Patent Application
20240398797
Disclosed herein are methods of treating metastatic castration-resistant prostate cancer (mCRPC) in a male human by administering the compound of formula I in combination with (a) abiraterone acetate and a corticosteroid or (b) apalutamide. Also disclosed herein are methods of achieving a composite response rate in a male human comprising administering the compound of formula I in combination with (a) abiraterone acetate plus a corticosteroid or (b) apalutamide.
Prostate cancer is the most common non-cutaneous malignancy in men and the second leading cause of death in men from cancer in the western world. Prostate cancer results from the uncontrolled growth of abnormal cells in the prostate gland. Once a prostate cancer tumor develops, androgens, such as testosterone, promote prostate cancer tumor growth. Not all prostate cancer is the same. It ranges from cancer confined to the prostate gland, i.e., localized, to cancer that has spread outside of the prostate to the lymph nodes, bones, or other parts of the body, i.e., metastatic. At its early stages, localized prostate cancer is often treated with local therapy including, for example, surgical removal of the prostate gland and radiotherapy. However, when local therapy fails to cure prostate cancer, as it does in up to a third of men, the disease progresses into incurable metastatic disease (i.e., disease in which the cancer has spread from one part of the body to other parts).
Suppressing the androgen axis is the backbone of treatment of advanced prostate cancer. Androgen deprivation therapy (ADT) reduces testosterone to castrate levels (≤50 ng/mL) through medical or surgical approaches. ADT is a lifelong therapy of prostate cancer treatment for men with metastatic disease. Almost all prostate cancers initially respond to ADT, but in many, the response is short-lived with such men having prostate cancer that is castration resistant (CRPC). Various mechanisms are thought to be involved in castration resistance, including amplification, overexpression or mutation of the androgen receptor (AR), constitutive activation of AR, alternative splicing events, intra-tumoral androgen synthesis or androgen synthesis by the adrenal glands, activation of other ligands, and proliferation of prostate tumor cells independent of androgen.
Androgen signaling inhibitors (ASIs) target the androgen-signaling pathway through a variety of mechanisms. Abiraterone acetate (AA) is a prodrug of abiraterone, which is an irreversible, highly selective Cytochrome p450 (CYP) 17 inhibitor that targets 17α-hydroxylase and C17,20-lyase activities resulting in reduced intratumoral production of androgens reducing as well their synthesis in the adrenal glands and the testes. Apalutamide (APA) targets the ligand binding domain of the AR, which inhibits the androgen receptor and prohibits nuclear translocation, DNA binding and transcription without AR agonistic effects. More recently, agents that target the AR N-terminal domain (NTD), e.g., the compound of formula I, are being investigated as a different therapeutic approach to treating prostate cancer. Accordingly, a need exists for the identification and development of methods for the treatment of prostate cancer that achieve complete blockage of the androgen receptor by combining ASIs with AR NTD inhibitors.
Described herein are methods of treating metastatic castration-resistant prostate cancer (mCRPC) in a male human, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and a therapeutically effective amount of abiraterone acetate plus a therapeutically effective amount of a corticosteroid to said male human.
In some embodiments, prior to administration of the compound of formula I and abiraterone acetate plus a corticosteroid, the male human has been administered docetaxel. In certain embodiments, prior to administration of the compound of formula I and abiraterone acetate plus a corticosteroid, the male human has been diagnosed with non-metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, or locally advanced prostate cancer.
In some embodiments, abiraterone acetate is administered orally to the male human at a dose of about 500 mg per day to about 1000 mg per day. In certain embodiments, abiraterone acetate is administered orally to the male human at a dose of about 1000 mg per day.
In some embodiments, the corticosteroid is prednisone, a prednisolone, or dexamethasone. In certain embodiments, the corticosteroid is administered to the male human at a dose of about 5 mg twice per day.
Also described herein are methods of treating mCRPC in a male human, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and a therapeutically effective amount of apalutamide to said male human. In some embodiments, apalutamide is administered orally to the male human at a dose of about 240 mg per day.
In some embodiments, the compound of formula I is administered orally to the male human at a dose of from about 600 mg per day to about 1000 mg per day. In certain embodiments, the compound of formula I is administered orally to the male human at a dose of: (a) about 600 mg per day; (b) about 800 mg per day; or (c) about 1000 mg per day.
In some embodiments, prior to administration of the compound of formula I and apalutamide, the male human has been administered docetaxel. In certain embodiments, prior to administration of the compound of formula I and apalutamide, the male human has been diagnosed with non-metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, or locally advanced prostate cancer.
In some embodiments, administration provides a composite response rate in the male human In certain embodiments, the composite response rate comprises a PSA90, an objective response rate, or both. In certain embodiments, the composite response rate is at 12 weeks post administration.
In certain embodiments, the treatment is a therapeutically effective amount of the compound of formula I in combination with (a) is a therapeutically effective amount of abiraterone acetate plus is a therapeutically effective amount of a corticosteroid or (b) is a therapeutically effective amount of apalutamide each (a) and (b) in combination with androgen deprivation therapy. In some embodiments, the androgen deprivation therapy consists of bilateral orchiectomy or gonadotropin-releasing hormone agonists or antagonists.
In certain embodiments, administration of the compound of formula I is further in combination with androgen deprivation therapy. In some embodiments, the androgen deprivation therapy consists of bilateral orchiectomy or gonadotropin-releasing hormone agonists or antagonists.
Further described herein are methods of achieving a composite response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of compound of formula I and a therapeutically effective amount of abiraterone acetate plus a therapeutically effective amount of a corticosteroid to said male human.
Still further described herein are methods achieving a composite response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of compound of formula I and apalutamide to said male human. In certain embodiments, the composite response rate comprises a PSA90, an objective response rate, or both. In certain embodiments, the composite response rate is at 12 weeks post administration.
It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Finally, although an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.
The transitional terms “comprising,” “consisting essentially of,” and “consisting” are intended to connote their generally in accepted meanings in the patent vernacular; that is, (i) “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; (ii) “consisting of excludes any element, step, or ingredient not specified in the claim; and (iii) “consisting essentially of limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed invention. More specifically, the basic and novel characteristics relates to the ability of the method to provide at least one of the benefits described herein, including but not limited to the ability to improve the survivability of the male human population relative to the survivability of the comparative male human population described elsewhere herein.
Embodiments described in terms of the phrase “comprising” (or its equivalents), also provide, as embodiments, those which are independently described in terms of “consisting of and “consisting essentially of.”
When a value is expressed as an approximation by use of the descriptor “about,” it will be understood that the particular value forms another embodiment. In general, use of the term “about” indicates approximations that can vary depending on the desired properties sought to be obtained by the disclosed subject matter and is to be interpreted in the specific context in which it is used, based on its function. The person skilled in the art will be able to interpret this as a matter of routine. In some cases, the number of significant figures used for a particular value may be one non-limiting method of determining the extent of the word “about.” In other cases, the gradations used in a series of values may be used to determine the intended range available to the term “about” for each value. Where present, all ranges are inclusive and combinable. That is, references to values stated in ranges include every value within that range.
If not otherwise specified, the term “about” signifies a variance of ±10% of the associated value, but additional embodiments include those where the variance may be ±5%, ±15%, ±20%, ±25%, or ±50%.
It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment(s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Finally, while an embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.
When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”
The present invention may be understood more readily by reference to the following description taken in connection with the accompanying Drawing and Examples, all of which form a part of this disclosure. It is to be understood that this invention is not limited to the specific products, methods, conditions or parameters described or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of any claimed invention. Similarly, unless specifically otherwise stated, any description as to a possible mechanism or mode of action or reason for improvement is meant to be illustrative only, and the invention herein is not to be constrained by the correctness or incorrectness of any such suggested mechanism or mode of action or reason for improvement. Throughout this text, it is recognized that the descriptions refer to various compounds, compositions and methods of using said compounds and compositions. That is, where the disclosure describes or claims a feature or embodiment associated with a composition or a method of using a composition, it is appreciated that such a description or claim is intended to extend these features or embodiment to embodiments in each of these contexts (i.e., compositions and methods of using).
The androgen receptor (AR) is a member of the steroid and nuclear receptor superfamily. Among this large family of proteins, only five vertebrate steroid receptors are known and include the androgen receptor, estrogen receptor, progesterone receptor, glucocorticoid receptor, and mineralocorticoid receptor. AR is a soluble protein that functions as an intracellular transcriptional factor. AR function is regulated by the binding of androgens, which initiates sequential conformational changes of the receptor that affect receptor-protein interactions and receptor-DNA interactions.
AR is mainly expressed in androgen target tissues, such as the prostate, skeletal muscle, liver, and central nervous system (CNS), with the highest expression level observed in the prostate, adrenal gland, and epididymis. AR can be activated by the binding of endogenous androgens, including testosterone and 5-dihydrotestosterone (5a-DHT).
The androgen receptor (AR), located on Xql 1-12, is a 110 kD nuclear receptor that, upon activation by androgens, mediates transcription of target genes that modulate growth and differentiation of prostate epithelial cells. Similar to the other steroid receptors, unbound AR is mainly located in the cytoplasm and associated with a complex of heat shock proteins (HSPs) through interactions with the ligand-binding domain. Upon agonist binding, AR goes through a series of conformational changes: the heat shock proteins dissociate from AR, and the transformed AR undergoes dimerization, phosphorylation, and translocation to the nucleus, which is mediated by the nuclear localization signal. Recruitment of other transcription co-regulators (including co-activators and co-repressors) and transcriptional machinery further ensures the transactivation of AR-regulated gene expression. All of these processes are initiated by the ligand-induced conformational changes in the ligand-binding domain.
AR signaling is crucial for the development and maintenance of male reproductive organs including the prostate gland, as genetic males harboring loss of function AR mutations and mice engineered with AR defects do not develop prostates or prostate cancer. This dependence of prostate cells on AR signaling continues even upon neoplastic transformation. Androgen depletion (such as using GnRH agonists) continues to be the mainstay of prostate cancer treatment. However, androgen depletion is usually effective for a limited duration and prostate cancer evolves to regain the ability to grow despite low levels of circulating androgens.
Castration resistant prostate cancer (CRPC) is a lethal phenotype and almost all of patients will die from prostate cancer. Interestingly, while a small minority of CRPC does bypass the requirement for AR signaling, the vast majority of CRPC, though frequently termed “androgen independent prostate cancer” or “hormone refractory prostate cancer,” retains its lineage dependence on AR signaling.
Prostate cancer is the second most common cause of cancer death in men in the US, and approximately one in every six American men will be diagnosed with the disease during his lifetime. Treatment aimed at eradicating the tumor is unsuccessful in 30% of men, who develop recurrent disease that is usually manifest first as a rise in plasma prostate-specific antigen (PSA) followed by spread to distant sites. Given that prostate cancer cells depend on androgen receptor (AR) for their proliferation and survival, these men are treated with agents that block production of testosterone (e.g., GnRH agonists), alone or in combination with anti-androgens (e.g., bicalutamide), which antagonize the effect of any residual testosterone on AR. The approach is effective as evidenced by a drop in PSA and regression of visible tumor (if present) in some patients; however, this is followed by regrowth as a castration resistant prostate cancer (CRPC) to which most patients eventually succumb. Recent studies on the molecular basis of CRPC have demonstrated that CRPC continues to depend on AR signaling and that a key mechanism of acquired resistance is an elevated level of AR protein. AR targeting agents with activity in castration sensitive and castration resistant prostate cancer have great promise in treating this lethal disease.
The course of prostate cancer from diagnosis to death is best categorized as a series of clinical states based on the extent of disease, hormonal status, and absence or presence of detectable metastases: localized disease, rising levels of prostate-specific antigen (PSA) after radiation therapy or surgery with no detectable metastases, and clinical metastases in the non-castrate or castrate state. Although surgery, radiation, or a combination of both can be curative for patients with localized disease, a significant proportion of these patients have recurrent disease as evidenced by a rising level of PSA, which can lead to the development of metastases, especially in the high-risk group—a transition to the lethal phenotype of the disease.
Androgen depletion is the standard treatment with a generally predictable outcome: decline in PSA, a period of stability in which the tumor does not proliferate, followed by rising PSA and regrowth as castration-resistant disease. Molecular profiling studies of castration-resistance prostate cancers commonly show increased androgen receptor (AR) expression, which can occur through AR gene amplification or other mechanisms.
Anti-androgens are useful for the treatment of prostate cancer during its early stages. However, prostate cancer often advances to a castration resistant state in which the disease progresses in the presence of continued androgen ablation or anti-androgen therapy. Instances of antiandrogen withdrawal syndrome have also been reported after prolonged treatment with anti-androgens. Antiandrogen withdrawal syndrome is commonly observed clinically and is defined in terms of the tumor regression or symptomatic relief observed upon cessation of antiandrogen therapy. AR mutations that result in receptor promiscuity and the ability of these anti-androgens to exhibit agonist activity might at least partially account for this phenomenon. For example, hydroxyflutamide and bicalutamide act as AR agonists in T877A and W741L/W741C AR mutants, respectively.
In the setting of prostate cancer cells that were rendered castration resistant via overexpression of AR, it has been demonstrated that certain anti-androgen compounds, such as bicalutamide, have a mixed antagonist/agonist profile. This agonist activity helps to explain a clinical observation, called the anti-androgen withdrawal syndrome, whereby about 30% of men who progress on AR antagonists experience a decrease in serum PSA when therapy is discontinued.
In the early stages of prostate cancer, the cancer is localized to the prostate. In these early stages, treatment typically involves either surgical removal of the prostate or radiation therapy to the prostate or observation only with no active intervention therapy in some patients. In the early stages where the prostate cancer is localized and requires intervention, surgery or radiation therapy are curative by eradicating the cancerous cells. About 30% of the time these procedures fail, and the prostate cancer continues to progress, as typically evidenced by a rising PSA level. Men whose prostate cancer has progressed following these early treatment strategies are said to have advanced or recurrent prostate cancer.
Because prostate cancer cells depend on the androgen receptor (AR) for their proliferation and survival, men with advanced prostate cancer are treated with agents that block the production of testosterone (e.g., GnRH agonists), alone or in combination with anti-androgens (e.g., bicalutamide), which antagonize the effect of any residual testosterone on AR. These treatments reduce serum testosterone to castrate levels, which generally slows disease progression for a period of time. The approach is effective as evidenced by a drop in PSA and the regression of visible tumors in some patients. Eventually, however, this is followed by regrowth referred to as castration-resistant prostate cancer (CRPC), to which most patients eventually succumb. Castration-resistant prostate cancer (CRPC) is categorized as non-metastatic or metastatic, depending on whether or not the prostate cancer has metastasized to other parts of the body.
In some embodiments, men with non-metastatic CRPC are characterized as having the following:
As used herein, the term “anti-androgen” carries its generally accepted meaning and may refer to a group of hormone receptor antagonist compounds that are capable of preventing or inhibiting the biologic effects of androgens on normally responsive tissues in the body. In some embodiments, an anti-androgen is a small molecule. In some embodiments, an anti-androgen is an AR antagonist. In some embodiments, an anti-androgen is an AR full antagonist. In some embodiments, an anti-androgen is a first-generation anti-androgen. In some embodiments, an anti-androgen is a second-generation anti-androgen.
As used herein, the term “AR antagonist”, “AR inhibitor”, and “AR signaling inhibitor” are used interchangeably herein and refer to an agent that inhibits or reduces at least one activity of an AR polypeptide. Exemplary AR activities include, but are not limited to, co-activator binding, DNA binding, ligand binding, or nuclear translocation.
An exemplary androgen receptor inhibitor is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro [3.4] oct-5-yl]-2-fluoro-N-methylbenzamide (also known as apalutamide, ARN-509, or JNJ-56021927; CAS No. 956104-40-8).
4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro [3.4] oct-5-yl]-2-fluoro-N-methylbenzamide (apalutamide)
Apalutamide is an androgen receptor inhibitor that binds directly to the ligand-binding domain of AR, impairing nuclear translocation, AR binding to DNA and AR target gene modulation, thereby inhibiting tumor growth and promoting apoptosis. Apalutamide binds AR with greater affinity than bicalutamide and induces partial or complete tumor regression in non-castrate hormone-sensitive and bicalutamide-resistant human prostate cancer xenograft models. Apalutamide lacks the partial agonist activity seen with bicalutamide in the context of AR overexpression. “Safety and Antitumor Activity of Apalutamide (ARN-509) in Metastatic Castration-Resistant Prostate Cancer with and without Prior Abiraterone Acetate and Prednisone” (Rathkopf, D. et al. Clin Cancer Res. 2017; 23 (14): 3544-3551) relates to the use of apalutamide as a treatment for metastatic castration-sensitive prostate cancer.
The compound of formula I (N-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl) propan-2-yl) phenoxy) methyl) pyrimidin-2-yl) methanesulfonamideN-(4-((4-(2-(3-chloro-4-(2-chloroethoxy)-5-cyanophenyl) propan-2-yl) phenoxy) methyl) pyrimidin-2-yl) methanesulfonamide) is an orally available and selective inhibitor of N-terminal domain of the AR and has the structure as follows:
(the compound of formula I)
The compound of formula I is disclosed in U.S. Pat. No. 20,210,332016A1 and WO2020/081999. In WO2020/081999 the compound of formula I is example A109.
The terms used herein carry their normally accepted meaning, but for avoidance of doubt, some of the definitions are provided herein.
The term “cancer” as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread).
The term “prostate cancer” as used herein refers to histologically or cytologically confirmed adenocarcinoma of the prostate.
The term “androgen-deprivation therapy (ADT)” refers to the reduction of androgen levels in a prostate cancer patient to castrated levels of testosterone (<50 ng/dL). Such treatments can include orchiectomy or the use of gonadotropin-releasing hormone agonists or antagonists. ADT includes surgical castration (orchiectomy) and/or the administration of luteinizing hormone-releasing hormone (“LHRH”)/gonadotropin-releasing hormone (GnRH) agonists or antagonists to a human. Examples of GnRH agonist or antagonist is or comprises leuprolide, buserelin, naferelin, histrelin, goserelin, deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100, KLH-2109 or triptorelin. In certain embodiments, examples of GnRH agonists include goserelin acetate, histrelin acetate, leuprolide acetate, and triptorelin pamoate.
The term “locally advanced prostate cancer” refers to prostate cancer where all actively cancerous cells appear to be confined to the prostate and the associated organs or neighbor organs (e.g., seminal vesicle, bladder neck, and rectal wall).
The term “high-risk localized prostate cancer” refers to locally advanced prostate cancer that has a probability of developing metastases or recurrent disease after primary therapy with curative intent. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT)<20 months, <19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 months, <12 months, or <11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months, or <1 month. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT)<10 months. In some embodiments, high risk for development of metastases is defined as having a high Gleason score or bulky tumor.
For the avoidance of doubt, the terms “castration-sensitive prostate cancer” and “hormone-sensitive prostate cancer” are equivalent and are used interchangeably.
The terms “castration-sensitive prostate cancer” and “hormone-sensitive prostate cancer” refer to cancer that is responsive to ADT either as localized disease, biochemical relapse or in the metastatic setting.
The terms “metastatic castration-sensitive prostate cancer” and “metastatic hormone-sensitive prostate cancer” refers to cancer that has spread (metastasized) to other areas of the body, e.g., the bone, lymph nodes or other parts of the body in a male, and that is responsive to ADT.
The terms “non-metastatic castration-sensitive prostate cancer” refers to cancer that has not spread (metastasized) from the prostate in a male, and that is responsive to ADT. In some embodiments, non-metastatic castration-sensitive prostate cancer is assessed with bone scan and computed tomography (CT) or magnetic resonance imaging (MRI) scans. The term “CRPC” as used herein refers to castration-resistant prostate cancer. CRPC is prostate cancer that continues to grow despite the suppression of male hormones that fuel the growth of prostate cancer cells.
The term “metastatic castration-resistant prostate cancer” refers to castration-resistant prostate cancer that has metastasized to other parts of the human body.
Metastatic castration-sensitive prostate cancer (CSPC) refers to prostate cancer that still responds to testosterone suppression therapy.
The term “NM-CRPC” as used herein refers to non-metastatic castration-resistant prostate cancer. In some embodiments, NM-CRPC is assessed with bone scan and computed tomography (CT) or magnetic resonance imaging (MRI) scans.
The term “high risk NM-CRPC” refers to probability of a man with NM-CRPC developing metastases. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT)<20 months, <19 months, <18 months, <17 months, <16 months, <15 months, <14 months, <13 months, <12 months, or <11 months, <10 months, <9 months, <8 months, <7 months, <6 months, <5 months, <4 months, <3 months, <2 months, or <1 month. In some embodiments, high risk for development of metastases is defined as prostate specific antigen doubling time (PSADT)<10 months. In some embodiments, high risk for development of metastases is defined as having local-regional recurrence (e.g. primary tumor bed, bladder neck, anastomotic area, pelvic lymph nodes).
The terms “co-administration”, “in combination”, or the like, as used herein, encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.
The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., apalutamide and a co-agent, are both administered to a patient simultaneously in the form of a single unit or single dosage form. The term “non-fixed combination” means that the active ingredients, e.g., apalutamide and a co-agent, are administered to a patient as separate units or separate dosage forms, either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides safe and effective levels of the two active ingredients in the body of the human male. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.
The term “continuous daily dosing schedule” refers to the administration of a particular therapeutic agent without any drug holidays from the particular therapeutic agent. In some embodiments, a continuous daily dosing schedule of a particular therapeutic agent comprises administration of a particular therapeutic agent every day at roughly the same time each day.
The terms “treat”, “treating”, and “treatment” refer to the eradication, removal, modification, management, or control of a tumor or primary, regional, or metastatic cancer cells or tissue and the minimization or delay of the spread of cancer.
The term “radiographic progression-free survival” or “rPFS” is defined as the occurrence of one of the following: (1) progression in bone, defined as the first bone scan with >2 new lesions compared with baseline is observed <12 weeks from randomization and is confirmed by a second bone scan taken ≥6 weeks later showing ≥2 additional new lesions (a total of ≥4 new lesions compared with baseline) or the first bone scan with ≥2 new lesions compared with baseline is observed ≥12 weeks from randomization and the ≥2 new lesions are verified on the next bone scan ≥6 weeks later (a total of ≥2 new lesions compared with baseline); (2) progression of soft tissue lesion measured by CT or MRI in modified RECIST 1.1 criteria; or (3) death.
The term “overall survival” or “OS” is defined as the time from randomization to the date of death from any cause.
The term “PFS2” means the time from initial study randomization to 2nd disease progression or death from any cause.
The term “time to PSA progression” is defined as the time from randomization to date of PSA progression based on Prostate Cancer Working Group 2 criteria. Scher H I, et al. J Clin Oncol 2008; 26:1148-1159.
The term “time to symptomatic progression” is defined as the easiest occurrent of a skeletal-related event, pain progression or worsening of disease-related symptoms requiring initiation of subsequent anti-cancer therapy, or development of clinically significant symptoms due to loco-regional tumor progression requiring surgical intervention or radiation.
The term “objective response rate” is defined per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1.
The term “duration of response” is defined according to response criteria of Prostate Cancer Working Group 3 (PCWG3) for prostate cancer or RECIST v1.1.
The term “randomization” as it refers to a clinical trial refers to the time when the patient is confirmed eligible for the clinical trial and gets assigned to a treatment arm.
The terms “kit” and “article of manufacture” are used as synonyms.
The term “subject” and “patient” and “human” are used interchangeably.
The term “adverse event” or “AE” is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non-investigational) product, whether or not related to that medicinal (investigational or non-investigational) product. (Definition per International Council on Harmonisation [ICH]). This includes any occurrence that is new in onset or aggravated in severity or frequency from the baseline condition, or abnormal results of diagnostic procedures, including laboratory test abnormalities.
The term “serious adverse event” or “SAE” is based on ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product, or is medically important.
The term “composite response rate” is defined as either 90% reduction in PSA level from baseline (PSA-90), or objective response in participants with measurable disease, or both at 12 weeks.
The term “PSA90 rate” or “PSA90” is defined as the proportion of participants with PSA decline >90% at 12 weeks from baseline.
The term “PSA50 rate” or “PSA50” is defined as the proportion of participants with PSA decline >50% at 12 weeks from baseline.
In the following disclosure, “methods of treating metastatic castration-resistant prostate cancer,” may alternatively be recited as “methods of treating a male human having metastatic castration-resistant prostate cancer.” For the sake of brevity, each possible alternative is not parsed out, but each are considered separately considered as if fully described.
Described herein are methods of treating mCRPC in a male human, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and abiraterone acetate and a corticosteroid to said male human.
In certain embodiments, the compound of formula I is administered daily to the male human. In further embodiments, the compound of formula I is administered orally to the male human. In some embodiments, the compound of formula I is administered orally to the male human on a continuous daily dosing schedule.
In some embodiments, the compound of formula I is administered orally to the male human at a dose of from about 600 mg per day to about 1000 mg per day, including all doses and subranges therebetween. In some embodiments, the compound of formula I is administered orally to the male human at a dose of about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg per day. In certain embodiments, the compound of formula I is administered orally to the male human at a dose of about 600 mg per day. In certain embodiments, the compound of formula I is administered orally to the male human at a dose of about 800 mg per day. In certain embodiments, the compound of formula I is administered orally to the male human at a dose of about 1000 mg per day.
In some embodiments, abiraterone acetate is administered at a dose of about 500 mg per day to about 1000 mg per day. In some embodiments, abiraterone acetate is administered at a dose of about 1000 mg per day.
In some embodiments, abiraterone acetate is administered in combination with a corticosteroid. In certain embodiments, the corticosteroid is prednisone, a prednisolone, or dexamethasone. In certain embodiments, the corticosteroid is prednisone. In certain embodiments, the corticosteroid is prednisolone. In certain embodiments, the corticosteroid is dexamethasone.
In further embodiments, the corticosteroid is administered at a dose of about 5 mg twice per day. In further embodiments, the prednisone is administered at a dose of about 5 mg twice per day. In further embodiments, the prednisolone is administered at a dose of about 5 mg twice per day.
In further embodiments, the dexamethasone is administered at a dose of about 0.5 mg to about 1.0 mg once daily, twice daily or three times daily. In further embodiments, the dexamethasone is administered at a dose of about 0.5 mg once daily. In further embodiments, the dexamethasone is administered at a dose of about 0.5 mg twice daily. In further embodiments, the dexamethasone is administered at a dose of about 0.5 mg three times daily. In further embodiments, the dexamethasone is administered at a dose of about 0.75 mg once daily. In further embodiments, the dexamethasone is administered at a dose of about 0.75 mg twice daily. In further embodiments, the dexamethasone is administered at a dose of about 0.75 mg three times daily. In further embodiments, the dexamethasone is administered at a dose of about 1.0 mg once daily. In further embodiments, the dexamethasone is administered at a dose of about 1.0 mg twice daily. In further embodiments, the dexamethasone is administered at a dose of about 1.0 mg three times daily.
In some embodiments, abiraterone acetate is administered once a day and the corticosteroid is administered once a day. In some embodiments, abiraterone acetate is administered once a day and the corticosteroid is administered twice a day. In some embodiments, abiraterone acetate is administered once a day and the corticosteroid is administered three times a day.
In certain embodiments the active ingredients, e.g., the compound of formula I and abiraterone acetate plus the corticosteroid, are administered to a patient as separate units or separate dosage forms, either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides safe and effective levels of the two active ingredients in the body of the human male. In certain embodiments, the compound of formula I may be administered prior to administration of abiraterone acetate plus the corticosteroid. In certain embodiments, the compound of formula I may be administered following administration of abiraterone acetate plus the corticosteroid.
In certain embodiments, prior to administration of the compound of formula I and abiraterone acetate plus the corticosteroid, the male human has been diagnosed with non-metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer, or locally advanced prostate cancer.
In some embodiments, administration of the compound of formula I and abiraterone acetate plus the corticosteroid provides a composite response rate in the male human. In some embodiments, administration of the compound of formula I and abiraterone acetate plus the corticosteroid provides an improved composite response rate in the male human.
Further described herein are methods of achieving a composite response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and abiraterone acetate plus a corticosteroid to said male human.
Further described herein are methods of improving a composite response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and abiraterone acetate plus a corticosteroid to said male human.
In any of the foregoing embodiments, the composite response rate comprises a PSA90, an objective response rate, or both. In certain embodiments, the composite response rate comprises a PSA90. In certain embodiments, the composite response rate comprises an objective response rate. In certain embodiments, the composite response rate comprises a PSA90 and an objective response rate. In certain embodiments, the composite response rate is at 12 weeks post administration.
In some embodiments, administration of the compound of formula I and abiraterone acetate plus a corticosteroid provides a PSA90 in the male human. In some embodiments, administration of the compound of formula I and abiraterone acetate plus a corticosteroid provides an improved PSA90 in the male human.
Further described herein are methods of improving PSA response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and abiraterone acetate plus a corticosteroid to said male human. In certain embodiments, the PSA response rate is PSA50. In certain embodiments, the PSA response rate is PSA90.
In some embodiments, administration of the compound of formula I and abiraterone acetate plus the corticosteroid provides an objective response rate in the male human. In some embodiments, administration of the compound of formula I and the abiraterone acetate plus the corticosteroid provides an improved objective response rate in the male human.
Further described herein are methods of improving objective response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and abiraterone acetate plus a corticosteroid to said male human.
In some embodiments, administration of the compound of formula I and the abiraterone acetate plus the corticosteroid provides an improvement in incidence and severity of adverse events in the male human. In certain embodiments, the adverse events comprise dose-limiting toxicities.
Further described herein are methods of improving incidence and severity of adverse events in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and abiraterone acetate plus a corticosteroid to said male human. In certain embodiments, the adverse events comprise dose-limiting toxicities.
In some embodiments, administration of the compound of formula I, abiraterone acetate plus a corticosteroid provides an improvement in radiographic progression-free survival (rPFS) in the male human.
Further described herein are methods of improving rPFS in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and abiraterone acetate plus a corticosteroid to said male human.
In any of the foregoing embodiments, the improvement may be relative to a population of male humans with mCRPC who did not receive an androgen receptor signaling inhibitor. In any of the foregoing embodiments, the improvement may be relative to a population of male humans with mCRPC who received docetaxel. In any of the foregoing embodiments, the improvement may be relative to a population of male humans with mCRPC who received a placebo. In any of the foregoing embodiments, the improvement may be relative to a population of male humans with mCRPC who received no treatment.
In some embodiments, the population to whom the compound of formula I and abiraterone acetate plus a corticosteroid is administered and the comparative population both have been previously been treated by the same or similar prior treatment regimen.
Described herein are methods of treating mCRPC in a male human, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and a therapeutically effective amount of apalutamide to said male human.
In further embodiments, the compound of formula I is administered daily to the male human. In still further embodiments, the compound of formula I is administered orally to the male human. In some embodiments, the compound of formula I is administered orally to the male human on a continuous daily dosing schedule.
In some embodiments, the compound of formula I is administered orally to the male human at a dose of from about 600 mg per day to about 1000 mg per day, including all doses and subranges therebetween. In some embodiments, the compound of formula I is administered orally to the male human at a dose of about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, or about 1000 mg per day. In certain embodiments, the compound of formula I is administered orally to the male human at a dose of about 600 mg per day. In certain embodiments, the compound of formula I is administered orally to the male human at a dose of about 800 mg per day. In certain embodiments, the compound of formula I is administered orally to the male human at a dose of about 1000 mg per day.
In some embodiments, abiraterone acetate is administered at a dose of about 500 mg per day to about 1000 mg per day. In some embodiments, abiraterone acetate is administered at a dose of about 1000 mg per day.
In further embodiments, apalutamide is administered daily to the male human. In still further embodiments, apalutamide is administered orally to the male human. In some embodiments, apalutamide is administered orally to the male human on a continuous daily dosing schedule.
In some embodiments, apalutamide is administered orally to the male human at a dose of about 30 mg per day to about 480 mg per day. In further embodiments, apalutamide is administered orally to the male human at a dose of about 180 mg per day to about 480 mg per day. In certain embodiments, apalutamide is administered orally to the male human at a dose of: (a) about 30 mg per day; (b) about 60 mg per day; (c) about 90 mg per day; (d) about 120 mg per day; or (d) about 240 mg per day. In some embodiments, apalutamide is administered orally to the male human at a dose of about 240 mg per day. In certain embodiments, apalutamide is administered orally to the male human at a dose of about 60 mg and at a frequency of four times per day.
In certain embodiments the active agents, e.g., the compound of formula I and apalutamide, are administered to a patient as separate units or separate dosage forms, either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides safe and effective levels of the two active ingredients in the body of the human male. In certain embodiments, the compound of formula I may be administered prior to administration of apalutamide. In certain embodiments, the compound of formula I may be administered following administration of apalutamide.
In some embodiments, administration of the compound of formula I and apalutamide provides a composite response rate in the male human. In some embodiments, administration of the compound of formula I and apalutamide provides an improved composite response rate in the male human.
Further described herein are methods of achieving a composite response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and apalutamide to said male human
Further described herein are methods of improving a composite response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and apalutamide to said male human.
In any of the foregoing embodiments, the composite response rate comprises a PSA90, an objective response rate, or both. In certain embodiments, the composite response rate comprises a PSA90. In certain embodiments, the composite response rate comprises an objective response rate. In certain embodiments, the composite response rate comprises a PSA90 and an objective response rate. In certain embodiments, the composite response rate is at 12 weeks post administration.
In some embodiments, administration of the compound of formula I and apalutamide provides a PSA90 in the male human. In some embodiments, administration of the compound of formula I and apalutamide provides an improved PSA90 in the male human.
Further described herein are methods of improving PSA response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and apalutamide to said male human. In certain embodiments, the PSA response rate is PSA50. In certain embodiments, the PSA response rate is PSA90.
In some embodiments, administration of the compound of formula I and apalutamide provides an objective response rate in the male human. In some embodiments, administration of the compound of formula I and apalutamide provides an improved objective response rate in the male human.
Further described herein are methods of improving objective response rate in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and apalutamide to said male human.
In some embodiments, administration of the compound of formula I and apalutamide provides an improvement in incidence and severity of adverse events in the male human. In certain embodiments, the adverse events comprise dose-limiting toxicities.
Further described herein are methods of improving incidence and severity of adverse events in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and apalutamide to said male human. In certain embodiments, the adverse events comprise dose-limiting toxicities.
In some embodiments, administration of the compound of formula I, apalutamide provides an improvement in radiographic progression-free survival (rPFS) in the male human.
Further described herein are methods of improving rPFS in a male human with mCRPC, said methods comprising, consisting of, or consisting essentially of, administering a therapeutically effective amount of the compound of formula I and apalutamide to said male human.
In any of the foregoing embodiments, the improvement may be relative to a population of male humans with mCRPC who did not receive an androgen receptor signaling inhibitor. In any of the foregoing embodiments, the improvement may be relative to a population of male humans with mCRPC who received docetaxel. In any of the foregoing embodiments, the improvement may be relative to a population of male humans with mCRPC who received a placebo. In any of the foregoing embodiments, the improvement may be relative to a population of male humans with mCRPC who received no treatment.
In certain embodiments, the androgen receptor signaling inhibitor is apalutamide.
In some embodiments, the population to whom the compound of formula I and apalutamide is administered and the comparative population both have been previously been treated by the same or similar prior treatment regimen.
In further embodiments, administration of the compound of formula I in combination with (a) abiraterone acetate plus a corticosteroid or (b) apalutamide, each (a) and (b) further in combination with androgen deprivation therapy. at least one GnRH agonist or antagonist. In some embodiments, the compound of formula I is administered in combination with abiraterone acetate plus a corticosteroid or apalutamide is further in combination with at least one GnRH agonist or antagonist. In some embodiments, the compound of formula I is administered in combination with abiraterone acetate, a corticosteroid, and at least one GnRH agonist or antagonist. In further embodiments, the compound of formula I is administered in combination with apalutamide and at least one GnRH agonist or antagonist.
In certain embodiments, administration of the compound of formula I in combination with abiraterone acetate plus a corticosteroid or apalutamide is further in combination with androgen deprivation therapy. In some embodiments, the compound of formula I is administered in combination with abiraterone acetate plus a corticosteroid, and androgen deprivation therapy. In further embodiments, the compound of formula I is administered in combination with apalutamide and androgen deprivation therapy.
In some embodiments, the androgen deprivation therapy consists of bilateral orchiectomy or gonadotropin-releasing hormone agonists or antagonists. In certain embodiments, castrated levels of testosterone are maintained by administering a GnRH agonist or antagonist or by orchiectomy.
In further embodiments, administration of the compound of formula I in combination with abiraterone acetate plus a corticosteroid or apalutamide is further in combination with at least one GnRH agonist or antagonist. In some embodiments, the compound of formula I is administered in combination with abiraterone acetate, a corticosteroid, and at least one GnRH agonist or antagonist. In further embodiments, the compound of formula I is administered in combination with apalutamide and at least one GnRH agonist or antagonist.
In still further embodiments, the at least one GnRH agonist or antagonist is or comprises leuprolide, buserelin, naferelin, histrelin, goserelin, deslorelin, degarelix, ozarelix, ABT-620 (elagolix), TAK-385 (relugolix), EP-100, KLH-2109 or triptorelin.
Physicians can prescribe GnRH agonists in accordance with instructions, recommendations and practices. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is leuprolide. In some embodiments, leuprolide is administered as a depot injection at a dose of about 7.5 mg every 4 weeks, or 22.5 mg every 3 months, or about 30 mg every 4 months, or about 45 mg every 6 months. In some embodiments, leuprolide is administered at about 0.01 mg to about 200 mg of leuprolide over a period of about 3 days to about 12 months, preferably about 3.6 mg of leuprolide over a period of about 3 days to about 12 months. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is buserelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is naferelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is histrelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is histrelin acetate. In some embodiments, histrelin acetate is administered at about 50 mg of histrelin acetate over a period of 12 months of histrelin acetate or about 50 μg per day of histrelin acetate. In some embodiments the GnRH agonist or antagonist is goserelin. In some embodiments, goserelin is administered as a subcutaneous implant at a dose of about 3.6 mg every 4 weeks or about 10.8 mg every 12 weeks. In some embodiments, goserelin is administered at about 0.01 mg to about 20 mg of goserelin over a period of about 28 days to about 3 months, preferably about 3.6 mg to about 10.8 mg of goserelin over a period of about 28 days to about 3 months. In some embodiments the GnRH agonist or antagonist is deslorelin. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is degarelix. In some embodiments, degarelix is administered as a subcutaneous injection at a dose of about 240 mg followed by about 80 mg administered every 4 weeks. In some embodiments the GnRH agonist or antagonist is ozarelix. In some embodiments the GnRH agonist or antagonist is ozarelix. In some embodiments the GnRH agonist or antagonist is ABT-620 (elagolix). In some embodiments the GnRH agonist or antagonist is TAK-385 (relugolix). In some embodiments the GnRH agonist or antagonist is EP-100. In some embodiments the GnRH agonist or antagonist is KLH-2109. In some embodiments, the gonadotropin-releasing hormone agonist or antagonist is triptorelin. In some embodiments, triptorelin is administered at about 0.01 mg to about 20 mg of triptorelin over a period of about 1 month, preferably about 3.75 mg of triptorelin over a period of 1 month.
In certain embodiments, administration of the compound of formula I in combination with abiraterone acetate plus a corticosteroid or apalutamide is further in combination with orchiectomy. In further embodiments, the orchiectomy is bilateral orchiectomy.
In some embodiments, the male human has previously been administered docetaxel. In some embodiments, prior to administration of the compound of formula I and the abiraterone acetate plus a corticosteroid, the male human has previously been administered docetaxel. In some embodiments, prior to administration of the compound of formula I and apalutamide, the male human has previously been administered docetaxel. In certain embodiments, docetaxel has been administered intravenously at a dose of about 75 mg/m2. In certain embodiments, docetaxel has been administered intravenously at a dose of about 75 mg/m2 every 3 weeks for 6 cycles.
In some embodiments, the male human has not previously been administered apalutamide. In some embodiments, prior to administration of the compound of formula I and the abiraterone acetate plus a corticosteroid, the male human has not previously been administered apalutamide. In some embodiments, prior to administration of the compound of formula I and apalutamide, the male human has not been administered apalutamide.
Therapeutic agents described herein are administered in any suitable manner or suitable formulation.
Unless otherwise specified, the terms “effective amount” or “therapeutically effective amount,” as used herein, refer to an amount of an anti-androgen being administered that treats the underlying disease or condition including. halting or slowing the progression of the disease or condition.
The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means that the beneficial effects of that formulation, composition or ingredient on the general health of the male human being treated substantially outweigh its detrimental effects, to the extent any exist.
The compound of formula I, abiraterone acetate, corticosteroid, and apalutamide are each individually present in solid oral dosage forms. In some embodiments, they are formulated as an oral dose form, a unit oral dose form, or a solid dose form (e.g., a capsule, tablet, or pill). In some embodiments, for example, they are each formulated as a tablet.
To prepare the pharmaceutical compositions of this invention, the active pharmaceutical ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g., oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
In solid oral preparations such as, for example, dry powders for reconstitution or inhalation, granules, capsules, caplets, gel caps, pills and tablets (each including immediate release, timed release and sustained release formulations), suitable carriers and additives include but are not limited to diluents, granulating agents, lubricants, binders, glidants, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated, gelatin coated, film coated or enteric coated by standard techniques.
Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile solutions or suspensions, metered aerosol or liquid sprays, drops, or suppositories for administration by oral, intranasal, sublingual, intraocular, transdermal, rectal, vaginal, dry powder inhaler or other inhalation or insufflation means.
These formulations are manufactured by conventional formulation techniques. For preparing solid pharmaceutical compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as diluents, binders, adhesives, disintegrants, lubricants, antiadherents, and glidants. Suitable diluents include, but are not limited to, starch (i.e. corn, wheat, or potato starch, which may be hydrolized), lactose (granulated, spray dried or anhydrous), sucrose, sucrose-based diluents (confectioner's sugar; sucrose plus about 7 to 10 weight percent invert sugar; sucrose plus about 3 weight percent modified dextrins; sucrose plus invert sugar, about 4 weight percent invert sugar, about 0.1 to 0.2 weight percent cornstarch and magnesium stearate), dextrose, inositol, mannitol, sorbitol, microcrystalline cellulose (i.e. AVICEL microcrystalline cellulose available from FMC Corp.), dicalcium phosphate, calcium sulfate dihydrate, calcium lactate trihydrate and the like. Suitable binders and adhesives include, but are not limited to acacia gum, guar gum, tragacanth gum, sucrose, gelatin, glucose, starch, and cellulosics (i.e. methylcellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, and the like), water soluble or dispersible binders (i.e. alginic acid and salts thereof, magnesium aluminum silicate, hydroxyethylcellulose [i.e. TYLOSE available from Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidone, polymethacrylates and pregelatinized starch) and the like. Suitable disintegrants include, but are not limited to, starches (corn, potato, etc.), sodium starch glycolates, pregelatinized starches, clays (magnesium aluminum silicate), celluloses (such as crosslinked sodium carboxymethylcellulose and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar, locust bean, karaya, pectin, and tragacanth gum), cross-linked polyvinylpyrrolidone and the like. Suitable lubricants and antiadherents include, but are not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc waxes, stearowet, boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate and the like. Suitable glidants include, but are not limited to, talc, cornstarch, silica (i.e. CAB-O-SIL silica available from Cabot, SYLOID silica available from W.R. Grace/Davison, and AEROSIL silica available from Degussa) and the like. Sweeteners and flavorants may be added to chewable solid dosage forms to improve the palatability of the oral dosage form. Additionally, colorants and coatings may be added or applied to the solid dosage form for ease of identification of the drug or for aesthetic purposes. These carriers are formulated with the pharmaceutical active to provide an accurate, appropriate dose of the pharmaceutical active with a therapeutic release profile.
Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, starches, cellulose, and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl methylcellulose), polyvinyl pyrrolidone, and mixtures thereof.
Examples of fillers suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, microcrystalline cellulose, powdered cellulose, mannitol, lactose, calcium phosphate, starch, pre-gelatinized starch, and mixtures thereof.
The binder or filler in pharmaceutical compositions is typically present in from about 50 to about 99 weight percent of the pharmaceutical composition or dosage form.
Disintegrants can be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary skill in the art. Typical pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant. Disintegrants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, croscarmellose sodium, crospovidone, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, other celluloses, gums, and mixtures thereof.
Lubricants that can be used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, sodium stearyl fumarate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Lubricants are typically used in an amount of less than about 1 weight percent of the pharmaceutical compositions or dosage forms into which they are incorporated.
Compressed tablet formulations may optionally be film-coated to provide color, light protection, and/or taste-masking. Tablets may also be coated so as to modulate the onset, and/or rate of release in the gastrointestinal tract, so as to optimize or maximize the biological exposure of the patient to the API.
Hard capsule formulations may be produced by filling a blend or granulation of the compound of formula I into shells consisting of, for example, gelatin, or hypromellose.
Soft gel capsule formulations may be produced.
Pharmaceutical compositions intended for oral use may be prepared from the solid dispersion formulations, and blended materials described above in accordance with the methods described herein, and other methods known to the art for the manufacture of pharmaceutical compositions. Such compositions may further contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, granulating, and disintegrating agents, binding agents, glidants, lubricating agents, and antioxidants, for example, propyl gallate, butylated hydroxyanisole, and butylated hydroxy toluene. The tablets may be uncoated, or they may be film coated to modify their appearance or may be coated with a functional coat to delay disintegration, and absorption in the gastrointestinal tract, and thereby provide a sustained action over a longer period.
Compositions for oral use may also be presented as capsules (e.g., hard gelatin) wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or starch, or as soft gelatin capsules wherein the active ingredient is mixed with liquids or semisolids, for example, peanut oil, liquid paraffin, fractionated glycerides, surfactants or olive oil. Aqueous suspensions contain the active materials in mixture with excipients suitable for the manufacture of aqueous suspensions. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in mixture with a dispersing or wetting agent, suspending agent, and one or more preservatives. In certain embodiments of the invention, the pharmaceutical compositions of the invention include a diluent system, disintegrant, salt, lubricant, glidant, and filmcoat, at concentrations of from about 3% w/w to about 58% w/w, from about 4% w/w to about 20% w/w, from about 4% w/w to about 20% w/w, from about 0.5% w/w to about 4% w/w, from about 0% w/w to about 2% w/w, and from about 1% w/w to about 5% w/w respectively, or at from about 18% w/w to about 40% w/w, from about 7% w/w to about 15% w/w, from about 7% w/w to about 18% w/w, from about 1.0% w/w to about 3.0%, from about 0.1% w/w to about 1.0% w/w, and from about 2.0% w/w to about 4.0% w/w, respectively. In certain embodiments, the solid dispersion formulations are blended with a diluent, one or more disintegrating agents, lubricants, and glidants. An exemplary blended composition or oral dosage form includes mannitol, microcrystalline cellulose, croscarmellose sodium, sodium chloride, colloidal silica, sodium stearyl fumarate, and magnesium stearate.
The disintegrant may be present in a concentration from about 4% w/w to about 20% w/w or from about 7% w/w to about 15% w/w. A salt may be also present, which may be sodium chloride, potassium chloride or a combination thereof. The combination of salts and disintegrant is present at a concentration from about 5% w/w to about 35% w/w of the final pharmaceutical composition.
In certain embodiments, inactive ingredients of the core tablet are: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. In other embodiments, the tablets are finished with a film-coating consisting of the following excipients: iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide
In other embodiments, a single unit dosage of the pharmaceutical composition comprises, consists of, or consists essentially of about 200 mg of the compound of formula I. The total daily dose of the compound of formula I may be about 600 mg per day. The total daily dose of the compound of formula I may be about 800 mg per day. The total daily dose of the compound of formula I may be about 1000 mg per day.
All formulations for oral administration are in dosage form suitable for such administration.
For use in the therapeutic methods of use described herein, kits and articles of manufacture are also described herein. Such kits include a package or container that is compartmentalized to receive one or more dosages of the pharmaceutical compositions disclosed herein. Suitable containers include, for example, bottles. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.
The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
A kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
In certain embodiments, the pharmaceutical compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
The following example is provided for illustrative purposes only and not to limit the scope of the claims provided herein.
A non-limiting example of a Phase 1b Study the compound of formula I in combination with abiraterone acetate plus prednisone or prednisolone or apalutamide in metastatic castration-resistant prostate cancer is provided herein.
The primary and secondary objectives and endpoints are provided in Table 1.
The study described in this example is a Phase 1b, open-label, multicenter study to evaluate the safety, pharmacokinetics, pharmacodynamics and antitumor activity of the compound of formula I in combination with AAP (Group A) or apalutamide (Group B) in participants with mCRPC with no prior second-generation ARSI treatment. The Study Evaluation Team (SET) continuously monitors all safety data, including DLTs and late-occurring toxicities. SET decisions (including dose escalation, determination of the RP2D, and dose expansion) are based on review of all available data, including pharmacokinetics, pharmacodynamics, safety, and antitumor activity.
This study enrolls adult mCRPC patients who have not received prior therapy with second-generation ARSIs for mCSPC, nmCRPC, or mCRPC. Participants may have received prior docetaxel for mCSPC with a maximum duration of 6 cycles (but must not have had disease progression during, or within 6 months of completing chemotherapy).
Approximately 18 evaluable participants are enrolled to the dose-finding portion of the study for each Group (A and B). In the dose expansion portion of the study, depending on efficacy detected in the dose-finding portion, up to 23 additional participants are enrolled for each Group. Participants continue on study treatment until death, radiographic progression, or unequivocal clinical progression, whichever occurs first.
Descriptions and administration instructions for study drugs are provided in Table 2.
Participants in the study must not have received second-generation ARSI treatment prior to enrollment. Participants may have had prior treatment with docetaxel for mCSPC with a maximum duration of 6 cycles (but must not have had disease progression during chemotherapy, or within 6 months of completing chemotherapy). Eligible participants are assigned sequentially to Group A or Group B. However, the sponsor may assign a participant to the alternative Group as clinically appropriate, based on the participant's baseline medical history and risk factors.
Dose levels for the compound of formula I in Part 1 are summarized in Table 3.
#The SET, after evaluating all safety and PK data emerging from DL1, may decide to open DL-1 even if DLT/treatment delay criteria are not met.
The first evaluable participant is accrued to DL1 for each Group. The dose-limiting toxicity (DLT) evaluation period is defined as the first 28 days (1 cycle) of combination treatment and is described in Section 4.1.3.
The planned minimum number of participants in either Group A or B is 6 and the planned maximum number is 18If the SET opens a higher dose level, participants in the lower dose levels are escalated into the higher dose level if they have passed the DLT period.
The RP2D is determined after review of all available pharmacokinetic, pharmacodynamic, safety, and efficacy data. The toxicity probability at each dose level is estimated based on isotonic estimates and the selection of the MTD is guided as the highest dose level, for which the isotonic estimate of the DLT rate is below the target rate of 28%, with consideration of all available PK, pharmacodynamic, safety, and efficacy data. If an MTD is determined, the RP2D regimen(s) may be lower than the MTD. If the MTD cannot be determined based on lack of toxicity, maximum administered dose (MAD) may be defined (Table 3).
The DLT evaluation period is defined as the first 28 days (1 cycle) of combination treatment. DLTs are assessed by the SET, along with safety, pharmacokinetic, and other available data. A DLT is defined as one of the following toxicities occurring in the DLT evaluation period (the SET may assess a toxicity that occurs outside the DLT evaluation period as a DLT, on a case-by-case basis), and is related to the compound of formula I, AAP, or apalutamide as assessed by the investigator and/or sponsor:
Approximately 18 evaluable participants are enrolled to the dose-finding portion of the study for each Group (A and B). In the dose expansion portion of the study, depending on efficacy detected in the dose-finding portion, up to 23 additional participants will be enrolled for each Group. Participants who are non-evaluable for futility analysis will be replaced. The total planned number of participants in this study is approximately 41 for each Group
Participants continue to receive study drug until radiographic disease progression, death, unequivocal clinical progression, unacceptable toxicity, withdrawal of consent, or lost to follow-up, whichever comes first. The end of study (study completion) is defined as the last assessment for the last participant on study.
Screening for eligible participants is performed within 30 days before administration of the study treatment.
The inclusion and exclusion criteria for enrolling participants in this study are described below.
Each potential participant must satisfy all of the following criteria to be enrolled in the study:
Any potential participant who meets any of the following criteria is excluded from participating in the study:
Composite response rate is used for the primary efficacy measure analysis. Other evaluations include investigator-assessed tumor measurements (i.e., chest, abdomen, and pelvis computed tomography [CT] or magnetic resonance imaging [MRI] scans and whole-body bone scans [99mTc]) and survival status.
Blood samples are collected to measure the plasma concentration of the compound of formula I and, if warranted, its metabolites, when dosed with the combination agent. Systemic (serum or plasma) concentrations of each combination agent, and population PK parameters and derived exposure are determined.
Changes in PSA are evaluated as pharmacodynamic markers of AR inhibition. Additional exploratory pharmacodynamic biomarkers may be evaluated in whole blood or plasma.
Biomarker samples are collected and, if deemed to be of scientific value, are evaluated to understand the mechanism of action of the compound of formula I in combination with A) AAP and B) apalutamide or may help to identify subgroups that respond differently to the study drug combinations. Samples collected for biomarker evaluations include archival tumor specimens, whole blood, plasma, serum, and tumor biopsies at baseline and at progression, if available.
Safety assessments are based on medical review of AE reports and the results of vital sign measurements, physical examinations, clinical safety laboratory tests, electrocardiograms (ECG), Eastern Cooperative Oncology Group Performance Score, and other safety evaluations at specified timepoints.
The BOIN method will determine the RP2D for the compound of formula I in separate combinations with (A) AAP and (B) apalutamide with an upper bound for the true DLT rate equal to 28%.
The sponsor will monitor the futility of each combination separately by applying Simon's 2-stage which will test for the null hypothesis of composite response rate of <48% against composite response rate >70%.
Statistical analysis are performed for each treatment combination separately. Bayesian Optimal Interval (BOIN) design is applied to find the RP2D of the compound of formula I in separate combinations with AAP and apalutamide. Simon's 2-stage design is utilized to evaluate the futility of each combination. In the first stage, data from participants treated at the RP2D in the dose-finding portion of the study are used to evaluate futility. Data is summarized using descriptive statistics. Continuous variables are summarized using the number of observations, mean, standard deviation (SD), median, and range. Categorical values are summarized using the number of observations and percentages as appropriate.
In general, dose interruptions/modifications should be managed as described in Table 4:
The following general principles should be followed:
Dose escalation is permitted after resolution of toxicities to Grade≤1 or baseline. The investigator's rationale to re-escalate treatment must be discussed with the sponsor's medical monitor on an individual basis prior to implementation
After the DLT period, at each dose level, up to 2 dose reductions are permitted (e.g., from 1000 mg to 800 mg; from 800 mg to 600 mg), based on review of emerging safety and pharmacokinetic data.
For abiraterone acetate, up to 2 dose-level reductions are permitted. At each dose-level reduction, the dose is reduced by 250 mg of AA: 1000 mg to 750 mg, or 750 mg to 500 mg. Doses below 500 mg are not permitted. Dosing of prednisone may be decreased from 5 mg BID to 5 mg once daily, at the investigator's discretion.
For apalutamide, up to 2 dose reductions are allowed. At each dose-level reduction, the dose is reduced by one tablet (60 mg) of apalutamide: 240 mg to 180 mg, or 180 mg to 120 mg. Doses below 120 mg apalutamide are not permitted.
If a participant has clinical progression—i.e. worsening ECOG PS to >3, use of opiates for ≥3 weeks, radiotherapy or surgery for the treatment of tumor progression-even if no radiographic disease progression is confirmed-study treatment can be stopped based on physician's discretion and subsequent treatment initiated.
Participants with clinical benefit as deemed by the investigator despite PSA and/or radiographic progression may continue treatment after consultation with the sponsor.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, compositions, formulations, or methods of use of the invention, may be made without departing from the spirit and scope thereof.
The invention is further defined by the following numbered embodiments:
1. A method of treating metastatic castration-resistant prostate cancer (mCRPC) in a male human, said method comprising administering a therapeutically effective amount of a compound of formula I and a therapeutically effective amount of abiraterone acetate plus a therapeutically effective amount of a corticosteroid to said male human
2. The method of embodiment 1, wherein the compound of formula I is administered orally to the male human at a dose of from about 600 mg per day to about 1000 mg per day.
3. The method of embodiment 1 or 2, wherein the compound of formula I is administered orally to the male human at a dose of:
17. The method of embodiment 16, wherein the compound of formula I is administered orally to the male human at a dose of from about 600 mg per day to about 1000 mg per day.
18. The method of embodiment 16 or 17, wherein the compound of formula I is administered orally to the male human at a dose of:
31. A method of achieving a composite response rate in a male human with metastatic castration-resistant prostate cancer (mCRPC), said method comprising administering a therapeutically effective amount of the compound of formula I and apalutamide to said male human
32. The method of embodiment 30 or 31, wherein the compound of formula I is administered orally to the male human at a dose of from about 600 mg per day to about 1000 mg per day.
33. The method of any one of embodiments 30 to 32, wherein the composite response rate comprises a PSA90, an objective response rate, or both.
34. The method of any one of embodiments 30 to 33, wherein the composite response rate is at 12 weeks post administration of the compound of formula I and apalutamide.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/074400 | 9/1/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63239616 | Sep 2021 | US |
