[1 ] Prostate cancer is a significant cause of cancer morbidity and mortality. In the United States alone, approximately 225,000 men are now diagnosed with prostate cancer annually, and approximately 25,000 die from the disease.

[2] Prostate cancers initially require androgens for growth, and the initial treatment for metastatic prostate cancer is designed to deprive tumor cells of androgen, either by surgical castration (bilateral orchiectomy) or by medical castration (administration of a luteinizing hormone releasing hormone (LHRH) analog). While most patients initially respond to such androgen deprivation treatment (ADT), nearly all patients eventually progress with a more aggressive form of prostate cancer alternatively termed "hormone refractory", "androgen independent", or "castration resistant" prostate cancer (CRPC). The Prostate Cancer Working Croup now recommends referring to these patients as castration-resistant, because a substantial number of patients with CRPC (more than 50% in some studies) respond to secondary hormonal manipulations, and occasionally may respond to hormonal manipulations even late in the course of the disease. Most prostate cancers that progress during initial androgen deprivation therapy appear to remain highly dependent on signaling by the androgen receptor for their growth, but adapt to the low systemic androgen environment, e.g., by increasing the expression of the androgen receptor, mutation, phosphorylation or co- activation of the androgen receptor, or by synthesis of a local source of androgens in the tumor itself due to the conversion of adrenal androgenic steroids or the de novo synthesis of androgens.

[3] Progression to CRPC generally marks the onset of a more accelerated and lethal form of the disease; however, because androgen deprivation treatment is monitored by frequent testing of the serum prostate specific antigen (PSA), there is a relatively large population of men with asymptomatic CRPC and a rising PSA as the only evidence of disease progression. Furthermore, current trends in the treatment of prostate cancer are shifting to earlier intervention with hormonal therapy in the state of rising PSA, before the onset of clinically detectable metastases. These trends further increase the population of men with asymptomatic metastatic CRPC.

[4] Men with metastatic prostate cancer and disease progression after medical or surgical castration may be eligible to receive cytotoxic chemotherapy. But as this is considered palliative therapy, many patients and their physicians do not opt for chemotherapy until the onset of disease-related symptoms. For this reason, patients with asymptomatic CRPC often receive secondary hormonal maneuvers, including anti- androgens, anti-androgen withdrawal, estrogens, ketoconazole and other forms of adrenal suppression with corticosteroids or aminoglutethimide. Although commonly used in routine medical practice, the benefits of such maneuvers are usually short-lived and have not been shown to prolong survival. The current trends in the hormonal management of prostate cancer coupled with the lack of highly effective secondary hormonal maneuvers contribute to a large unmet medical need for an effective treatment for asymptomatic metastatic CRPC.

[5] Deforolimus is a unique analog of rapamycin that demonstrated antiproliferative activity in a broad range of human tumor cell lines in vitro and in vivo. Deforolimus has demonstrated in vivo activity in murine tumor xenograft models utilizing human tumor cell lines representing glioblastoma, prostate, breast, lung, colon, and pancreatic cancers. Other rapamycin analogs have shown activity against prostate cancer models in vitro and in vivo, producing greater activity in PTEN deficient prostate cancer xenografts. Furthermore, a clinical study in men scheduled for prostatectomy showed that the administration of a rapamycin analog (temsirolimus) could inhibit mTOR in human prostate tumor cells, with more mTOR inhibition being observed in PTEN deficient prostate cancer specimens.

[6] Deforolimus is currently in clinical development for the treatment of advanced cancers, and has shown evidence of anti-tumor activity in several tumor types, such as sarcomas, for which orally administered deforolimus is currently in a Phase 3 study. Intravenous deforolimus, given as a single agent for treating taxane-refractory prostate cancer, was well-tolerated but unfortunately failed to produce objective or PSA responses in that study. However, some patients remained on study for prolonged time periods without clinical progression, because they were believed to be deriving clinical benefit.

[7] Given the lack of more positive results in that prostate cancer study, one could imagine shifting the focus to other classes of agents for treating prostate cancer patients. Alternatively, various rationales may be proposed for considering moving beyond the single agent use of the mTOR inhibitor in favor of combining its administration with that of one or more additional drugs.

[8] A general rationale for drug combinations is that targeting multiple different cellular pathways may result in enhanced efficacy. In particular cases that general strategy may be supplemented by quite plausible mechanistic rationales and in some cases by promising in vitro or animal data. However, combining drugs can also compound side effect issues, e.g., by combining or compounding the drugs' respective toxicities or through biological mechanisms not necesarily fully understood. While some combination therapies have led to positive clinical results in treating certain cancers, others have unfortunately proved too toxic for human patients or proved no better than one of the individual drugs— notwithstanding proposed theoretical advantages, mechanistic rationales or intriguing results on isolated cells or in animal studies. Hopes based on positive examples unfortunately must be tempered by the flow of unexpected disappointments in cancer drug development.

[9] Consider, for instance, the clinical development of Avastin™ (bevacizumab), the highly regarded, targeted, anti-angiogenic agent which blocks the action of VECF. Avastin and has been approved in combination with carboplatin and paclitaxel for treating certain non-small cell lung cancers and in combination with 5-FU-based (antimetabolite) chemotherapy for treating certain colorectal cancers. Additional clinical trials studied the combination of Avastin with the EGFR inhibitor, Tarceva™ (erlotinib), another targeted agent used as a single agent for treating certain lung cancers. Avastin and Tarceva had each been found to be effective in combinations with other drugs, and both had applicability to lung caner. Unfortunately, a clinical trial combining them failed to demonstrate extension of lung cancer patients' lives any more than with tarceva alone. Likewise, clinical studies combining Avastin with gemcitabine for first line treatment of certain pancreatic cancers failed to meet the study's primary endpoints. Studies of Avastin plus the EGFR inhibitor, Erbitux™ (cetuximab), for colorectal cancer and again of Avastin/chemotherapy plus the EGFR inhibitor, Vectibix™ (panitumumab), for colon cancer also met with unexpected disappointment.

[10] As reported in the Wall Street Journal's Health Blog on Oct 7, 2008,

Researchers have been struggling for a while now to find effective combinations of the targeted cancer medicines that every drug company's trying to bring to market.

You'd think two would often be better than one. Traditional chemotherapy is all about multi-drug combinations, and combining two targeted drugs that attack different parts of the cancer cell sounds like a sensible treatment, albeit a very expensive one.

But some combinations just don't help. One study of colon cancer patients showed that combining Avastin with ImClone's Erbitux didn't improve outcomes; another found combining Avastin plus Amgen's Vectibix wasn't helpful.

"It shows you can't throw things into a pot and assume they'll work," Robert Mayer of the Dana-Farber Cancer Institute, told the Health Blog earlier this year.

[1 1 ] In fact, the National Colorectal Cancer Roundtable published these words on that study of conventional chemotherapy plus Avastin with or without Vectibix, mentioned above ("PACCE" study): Patients in the PACCE trial were informed that the interim analysis showed lower efficacy and higher toxicity and should stop the Vectibix. The data are the opposite of what most expected. It was astonishing that patients who received Vectibix and Avastin did significantly worse than patients with Avastin, significant less tumor shrinkage, shorter time until the tumor started to grow again and shorter survival.

In addition, patients had more life threatening toxicities including death. A lot of questions are raised as to how this is possible. We need be cautious when using Vectibix in combination with other therapies since we don't know why we see these concerning PACCE data.

[12] CancerConsultants.com offered this description:

Researchers have been hopeful that combining biologic therapies that target different pathways may provide additional benefit for the treatment of various cancers. Because Erbitux and Vectibix target the epidermal growth factor receptor (EGFR) pathway and Avastin targets the vascular endothelial growth factor (VEGF) pathway, and because synergistic activity between the two agents has been noted in laboratory studies, researchers speculated that a combination of the two agents may provide more anticancer activity than either agent used alone in combination with chemotherapy. However, there have been conflicting results regarding the efficacy of the combination of these two targeted agents in colorectal cancer.

and concluded,

Overall, it appears that there is a class effect in which the combination of agents targeted against the EGFR and VEGF provide no clinical benefit and may in fact result in worse outcomes as initial therapy in metastatic colorectal cancer patients. Initial findings from both the CAIRO and PACCE trials were unexpected as preclinical models predicted that the combination of agents targeted against these pathways increased growth inhibition of malignant cells.

[13] A number of seemingly logical drug combinations, specifically involving mTOR inhibitors, have also disappointed. As reported in a March 1 6, 2006 press release from Wyeth,

Wyeth ... announced today its decision to discontinue the HORIZON phase 3 clinical trial program of Wyeth's investigational drug temsirolimus oral tablets in combination with letrozole (Femara ^® ), a currently approved breast cancer therapy, for first-line use in postmenopausal women with hormone-receptor positive metastatic breast cancer. This decision was based upon the recommendation of an Independent Data Monitoring Committee (IDMC) after review of data from a planned interim analysis.

The HORIZON study compared the combination of temsirolimus oral tablets and letrozole versus letrozole alone. The IDMC advised that continuation of the trial was unlikely to achieve the targeted level of efficacy for the combination therapy compared to letrozole alone. The IDMC concluded, therefore, that the risk/benefit ratio for treatment of metastatic breast cancer did not favor continuation and recommended that the trial be discontinued. "While not the anticipated outcome, it is unfortunately not unusual for cancer drugs to work in some tumor types and not others, or even work in only some specific subpopulations of cancer patients," says Gary L. Stiles, M. D., FACC, Executive Vice President and Chief Medical Officer, Wyeth Pharmaceuticals. "We remain committed to studying temsirolimus in other cancer indications."

While the phase 3 trial for women with hormone-receptor positive metastatic breast cancer involved an oral formulation of temsirolimus, two other phase 3 clinical trials studying temsirolimus in renal cell carcinoma and mantle cell lymphoma using an intravenous formulation are continuing. After a recent review of the data, the IDMC for the renal cancer study indicated that study continue as planned.

[14] As another case in point, some have suggested combining mTOR inhibitors and antimetabolite drugs for the treatment of various other cancers (see, for example, US Pat. No. 5,206,01 8; WO 02/06601 9 and US Pat. Appln. No. 2004/01 45741 ; US Pat. No. 7,091 ,21 3; WO 02/080975 and US Pat. Appln. Nos. 2002-01 83239 and 2006- 0035904; and 2002-01 83240 and 2005-01 871 84). However, clinical trials with combinations of mTOR inhibitors and antimetabolites have revealed serious toxicities. In particular, Phase I clinical trials using temsirolimus in combination with 5-fluorouracil (5FU) and leuvocorin for the treatment of patients with advanced solid tumors have been terminated for unacceptable toxicity (CJ. Punt et ai, Ann. Oncol., 2003, 14: 931 - 937). Similarly, Phase I clinical trials using everolimus and gemcitabine in patients with advanced cancers (S. Pacey et ai, J. Clin. Oncol., 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition), Vol. 22, No. 14S OuIy 1 5 Supplement): 31 20) have been stopped because a majority of patients could not tolerate the combination therapy. While subsequent combinations of an mTOR inhibitor with capecitabine, with specified dosing schedules and dose levels, were fortunately found to be suitably tolerated by patients, that could hardly have been predicted from the prior experiences.

Summary of the Invention

[15] This invention provides a new approach for treating prostate cancer patients, including among others men with castration resistant prostate cancer (CRPC), and including CRPC cases which are metastatic and/or asymptomatic. Thus, the patients may have responded to prior treatment and may be apparently asymptomatic or they may have failed to respond or to respond adequately to prior treatment, may have relapsed and may represent refractory cases.

[16] One aspect of the invention involves administering to such a patient a treatment effective amount of an mTOR inhibitor daily for five consecutive days per week ("qdx5/7"), i.e., with a two day "holiday" between each 5-day course of treatment with the mTOR inhibitor, in combination with the anti-androgen therapy.

[1 7] The patient will have already undergone surgical castration (bilateral orchiectomy) or is being treated concurrently with an agent inducing medical castration, such as a luteinizing hormone releasing hormone ("LHRH") analog. Suitable LHRH analogs and their use in such settings are well known. Non-limiting examples include buserelin, goserelin, histrelin, nafarelin, triptorelin and leuprorelin or leuprolide acetate products.

[18] Non-limiting examples of mTOR inhibitors for use in practicing this invention include rapamycin and rapamycin analogs, and may be administered by any pharmaceutically acceptable route, a variety of which are known for that class of drugs. Oral administration is currently of particular interest. The mTOR inhibitors of greatest current interest include rapamycin and rapamycin analogs in which the hydroxyl group at position 43 is replaced, especially those analogs currently in clinical development for treating cancer, such as deforolimus, everolimus and temsirolimus. These and other mTOR inhibitors are discussed in greater detail below. Their synthesis, characterization (physico-chemical, pharmacologic, pharmaceutical, etc. properties), formulation for various routes of administration, and use are well known.

[19] Daily dosing levels of the mTOR inhibitor range from 2 - 160 mg on each of the five consecutive days per week, with doses of 1 0 - 60 mg being of particular current interest, especially doses from 20 - 40 mg, and especially so in the case of deforolimus. A 40 mg dose of deforolimus administered orally on each of the five days per week is typical in the practice of this invention. Alternatively, everolimus, temsirolimus or sirolimus may be used, and may be administered orally, in some embodiments at levels of 3 - 50 mg qdx5/7, with dose levels of 3 - 20 mg, e.g., 5, 1 0, 1 5 and 20 mg of particular interest. [20] An anti-androgen therapy of particular interest comprises oral administration of an effective androgen blocking amount of a non-steroidal anti-androgen, such as bicalutamide, flutamide or nilutamide. Typical doses of those agents when given orally in the practice of this aspect of the invention include the following: for bicalutamide, 25 - 1 50 mg (usually 50 or 1 50 mg) once per day; for flutamide, 250 mg three times per day; and, for nilutamide, 300 mg once per day for the first 30 days and 1 50 mg/day thereafter. Oral administration of 50 mg of bicalutamide daily is of particular interest as the anti-androgen therapy, especially in subjects also being treated (p.o.) with 40 mg of deforolimus qdx5/7.

[21 ] The invention also provides a pharmaceutical pack, such as a blister pack, containing an mTOR inhibitor and an anti-androgen in one or more unit dosage forms for the treatment of a patient with prostate cancer with those two agents in accordance with the method of this invention. Each pack contains the mTOR inhibitor and anti- androgen for one or more days of the treatment regimen described herein. In some cases, the pack contains the appropriate medication for one or more weeks of the treatment regimen.

[22] Of particular interest are blister packs containing one or more sets of seven blisters, each set containing unit dosage products for practicing the treatment method of this invention for one week. Thus, each of the first five blisters per set of seven holds one or more tablets, capsules or other unit dosage products comprising one day's dose of an mTOR inhibitor-containing composition and another one or more unit dosage products comprising one day's dose of the anti-androgen composition. The last two blisters of each set of seven contains the daily dose of the anti-androgen in one or more unit dosage products and optionally one or more mock unit dosage products having the size, shape and color of the mTOR inhibitor unit dosage product, but lacking the mTOR inhibitor.

[23] This is illustrated by a blister pack in which the first 5 blisters per set of seven each hold a 40 mg deforolimus tablet and a 50 mg bicalutamide tablet. The last two blisters of the set of seven each have one 50 mg bicalutamide tablet and optionally a mock tablet of the size, shape and color of the deforolimus tablet, but containing no deforolimus. Of course, in some embodiments a daily dose is divided among more than unit dosage product, e.g., replacing a 40 mg deforolimus tablet, as in the preceding description, with two 20 mg tablets or four 1 0 mg tablets, for example.

[24] In other examples, 5, 1 0, 1 5, or 20 mg of sirolimus, everolimus or temsirolimus is substituted for the 40 mg of deforolimus in the first five blisters per set of seven in the preceding paragraph. [25] Also, in further examples, the set of seven blisters is replaced by a set of seven pairs of blisters to permit additional segregation of unit dosage products.

[26] More generally, in one embodiment, such a pharmaceutical pack contains one or more blisters, each containing (a) 20 - 40 mg of an mTOR inhibitor, or (b) a treatment effective amount of an anti-androgen, or (c) both, and each agent is present in its respective unit dosage form or in a combined unit dosage form, formulated for oral administration. To avoid patient confusion or compliance issues, a mock unit dosage form may be included in the size, shape and color of the mTOR inhibitor unit dosage form for the two days of "holiday" on which the mTOR inhibitor is not taken.

Detailed Description

I - mTOR Inhibitors

[27] mTOR inhibitors include any compound, or a pharmaceutically acceptable salt thereof, that inhibits cell replication by blocking the progression of the cell cycle from Gl to S phase. mTOR inhibitors of particular current interest include rapamycin (sirolimus) and analogs thereof that retain mTOR inhibitory activity, especially those noted elsewhere herein.

[28] Rapamycin is a macrolide, discovered in the 1 970's as a fermentation producr of Streptomyces hygroscopicus. Rapamycin is a potent immunosuppressive agent and is used clinically to prevent rejection of transplanted organs. It has also been reported to have a wide range of interesting pharmacologic activities, including certain anti-cancer activity. See e.g. US Pat. appln 2001 /0010920.

[29] Because there is more than one accepted convention for numbering the atoms of rapamycin and its analogs, the numbering convention used herein is depicted below:

For reference, the R group for a number of compounds is set forth in the following table:

Compound -R

Sirolimus (Rapamycin) -OH

Deforolimus (AP23573) -OP(O)(Me) ₂

Temsirolimus (CCI-779) -OC(O)C(CH ₃ KCH ₂ OH)

Everolimus (RADO01) -OCH ₂ CH ₂ OH

Biolimus -OCH ₂ CH ₂ OEt

ABT-578 -Tetrazole

[30] mTOR inhibitors currently in clinical development as anti-cancer agents include deforolimus, temsirolimus and everolimus. After promising initial clinical studies, the potential clinical significance of these three compounds is being evaluated more fully in several phase H-III trials on patients with solid tumors and some hematological malignancies.

[31 ] Temsirolimus is a soluble ester prodrug of rapamycin (rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid), which is disclosed in U.S. Pat. No. 5,362,71 8. It has demonstrated inhibitory effects on tumor growth in both in vitro and in vivo models. It exhibits cytostatic, as opposed to cytotoxic properties, and may delay the time to progression of tumors or time to tumor recurrence. As disclosed in WO 00/240000, it may be useful for the treatment of cancers of various origins, including renal, breast, cervical, uterine, head and neck, lung, prostate, pancreatic, ovarian, colon, lymphoma and melanoma.

[32] The mTOR inhibitor everolimus (RADOOl , Certican™) is 40-O-(2- hydroxy)ethyl-rapamycin, the structure and synthesis of which is disclosed in WO 94/0901 0. It has been shown to be a potent immunosuppressive agent (U.S. Pat. No. 5,665,772) and to have antineoplastic properties (see, e.g., A. Boulay et al., Cancer Res., 2004, 64: 252-261 ). As a result of these properties, it is currently marketed in certain countries as an immunosuppressant for prevention of allograft rejection (B. Nashan, Ther. Drug. Monit., 2002, 24: 53-58) and is undergoing clinical studies as an anti-cancer agent (S. Huang and PJ. Hougthon, Curr. Opin. Invest. Drugs, 2002, 3: 295- 304; M. M. Mita et al., Clin. Breast Cancer, 2003, 4: 1 26-1 37; M. Hidalgo and EJ. Rowinsky, Oncogene, 2000, 19: 6680-6686).

[33] The mTOR inhibitor of particular interest is deforolimus, a phosphorous- containing rapamycin derivative (See WO 03/064383, Example 9 therein). Like temsirolimus and everolimus, deforolimus has demonstrated antiproliferative activity in a varietyof PTEN-deficient tumor cell lines, including glioblastoma, prostate, breast, pancreas, lung and colon (E.K. Rowinsky, Curr. Opin. Oncol., 2004, 1 6: 564-575). deforolimus has been designated as a fast-track product by the U.S. Food and Drug Administration for the treatment of soft-tissue and bone sarcomas. Deforolimus is currently in multiple clinical trials targeting certain hematologic malignancies and solid tumors.

[34] The foregoing compounds are non-limiting examples of potent mTOR inhibitors. For additional information on deforolimus, see US Patent No. 7,091 ,213. For recent references on temserolimus (CCI779), see WO 2004/026280, WO 2005/01 1 688, WO 2005/070393, WO 2006/0861 72 and WO 2006/08931 2. For everolimus, see US Patent No. 6,384,046, US 6, 1 97,781 , US 6,004,973 and WO 2002/06601 9 and references cited therein. Other mTOR inhibitors of interest include 42-desmethoxy derivatives of rapamycin and its various analogs, as disclosed, e.g., in WO 2006/0951 85 (in which such compounds are referred to as "39-desmethoxy" compounds based on their numbering system).

[35] Additionally, a large number of other structural variants of rapamycin have now been reported, typically arising as alternative fermentation products and/or from synthetic efforts. For further background and references to the extensive literature on analogs, homologs, derivatives and other compounds related stucturally to rapamycin ("rapalogs"), see, e.g., WO/2007/1 4321 2 and references cited therein.

[36] A variety of oral and parenteral dosage forms are known for rapamycin and a number of rapamycin analogs. See e.g., US Patent No. 7,091 ,21 3. Some are currently in use in various treatment methods, monotherapies or otherwise. Those same dosage forms may likewise be used in the practice of the combination therapy disclosed herein. Solid dosage forms are often of particular interest for oral administration and include among others conventional admixtures, solid dispersions and nanoparticles, typically in tablet, capsule, caplet, gel cap or other solid or partially solid form. Such formulations may optionally contain an enteric coating. Numerous materials and methods for such oral formulations are well known. A typical example of the use of conventional materials and methods to formulate an mTOR inhibitor is shown in US Patent Application US 2004/0077677 and Published International Patent Application WO04026280 (CCI-779). See also US patents US61 97781 , US6589536, US65551 32, US5985321 , US6565859 and US5932243.

[37] Oral dosage forms (e.g., tablets, capsules, etc.) for the mTOR inhibitor are of particular interest. For further background on deforolimus-containing tablets, for instance, see WO 2008/060546. [38] In addition to the foregoing, a wide variety of other methods and materials are also well known to those working in the field of macrolides like rapamycin and its derivatives. For additional background and examples of appropriate formulation technologies, see e.g., WO 03/064383 and US Published Patent Application 20050032825.

Il - Anti-androgens

[39] Anti-androgens include several well-known classes of agents, of which the nonsteroidal anti-androgens are of particular interest for this invention. Examples include bicalutamide (Casodex ^® ), flutamide (Eulexin ^® ), and nilutamide (Nilandron ^® ). Anti-androgens compete with the male hormone testosterone for binding to the androgen receptors on prostate cancer cells. These medications represent a form of hormone blockade by preventing the hormone from triggering signal transduction rather than by reducing hormone release from the body, as is the case for LHRH agonists, like Lupron ^® (leuprolide acetate) and Zoladex ^® (Coserelin Acetate) which are given by injection or via subcutaneous depot.

[40] An anti-androgen, like bicalutamide, which blocks the function of testosterone, is often used in combination with steps to reduce the body's relase of testosterone, i.e. either surgical castration or "medical castration" (through treatment with an LHRH agonist). The recommended dose for bicalutamide therapy in combination with an LHRH agonist is one 50 mg tablet once daily (morning or evening), with or without food. It is recommended that bicalutamide be taken at the same time each day and that treatment with bicalutamide bestarted at the same time as treatment with an LHRH analog.

[41 ] As noted previously, other anti-androgens, like flutamide and nilutamide may be used in place of bicalutamide. A potential disadvantage of flutamide is that it can have a somewhat higher incidence of side effects (diarrhea and liver enzyme abnormalities), which although inconvenient, should not be dangerous.

[42] The dose levels noted thus far for the anti-androgens may be used in the practice of this invention as well.

III. LHRH Agonists

[43] LHRH agonists are synthetic analogs of the natural CnRH decapeptide with certain amino acid substitutions which slowtheir rate of degradation. Some available LHRH agonists include leuprolide (Lupron, Eligard), buserelin (Suprefact, Suprecor), nafarelin (Synarel), histrelin (Supprelin), goserelin (Zoladex), deslorelin (Suprelorin, Ovuplant) and Triptorelin. [44] These medications can be administered intranasally, by injection, or by implant. Injectables have been formulated for daily, monthly, and quarterly use; and implants can last from 6 to 1 2 months. Any of the approved LHRH agonists may be chosen for administration, using the approved dose level and protocol, to patients being treated with the combination of mTOR inhibitor and anti-androgen described herein.

IV. Pharmaceutical Compositions

[45] Pharmaceutical compositions containing the mTOR inhibitor and the anti- androgen for use in the treatment method of this invention, as well as the LHRH agonist, are either commercially available in the case of approved agents or may be prepared in dosage unit form using well known materials and methods, as referenced in various portions of this document.

[46] The expression "unit dosage form", is usually used herein to refer to a physically discrete unit, such as a tablet or capsule containing one or both of the mTOR inhibitor and anti-androgen (with or without one or more additional agents) with which a patient may be treated.

[47] After formulation with one or more appropriate physiologically acceptable carrier(s) or excipient(s) in a desired dosage, the pharmaceutical compositions can be administered to humans or other mammals by any suitable route. Various delivery systems are known and can be used to administer such compositions, including, tablets, capsules, injectable solutions, encapsulation in liposomes, microparticles, microcapsules, etc. Methods of administration include, but are not limited to, dermal, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, pulmonary, epidural, ocular, and oral routes. As previously noted, oral administration of the mTOR inhibitor and the anti-androgen is of particular interest, as is the use of solid dosage forms for such administration, such as capsules, tablets, pills, powders, and granules. See e.g. WO 2007/14321 2 and references cited therein for additional background on formulation. For further background information on formulations of rapamycin derivatives or analogs, see, for example, U.S. Pat. Nos. 5, 1 82,293 and 4,837,31 1 (tablets, capsules and other oral formulations as well as intravenous formulations) and U.S. Pat. Nos. 5,536,729 and 5,559,1 21 (illustrative formulation for oral administration); U.S. Pat. Nos. 5, 145,684 (nanoparticles) and 5,989,591 (solid dosage forms) and WO 98/59358. For additional background information on temsirolimus, see e.g., U.S. Pat. Nos. 2003-01 53593 and 2005-01 871 84 and PCT application No. WO 02/080975. For everolimus, see e.g., WO 03/064383. V - Pharmaceutical Packs

[48] This invention also provides pharmaceutical packs (such as blister packs, lidded blisters or blister cards, as non-limiting examples) containing an mTOR inhibitor and an anti-androgen in one or more unit dosage forms for use in the treatment of a patient with prostate cancer in accordance with the the treatment method described herein. A variety of designs for such packaging are available, well known, and suitable for use in this invention. See e.g., US Patent No. 7, 337,906 and references cited therein. Generally such packs are composites have, among other elements, a backing sheet bearing one or more bubbles, receptacles or "blisters", each of which containing one or more unit dosage forms. The blisters may be arrayed and optionally labeled to indicate that each blister or set of blisters contains one day's medications. Each pack may contain blisters in multiples of seven to provide one or more weekly courses of the combination therapy of this invention.

[49] One illustrative embodiment provides a blister card, or portion of a blister card, containing seven blisters, each of the seven blisters containing a daily dose of anti-androgen and five of the seven containing, in addition, a daily dose of the mTOR inhibitor.

[50] The respective agents may be provided in separate unit dosage forms, e.g. one or more mTOR inhibitor unit dosage forms and one or more anti-androgen unit dosage forms, or may be combined into a combination dosage form containing a mixture of both agents. A combination dosage form may be provided, for example, by one or more capsules, each containing granules of a composition comprising the mTOR inhibitor and granules of a composition comprising the anti-androgen. For the two blisters which house the medication for the two days per week on which the mTOR inhibitor is not administered, the unit dosage product contains anti-androgen but not the mTOR inhibitor.

[51 ] In embodiments in which five of the seven blisters contain two different unit dosage forms, e.g., mTOR inhibitor tablets and anti-androgen tablets, the remaining two blisters may contain only the single unit dosage product containing the anti- androgen. To avoid patient confusion or risk of compliance issues, those two blisters for the two days on which mTOR inhibitor is not taken may optionally contain, in addition to the anti-androgen unit dosage product, a mock unit dosage product with the size, shape and color (but without the mTOR inhibitor compound) of the mTOR inhibitor-bearing unit dosage product taken on the other five days.

[52] In some embodiments, a daily dose of an agent may be divided among one or more unit dosage products. For example, in cases in which the qdx5/7 daily dose of deforolimus is 40 mg, for instance, that dose may be provided by a single 40mg tablet, two 20 mg tablets or four 10 mg tablets.

[53] In those embodiments in which a daily dose of one or both agents is provided via more than one unit dosage product, those products (e.g., where the medication for a given day is distributed among two or more tablets or capsules), they may be present in the same blister, as described above, or they may be disposed in a set of blisters for each day.

[54] Thus, a pack may contain medication for one or more weeks, represented by one or more sets of seven blisters, optionally labeled. This is illustrated by a pack in which the first five blisters of a card contain one or more tablets or capsules, each of which containing both drugs, followed by two blisters in which the tablet(s) or capsule(s) contain only a daily dose of anti-androgen. For example, blisters 1 - 5 may each hold one capsule loaded with a composition containing 40 mg deforolimus and 50 mg bicalutamide, while blisters 6 and 7 contain a capsule loaded with a composition containing the 50 mg of bicalutamide (without any deforolimus). In alternative embodiments, the contents of each blister are distributed among two or more tablets, capsules or other dosage forms.

[55] A pharmaceutical pack of this invention may be accompanied by instructions providing information on the contents, dosages, dosing schedule, storage, administration in accordance with the method of this invention, effects of food or drink, contraindicated drugs, possible side effects and other information potentially useful to the patient. The instructions may be in the form of a label on a surface of the pack or on a surface of a box or other package housing the pharmaceutical pack and/or in the form of an insert included in the box or other other package. The instructions can also be printed on the box/package or can be provided in a computer-readable form. The instructions or package insert may be in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceutical or biological products, reflecting approval by that agency of manufacture, use or sale for human administration.

Examples

[56] The following examples describe approaches for practicing the invention.

However, it should be understood that these examples are for illustrative purposes only and are not meant to limit the scope of the invention. Furthermore, unless the description in an Example is presented in the past tense, the text, like the rest of the specification, is not intended to suggest that experiments were actually performed or data were actually obtained.

Materials

Deforolimus may be prepared as described in US Patent No. 7,091 ,21 3 and is supplied in the form of 10 mg enteric coated tablets which may be prepared as described in WO 2008/060546 and dispensed on a blister card.

Bicalutamide may be obtained as 50 mg Casodex™ tablets (AstraZeneca) and may be dispensed from a bottle, blister card or other packaging, or from a combined blister pack also containing deforolimus tablets, as described infra.

Example 1: Treatment with deforolimus (40 mg, p.o., qdx5) and bicalutamide (50 mg, p.o., qdx7)

Prostate cancer patients to be treated in this example have already undergone bilateral orchiectomy or are undergoing therapy with an LHRH analog.

A 50 mg dose of bicalutamide is self-administered by each patient orally every day. in addition, a 40 mg dose of deforolimus is self-administered orally, in the form of four 1 0 mg enteric coated tablets, each day for 5 consecutive days each week.

Deforolimus should be taken with water 2 hours after a light meal (i.e.: toast, tea, etc.). Patients may be instructed to consume only water for 2 hours after dosing with the deforolimus.

During the course of treatment, patients should consult their care giver before taking any strong inducers or inhibitors of CYP3A and before consuming grapefruit or grapefruit juice.

Progression, spread or remission of the cancer and the condition of the patient may be followed by periodic monitoring of one or more indicators, such as Prostate Specific Antigen level, bone scan, CT scan of abdomen and pelvis, levels of circulating tumor cells, etc.