FOSFESTROL FOR USE IN CURATIVE OR PALLIATIVE TREATMENT OF PROSTATE CANCER

Abstract

The present invention relates to the use of Fosfestrol (diethylstilbestrol diphosphate) in a method of curative or palliative treatment of prostate cancer in male mammals, said method comprising orally administering Fosfestrol in a daily dosage of at least 1,000 mg.

The inventors have discovered that Fosfestrol when administered in very high oral dosages is effective in the treatment of prostate cancer, especially hormone resistant prostate cancer, without giving rise to serious side effects, such as thromboembolic toxicity or mortality.

The invention further provides an oral dosage unit comprising at least 500 mg, of Fosfestrol.

Claims

1. A method of curative or palliative treatment of castrate-resistant prostate cancer in male mammals, comprising orally administering a daily amount of at least 1,000 mg fosfestrol (diethylstilbestrol diphosphate).

2. The method according to claim 1, wherein the method comprises orally administering a daily amount of 1,000-4,500 mg fosfestrol.

3. The method according to claim 1, wherein the fosfestrol is administered daily for at least 7 days.

4. The method according to claim 1, wherein the method comprises orally administering at least 12.5 mg of fosfestrol per kg of bodyweight.

5. The method according to claim 1, wherein the method comprises at least twice daily oral administration of fosfestrol.

6. (canceled)

7. The method according to claim 1, wherein the castrate-resistant prostate cancer has developed after treatment with anti-androgen or an inhibitor of 17μhydroxylase/C 17,20 lyase (CYP17A1).

8. The method according to claim 7, wherein the castrate-resistant prostate cancer has developed after treatment with Abiraterone.

9. The method according to claim 1, wherein the mammal is a human.

10. An oral dosage unit comprising at least 500 mg of fosfestrol.

11. The oral dosage unit according to claim 10, in the form of a tablet or capsule.

12. The oral dosage unit according to claim 10, having a weight of 0.5-2.0 g.

13. The oral dosage unit according to claim 10, comprising 20-80 wt. % of one or more pharmaceutically acceptable excipients.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0029] A first aspect of the invention concerns Fosfestrol (diethylstilbestrol diphosphate) for use in a method of curative or palliative treatment of prostate cancer in male mammals, said method comprising orally administering Fosfestrol in a daily dosage of at least 1,000 mg.

[0030] The term ‘Fosfestrol’ as used herein refers to a diethylstilbestrol moiety of which both the hydroxyl groups are phosphated. The term ‘Fosfestrol’ also encompasses pharmaceutically acceptable salts of Fosfestrol.

[0031] The term ‘pharmaceutically acceptable salt’, as used herein, means those salts of compounds of the invention that are safe and effective for use in mammals and that possess the desired biological activity. Descriptions of counter ions for pharmaceutically acceptable salts of pharmaceutical compounds can be found in P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts, Properties, Selection and Use, Wiley VCH (2002).

[0032] The diethylstilbestrol moiety in the DES phosphate of the present invention may be in the trans-form or the cis-form. Naturally, also mixtures of the trans- and cis-form may be employed.

[0033] The term ‘cancer’ as used herein refers to a malignant neoplasm involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body.

[0034] The term ‘curative treatment’ as used herein refers to a treatment that aims to cure a disease or to improve symptoms associated with a disease.

[0035] The term ‘palliative treatment’ as used herein refers to a treatment or therapy that does not aim at curing a disease but rather at providing relief.

[0036] The term ‘oral’ as used herein, unless indicated otherwise, is synonymous to ‘per oral’.

[0037] The term ‘dosage’ as used herein refers to the amount of a pharmaceutically active substance that is administered to a mammal. Hence, the term ‘dosage’ does not include any carrier or other pharmaceutically acceptable excipient that is part of a ‘dosage unit’ to be administered.

[0038] In this document and in its claims, the verb ‘to comprise’ and its conjugations are used in their non-limiting sense to mean that items following the word are included, without excluding items not specifically mentioned. In addition, reference to an element by the indefinite article ‘a’ or ‘an’ does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article ‘a’ or ‘an’ thus usually means ‘at least one’.

[0039] Hormone-dependent cancers refer to those types of cancer that grow faster in the presence of particular hormones. This type of cancer is usually treated with hormone therapy. Hormone therapy involves blocking in vivo production or action of these hormones. Therefore, hormone therapy actually is anti-hormone therapy. Cancer of the prostate usually is a hormone-dependent cancer and may be treated by the present method.

[0040] In the case of hormone-dependent prostate cancer, androgen ablation therapy (e.g. orchiectomy, treatment with LHRH analogs or LHRH antagonists) is used as first line treatment to decrease the production of androgens, particularly testosterone, in order to stop or limit the growth of prostate cancer. Androgens are key drivers of prostate tumor growth. The androgen ablation therapies reduce the plasma levels of androgen, thereby reducing the growth potential of the prostate tumor. The androgen ablation therapies are successful for a certain period of time, however all prostate tumors eventually become resistant to this treatment approach. After failure of the androgen ablation therapy, secondary hormone treatments with anti-androgens are used to slow the growth of the prostate tumor.

[0041] After exposure for a certain time to hormone therapy prostate cancer often obtain the ability to grow without hormones and are therefore called ‘hormone-independent’. Once these cancers become hormone-independent, treatment usually is switched to chemotherapy.

[0042] Hormone-independent prostate cancer is also called hormone-refractory or castration-resistant prostate cancer. These terms are used interchangeably in the following and are considered to have the meaning of ‘castration-resistant prostate cancer’. Nowadays, the term ‘castration resistant’ has replaced ‘hormone refractory’ because while these prostate cancers are no longer responsive to castration treatment (reduction of available androgen/testosterone), they still show some reliance upon hormones for androgen receptor activation.

[0043] The present invention encompasses the treatment of hormone-dependent as well as hormone-independent cancers. The present method is particularly suited for treatment of hormone-independent cancers, especially for treatment of hormone-independent cancers that have developed after treatment of hormone dependent cancers with hormone therapy.

[0044] The present method of treatment is advantageously applied to treat a prostate cancer that does not respond to treatment with anti-androgen or an inhibitor of 17α hydroxylase/C17,20 lyase (CYP17A1), especially a prostate cancer that does not respond to treatment with an inhibitor of 17α hydroxylase/C17,20 lyase (CYP17A1), more particularly to treatment with Abiraterone. The present method is particularly suited for treatment of hormone-independent prostate cancer that has developed after treatment of hormone-dependent prostate cancer with anti-androgen or an inhibitor of 17α hydroxylase/C17,20 lyase (CYP17A1), notably Abiraterone.

[0045] As explained herein before, Fosfestrol in the context of the present invention also encompasses pharmaceutically acceptable salts of Fosfestrol. Pharmaceutically acceptable salts include those formed from cations of alkali metals such as sodium, lithium, potassium, and earth alkali metals such as calcium and magnesium.

[0046] In a preferred embodiment the Fosfestrol is an alkali metal salt, notably a sodium and/or a potassium salt. More preferably, the Fosfestrol is in the potassium salt form.

[0047] The present method of treatment may be used to treat several kinds of mammals, e.g. humans, horses, cattle etc. The present method is particularly suited for the treatment of humans.

[0048] The Fosfestrol dosage may vary depending upon the specific conditions and patients undergoing treatment. The therapeutically effective dosage of the compound can be provided as repeated doses within a prolonged treatment regimen that will yield clinically significant results.

[0049] The actual dosage of the compound will vary according to factors such as the disease indication and particular status of the subject such as for example, age, size, fitness, extent of symptoms, susceptibility factors and the like, and other factors such as time and route of administration, other drugs or treatments being administered concurrently. Dosage regimens can be adjusted to provide an optimum therapeutic response.

[0050] Typically, the present method comprises administering Fosfestrol in a daily oral amount of at least 1,000 mg, more preferably of 1,000-4,500 mg and most preferably of 1,000-2,000 mg.

[0051] Expressed differently, it is preferred to administer Fosfestrol orally in a daily amount of at least 12.5 mg per kg of bodyweight, more preferably of 12.5-60 mg per kg of bodyweight and most preferably of 12.5-27 mg per kg of bodyweight.

[0052] The duration of the present method of treatment typically exceeds 7 days. More particularly, the present method has a duration of at least 14 days, especially of at least 28 days.

[0053] The aforementioned daily amount may be administered once daily of it may be administered in the form of two or more separate doses at more or less regular intervals. According to a particularly preferred embodiment, the present method of treatment comprises orally administering at least two doses per day, more preferably two doses of each at least 200 mg Fosfestrol per day, even more preferably it comprises orally administering at least 3 doses of at least 200 mg Fosfestrol per day.

[0054] Another aspect of the invention relates to an oral dosage unit comprising at least 500 mg, preferably at least 800 mg and most preferably at least 1,000 mg, of Fosfestrol.

[0055] The oral dosage unit of the present invention can advantageously be applied in the curative or palliative treatment of prostate cancer as defined herein before.

[0056] The oral dosage units is preferably selected from the group consisting of tablets, granulates, capsules and powders and liquids. Even more preferably, the oral dosage unit is a tablet or capsule.

[0057] The oral dosage units typically have a weight of between 0.5 and 2.0 g, more preferably of 0.75-1.5 g and most preferably of 0.8-1.2 g. In another embodiment, the oral dosage units comprise between 20 and 80 wt. % of pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient is suitably selected from coloring agents, flavoring or taste masking agents, diluents, binders, lubricants, disintegrants, stabilizers, surfactants, glidants, plasticizers, preservatives, sweeteners and combinations thereof.

[0058] The disintegrants are advantageously chosen from the group consisting of lactose, anhydrous lactose, crospovidone, croscarmellose sodium, sodium starch glycolate, hydroxypropyl cellulose, polacrilin potassium, pregelatinized starch, microcrystalline cellulose and combinations thereof. In a preferred embodiment the oral dosage units comprise up to 7 wt. %, preferably 2-5 wt. % of disintegrants.

[0059] The dosage unit of the present invention may suitably take the shape of a compressed tablet. Such a tablet may suitably comprise two or more layers of different composition, for example a core comprising Fosfestrol as defined herein before encased in a coating.

[0060] The dosage units of the present inventions are conveniently produced in a tabletting machine. In order to enable easy removal of the tablets from the moulds, the dosage unit typically contains between 0.2 and 4.0 wt. % of a lubricant or gliding agent. Preferably, the lubricant or gliding agent is selected from the group consisting of talc, sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated castor oil, hydrogenated soybean oil, polyethylene glycol, starches, anhydrous colloidal silica and combinations thereof.

[0061] The following examples are meant to further illustrate the invention and some of its preferred embodiments without intending to limit its scope.

EXAMPLES

Example 1

[0062] The in vitro direct cytotoxicity of DES and Fosfestrol in hormone-dependent (LNCaP) and hormone-independent (DU-145) prostate cancer cell lines was tested.

[0063] Cells were maintained in vitro in RPMI 1640 containing 10% (v/v) heat inactivated fetal bovine serum (FBS) and 2 mM L-glutamine (growth media) at 37° C. in 5% CO.sub.2 and humidified conditions. Cells were harvested, washed, re-suspended into growth medium and counted. The cells were re-suspended into assay media (RPMI 1640+1% (v/v) heat inactivated FBS+ and 2 mM L-glutamine) at 0.5×10.sup.5 cells/ml for DU-145 cells and 1×10.sup.5 for LNCaP cells, and plated into 96-well assay plates (Corning, black-wall plates) and 50 μl/well aliquots.

[0064] Plates were incubated O/N at 37° C. in 5% humidified CO.sub.2 prior to addition of the compounds. DES was dissolved in 100% DMSO at stock concentration of 60 mM. Fosfestrol was dissolved in sterile water at stock concentration of 60 mM. Stocks of all compounds were then serially diluted. Final concentrations to which cells were exposed were: 300, 150, 75, 37.5, 18.75, 9.4, 4.7, 2.3, 1.2 and 0.6 μM. Positive control was Taxotere. Taxotere was diluted in 100% DSMO to give a stock concentration of 1 mM. Stock was serial diluted and final concentration to which cells were exposed was: 1000, 333.3, 111.1, 37.0, 12.3, 4.1, 1.4, 0.5, and 0.2 nM.

[0065] Plates were incubated for 72 hrs at 37° C. in 5% humidified CO-2 after addition of the compounds. Viability of the cells was assessed with the Cell titer blue® (Promega) assay. 10 μl of Cell titer Blue™ reagents was added to each test/blank well. Plates were incubated for 3 hrs at 37° C. in 5% humidified CO.sub.2 prior to analysis. Fluorescence was measured with a Flex II station plate reader. Excitation wavelength was 570 nm, emission wave length was 600 nm, cut off was 590 nm. Raw data was processed by GraphPad Prism to calculate mean, standard deviation and IC.sub.50 values.

[0066] The results so obtained are shown in Table 1.

TABLE-US-00001 TABLE 1 IC.sub.50 value (μM) LNCaP DU-145 DES 27 62 Fosfestrol 70 84 Taxotere (control) 0.002 0.004

CONCLUSION

[0067] These results show that DES and Fosfestrol are both cytotoxic in LNCaP and DU-145 prostate cancer cells.

Example 2

[0068] A 1 kg batch of 500 mg Fosfestrol tablets was prepared by direct compression as described below.

[0069] Fosfestrol and excipients were first passed over a 0.85 mm sieve. Next, 500 gram of fosfestrol tetrasodium was blended with 435 gram of silicified Microcrystalline Cellulose (Prosolv smcc 90™) and 50 gram of croscarmellose sodium (Ac-di-Sol™) for 20 minutes in a V-blender. Added to the mixture was 15 grams of magnesium stearate and blending was continued for 5 minutes.

[0070] Tablets of 1,000 mg each were prepared on a Korsch EKO, using oval punches.

Example 3

[0071] A patient study was conducted in chemo and hormone resistant prostate cancer patients to explore the effects of high dose oral Fosfestrol treatment.

[0072] 11 patients were included into the study and all had undergone at least 2 prior treatments (mostly Taxotere and Estramustine) with a maximum of prior 4 treatments.

[0073] Patients were treated with three times 360 mg/d oral Fosfestrol for 4 weeks. Total Fosfestrol dose per day was 1,080 mg. All other treatments were stopped during high dose oral Fosfestrol therapy.

[0074] PSA decline was used to measure objective response. 72% of the patients showed a PSA decline of >50% during high dose oral Fosfestrol treatment. In addition, 54% of the patients experienced a >80% PSA decline.

[0075] Treatment was accompanied by minor toxicities and no thromboembolic side effects were detected.

CONCLUSION

[0076] This study showed that high dose oral Fosfestrol is effective and safe to use in heavily pretreated chemo and hormone resistant prostate cancer patients.