17 inhibitors or modulators, antiandrogens, chaperone inhibitors (targeting heat shock proteins, Hsp-27 inhibitor), androgen-receptor modulator (blocking transactivation domain of the receptor).
  • Vaccine treatment e.g., with Sipuleucel
  • Sipuleucel is intended to boost the body's immune system to recognize the prostate tumor and lodge an anti-tumor immune response.
  • This form of therapy is not "off the shelf, as each vaccine is made from the unique white cells from each individual patient after exposing in a lab to prostate acid phosphatase (PAP).
  • PAP prostate acid phosphatase
  • Another immunotherapy strategy that is sometimes an embodiment utilizes ipilimumab (a CTLA-4 antagonist).
  • Castration resistant prostate cancer is the term used for those patients for which androgen deprivation or androgen suppression therapy is no longer effective at slowing the proliferation of the prostate tumor or the metastasis, and it is a stage of the disease that is associated with primary or acquired resistance to therapy and for which there are few therapeutic options, one being broad cancer chemotherapy (docetaxel and cabazitaxel being examples).
  • other therapy is or comprises Lupron therapy.
  • the present disclosure provides methods that comprise a step of administering a galeterone therapy regimen to a population of prostate cancer patients, wherein the administering is performed without regard to food intake by the patients, and/or wherein the galeterone therapy regimen comprises administration of at least one dose of a galeterone composition that, when administered to the population, achieves an average AUC of about 400 h
  • administering a galeterone therapy regimen to a population of prostate cancer patients wherein the administering is performed with regard to food intake by the patients.
  • administering a galeterone therapy regimen to a population of prostate cancer patients wherein the administering is performed in patients in a fasted state.
  • an average AUC is about 875 h ⁇ ng/mL to about 4,500 h ⁇ ng/mL. In some embodiments, an average AUC is about 900 h ⁇ ng/mL to about 4,500 h ⁇ ng/mL. In some embodiments, an average AUC is about 1,300 h ⁇ ng/mL to about 3,300 h ⁇ ng/mL. In some embodiments, an average AUC is about 875 h ⁇ ng/mL to about 3,500 h ⁇ ng/mL.
  • an average AUC is about 400 h ⁇ ng/mL, 500 h ⁇ ng/mL, 600 h » ng/mL, 700 h ⁇ ng/mL, 800 h » ng/mL, 900 h » ng/mL, 1,000 h ⁇ ng/mL, 1 ,200 h ⁇ ng/mL, 1,400 h ⁇ ng/mL, 1,600 h ⁇ ng/mL, 1,800 h ⁇ ng/mL, 2,000 h ⁇ ng/mL, 2,200 h ⁇ ng/mL, 2,300 h ⁇ ng/mL, 2,400 h ⁇ ng/mL, 2,600 h ⁇ ng/mL, 2,800 h ⁇ ng/mL, 3,000 h ⁇ ng/mL, 3,200 h ⁇ ng/mL, 3,400 h ⁇ ng/mL, 3,600 h ⁇ ⁇ ng/mL, 3,
  • a patient population includes one or more subjects suffering from metastatic disease.
  • a patient population includes one or more subjects (e.g., comprises or consists of subjects) suffering from an anti-androgen resistant disease.
  • a patient population suffering from anti-androgen resistant disease may have previously been treated with an antiandrogen therapy, such as, e.g., castration, treatment with an androgen receptor antagonist, or a combination thereof.
  • an antiandrogen therapy such as, e.g., castration, treatment with an androgen receptor antagonist, or a combination thereof.
  • some or all patients may have disease that initially responded to the anti-androgen therapy, but subsequently became insensitive to the therapy (e.g. , worsened despite continued anti-androgen treatment). In some embodiments, some or all patients may have disease that was always insensitive to antiandrogen therapy and/or may not have previously received anti- androgen therapy.
  • a patient population includes one or more subjects (e.g., comprises or consists of subjects) suffering from an androgen dependent disease, disorder or condition, selected from the group consisting of diseases disorders or conditions that are characterized or marked by excessive production of adrenal or gonadal androgens; adrenal adenomas, carcinomas, or hyperplasia; Ley dig cell tumors in men; arrhenoblastomas and polycystic ovarian syndrome in women; and combinations thereof.
  • an androgen dependent disease, disorder or condition selected from the group consisting of diseases disorders or conditions that are characterized or marked by excessive production of adrenal or gonadal androgens; adrenal adenomas, carcinomas, or hyperplasia; Ley dig cell tumors in men; arrhenoblastomas and polycystic ovarian syndrome in women; and combinations thereof.
  • an androgen dependent disease disorder or condition may be or comprise Kennedy's disease, breast cancer, prostate cancer, bladder cancer, pancreatic cancer, ovarian cancer, acne, hidradenitis supprurativa, androgenic alopecia, keratosis pilaris, begin prostatic hyperplasia, hirsutism, or any combination thereof.
  • an androgen-dependent disease, disorder or condition is or comprises pancreatic cancer, which, in some embodiments, may be associated with increased levels of androgen receptor compared to a reference.
  • a patient population includes one or more subjects (e.g., comprises or consists of subjects) who received previous therapy for treatment of cancer (e.g. , prostate cancer). In some embodiments, a patient population includes one or more subjects (e.g., comprises or consists of subjects) who have not received previous therapy for treatment of cancer (e.g. , prostate cancer). In some embodiments, a patient population consists of patients who have not received previous therapy for treatment of prostate cancer.
  • a patient who received previous therapy may have received previous therapy selected from the group consisting of medical castration, surgical castration, immunotherapy, radiation therapy, surgery, and combinations thereof.
  • a patient population includes one or more subjects (e.g., comprises or consists of subjects) who have received and/or are receiving other therapy, e.g., so that the galeterone composition is administered in combination with the other therapy.
  • other therapy may comprise or consist of therapy for cancer (e.g., as described herein), pain, nausea, constipation, for treatment of one or more side effects (e.g., pruritis, hair loss, sleeplessness, etc) associated with cancer therapy, etc, or any combination thereof.
  • galeterone therapy as described herein is not administered in combination with an agent whose proper metabolism relies on CYP17 activity (given that galeterone inhibits CYP17).
  • a galeterone therapy regimen is characterized by a rate of treatment-emergent adverse events that does not exceed about 3% for grade 3 events of any of abdominal pain, increased alkaline phosphatase, increased ALT, decreased appetite, arthralgia, increased AST, back pain, increased bilirubin, constipation, cough, diarrhea, dizziness, fall, fatigue, nausea, pruritus, rash, urinary tract infection, vomiting or decreased weight.
  • galeterone therapy is characterized by a rate of treatment-emergent adverse events that does not exceed about 10% for grade 1 or 2 events of any of abdominal pain, increased alkaline phosphatase, increased ALT, decreased appetite, arthralgia, increased AST, back pain, increased bilirubin, constipation, cough, diarrhea, dizziness, fall, fatigue, pruritus, rash, urinary tract infection, vomiting or decreased weight.
  • administering galeterone therapy in accordance with the present disclosure is characterized by a dose-limiting toxicity rate of not more than 35% across the population. In some embodiments, administering is characterized by a dose-limiting toxicity rate of not more than 30% across the population. In some embodiments, administering is characterized by a dose-limiting toxicity rate of not more than 25% across the population. In some embodiments, administering is characterized by a dose-limiting toxicity rate of not more than 20% across the population. In some embodiments, administering is characterized by a dose-limiting toxicity rate of not more than 15% across the population. In some embodiments, administering is characterized by a dose-limiting toxicity rate of not more than 10% across the population. In some embodiments, administering is characterized by a dose-limiting toxicity rate of not more than 5% across the population.
  • AUC as described herein is that achieved within a selected time period following administration of a dose in a galeterone therapy regimen described herein. In some embodiments, such time period begins at the dose administration (i.e., 0 hours after dose administration) and extends for about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 14, about 16, about 18, about 20, about 22, about 24, about 30, about 40, or more hours after the dose administration, In some embodiments, AUC is that achieved from 0 hours to 12 hours following administration of a dose described herein. In some embodiments, AUC is that achieved from 0 hours to 18 hours following administration of a dose described herein. In some embodiments, AUC is that achieved from 0 hours to 24 hours following administration of a dose described herein. In some embodiments, AUC is that achieved from 0 hours to 36 hours following administration of a dose described herein.
  • a galeterone composition comprises galeterone or a prodrug (e.g., an acetate prodrug) of galeterone or a pharmaceutically acceptable salt thereof (i.e., of either galeterone or a acetate prodrug thereof).
  • a galeterone composition comprises galeterone or a pharmaceutically acceptable salt thereof.
  • a galeterone composition comprises a prodrug (e.g., an acetate prodrug) of galeterone or a pharmaceutically acceptable salt thereof.
  • a pharmaceutically acceptable salt is a hydrochloride salt. In some embodiments, a pharmaceutically acceptable salt is an acetic acid salt.
  • a galeterone therapy regimen comprises or consists of at least one dose of about 200 mg to about 5,000 mg of galeterone a prodrug (e.g., an acetate prodrug) of galeterone.
  • a prodrug e.g., an acetate prodrug
  • a galeterone therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 200 mg, 400 mg, 600 mg, 800 mg, 1,000 mg, 1,200 mg, 1,400 mg , 1,600 mg, 1,800 mg, 2,000 mg, 2,200 mg, 2,400 mg, 2,500 mg, 2,550 mg, 2,600 mg, 2,800 mg, 3,000 mg, 3,200 mg, 3,400 mg, 3,600 mg, 3,800 mg, 4,000 mg, 4,200 mg, 4,400 mg, 4,600 mg, 4,800 mg, 5,000 mg, or a dose between any two of these values, of galeterone or a pharmaceutically acceptable salt thereof.
  • a galeterone therapy regimen comprises at least one (or includes or consists of exactly one) dose of a composition that delivers about 200 mg, 400 mg, 600 mg, 800 mg, 1,000 mg, 1,200 mg, 1,400 mg, 1,600 mg, 1,800 mg, 2,000 mg, 2,200 mg, 2,400 mg, 2,500 mg, 2,550 mg, 2,600 mg, 2,800 mg, 3,000 mg, 3,200 mg, 3,400 mg, 3,600 mg, 3,800 mg, 4,000 mg, 4,200 mg, 4,400 mg, 4,600 mg, 4,800 mg, 5,000 mg, or a dose between any two of these values, of galeterone or a pharmaceutically acceptable salt thereof.
  • a galeterone therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 200 mg, 400 mg, 600 mg, 800 mg, 1,000 mg, 1,200 mg, 1,400 mg, 1,600 mg, 1,800 mg, 2,000 mg, 2,200 mg, 2,400 mg, 2,500 mg, 2,550 mg, 2,600 mg, 2,800 mg, 3,000 mg, 3,200 mg, 3,400 mg, 3,600 mg, 3,800 mg, 4,000 mg, 4,200 mg, 4,400 mg, 4,600 mg, 4,800 mg, 5,000 mg, or a dose between any two of these values, of a prodrug (e.g., an acetate prodrug) of galeterone or a pharmaceutically acceptable salt thereof.
  • a prodrug e.g., an acetate prodrug
  • a galeterone therapy regimen comprises at least one (or includes or consists of exactly one) dose of about 2,550 mg of galeterone or a pharmaceutically acceptable salt thereof. In some embodiments, a galeterone therapy regimen comprises at least one dose of about 2,550 mg of a prodrug (e.g., an acetate prodrug) of galeterone or a
  • a galeterone therapy regimen comprises a plurality of doses of a galeterone composition.
  • a galeterone therapy regimen comprises, for example 2, 5, 10, 20, 30, 60, 90, 180, 365 doses or a number of doses between any two of these values and/or comprises a repeated pattern of doses (e.g., at least one cycle of once daily doses, which cycle may be repeated, optionally with a period of alternative administration, or optionally no administration,, separating different cycles).
  • galeterone therapy in accordance with the present disclosure comprises administering a galeterone composition that includes active agent (e.g, galeterone, a galeterone prodrug, and/or a pharmaceutically acceptable salt of either) in non-crystalline form.
  • a galeterone therapy comprises administering a spray-dried galeterone composition.
  • a galeterone composition comprises polyvinylpyrrolidone (copovidone).
  • a galeterone composition comprises active agent (e.g, galeterone, a galeterone prodrug, and/or a pharmaceutically acceptable salt of either) and copovidone in a ratio of about 1 : 1.
  • a galeterone composition comprises (e.g, galeterone, a galeterone prodrug, and/or a pharmaceutically acceptable salt of either) and copovidone in a ratio of about 1 :2, 1 : 1, 2: 1 or a ratio between any two of these values.
  • administering galeterone therapy in accordance with the present disclosure is performed independent of PSA level. In some embodiments, such administering is performed independent of any change in PSA level.
  • a patient population comprises or consists of Caucasian individuals. In some embodiments, a patient population comprises or consists of African American or black individuals. In some embodiments, a patient population comprises or consists of Asian individuals. In some embodiments, a patient population comprises or consists of Hispanic individuals.
  • a patient population comprises or consists of patients suffering from castration resistant prostate cancer (CRPC).
  • CRPC castration resistant prostate cancer
  • a patient population comprises patients suffering from CRPC.
  • a patient population consists of patients suffering from CRPC.
  • a patient population comprises or consists of patients suffering from metastatic castration resistant prostate cancer (mCRPC). In some embodiments, a patient population comprises patients suffering from mCRPC. In some embodiments, a patient population consists of patients suffering mCRPC.
  • mCRPC metastatic castration resistant prostate cancer
  • a patient population comprises or consists of patients suffering from non-metastatic castration resistant prostate cancer (nmCRPC). In some embodiments, a patient population comprises patients suffering from nmCRPC. In some embodiments, a patient population consists of patients suffering nmCRPC.
  • nmCRPC non-metastatic castration resistant prostate cancer
  • a patient population comprises or consists of patients previously or concurrently treated with one or more of chemotherapy, ketoconazole, abiraterone acetate and enzalutamide. In some embodiments, a patient population comprises patients previously or concurrently treated with one or more of chemotherapy, ketoconazole, abiraterone acetate and enzalutamide. In some embodiments, a patient population consists of patients previously or concurrently treated with one or more of chemotherapy, ketoconazole, abiraterone acetate and enzalutamide.
  • a galeterone therapy comprises assessing a level of one or more biomarkers indicative of a stage or a form of prostate cancer. In some embodiments, a galeterone therapy comprises assessing a level of one or more biomarkers selected from a steroidogenic pathway marker, AR splice variant, marker of resistance and marker of metastatic disease.
  • a galeterone therapy regimen is characterized in that the administering achieves, over a designated time period, one or more of the following changes in median range of a steroidogenic pathway marker:
  • a galeterone therapy regimen comprises or consists of once daily dosing of the galeterone composition. In some embodiments, galeterone therapy regimen comprises once daily dosing of the galeterone composition. In some embodiments, a galeterone therapy regimen consists of once daily dosing of the galeterone composition.
  • a galeterone therapy regimen comprises or consists of divided daily dosing of galeterone composition.
  • a galeterone therapy regimen comprises divided daily dosing of galeterone composition.
  • a galeterone therapy regimen consists of divided daily dosing of galeterone composition.
  • divided dosing comprises twice daily dosing.
  • divided dosing comprises dosing three times per day.
  • ARMOR2 part 1 permitted the enrollment of abiraterone-refractory patients, provided it had been discontinued >4 weeks before enrollment and that the duration of therapy was >6 months before PSA progression or >6 weeks with documentation of an initial response followed by PSA progression. Prior ketoconazole treatment was permitted upon agreement between the investigator and the study sponsor.
  • ARMOR1 (NCT00959959) was a phase 1, multicenter, open-label, dose-escalation study conducted in collaboration with the Department of Defense Prostate Cancer Clinical Trials Consortium, designed to assess the tolerability, safety, and efficacy of oral galeterone for chemotherapy -naive patients with CRPC.
  • the primary goals were to find the optimal dose of galeterone with an acceptable safety profile, defined as an observed dose-limiting toxicity (DLT) rate of ⁇ 35%, and to identify a dose for further phase 2 study.
  • DLT dose-limiting toxicity
  • the dose equivalence component of ARMOR2 (i.e., part 1 ; NCT01709734) evaluated the pharmacokinetics (PK), safety, and efficacy of a new formulation of galeterone with improved bioavailability.
  • PK pharmacokinetics
  • SDD spray dry dispersion
  • galeterone capsules (micronized powder, 325 mg) were administered orally as (1) 650 mg in the evening, (2) 975 mg in the evening, (3) 975 mg in the morning, (4) 1,300 mg in the evening, (5) 1,950 mg in the evening, (6) 1,950 mg divided into morning and evening doses, (7) 2,600 mg in the evening, or (8) 2,600 mg divided into morning and evening doses, according to the cohort they entered. All doses were administered with a patient-selected meal, except for the 975 mg morning dose cohort, which received a high-fat, high-calorie nutritional supplement (Novasource ® Renal, Nestle HealthCare Nutrition, Florham Park, NJ) in place of the meal. Enrollment target was 6 patients per dose cohort.
  • DLTs were defined as any study drug-related grade 3 or higher adverse event (AE; National Cancer Institute Common Terminology Criteria for AEs [CTCAE] version 4.0) considered to be possibly, probably, or definitely related to the study drug.
  • AE National Cancer Institute Common Terminology Criteria for AEs [CTCAE] version 4.0
  • galeterone SDD tablets (425 mg) were administered at doses of 1,700 mg, 2,550 mg, and 3,400 mg once daily without regard to food. Enrollment target was 6 patients per dose level. Dose escalation occurred when no clinically significant grade 2 or greater sustained AEs or serious, unexpected grade 3 or higher AEs occurred in a dose group 2 weeks after the last patient in that cohort received his first dose.
  • Safety assessments conducted at baseline and every 2 weeks during the 12-week study and every 4 weeks during the optional extension phase included physical examination, vital signs, electrocardiogram (ECG), serum chemistry, hematology, urinalysis, and performance status. AEs that occurred during the study and up to 30 days after the last dose of study drug were collected, coded according to Medical Dictionary of Regulatory Activities version 12.1, and graded using CTCAE version 4.0. PSA was determined at each study visit.
  • Additional samples were obtained in consenting patients on day 1 at 8, 12, 16, and 24 hours postdose and on day 84 at 2, 3, 4, 5, 6, 8, 12, 16, and/or 24 hours postdose. Blood samples were also obtained at each study visit of ARMOR2 part 1 for determination of pregnenolone, 17-hydroxyprogesterone, deoxycorticosterone, 11-deoxy Cortisol, corticosterone, Cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, and testosterone concentrations.
  • DHEAS dehydroepiandrosterone sulfate
  • PSA50 and >30% [PSA30]), maximal decrease in PSA from baseline to 12 weeks or PSA nadir, changes from baseline in tumor response as assessed by bone scan and computed tomography or magnetic resonance imaging using PCWG2 and Response Evaluation Criteria in Solid Tumors [RECIST] vl. l).
  • PSA efficacy was based on the intent-to-treat population (ITT), defined as enrolled patients who received at least 1 dose of study drug. Response was based on measurable disease in both studies. Time-to-progression (TTP), PFS, and OS were the endpoints assessed in the ARMORl extension phase. Descriptive statistics were used for most variables (n, mean, standard deviation [SD], median, minimum, and maximum for continuous variables and frequency and percentage for categorical variables).
  • ECOG Eastern Cooperative Oncology Group
  • NA not applicable
  • PSA prostate specific antigen
  • Galeterone tablets were well tolerated at all doses as assessed by the IMC. Safety reviews were completed after all patients were dosed in each cohort, and the IMC recommended continued escalation. Most patients (93%) experienced at least 1 TEAE, with the majority (91%) being grade 1 or 2 in severity and comparable among cohorts. Most (72%) AEs required no intervention. There were no DLTs at any dose level. The most common TEAEs were nausea (13 patients [46.4%]), fatigue (9 patients [32.1%]), pruritus (9 patients [32.1%]), vomiting (8 patients [28.6%]), and decreased appetite (6 patients [21.4%]) (Table 3).
  • the most common treatment-related TEAEs were nausea (10 patients [35.7%]), pruritus (9 patients [32.1%]), fatigue, vomiting and decreased appetite (6 patients [21.4%] for each), and constipation, diarrhea, increased ALT level, and dizziness (3 patients [10.7%]) for each).
  • Pruritus 11 (22.4) 0 9 (32.1) 0
  • Urinary tract infection 4 (8.2) 0 4 (14.3) 0
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • PK pharmacokinetic
  • the PK analysis of ARMOR2 characterized the PK of galeterone.
  • the ARMOR2 part 1 PK parameters after single doses of 1,700 mg, 2,550 mg, and 3,400 mg of the SDD tablet formulation were similar between doses. Exposure, expressed as AUC from predose to 6 hours postdose (AUCo-e), was 2,646 ⁇ 1,748 h ⁇ ng/mL, 2,684 ⁇ 2,043 h ⁇ ng/mL, and 2,528 ⁇ 1,529 h ⁇ ng/mL for the 1,700-mg, 2,550-mg, and 3,400-mg doses, respectively.
  • the formulation when administered to a selected subject group provides in said selected subject group an average AUG within the range of about 800 ng-h/mL to about 8,000 ng-h/mL: or within a range of 875 ng-h/mL to about 7,400 ng-h mL: 900 ng-h/mL to about 7,200 ng-h/mL: 1 ,000 ng-h/mL to about 7,000 ng- h mL; 1,500 ng-h/mL to about 6,000 ng-h/mL; 1,700 ng-h/mL to about 5,000 ng-h/mL; 875 ng-h/mL to about 4,500 ng-h/mL; 900 ng-h/mL to about 4,500 ng-h/mL; 1 ,300 ng-h/mL to about 3,300 ng-h/mL; 875 ng-h/mL to about 3,500 ng-h/mL.
  • the formulation when administered to a selected subject group provides in said selected subject group an average Cmax within the range of about 180 ng/mL to about 2,500 ng/mL per 2,550 mg; or within a range of 220 ng/mL to about 2,000 ng/mL; or within a range of 300 ng/mL to about 1 ,800 ng/mL; or within a range of 400 ng/mL to about 1,400 ng/mL; or within a range of 500 ng/mL to about 1 ,200 ng/mL.
  • the ITT population for PSA efficacy included 49 patients. Across all doses tested, 24 of 49 (49.0%) achieved a PS A30 and 11 of 49 patients (22.4%) demonstrated PSA50 (Fig. 1A).
  • one patient in the 650-mg/day group discontinued his gonadotropin-releasing hormone analog and one patient in the 975-mg/day group underwent transurethral resection of the prostate. Excluding these patients, across groups the PSA30 was 51.1% (24 of 47) and the PSA50 was 23.4% (11 of 47). An increase in response rate was observed with higher doses.
  • the ITT population for PSA efficacy in treatment-naive patients included 25 patients. Three patients had received prior abiraterone treatment. Across the 3 doses in treatment naive patients, the decline in PSA from baseline in the ITT population was >30% in 16 of 25 patients (64.0%) and >50% in 12 of 25 patients (48.0%) (Figure IB). In the 2,550-mg dose cohort, 8 of 11 treatment-naive patients (72.7%) had a >30% decline in PSA from baseline and 6/11 patients (54.4%) had a >50% decline in PSA from baseline. In the 1,700- mg dose cohort 50% (3 of 6 patients) achieved a PSA30 and PSA50.
  • Galeterone resulted in overall reductions in median serum testosterone, DHEAS, and androstenedione concentrations.
  • Median corticosterone level was increased from a median baseline of 204 ng/dL to 1,377.5 ng/dL at week 12, and Cortisol and deoxycorticosterone levels were generally unchanged ⁇ Table 5).
  • Results of ARMOR 1 and ARMOR2 part 1 demonstrated that galeterone, an agent that inhibits androgen production, blocks the ligand binding domain of AR, and suppresses AR levels in vitro, is safe and shows promising PSA responses in patients with mCRPC.
  • Results from phase 1 healthy volunteer PK studies and the PK results of ARMOR2 part 1 support a 2,550 mg/day-dose of galeterone SDD tablet for use in future trials.
  • steroidogenic marker results showed no change in deoxycorticosterone or Cortisol and a small increase in corticosterone, relative to large increase observed with abiraterone in corticosterone even in the absence of coadministration of steroids with galeterone (30). Observed androgen reductions were similar to those reported with abiraterone administered with prednisone (30).
  • ARMOR2 part 1 served as a bridging study between the original capsule formulation and the SDD tablet formulation, which was developed to have improved relative bioavailability over the capsule.
  • the SDD tablet was shown to result in dose-related increases in exposure that were similar in fed and fasted states that plateaued at doses above 2,550 mg (31). Additionally, it was found that the exposure after 1,700 mg of the SDD tablet was similar to that with 2,600 mg of the original capsule formulation— the dose in ARMORl that resulted in the best efficacy numbers(27).
  • ARMOR2 part 1 evaluated increasing doses of the SDD tablet formulation starting at the 1,700-mg dose. No increase in exposure was observed with higher doses.
  • phase I, ARMOR3-SV study will target splice variant (AR-V7) positive tumors and is based on PSA responses seen patients with C-terminal loss in the treatment naive cohort of ARMOR2 (31).
  • the efficacy and safety results from ARM0R1 and ARMOR2 part 1 and the PK results from phase I healthy volunteer studies and ARMOR2 part 1 support the recommended dose of galeterone for ARMOR2 part 2 and the phase III study of 2,550 mg/d using the SDD tablet formulation with improved bioavailability. Galeterone is well tolerated in CRPC patients and demonstrates pharmacodynamic changes consistent with its selective multifunctional AR signaling inhibition.
  • the objective of this study was to assess the pharmacokinetics of galeterone capsules under fasted and fed conditions, specifically a high-calorie/high-fat meal or liquid nutritional supplement in healthy volunteers.
  • AUCinf elimination half-life
  • t 1 ⁇ 2 elimination half-life
  • the PK parameters Cmax, AUCo- t , 3nd AUCinf were compared among the fed, supplement, and fasted treatments using an analysis of variance (ANOVA) model with sequence, subject within sequence, treatment, and period as the classification variables, using the natural logarithms of the data. Confidence intervals (90%) were constructed for the ratio, test-to- reference, of the three parameters using the log-transformed data and the two one-sided t-tests procedure. The point estimates and confidence limits were exponentiated back to the original scale.
  • ANOVA analysis of variance
  • CI confidence interval
  • Cmax maximum plasma concentration
  • AUCo-t area under the plasma- concentration time curve to the final sample with a concentration > the lower limit of quantitation, under the plasma-concentration time curve to infinity.
  • the formulation when administered to a selected subject group provides in said selected subject group an average Cmax within t e range of about 450 ng mL to about 600 ng/mL per 975 mg dose of galeterone, or within a range of 480 ng/mL to about 580 ng/mL per 975 mg dose of galeterone; or within a range of 500 ng/mL to about 560 ng/mL per 975 mg dose of galeterone.
  • Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2011 ;108: 13728-33.
  • Beer TM Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al.
  • Androgen receptor inactivation contributes to antitumor efficacy of 17 ⁇ alpha ⁇ - hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(lH-benzimidazole-l-yl)androsta- 5,16-diene in prostate cancer.
  • Mol Cancer Ther. 2008;7:2348-57 contributes to antitumor efficacy of 17 ⁇ alpha ⁇ - hydroxylase/17,20-lyase inhibitor 3beta-hydroxy-17-(lH-benzimidazole-l-yl)androsta- 5,16-diene in prostate cancer.

Abstract

L'invention concerne des technologies et des méthodes d'utilisation se rapportant à des régimes thérapeutiques au galétérone.
PCT/US2016/028898 2015-04-24 2016-04-22 Méthodes de traitement du cancer de la prostate WO2016172517A1 (fr)

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US10098896B2 (en) 2005-03-02 2018-10-16 University Of Maryland Baltimore C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens, in vitro biological activities, pharmacokinetics and antitumor activity

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