METHODS OF TREATING PROSTATE CANCER WITH MINIMAL SIDE EFFECTS

CROSS REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of priority to U.S. Provisional Application No. 63/083,955, filed on September 27, 2020, hereby incorporated by reference.

FIELD OF THE INVENTION

[002] The present invention is directed to methods of treating a prostate cancer, including metastatic prostate cancer, in a therapeutically effective dose and dosing schedule while minimizing undesired side effects to improve patient tolerance and/or compliance.

BACKGROUND OF THE INVENTION

[003] Prostate cancer is the most prevalent form of cancer in men and the second leading cause of death due to cancer in men in the United States. According to the National Cancer Institute, approximately 2.9 million men are currently living with prostate cancer in the United States, and approximately 190,000 men are newly diagnosed in the United States each year. Approximately one million prostate biopsies are performed yearly in the U.S. The vast majority of these biopsies are performed due to elevated levels of the prostate cancer marker pro state- specific antigen (PSA). Persistently elevated PSA levels and/or other clinical parameters that prompt initial biopsies contribute to stress and anxiety among both patients and their urologists.

[004] After diagnosis of prostate cancer by prostatic biopsy, most men with localized prostate cancer are treated with either active surveillance, surgery, or a form of radiation therapy. If the patient then progresses from the localized stage or presents with advanced or metastatic disease, androgen deprivation therapy (ADT) is the mainstay therapy. Androgens include testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone, and androstenedione. Most prostate cancers are androgen dependent and androgens, such as testosterone and DHT, promote the growth of cancerous prostate cells. ADT drastically reduces serum testosterone levels, blocks androgen receptor signaling, and delays prostate cancer progression. ADT serves as alternative to surgical castration and is valuable in the treatment of prostate cancer.

[005] One mode of ADT is castration, either by orchiectomy or chemically by a gonadotropinreleasing hormone (GnRH) agonist (GnRH receptor agonist) or antagonist, is the primary therapy in advanced prostate cancer, such as localized progressive and metastatic cancers. GnRH agonists, such as leuprolide acetate, or antagonists, such as degarelix or relugolix, are widely used for this therapy.

[006] Unfortunately, prostate cancer frequently becomes resistant and progresses during ADT therapies to become castration (or hormone) resistant prostate cancer (CRPC), which can be metastatic (mCRPC) or nonmetastatic (nmCRPC). Androgen receptor axis blocking (ARB) agents such as traditional antiandrogens (z.e., AR antagonists such as bicalutamide, enzalutamide, apalutamide, and darolutamide) or lyase inhibitors (z.e., androgen synthesis inhibitors such as abiraterone acetate (approved in combination with prednisone)) are approved for concomitant use with ADT for nmCRPC and mCRPC and even for castration sensitive (CSPC). However, ARB agent resistance eventually develops in all settings; initial failure rates are as high as 15-25% and progression is seen in 75-85% of the men in 9-15 months for mCRPC (ES Antonarakis, Clin Adv. Hem. One., 2006, 14:316-319 2016). The approvals of abiraterone (2011), enzalutamide (2012), apalutamide (2018), and darolutamide (2019) for mCRPC and nmCRPC has increased ARB agent resistance in the prostate cancer patient population for which hormonal therapies have been exhausted.

[007] Cytotoxic chemotherapies were approved for mCRPC and are often employed in ARB agent resistant patients. For these patients, docetaxel is used as a first-line drug and cabazitaxel is used where the patient’s disease has progressed on docetaxel. Disease progression can mean an increase in PSA (biochemical reoccurrence), and/or significant changes in the patient’s disease state such as new or larger metastases and/or changes in symptoms such as increased bone pain. These agents displaced mitoxanthrone (approved in 1996 with prednisone) as the cytotoxic chemotherapies of choice for mCRPC, as taxanes demonstrated an overall survival benefit, in contrast to mitoxanthrone that was considered just palliative care by reducing pain. However, all these agents pose substantial safety concerns due to hematologic toxicities (e.g., neutropenia including febrile neutropenia, thrombocytopenia, anemia, etc.,); neurotoxicities (e.g., neuropathies including peripheral neuropathy); gastrointestinal toxicities (e.g., grade 3 or 4 diarrhea, nausea, vomiting, etc.); cardiotoxicities (e.g., heart failure); among others.

[008] Additionally, drugs such as docetaxel and cabazitaxel must be administered by intermittent intravenous infusion requiring a functioning canula that is distressing to patients; time and labor intensive; and is prone to infection and injection site reactions. Patients require premedications prior to IV infusions of corticosteroids and antihistamines to prevent hypersensitivity reactions. Further, there are common adverse events such as alopecia, low grade nausea/vomiting/diarrhea, and fatigue, to name a few.

[009] Treatments for prostate cancer have numerous side effects that range in severity from tolerable to life-threatening. Side effects include erection problems, loss of libido, gastrointestinal problems, fatigue, osteoporosis, urinary problems, joint pain, weight loss, neutropenia, neurotoxicity, abnormal liver function, diarrhea, decreased appetite, among others. Common lifethreatening side effects caused by agents, such as mitoxantrone, docetaxel, cabazitaxel, or a platinum agent like carboplatin or cisplatin, include hematologic toxicities (e.g., neutropenias including febrile neutropenias, thrombocytopenias, etc.); neurotoxicities (e.g., neuropathies including peripheral neuropathy which may or may not be reversible); gastrointestinal toxicities (e.g., grade 3 or 4 diarrhea); loss of hearing; and cardiotoxicities (e.g., heart failure). Neutropenias, neuropathies, and/or gastrointestinal toxicities are seen for all cytotoxic chemotherapies, which include mitoxantrone, docetaxel, and cabazitaxel.

[0010] A recent study on docetaxel morbidity pooled the results from three randomized studies. Of patients < 75 years of age, neutropenia was observed in 15.4% and neurotoxicity in 21.9%. Overall, high grade AEs were in 51.3%. In those greater than or equal to 75 years of age, neutropenia was 25% and neurotoxicity was found in 22.2%. High grade AEs were observed in 66%. (Abdel-Rahman O Urologic Oncology, 202038:210-215.)

[0011] The taxane cabazitaxel, which, like docetaxel, binds to the taxane site on beta tubulin of microtubules, was discovered to have activity in docetaxel resistant cell lines in vitro as cabazitaxel had low affinity for P-glycoprotein, a multidrug resistance protein, and later was found to have benefit in mCPRC patients who had progressed on docetaxel in clinic. Intravenously administered, cabazitaxel 25 mg/m ² administered once every 3 weeks plus prednisone demonstrated PSA and radiographic response benefit, and a survival benefit vs. mitoxantrone of 15.1 months vs. 12.7 months; but also had significant (5%) treatment-related mortality due to neutropenia and/or diarrhea. Nonetheless, in 2010, cabazitaxel was approved and recommended as a therapy in patients with symptomatic CRPC who have progressed after receiving docetaxel.

[0012] In addition, when a patient develops resistance to docetaxel and/or cabazitaxel, other agents are sometimes prescribed including oxaliplatin and satraplatin. However, oxaliplatin plus gemcitabine caused grade 3-4 neutropenia and thrombocytopenia, and satraplatin plus prednisone caused hematologic and gastrointestinal toxicities. [0013] Prostate cancer treatment, however, has side effects including erection problems, loss of libido, gastrointestinal problems, fatigue, osteoporosis, urinary problems, joint pain, weight loss, neutropenia, neurotoxicity, abnormal liver function, diarrhea, decreased appetite, among others.

[0014] Consequently, development is needed for a new treatment that is easy and convenient to administer, does not cause undesired side effects, and increases patient tolerance when treating prostate cancer.

SUMMARY OF THE INVENTION

[0015] The invention encompasses methods of treating prostate cancer in a subject in need thereof by administering Compound 17ya to the subject,

Compound 17ya wherein Compound 17ya is administered in an amount of about 2 mg to about 108 mg and neutropenia and neurotoxicity are not observed in the subject during treatment. One embodiment of the invention encompasses methods wherein the amount of Compound 17ya is about 4.5 mg to about 72 mg per dose. Another embodiment of the invention encompasses methods wherein the amount of Compound 17ya is about 9 mg to about 63 mg per dose. Another embodiment of the invention encompasses methods wherein the amount of Compound 17ya is about 4.5 mg to about 32 mg per dose. Another embodiment of the invention encompasses methods wherein the amount of Compound 17ya is about 18 mg to about 45 mg per dose. Another embodiment of the invention encompasses methods wherein the amount of Compound 17ya is any of about 4.5 mg, 9 mg, 14 mg, 18 mg, 23 mg, 27 mg, 32 mg, 36 mg, 41 mg, 45 mg, 54 mg, 63 mg, 72 mg, or 81 mg. Yet in another embodiment of the invention, the dose is a daily dose. An embodiment of the invention encompasses methods wherein the subject is dosed to yield an AUCinf of less than 1950 hr*ng/mL. Another embodiment of the invention encompasses wherein the dose is oral and taken once, twice, or thrice daily. Yet another embodiment of the invention encompasses methods wherein Compound 17ya is dosed in a 21-day cycle, wherein Compound 17ya is administered once a day or twice a day for seven consecutive days followed by 14 days off. One embodiment of the invention encompasses methods wherein Compound 17ya is dosed once a day or twice a day for 14 consecutive days followed by seven days off. Another embodiment of the invention encompasses methods wherein Compound 17ya is dosed once a day or twice a day for a 21-day consecutive day cycle. Yet another embodiment of the invention encompasses methods where the subject is dosed for at least two to four 21-day consecutive cycles.

[0016] The invention also encompasses methods of treating prostate cancer in a subject in need thereof by administering Compound 17ya to the subject in an amount sufficient to reduce the prostate specific antigen by at least 15% from the amount of the baseline PSA level. One embodiment of the invention encompasses methods wherein the prostate specific antigen is reduced by at least 30% from the amount of the baseline PSA level. Another embodiment of the invention encompasses methods wherein the prostate specific antigen is reduced by at least 50% from the amount of the baseline PSA level.

[0017] The invention also encompasses methods of treating prostate cancer in a subject in need thereof by administering Compound 17ya to the subject,

Compound 17ya wherein Compound 17ya is in an amount of about 2 mg to about 108 mg and neutropenia and neurotoxicity are not observed in the subject during treatment. One embodiment of the invention encompasses methods wherein Compound 17ya is in an amount of about 2 mg to about 108 mg and neutropenia and neurotoxicity are not observed in the subject during treatment, and fatigue, nausea, and diarrhea, if present, are reversible. One embodiment of the invention encompasses methods wherein the diarrhea is grade 3 or lower diarrhea. Another embodiment of the invention encompasses methods wherein at least one of loperamide or bismuth subsalicylate are concurrently or consecutively administered with Compound 17ya.

[0018] The invention also encompasses using the methods described above for treating subjects that have metastatic castration resistant prostate cancer (mCRPC). An embodiment of the invention encompasses methods for treating subjects that are resistant to antiandrogen treatments. Another embodiment encompasses methods for treating subjects wherein the antiandrogen is at least one of darolutamide, apalutamide, enzalutamide, bicalutamide, or abiraterone acetate. Yet another embodiment encompasses methods for treating subjects that are taxane naive. One embodiment of the invention encompasses methods for treating subjects that have previously received taxane treatments (/'.<?., taxane experienced). One embodiment of the invention encompasses methods for treating subjects that are resistant to taxane treatments. Another embodiment of the invention encompasses methods for treating subjects that are resistant to antiandrogen and previously received taxane treatments. Another embodiment of the invention encompasses methods for treating subjects that are resistant to antiandrogen and taxane treatments. Yet another embodiment of the invention encompasses methods for treating subjects that have nonmetastatic castration sensitive prostate (nmCSPC), metastatic CSPC (mCSPC), or nonmetastatic CRPC (nmCRPC). These subjects may be resistant to antiandrogen treatments; resistant to taxane treatments; resistant to antiandrogen and taxane experienced; or resistant to antiandrogen and taxane treatments.

[0019] The invention encompasses methods of treating prostate cancer in a subject in need thereof by administering Compound 17ya to the subject,

Compound 17ya wherein Compound 17ya is in an amount effective to treat the cancer and neutropenia, neurotoxicity, or neuropathy is not observed in the subject during treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The subject matter regarded as the invention is particularly pointed out and distinctly claimed in the concluding portion of the specification. The invention, however, both as to organization and method of operation, together with objects, features, and advantages thereof, may best be understood by reference to the following detailed description when read with the accompanying drawings in which:

[0021] Figures 1A-1B illustrate concentration-time plots for Compound 17ya (hydrochloride salt) in the blood of patients with antiandrogen resistant metastatic castration-resistant prostate cancer (CRPC) treated with Compound 17ya (hydrochloride salt). Blood samples were taken at the indicated times after dosing on Day 8 of a 21-day once per day dosing cycle (continuous dosing). Subjects were treated with 9, 18, 27, 36, 45, 54, 63, 72, or 81 mg per day. The blood samples were taken when the subject returned to the clinic for the collection of samples and evaluation, and approximately 2-52 hours after the last dose. The concentrations (ng/mL) observed on Day 8 were normalized by dose administered (ng/mL/mg dose) and plotted on a plasma concentration versus time curve as illustrated in Figure 1A. The samples were grouped together in 3 -hour time intervals and the average of the time and concentration of each group was plotted in a plasma concentration versus time curve as illustrated in Figure IB.

[0022] Figure 2 illustrates the maximum PSA response of subjects treated with Compound 17ya after completing at least four 21-day continuously dosed cycles, as compared to the PSA level at the beginning of the 21-day cycle (baseline).

[0023] Figure 3 illustrates a swimmers’ plot of the subjects treated with Compound 17ya for at least four 21-day cycles illustrating their duration of response to the study drug. The arrow indicates treatment ongoing; X indicates treatment terminated; PD indicates treatment terminated for progressive disease; PI indicates treatment terminated by the principal investigator; and WC indicates that the subject withdrew consent.

[0024] Figures 4A-4B illustrate the effect on a subject with a metastatic castration resistant lymph node only disease after prostate cancer progression and subsequent treatment with Compound 17ya, having previously been treated with leuprolide, bicalutamide, sipuleucel-T, enzalutamide, and abiraterone. Figure 4A (left panel) illustrates a screening CT scan of the right anterior psoas muscle cancerous lymph node and the right panel illustrates the same lymph node after 8 months of treatment with Compound 17ya. This target lesion regressed by 33%. Figure 4B illustrates a coronal CT scan on day one of treatment (left panel) and after 15 months of treatment (right panel). Similar to above, target lesions A, B, and C were observed to regress following treatment for 15 months with Compound 17ya.

DETAILED DESCRIPTION OF THE INVENTION

[0025] The treatment of prostate cancer may be limited by a variety of factors that include effectiveness of active ingredient, methods of drug delivery, and/or tolerability. The discovery of new drugs addresses effectiveness. Newly developed drugs are more effective and combat the development of resistance to current treatments. Drug delivery can diminish side effects commonly associated with the method in which a new drug is administered to a patient population to enhance tolerability of the patient population. Drugs can be delivered via a variety of routes (orally, intravenously, etc.) or by using different formulations administered via the same route that can be optimized to diminish side effects for a particular active ingredient. Tolerability is a patient dependent factor, where individual subjects tolerate different levels of discomfort or morbidity caused by the undesirable side effects of a particular treatment. The quantity and severity of the side effects can negatively impact an effective treatment when those side effects impose a poor quality of life on the patient, a high cost associated with treatment, or adversely affect the health and well-being of the patient. Some side effects are non-treatable, while others may be treated with secondary medicines that may require additional prescriptions or simply the use of an over-the-counter medication.

[0026] Treatments for prostate cancer have numerous side effects depending on which treatment is used, although many side effects are common to multiple treatments. Side effects may include anemia, alopecia, cardiotoxicities such as heart failure, erection problems, hematologic toxicity, loss of hearing, loss of libido, gastrointestinal problems, fatigue, my elo suppression, osteoporosis, thrombocytopenia, urinary problems, joint pain, weight loss, neuropathy, neutropenia, neurotoxicity, abnormal liver function, diarrhea, decreased appetite, among others. Neurotoxicity is a frequent and dose-limiting side effect of chemotherapy, and apart from dose reduction or discontinuing the drugs implicated in the development of neurotoxicity, there is very little in the way of specific pharmacological management to reverse their side effects. Peripheral neuropathies are the most common neurological complications in patients receiving chemotherapy, especially with regimens containing taxanes, platinum, and vinca alkaloids.

[0027] Ideally, a novel treatment has few side effects including these expected side effects and few, if any, new side effects associated with the new treatment. Tolerability may be impacted by the drug delivery method or the drug itself. Ideally, novel prostate cancer treatments include a drug delivery method and/or dosing schedule that maximizes patient compliance while concurrently minimizing undesirable side effects that reduce patient tolerance.

[0028] Not to be limited by theory, the present invention maximizes drug delivery in a therapeutically effective window while concurrently increasing patient tolerance and minimizing undesirable side effects. In the present invention, many of the anticipated side effects associated with prostate cancer treatment are absent, including neutropenia, neurotoxicity, and/or myelosuppression, while side effects associated with the drug delivery method are minimal to nonexistent based on the dose and/or dosage regimen.

[0029] One of the major challenges in cancer therapeutics is developing agents that have potent anti-tumor activity while maintaining a tolerable side effect profile. The therapeutic index (TI) is a ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective. The larger the TI, the safer the drug is. The TI for most chemotherapeutic agents is relatively small providing for a narrow window between efficacy and limiting toxicity. Based upon the preclinical data that had been amassed regarding Compound 17ya, a relatively large TI was not anticipated, nevertheless, the data obtained in clinical trials demonstrates that the compound had a relatively large TI.

[0030] The invention encompasses methods of treating prostate cancer in a subject in need thereof by administering Compound 17ya to the subject, Compound 17ya wherein Compound 17ya is in an amount of about 2 mg to about 108 mg and neutropenia and neurotoxicity are not observed in the subject during treatment. Compound 17ya is also known as (2-(l/Z-indol-3-yl)-l/Z-imidazol-4-yl)(3,4,5-trimethoxypheny l)methanone (17ya).

[0031] The therapeutically effective amount will depend upon the specific formulation, dosing regimen, the mode of administration, the particular condition of the prostate cancer being treated and the desired outcome. It will also depend upon the stage of the condition, the age, and physical condition of the subject, the nature of concurrent therapy, if any, and like factors that are well known to the medical practitioner. Typically, the amount of Compound 17ya administered to the subject is sufficient to be therapeutically effective in the treatment of prostate cancer. Generally, the amount of Compound 17ya is about 2 mg to about 108 mg per dose. Preferably, the amount of Compound 17ya is about 4.5 mg to about 81 mg per dose and more preferably, the amount of Compound 17ya is about 4.5 mg to about 72 mg per dose, and most preferably, the amount of Compound 17ya is about 9 mg to about 63 mg per dose. Another embodiment of the invention encompasses methods wherein the amount of Compound 17ya is about 4.5 mg to about 32 mg per dose. Another embodiment of the invention encompasses methods wherein the amount of Compound 17ya is about 18 mg to about 45 mg per dose. Another embodiment of the invention encompasses methods wherein the amount of Compound 17ya is any of about 4.5 mg, 9 mg, 14 mg, 18 mg, 23 mg, 27 mg, 32 mg, 36 mg, 41 mg, 45 mg, 54 mg, 63 mg, 72 mg, or 81 mg. Alternatively, these dosages may be administered on a per day basis, e.g., once or twice a day.

[0032] The bioavailability of Compound 17ya may change depending on the specific formulation that was administered. Further, the bioavailability of Compound 17ya may change depending on whether the drug is administered to a subject when the subject has eaten or not. In other words, Compound 17ya may be administered to a subject with or without food, i.e., a fed or fasted state . If administered under a fed state, then the amount of Compound 17ya that is administered may be reduced to achieve the same or similar bioavailabilty of a larger dose.

[0033] The dosing may be scheduled to follow a 21 day cycle, wherein the dosing days and days off are followed as described below. The dose may be administered once a day or twice a day for seven consecutive days followed by 14 days off. Alternatively, the dose may be administered once a day or twice a day for 14 consecutive days followed by seven days off. Preferably, the dose may be administered once a day or twice a day for 21 consecutive days of the 21-day cycle. More preferably, the dose may be administered once a day or twice a day for at least four 21 -day cycles. Most preferably, the dose may be administered once a day or twice a day continuously until disease progression.

[0034] It is understood that lower or higher doses than those recited above may be required. It is also understood that doses will vary to obtain the parameters described below. Specific dosage and treatment regimens for any particular subject will depend upon a variety of factors, including the activity of the specific compound employed, the specific formulation employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, and condition or symptoms, and the judgment of the treating physician.

[0035] The invention encompasses methods employing the various formulations or dosage forms known to the skilled artisan for delivering Compound 17ya wherein the pharmacokinetic parameters such as bioavailability vary between formulations or dosage forms. In some embodiments of the invention, different formulations require the use of different doses of Compounds 17ya or its pharmaceutically acceptable salt as measured by weight (mg) to achieve the desired efficacy without side effects. Accordingly, Compound 17ya is dosed to obtain blood concentrations over time so that the total blood exposure as measured by the area under the curve (AUC) has a value of at least about 278.5 hr*ng/mL when measured from time zero to infinity (AUCinf). Alternatively, the AUC of Compound 17ya has a value of less than about 1,949.5 hr*ng/mL. Compound 17ya may also be dosed to obtain an AUC of about 278.5 hr*ng/mL to about 1,949.5 hr*ng/mL.

[0036] The invention encompasses methods of treating a subject with prostate cancer by administering Compound 17ya to yield an AUCinf of about 61.9 hr*ng/mL to about 3342 hr*ng/mL, whereby the subject does not experience neutropenias, neurotoxicities, or gastrointestinal toxicities. Typically, the method includes an AUCinf of about 140 hr*ng/mL to about 2506.5 hr*ng/mL. Preferably, the method yields an AUCinf of about 278.5 hr*ng/mL to about 2228 hr*ng/mL. And more preferably, the method of treating a subject with prostate cancer by administering Compound 17ya to yield an AUCinf of about 278.5 hr*ng/mL to about 1945.5 hr*ng/mL. The invention also encompasses methods of treating prostate cancer in a subject by administering Compound 17ya to obtain a peak blood level or concentration at steady state from about 45 ng/mL to about 315 ng/mL. Alternatively, Compound 17ya may be administered to obtain a trough blood level of about 0.4 ng/mL to about 24 ng/mL. Preferably, the trough blood level is about 1 ng/mL to about 18 ng/mL. More preferably, the trough blood level is about 2 ng/mL to about 16 ng/mL. In some embodiments, the invention encompasses methods of treating prostate cancer in a subject where the subject does not experience neutropenias, neurotoxicities, or grade 4 gastrointestinal toxicities.

[0037] In some embodiments of the invention, the dose given to a subject that achieves the ranges of AUC of Compound 17ya or blood concentrations of Compound 17ya stated above is any of about 4.5 mg, 9 mg, 14 mg, 18 mg, 23 mg, 27 mg, 32 mg, 36 mg, 41 mg, 45 mg, 54 mg, 63 mg, 72 mg, or 81 mg, whereby the subject does not experience neutropenias, neurotoxicities, and/or grade 4 gastrointestinal toxicities. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 4.5 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 9 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 14 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 18 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 23 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 27 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 32 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 36 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 41 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 45 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 54 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 63 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 72 mg. In one embodiment, the dose of Compound 17ya administered for treating a subject with prostate cancer whereby the subject does not experience neutropenias or neurotoxicities is about 81 mg.

[0038] The invention encompasses treating prostate cancer in a subject in need thereof by administering Compound 17ya to the subject in an amount sufficient to reduce the prostate specific antigen (PSA) by 30% from the amount of the baseline PSA level. Typically, the reduction in prostate specific antigen is about 15% from the baseline PSA level, preferably the reduction is about 30%, more preferably the reduction is about 50% from the baseline PSA level, and most preferably the reduction is greater than about 50% from the baseline PSA level. The PSA level may be determined using methodology commonly known to the skilled artisan such as Prostate Cancer Clinical Trials Working Group 3 (PCWG3, J. Clin. One., 2016, 34, 1402-1418) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Eur. J. Can., 2009, 45, 228-247) criteria. The primary endpoint used in pivotal efficacy studies for the treatment of prostate cancer was the median time to cancer progression by imaging (bone and CT scans).

[0039] As used herein, the term “baseline PSA level” refers to the prostate specific antigen level of a subject prior to treatment with Compound 17ya.

[0040] As used herein, the term “resistant to treatment” refers to disease progression while being administered for a particular treatment. Disease progression can mean an increase in PSA, and/or significant changes in the patient’s disease state such as new or larger metastases and/or changes in symptoms such as increased bone pain.

[0041] The invention encompasses methods of treating prostate cancer in a subject in need thereof by administering Compound 17ya to the subject, wherein Compound 17ya is administered in an amount of about 2 mg to about 108 mg and the amount does not cause measurable neutropenia, neurotoxicity, or myelosuppression during treatment. The method further encompasses methods of treating prostate cancer wherein the amount of Compound 17ya minimizes side effects such as diarrhea, fatigue, nausea, abnormal liver function tests, alopecia, and vomiting. In one method, the diarrhea is reversible grade 3 diarrhea or lower. The nausea may be mild to moderate nausea. Methods of the invention encompass treating prostate cancer in a subject in need thereof by administering Compound 17ya to the subject, wherein Compound 17ya is administered in an amount of about 2 mg to about 108 mg and the amount does not cause measurable neutropenia, neurotoxicity, or myelosuppression and diarrhea in grade 3 or less in the subject during treatment. The methods may further comprise reversible nausea and reversible fatigue. As used herein, the term “reversible” means the effect decreases in severity or becomes unmeasurable upon discontinued medication.

[0042] The methods further encompass the administration of an over-the-counter medication to countereffect side effects such as nausea, diarrhea, and/or fatigue. OTC medications include loperamide, and bismuth subsalicylate, among others. Administration may be concurrent or consecutive, e.g., administration only when symptoms appear.

[0043] Adverse events are reported on a grade 1 to 4 scale. Grade 3 adverse events are severe and undesirable adverse events (e.g., significant symptoms requiring hospitalization or invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation). Grade 4 adverse events are life threatening or disabling adverse events (e.g., complicated by acute, life- threatening metabolic or cardiovascular complications such as circulatory failure, hemorrhage, or sepsis; life-threatening physiologic consequences; need for intensive care or emergent invasive procedure or intervention).

[0044] The subjects encompassed by the invention include subjects with prostate cancer including, but not limited to, castration-resistant prostate cancer (CRPC), castration sensitive prostate cancer (CSPC) or androgen receptor axis blocking (ARB) resistant prostate cancer. Castration-resistant prostate cancer (CRPC) includes metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC). Castration sensitive prostate cancer (CSPC) includes metastatic castration sensitive prostate cancer (mCSPC) and nonmetastatic castration-sensitive prostate cancer (nmCSPC). In one method, the cancer is metastatic castration-resistant prostate cancer. Some subjects may be resistant to androgen receptor axis blocking agents, such as abiraterone or enzalutamide, and may have exhausted androgen receptor targeted approaches. Some subjects may be taxane therapy naive, whereas other subjects may be taxane experienced, resistant to a taxane agent, and may have exhausted taxane binding site targeted approaches.

[0045] The method of administration can be oral or injected. Preferably, the method of administration is oral. Oral administration includes, but is not limited to, oral tablet, capsule, or pill. Preferably, the method of administration is an oral capsule. Other methods for oral administration include, but are not limited to immediate release capsule, immediate release tablet, immediate release 3D printed tablet, modified release tablet, and modified release 3D printed tablet. Optionally, the tablet, capsule, or pill may include at least one coating to modify the time of drug release or protect the gastrointestinal track until release is desired. Coatings include, but are not limited to, at least one of immediate release, extended release, enteric coatings, or delayed release. It is understood that should a coating modify the time of drug delivery, then the drug dosage may be modified as well. Likewise, it is understood that should different formulations of a capsule, or different formulations of a tablet, modify the time or extent of drug delivery, then the drug dosage may be modified as well.

[0046] Compound 17ya can also be in the form of a hydrate, which means that the compound further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces. The compound used in the methods of the invention was synthesized using the methodology described in US Patent Nos. 8,592,465; 8,822,513; 9,029,408; 9,334,242; 9,447,049; and 10,301,285, and US publication No. 2020/24270, hereby incorporated by reference.

[0047] The invention includes “pharmaceutically acceptable salts” of Compound 17ya used in the method of the invention, which may be produced, by reaction of a compound of this invention with an acid or base. Certain compounds, particularly those possessing acid or basic groups, can also be in the form of a salt, preferably a pharmaceutically acceptable salt. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -tolucncsul Ionic acid, salicylic acid, A-acctylcystcinc and the like. Other salts are known to those of skill in the art and can readily be adapted for use in accordance with the present invention.

[0048] Suitable pharmaceutically-acceptable salts of amines of compounds used in the method of the invention may be prepared from an inorganic acid or from an organic acid. In one embodiment, examples of inorganic salts of amines are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.

[0049] Examples of organic salts of amines include, but are not limited to, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decanoates, enanthuates, ethanesulfonates, edetates, edisylates, estolates, esylates, fumarates, formates, fluorides, galacturonates gluconates, glutamates, glycolates, glucorate, glucoheptanoates, glycerophosphates, gluceptates, glycollylarsanilates, glutarates, glutamate, heptanoates, hexanoates, hydroxymaleates, hydroxycarboxlic acids, hexylresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobionates, laurates, malates, maleates, methylenebis(beta- oxynaphthoate), malonates, mandelates, mesylates, methane sulfonates, methylbromides, methylnitrates, methylsulfonates, monopotassium maleates, mucates, monocarboxylates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, napsylates, N- methylglucamines, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, phenylacetate, pectinates, phenylpropionates, palmitates, pantothenates, polygalacturates, pyruvates, quinates, salicylates, succinates, stearates, sulfanilate, subacetates, tartrates, theophyllineacetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, teoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates and valerates.

[0050] Examples of inorganic salts of carboxylic acids or hydroxyls may be selected from ammonium, alkali metals to include lithium, sodium, potassium, cesium; alkaline earth metals to include calcium, magnesium, aluminum; zinc, barium, cholines, quaternary ammoniums.

[0051] Examples of organic salts of carboxylic acids or hydroxyl may be selected from arginine, organic amines to include aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, /-butylamines, benethamines (iV-benzylphenethylamine), dicyclohexylamines, dimethylamines, diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, meglamines, A/-methyl- -glucamines, N,N’- dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolies, piperazines, procain, tris(hydroxymethyl)methylamines, triethylamines, triethanolamines, trimethylamines, tromethamines and ureas.

[0052] Typical salts include, but are not limited to, hydrofluoric, hydrochloric, hydrobromic, hydroiodic, boric, nitric, perchloric, phosphoric, sulfuric, acetate, citrate, maleate, malate, or mesylate. Preferred salts include hydrofluoric, hydrochloric, hydrobromic, hydroiodic, acetate, citrate, maleate, or mesylate. More preferred salts include hydrochloric, acetate, or maleate.

[0053] The salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of an existing salt for another ion or suitable ionexchange resin.

Pharmaceutical composition

[0054] The methods of the invention include the administration of a pharmaceutical composition including a pharmaceutically acceptable carrier and at least Compound 17ya described herein. Typically, the pharmaceutical composition may include Compound 17ya or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable excipient. The term "pharmaceutically acceptable excipient" refers to any suitable adjuvants, carriers, excipients, flavorant, or stabilizers, and can be used in pharmaceutical formulations either in solid or liquid form. Such forms include, but are not limited to, tablets, capsules, powders, solutions, suspensions, or emulsions.

[0055] Upon improvement of a subject's condition, a maintenance dose of a compound, composition or formulation may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Subjects may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. [0056] The solid unit dosage forms can be of the conventional type. The solid form can be a capsule and the like, such as an ordinary gelatin type containing the compounds and a carrier. Carriers include, but are not limited to, lubricants and inert fillers such as, lactose, sucrose, or cornstarch. The formulations may be tabulated with conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders like acacia, cornstarch, or gelatin, disintegrating agents, such as cornstarch, potato starch, or alginic acid, and a lubricant, like stearic acid or magnesium stearate.

[0057] The tablets, capsules, and the like can also contain a binder such as gum tragacanth, acacia, com starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0058] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets can be coated with shellac, sugar, or both. A symp can contain, in addition to active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.

[0059] For oral therapeutic administration, the formulation may include excipients and used in the form of tablets, capsules, elixirs, suspensions, symps, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compound in these compositions can, of course, be varied and can conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains from about 1 mg to about 108 mg of active compound, alternatively from about 2 mg to about 81 mg, alternatively from about 4 mg to 63 mg, or alternatively from about 9 or about 45 mg.

[0060] The formulations may be orally administered with an inert diluent, or with an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or they can be compressed into tablets, or they can be incorporated directly with the food of the diet. A preferred formulation is an oral formulation.

[0061] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0062] The compounds or pharmaceutical compositions used in the method of the present invention may also be administered in injectable dosages by solution or suspension of these materials in a physiologically acceptable diluent with a pharmaceutical adjuvant, carrier, or excipient. Such adjuvants, carriers and/or excipients include, but are not limited to, sterile liquids, such as water and oils, with or without the addition of a surfactant and other pharmaceutically and physiologically acceptable components. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols, such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions.

[0063] The formulation may also be administered parenterally. Solutions or suspensions of these formulations can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0064] When administering the formulations in the methods of the invention, the formulations may be administered systemically, concurrently, or sequentially. Administration can be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the desired site. Exemplary modes of administration include, without limitation, administering the compounds or compositions orally, topically, transdermally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes. Biological Activity

[0065] The invention is directed to methods of treating prostate cancer with Compound 17ya and formulations described above. Compound 17ya and formulations thereof have utility in treating prostate cancer. In certain instances, Compound 17ya and formulations thereof have utility in treating prostate cancer without side effects.

[0066] Compound 17ya’s clinical experience is based upon a Phase lb/2 clinical trial program in metastatic prostate cancer. From the safety perspective in the Phase lb portion of the clinical trial, there were no adverse events that were > grade 3 in severity at doses below 54 mg daily. At 54 mg, there was one > grade 3 event of fatigue; at 63 mg, there was one > grade 3 event each of fatigue, nausea, and vomiting; at 72 mg there were three > grade 3 events of diarrhea and one event of fatigue and one event of nausea; and at 81 mg there was one > grade 3 event each of anemia and nausea. At doses >72 mg, some patients experienced gastrointestinal adverse events (nausea, vomiting, and diarrhea) that were not adequately controlled by standard anti-emetic and anti-diarrheal treatments. Despite that at the >72 mg dose, the adverse events did not reach the protocol-defined level of a dose-limiting toxicity (DLT) the decision was made to establish 63 mg per day as the maximum tolerated dose (MTD).

[0067] Overall, the major treatment-emergent adverse events observed in the phase lb study were diarrhea (97%), fatigue (61%), and nausea (54%). A minority of these were > grade 3 (8% each). Decreased appetite, vomiting, and weight loss were each observed in 20% of patients. Anemia and neutropenia were observed in 15% (of which one case was > grade 3) and 13% of patients, respectively. Elevated liver enzymes were found in 13% of patients.

[0068] Similarly, in the subset of patients who received doses > 63 mg (n=54), the most common treatment-emergent adverse events were diarrhea (59%), fatigue (33%), nausea (31%), and decreased appetite (31%). Elevated liver enzymes were observed in 17-18% of patients. Adverse events that were > grade 3 in severity included: diarrhea (7%), fatigue (6%), ALT increase (6%), AST increase (4%), nausea (2%), vomiting (2%), and back pain (2%).

[0069] Compound 17ya can be dosed orally, with optional continuous dosing, to achieve efficacy (see Example 2) in a heavily pre-treated mCRPC patient population that is ARB agent resistant and taxane-experienced. Efficacy was demonstrated by standard metrics both in terms of serum PSA levels and RECIST 1.1 criteria for radiographic monitoring (tumor size). Unlike microtubule targeting agents such as docetaxel or cabazitaxel, or chemotherapy such as mitoxantrone or platinum agents, dose-limiting toxicities including neutropenia and neurotoxicity and severe gastrointestinal toxicities were not seen at doses of Compound 17ya below 72 mg, indicating that there is a therapeutic range within which ARB resistant and taxane- experienced mCRPC patients can be treated without neutropenias or neurotoxicities, or severe gastrointestinal toxicities. The ability to treat ARB resistant mCPRC with Compound 17ya without these side effects is unprecedented and represents a significant step forward in the treatment of mCRPC. Importantly, this activity was achieved using an orally active microtubule targeting agent that was tolerated when dosed with continuous daily doses for >84 days. All previously approved chemotherapies for prostate cancer including microtubule targeted agents required intravenous infusions forcing clinicians to administer the drug as a large bolus dose in the clinical setting. The large bolus dose produced very high blood levels leading to many off- target toxicities necessitating a long off drug period before the next drug administration cycle can begin. Often drug administration cycles were 21 days in length. Unprecedentedly, the invention allows continuous oral dosing of Compound 17ya which can be administered to exert efficacy in an ARB resistant mCRPC population as described herein but without the expected side effects. The skilled artisan can tailor therapy to achieve efficacy without side effects in view of the oral pharmacokinetics of Compound 17ya disclosed herein in the same ARB resistant mCRPC population where T1/2 was about 6 hours and none of the expected side effects were seen at steady state blood concentrations less than 315 ng/mL of Compound 17ya or steady state blood exposures (AUCinf) of less than 1950 hr*ng/mL of Compound 17ya, as described herein.

[0070] When administering the compounds and formulations described herein, the formulations can be administered systemically or directly to a specific site where the cancer is present. Administration may be accomplished in any manner effective for delivering the compounds or the pharmaceutical compositions to the cancer site. Administration methods include, but are not limited to, oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, by intracavitary or intravesical instillation, intraocular, intraarterial, intralesional, or by application to the mucous membrane. Mucous membranes include those found in the nose, throat, and/or bronchial tubes, among others. Preferably, the formulation is administered orally. Administration may be simultaneous or sequential with additional compounds or formulations to treat prostate cancer, or treatments used to address side effects associated with the compounds or dosages.

[0071] The following examples are presented in order to more fully illustrate the preferred embodiments of the invention. They should in no way, however, be construed as limiting the broad scope of the invention.

EXAMPLES

[0072] The Examples set forth below are for illustrative purposes only and are not intended to limit, in any way, the scope of the present invention.

EXAMPLE 1

Pharmacokinetics of Compound 17ya in mCRPC subjects resistant to antiandrogen therapy

[0073] A single blood sample was collected from ARB agent resistant subjects with metastatic castration-resistant prostate cancer (mCRPC) treated with Compound 17ya (hydrochloride salt) on Day 8 of a 21 -days of continuous once per day (daily) dosing cycle where subjects were treated with 9, 18, 27, 36, 45, 54, 63, 72, or 81 mg per day. The blood samples were taken when the subject returned to the clinic for the collection of samples evaluation and approximately 2-52 hour after the last dose. The concentrations (ng/mL) observed on Day 8 were normalized by dose administered (ng/mL/mg dose) and plotted on a plasma concentration versus time curve as illustrated in Figure 1A.

[0074] The samples were grouped together in 3-hour time intervals and the average of the time and concentration of each group was plotted in a plasma concentration versus time curve as illustrated in Figure IB. The mean concentrations determined in this assessment were included in Table 1. The estimated concentrations for the 54 mg, 63 mg and 72 mg doses were taken by multiplying the mean concentration (ng/mL/mg dose) by the dose to arrive at an estimated concentration (ng/mL).

[0075] The estimated concentrations above are estimates of the plasma concentration vs. time profile of Compound 17ya at the stated doses. It was assumed that Compound 17ya exhibited linear kinetics within the dose range tested and that on Day 7 Compound 17ya achieved steady state. From the data above, a dose normalized steady state AUCinf was calculated to be 30.9444 hr*ng/mL per mg of Compound 17ya. A dose normalized blood concentration at steady state achieved immediately after dosing achieved was calculated to be about 5 ng/mL per mg of Compound 17ya. Approximately 24 hours later, the dose normalized blood concentration was calculated to be about 0.2 ng/mL per mg of Compound 17ya. Based on the above data, a skilled practitioner can adjust the dose for any given patient to achieve a target range of AUCinf (hr*ng/mL) or blood concentration (ng/mL) of Compound 17ya necessary to impart an effective therapy without the side effects of neurotoxicity, neuropathy, or neutropenia, as described herein. [0076] Based on the calculated plasma concentrations for the dosing range of Compound 17ya, an estimated AUCinf (AUCo-24h or AUCo-t) was determined to be: 1671 hr*ng/mL for a dose of 54 mg of Compound 17ya; 1949 hr*ng/mL for a dose of 63 mg of Compound 17ya; and 2228 hr*ng/mL for a dose of 72 mg of Compound 17ya.

[0077] The plasma concentrations were calculated, not observed, and the conclusions drawn from the analysis may be limited. Nevertheless, it was estimated that the T% of Compound 17ya is likely <6 hours. Therefore, the plasma concentration of Compound 17ya probably achieves steady state within 30-42 hours of administration. Since the subjects received daily doses on Days 1-7 prior to the sample on Day 8, it is very likely that the pharmacokinetics of Compound 17ya achieved steady state at the time of analysis. EXAMPLE 2

PSA response to the administration of Compound 17ya (Figure 2)

[0078] Male subjects, who have also become resistant to androgen receptor axis blocking agents such as abiraterone or enzalutamide, were treated with Compound 17ya (hydrochloride salt) for metastatic castration resistant prostate cancer (mCRPC). Thirty percent of men had previously taken both abiraterone and enzalutamide. Thirty men were taxane naive and nine men had previous IV taxane therapy.

[0079] Efficacy: Compound 17ya was administered orally to subjects at different doses. Doses included 9 mg, 27 mg, 36 mg, 63 mg, and 72 mg per day of Compound 17ya formulated into an oral formulation. Initially, the subjects received the dose daily for seven consecutive days followed by 14 days with no drug. Then the subjects received the dose daily for 14 days consecutively followed by 7 days with no drug. Subsequently, the dosage days were increased to include 21 consecutive days without any off days. The PSA level for each subject was tested prior to administration of Compound 17ya (baseline PSA) and again after administration of Compound 17ya.

[0080] Efficacy (antitumor activity) was assessed by serum PSA and standard local imaging with bone and CT scans. In eight men that received at least four 21 -day continuously dosed cycles of oral Compound 17ya at any dose, based upon their 21-day cycle baseline PSA levels, 6/8 (75%) had decreases in their PSA levels; 4 subjects (50%) demonstrated a > 30% decline; and 2 subjects (25%) had a > 50% decline in serum PSA. Based upon PCWG3 and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, objective tumor responses (partial responses) were seen in 2 subjects (25%) (soft tissue and bone) and 5/8 subjects (63%) had stable disease.

[0081] One example of a partial response is illustrated in Figure 4 demonstrating the decreased size of the metastatic lymph node. Objective tumor responses and PSA declines lasted longer than 12 weeks. The primary endpoint used in this efficacy study for the treatment of metastatic castration-resistant prostate cancer was median time to cancer progression by imaging (bone and CT scans).

[0082] A subject with metastatic castration resistant node only disease was dosed after prostate cancer progression following treatment with leuprolide, bicalutamide, sipuleucel-T, enzalutamide, or abiraterone. See Figure 4A-B. After oral administration of Compound 17ya for 11 months, this subject experienced a -63% PSA change from baseline (not shown). Figure 4 A (left panel) illustrates a screening CT scan: the right anterior psoas muscle cancerous lymph node (1.7 cm X 1.5 cm). Figure 4A (right panel) illustrates a screening CT scan 8 months later: the right anterior psoas muscle cancerous lymph node (1.1 cm X 1.0 cm). Figure 4B illustrates a coronal CT scan on day one of treatment (left panel) and after 15 months of treatment (right panel), which resulted in about - 33% growth (or 33% regression) of the tumor.

[0083] Figure 2 illustrates the PSA response of the subjects treated with Compound 17ya after completing at least four 21 -day continuously dosed cycles, based on a PSA level at the beginning of the 21 -day cycle (baseline). Figure 3 illustrates the duration of treatment in subjects receiving dosages of 9 mg, 27 mg, 36 mg, 63 mg, or 72 mg per day of Compound 17ya. Treatment of subjects was discontinued upon observation of progressive disease (PD) or death, or withdrawal from the study for other reasons. Figure 3 demonstrates multiple subjects benefitting for at least 6 months.

[0084] The dose-limiting toxicity of Compound 17ya was discovered to be diarrhea and was found to be present in some subjects at 72 mg per day (3 of 11 men had reversible Grade 3 diarrhea). No Grade 3 diarrhea was observed at doses less than 72 mg per day. At daily doses of 63 mg of Compound 17ya and lower, the most common adverse events were mild to moderate nausea, vomiting, diarrhea and fatigue, which were manageable with OTC medicines such as loperamide or bismuth subsalicylate. There were no reports of neurotoxicity and no neutropenia at doses 63 mg and lower in this study in which subjects were administered via oral daily dosing, even in the case of multiple cycles of 21-day continuously dosed cycles (e.g., at least four cycles or >84 days of continuous oral dosing).

[0085] Efficacy, determined by PSA declines and tumor responses, was observed at a wide range of doses from 9 mg to 72 mg per day. Only at the 72 mg dose was the dose-limiting toxicity seen as Grade 3 diarrhea. Typical dose-limiting toxicities of neurotoxicity and neutropenia were not observed at daily doses of 63 mg and lower during continuous dosing.

[0086] Unlike microtubule targeting agents such as docetaxel or cabazitaxel, or chemotherapy such as mitoxantrone or platinum agents, dose-limiting toxicities including neutropenia and neurotoxicity and severe gastrointestinal toxicities were not seen at doses of Compound 17ya below 72 mg, indicating that there is a therapeutic range within which ARB resistant and taxane- experienced mCRPC patients can be treated with Compound 17ya without neutropenias or neurotoxicities, or severe gastrointestinal toxicities. The ability to treat ARB resistant mCPRC with Compound 17ya without these side effects is unprecedented and represents a significant step forward in the treatment of mCRPC. Clinical pharmacokinetics allowed the definition of an upper limit to the therapeutic index (efficacy without dose-limiting side effects or toxicities) as a dose that produced a blood exposure of Compound 17ya of less than or equal to AUCinf of about 1950 hr*ng/mL. Further, Compound 17ya may be used in patients which have progressed while taking other anti-tubulin agents such as taxanes or vinca alkaloids. Disease progression can mean an increase in PSA, and/or significant changes in the patient’s disease state such as new or larger metastases and/or changes in symptoms such as increased bone pain.

EXAMPEE 3

Efficacy in Phase lb/2 Clinical Data of Compound 17ya

[0087] Compound 17ya was well tolerated in the patients that received it and it demonstrated therapeutic efficacy in phase lb (dose-finding study) and phase 2 (63 mg once daily) clinical trials. In patients who received at least one dose of >63 mg daily Compound 17ya (n=55; 14 patients from phase lb and 41 patients from phase 2), the median (range) duration on study was 4.2 (0.9 - 28+) months. In this same population, radiographic progression free survival (PFS) was 7.4 months. ORR was 20.7% in those with measurable disease at baseline (n=29) including five partial responses and one complete response, and 20% had a reduction in tumor size or at least a 30% reduction in PSA. Of particular note, two patients have been receiving Compound 17ya for greater than 2 years without disease progression.

[0088] Treatment-emergent adverse events: the most common adverse events of any grade in

>10% of patients and the incidence of all Grade 3 to 5 adverse events as summarized in Table 2.

Alt, alanine aminotransferase; AST, aspartate aminotransferase

EXAMPLE 4

Bioavailabilities of Oral Formulations A and B of Compound 17ya

[0089] Phase lb/2 clinical trials utilized the oral formulation described Examples 1-3 (referred as Formulation A in this example). Subsequent to the phase lb/2 trials, a novel oral formulation of Compound 17ya was developed (Formulation B). In order to determine any differences between the two formulations, a pharmacokinetic study was performed in order to determine comparative bioavailability and food effects between the distinct formulations. Formulation A was selected in the phase 2 study at a dose of 63 mg daily dosing. The AUCo-24 (ng*hr/mL) of the 63 mg dose of Formulation A was determined to be comparable to the 31.5 mg daily dosing of Formulation B. Under fasted conditions, the oral AUCo-24 (ng*hr/mL) was 1006.16 +/- 376.29 for 63 mg of Formulation A and 973.58 +/- 307.87 (ng*hr/mL) for 31.5 mg of Formulation B, demonstrating similar blood exposure for Formulation B at half the dose. Accordingly, 32 mg of Formulation B produced AUCinf of about 1950 ng*hr/mL. Likewise, other formulations may have variable oral bioavailabilities, necessitating the knowledge of the TI in terms of AUC and blood concentrations of Compound 17ya, as described above, in order to dose these formulations within the therapeutic range.

[0090] All of the features described herein (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined with any of the above aspects in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.