SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jul. 31, 2019, is named NYMOX-0505230_ST25.txt and is 474 bytes in size.

BACKGROUND

1. Field of the Embodiments

The embodiments include methods of treating prostate cancer in mammals having prostate cancer, and more specifically to methods of preventing and/or reducing multi-focal prostate cancer development and progression by administering to a low grade, low risk, localized (T1c) prostate cancer tumor a composition comprising a pharmaceutically active ingredient capable of inducing necrosis of the low grade, low risk, localized prostate cancer tumor and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutically active ingredient is fexapotide triflutate (“FT”). The methods include, but are not limited to, administering the compositions intramuscularly, orally, intravenously, intraperitoneally, intraprostatically, intracerebrally (intraparenchymally), intracerebroventricularly, intralesionally, intraocularly, intraarterially, intrathecally, intratumorally, intranasally, topically, transdermally, subcutaneously, or intradermally to patients in need thereof, wherein targeted administration of the compositions to the low grade, low risk, localized (T1c) prostate cancer tumor reduces prostate cancer incidence, in prostate cancer grade, and in prostate cancer progression (worsening) throughout the entire hemi-prostate where the initial unifocal tumor was located and treated.

2. Description of Related Art

The essence of many medical treatments and procedures involves the removal or destruction of harmful or unwanted tissue. Examples of such treatments include the surgical removal of cancerous or pre-cancerous growths, the destruction of metatastic tumors through chemotherapy, and the reduction of glandular (e.g. prostate) hyperplasia. Other examples include the removal of unwanted facial hair, the removal of warts, and the removal of unwanted fatty tissue.

There is a need for an effective composition that will destroy and hence either facilitate the removal of or inhibit the further growth of harmful or unwanted cells and tissue but will have mainly local effects and minimal or absent systemic toxicity. There also is a need to reduce the need for invasive surgical intervention, even after treatment with an effective composition.

Some agents known to have the ability to destroy and hence either facilitate the removal of or inhibit the further growth of harmful or unwanted cells and tissue are disclosed in U.S. patent application Ser. No. 14/808,713, filed Jul. 24, 2015, entitled: METHODS OF REDUCING THE NEED FOR SURGERY IN PATIENTS SUFFERING FROM BENIGN PROSTATIC HYPERPLASIA; U.S. patent application Ser. No. 14/606,683, filed Jan. 27, 2015, entitled: METHOD OF TREATING DISORDERS REQUIRING DESTRUCTION OR REMOVAL OF CELLS, U.S. application Ser. No. 14/738,551, filed Jun. 12, 2015, entitled: COMBINATION COMPOSITIONS FOR TREATING DISORDERS REQUIRING REMOVAL OR DESTRUCTION OF UNWANTED CELLULAR PROLIFERATIONS, U.S. patent application Publication Nos. 2007/0237780 (now abandoned); 2003/0054990 (now U.S. Pat. No. 7,172,893); 2003/0096350 (now U.S. Pat. No. 6,924,266); 2003/0096756 (now U.S. Pat. No. 7,192,929); 2003/0109437 (now U.S. Pat. No. 7,241,738); 2003/0166569 (now U.S. Pat. No. 7,317,077); 2005/0032704 (now U.S. Pat. No. 7,408,021); and 2015/0148303 (now U.S. Pat. No. 9,243,035), the disclosures of each of which are incorporated by reference herein in their entirety.

One of the agents disclosed in these documents is fexapotide triflutate, or FT. FT has been shown to reduce prostate glandular cells, to ameliorate or reduce LUTS, and to treat BPH in men with prostate enlargement. FT also has been disclosed as useful in reducing the onset of prostate cancer by treating BPH in a mammal having BPH in which the compositions containing FT are administered to the mammal in transition zone (central) prostate. See, e.g., U.S. Pat. No. 10,183,058, the disclosure of which is incorporated by reference herein in its entirety.

Prostate cancer is known as a disease with an extremely high prevalence relative to its clinical incidence in the population. Prostate cancer has a high asymptomatic incidence and a long asymptomatic duration. Prostate cancer has an interval of 7 to 14 years on average during which the cancer is present but is preclinical because it is not detected by typical clinical or laboratory examinations (see Etzioni, R et al.,Am J Epidemiol. Vol. 148, pp. 775-85 (1998); and Gulati, R, et al.,Cancer Epidemiol Biomarkers Prev; Vol. 20(5), pp. 740-50 (2011)). These preclinical asymptomatic prostate cancers prior to their overt diagnosis are a reasonable target for treatment which can benefit patients before the cancers have become clinically apparent or detected otherwise.

Prostate cancer is often considered a multifocal disorder in which the prostate gland includes multiple adenocarcinoma foci of varying heterogeneity. This makes the cancer difficult to treat effectively, often resulting in radical prostatectomy, which causes numerous life altering issues for men including erectile dysfunction and urinary incontinence. Some prostate cancers, however, or unifocal prostate cancer, which has been reported in from about 20 to about 35% of radical prostatectomy specimens. Mazzucchelli, et al., “Pathology of Prostate Cancer and Focal Therapy (‘Male Lumpectomy’),”Anticancer Research, Vol. 29, pp. 5155-5162 (2009); Ibeawuchi, et al., “Genome-Wide Investigation of Multifocal and Unifocal Prostate Cancer—Are They Genetically Different?”Int. J. Mol. Sci., Vol. 14, ppp. 11816-11829 (2013).

Due to the severity of radical prostatectomy, recent studies have reported on focal therapy in which a portion of the prostate is preserved, although the efficacy of focal therapy of prostate cancer and preventing cancer progression remains uncertain. Quann, et al., “Current prostate biopsy protocols cannot reliably identify patients for focal therapy; . . . ”,Int. J. Clin. Exp. Pathol., Vol. 3(4), pp. 401-407 (2010). Identifying, targeting, and focally destroying a specific tumor has yet to be realized (Mazzucchelli at 5159), and to date focal therapy involves ablation of large portions, (e.g., hemiablation), of the prostate. It therefore was not heretofore known or expected that treating a low grade low risk unifocal prostate cancer tumor by targeting just the unifocal tumor would be effective in reducing cancer incidence, cancer grade, and cancer progression (worsening) throughout the entire lobe in which the unifocal tumor was located. As a consequence, the clinical trials in which FT was assessed to treat only the unifocal prostate cancer was not designed, and not expected to be effective in treating the lobe of the prostate in which the unifocal tumor was located.

A common technique used in identifying and monitoring prostate cancer is assessing PSA levels in conjunction with biopsy evaluation. Typical biopsy of the prostate usually involves taking numerous samples through the prostate gland, and assessing the tissue using a Gleason Score. The Gleason Score measures how abnormal a cancer cell looks like under a microscope and is a good indicator of how quickly the cells are likely to grow and spread. The Gleason Score is calculated by adding together the two grades of cancer that make up the largest areas of the biopsied tissue sample, and is often represented as two numbers, such as 3+3, along with the total score, such as 6. The following table provides a classification of the groups of prostate cancer and the associated risks:

Risk GroupISUP Grade GroupGleason ScoreLowGrade Group 1Gleason Score ≤6Intermediate FavorableGrade Group 2Gleason Score 7(3 + 4)Intermediate UnfavorableGrade Group 3Gleason Score 7(4 + 3)HighGrade Group 4Gleason Score 8HighGrade Group 5Gleason Score 9-10

For low grade low risk localized (T1c) prostate cancer in which the Gleason Score is ≤6, Active Surveillance (AS) is the ordinary course of treatment. This is because, while some may very well mature to high risk cancer requiring radical prostatectomy (e.g., Gleason Score ≥8), many do not. As noted above, up to about 35% of prostates surgically removed only have low grade low risk localized (T1c) prostate cancer. Accordingly, those patients who had their prostates surgically removed but still did not have high risk cancerous tumors needlessly suffered the deleterious effects of radical prostatectomy surgery. Accordingly, the typical standard of care is that, when the Gleason Score is 7 or above, especially when the primary pattern is 4, corrective measures are taken, either by removing a large portion of the prostate, chemotherapy or radiation, or a radical prostatectomy. It therefore would be desirable to discover a safe and effective manner of treating prostate cancer patients in the low and/or low and intermediate risk groups by focal treatment of a single foci, in which case the treatment is effective in ameliorating, reducing, and/or preventing the progression of the cancer throughout the prostate lobe in which the single foci was located.

Throughout this description, including the foregoing description of related art, any and all publicly available documents described herein, including any and all U.S. patent published patent applications, are specifically incorporated by reference herein in their entirety. The foregoing description of related art is not intended in any way as an admission that any of the documents described therein, including pending U.S. patent applications, are prior art to the present disclosure. Moreover, the description herein of any disadvantages associated with the described products, methods, and/or apparatus, is not intended to limit the embodiments. Indeed, aspects of the embodiments may include certain features of the described products, methods, and/or apparatus without suffering from their described disadvantages.

SUMMARY OF THE EMBODIMENTS

There remains a need in the art for new, less toxic, and less frequent, and less invasive treatments for preventing or reducing the progression or incidence of prostate cancer. There also remains a need in the art for such treatments that reduce the incidence of multifocal prostate cancer at least in the lobe (or hemisphere) in which the initially treated foci were located. The embodiments satisfy these needs.

This disclosure is premised in part on the discovery that pharmaceutically active ingredients capable of inducing necrosis of the low grade, low risk, localized prostate cancer tumor are capable of being administered to a single low grade, low risk prostate cancer foci or tumor (i.e., Gleason Score ≤6), but yet have an unexpected effect of reducing multifocal cancer incidence, reducing multifocal cancer grade, and reducing multifocal progression (worsening) in the prostate lobe in which the low grade, low risk, localized prostate cancer tumor was located. Suitable pharmaceutically active ingredients capable of inducing necrosis of such tumors, include, for example, fexapotide triflutate, (FT), a peptide described by the amino acid sequence Ile-Asp-Gln-Gln-Val-Leu-Ser-Arg-Ile-Lys-Leu-Glu-Ile-Lys-Arg-Cys-Leu, Zytiga (abiraterone acetate), Apalutamide, abazitaxel, Casodex (Bicalutamide), Eligard and Lupron, (Leuprolide Acetate), Erleada (Apalutamide), Firmagon (Degarelix), Flutamide, Goserelin Acetate, Jevtana (Cabazitaxel), Mitoxantrone Hydrochloride, Nilandron (Nilutamide), Provenge (Sipuleucel-T), Sipuleucel-T, Taxotere (Docetaxel), Xofigo (Radium 223 Dichloride), Xtandi (Enzalutamide), Zoladex (Goserelin Acetate), and mixtures and combinations thereof. Such administration was found, after several years of ongoing follow up, to be effective in reducing cancer incidence, reducing cancer grade, and reducing cancer progression (worsening) in the prostate lobe (hemi-prostate) where the initial unifocal tumor was located and treated. The embodiments therefore are capable of vastly improving the quality of life of many men suffering from prostate cancer that would have otherwise undergone a more aggressive treatment, like ablation of a large portion of the prostate, chemotherapy, radiation, or radical prostatectomy.

Some embodiments are directed to methods of reducing cancer incidence, reducing cancer grade, and reducing cancer progression (worsening) in mammals having low grade or at low risk of prostate cancer (i.e., Gleason Score ≤6) by administering to the mammal a therapeutically effective amount of a composition comprising at least one pharmaceutically active ingredient capable of inducing necrosis of the low grade, low risk, localized prostate cancer tumor. The method includes administering a therapeutically effective amount of the composition to a single cancerous foci (unifocal tumor) in the prostate of the mammal, and reducing treatment side hemi-prostate Gleason grade increase by an amount of from about 15% to about 100%, when compared to active surveillance, when measured at least 18 months after treatment.

The compositions can be administered intramuscularly, orally, intravenously, intraperitoneally, intracerebrally (intraparenchymally), intracerebroventricularly, intratumorally, intralesionally, intradermally, intrathecally, intranasally, intraocularly, intraarterially, topically, transdermally, via an aerosol, infusion, bolus injection, implantation device, sustained release system etc.

In another embodiment, the composition includes a therapeutically effective amount of FT that is administered in an amount ranging from about 2.0 mg to about 20 mg. The methods also include administering a therapeutically effective amount of FT to a single cancerous foci (unifocal tumor) in the prostate of the mammal, and reducing the percentage of mammals exhibiting ≥1 new focus in the in the prostate lobe where the original foci was treated with an increase in Gleason grade primary pattern (new multifocal with Gleason primary pattern ≥4) increase by an amount of from about 50% to about 100%, when compared to active surveillance, when measured at least 18 months after treatment, or from about 45% to about 100%, when compared to active surveillance, when measured at least 36 months after treatment, or from about 45% to about 100%, when compared to active surveillance, when measured at least 48 months after treatment. In another embodiment, the method reduces treatment side hemi-prostate Gleason grade increase by an amount of from about 45% to about 70%, when compared to active surveillance, when measured at least 36 months after treatment. In another embodiment, the method includes administering a therapeutically effective amount of FT to a single cancerous foci (unifocal tumor) in the prostate of the mammal, and reducing the percentage of mammals exhibiting 1 new focus in the prostate lobe where the original foci was treated with an increase in Gleason grade (new multifocal with Gleason upgrade) by an amount of from about 40% to about 100%, when compared to active surveillance, when measured at least 18 months after treatment, or from about 50% to about 90%, when compared to active surveillance, when measured at least 36 months after treatment, or from about 15% to about 80%, when compared to active surveillance, when measured at least 48 months after treatment.

In another embodiment, the method includes administering a therapeutically effective amount of FT to a single cancerous foci (unifocal tumor) in the prostate of the mammal, and reducing the percentage of mammals having conventional cancer treatment (surgery, radiotherapy, or chemotherapy), and exhibiting ≥1 new focus in the prostate lobe where the original foci was treated with an increase in Gleason grade (new multifocal with Gleason upgrade) by an amount of from about 40% to about 100%, when compared to active surveillance, when measured at least 18 months after treatment, or from about 50% to about 90%, when compared to active surveillance, when measured at least 36 months after treatment, or from about 15% to about 80%, when compared to active surveillance, when measured at least 48 months after treatment. The methods also include administering a therapeutically effective amount of FT to a single cancerous foci (unifocal tumor) in the prostate of the mammal, and reducing the percentage of mammals having conventional cancer treatment (surgery, radiotherapy, or chemotherapy), and exhibiting ≥1 new focus in the in the prostate lobe where the original foci was treated with an increase in Gleason grade primary pattern (new multifocal with Gleason primary pattern ≥4) by an amount of from about 65% to about 100%, when compared to active surveillance, when measured at least 18 months after treatment, or from about 65% to about 100%, when compared to active surveillance, when measured at least 36 months after treatment, or from about 60% to about 100%, when compared to active surveillance, when measured at least 48 months after treatment.

Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the embodiments as claimed. Other objects, advantages, and features will be readily apparent to those skilled in the art from the following detailed description of the embodiments.

