MXPA00000198A - Methods to potentiate intravenous estramustine phosphate - Google Patents

Abstract

Estramustine phosphate is an anti-mitotic chemotherapeutic drug with proven efficacy against cancer. The invention describes methods which potentiate the therapeutic benefit of intravenous estramustine phosphate. The invention provides for intravenous estramustine phosphate to be administrated at a high dosage exceeding 1300 mg as a single dose. Efficacious enhancement of estramustine phosphate pharmacokinetics is thereby achieved. Further provided, estramustine phosphate may be intravenously administered for use in combinational regimens with other chemotherapeutic agent. The therapeutic advantages achieved using the intravenous estramustine phosphate formulation are applicable to treatment of a variety of cancers including prostate cancer, breast cancer, lung cancer, colorectal cancer, pancreatic cancer, ovarian cancer, melanoma, and other cancers.

Description

METHODS FOR POTENTIATING INTRAVENOUS ESTRAMUSTIN PHOSPHATE REFERENCES TO RELATED REQUESTS This request claims priority to the provisional request of E. U. A. Series No. 60 / 079,542, which was filed on March 27, 1998.

BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the use of estramustine phosphate, a mustard carbamate derivative which is not estradiol-7b-phosphate nitrogen, as a high-dose infusion. The present invention further relates to methods for enhancing intravenously administered estramustine phosphate and methods for treating cancer by intravenously administering estramustine phosphate intravenously.

Discussion of Background It has been shown that the cytotoxic effects are due to the intact estramustine molecule (Hartley-Asp, 1982). Studies in tissue cultures have shown that estramustine (MS) is an anti-mitotic agent, which causes a dose-dependent block of metaphase tumor cell division (Hartley-Asp, 1984). The metaphase arrest is known to be caused by an interference of drugs with the microtubule structure that forms the mitotic spindle. It has been shown that, with the aid of immunohistochemistry, interphase microtubule dose-dependent disorders occur in cultured human prostate cells (Mareel 1988, Dahllof 1993). Treatment with EM in vitro inhibited the assembly of microtubules composed only of tubulipa, demonstrating a direct interaction with tubulin (Dahllof 1993). In addition, an interaction with microtubule-associated proteins (MAPs) has been demonstrated (Stearns 1988). MAPs are high molecular weight proteins that are thought to be important in stabilizing microtubules. That EM exhibits the mechanism of action of an antimitotic agent has been confirmed in vivo (Eklov, 1992). In this way, estramustine phosphate is an antimitotic agent currently used in the treatment of advanced adenocarcinoma of the prostate. As an individual agent, its activity is hormone refractory prostate cancer is comparable to that of several other cytotoxic agents that have been studied in a series of randomized, multi-institutional analyzes by the National Prostatic Cancer Project (Murphy, 1983). Since the drug is usually administered orally at a dose of 10-15 mg / kg / day, it has been tested for intravenous administration in several countries. However, estramustine phosphate when administered intravenously has been used at doses and according to a program that runs parallel to the oral administration of the drug, that is, at the recommended doses of 300-60 mg given daily in an intravenous usually repeated for several consecutive days. Then this is followed by the drug administered. In the published material, details of approximately 500 patients can be found who were treated with the intravenous formulation initially followed by oral treatment. Induction programs using 300-600 mg of intravenous formulation daily for 7-21 days, followed by daily oral doses, were typical in these studies. The drug was administered as a slow intravenous injection or as a bolus at 300 mg / day, and thrombophlebitis and local irritation at the peripheral intravenous injection sites were considered major limitations of drug administration requiring the establishment of central line administration in many patients or the discontinuation of treatment. At 450 mg / day, Nagel and Kölln (1977), established that this leads to "severe gastrointestinal problems that were taken 300 mg / day as the maximum intravenous daily dose". In a compilation, by Andersson and others of 245 patients who received 300-600 mg / day for 21 days followed by the same dose once or twice daily for 2 months, 20% of patients exhibited thrombophlebitis, 17% exhibited gastrointestinal problems and 9% exhibited liver disorders. Toxicities resulting from such repeated dosing schedules usually require discontinuation of the drug (Lundgren, 1995), Maier (1990), daily administered intravenous dose of 900 mg / day for 7-10 days, followed by oral therapy, without reporting phlebitis but severe liver problems occurred in 11 of 18 patients (61%) with one death due to toxic liver failure. The prior art in this manner typically used intravenous estramustine phosphate formulations as a single agent method to initiate a long-term oral estramustine therapy. In addition, intravenous administration of estramustine phosphate at higher doses is generally considered prohibitive due to toxicity. It is neither known nor obvious in the art that administration of a high dose, individual dose of estramustine phosphate is intravenously reliable. Although the dosage of up to 1200 mg / m2 has been given orally (Keren-Rosenberg, 1997), differences in drug metabolism and bioavailability do not allow extrapolation to the high-dose intravenous formulation, with relative bioavailability of estramustine after administration oral that was only 44%. (Gunnarsson, 1984), with the dephosphorylated phosphate portion in the oral formulation in contrast to the intravenous formulation. In addition, it is not known in the art that intravenous estramustine phosphate can be used in combination chemotherapy regimens, including the use of higher dose intravenous estramustine phosphate. Furthermore, it is not known in the art that intravenous estramustine phosphate has clinical utility for cancers other than the indication of prostate cancer. In the previous work of Dr. Beryl Hartley-Asp, a co-inventor of this invention, he was the first to recognize the synergistic potential of estramustine phosphate with other cytotoxic agents, (Mareel 1988). In several experiments, it was shown that prolonged exposure to estramustine was necessary to obtain potentiation. Consequently, daily dosing became necessary leading to the use of ORAL preparation as previous data of intravenous (IV) preparation which suggested that obtaining high constant levels could not be clinically obtainable with intravenous dosing. The effects of additive and possibly synergistic anti-microtubule on cells in vitro have been shown for estramustine and many other cytotoxic agents (Mareel 1988, Speicher 1992, Pienta 1993, Batra, 1996). In this way, the combination of estramustine phosphate with other drugs in humans has been carried out using ORAL administration of estramustine phosphate. The phase II trials (Seidman, 1992, Hudes, 1992, Pienta, 1994, Hudes, 1996) with estramustine phosphate combined with vinblastine, have been performed in hormone refractory prostate cancer. In these analyzes, a 50-75% reduction in prostate-specific antigen was demonstrated among 88 patients. The most frequent toxicity was mild to moderate nausea. Of particular observation is the incidence of 10.5% (4/37) of major cardiovascular toxicity including a deep vein thrombosis (DVT), a myocardial infarction, an episode of congestive heart failure and a reversible neurological event, which required the arrest of therapy in these patients and that can be attributed to estramustine phosphate. In another phase II analysis conducted by Pienta et al. (1994), estramustine phosphate (oral) was combined with etoposide. We were able to evaluate 52 patients: including 20 patients with soft tissue disease, where we observed 3 complete responses (CR) (15%) and 6 partial responses (PR) (30%). In 32 patients with metastases from bone metastases, 8 patients improved (25%), and 12 patients were stable (38%). The 13 men (25%) had a 75% reduction in prostate specific antigen, and 28 men (54%) had a 50% reduction. A phase I-II study of Taxol (Hudes, 1992) and estramustine phosphate was performed in 17 patients with hormone-refractory prostate cancer. Six patients had the measurable disease and 3 of them obtained a PR of 2 +, 6 and 8 months. The prostate specific antigen (PSA) was reduced by >; 50% in 58.8%. The average duration of the response was 7 months. The degree of granulocytopenia and mucositis 3-4 occurred in 2 patients, grade 1-2 nausea (70.5%) and grade 3 in one patient. Edema was seen in 8 patients (48%) and transient hepatic enzyme elevation of grade 1-3 in 6 patients (35.2%).

In a recent study, Petrylak et al. (1997), using escalated doses of docetaxel with orally given estramustine phosphate, demonstrated a 62% total prostate specific antigen response regimen. In patients with the two-dimensional measurable disease, 3 (43%) obtained a partial response in the lymph nodes, and one obtained a lower response in the ischial mass. This shows that the combination treatment with estramustine phosphate ORAL is effective. However, combinations of intravenous estramustine phosphate with these cytotoxic agents are not known in the art. Differences in metabolism, particularly with respect to the phosphate moiety, in oral versus intravenous estramustine phosphate formulations make combination therapies with the non-obvious intravenous formulation. In contrast to other anti-mitotic agents, the effect of estramustine phosphate appears to depend on the presence of the estramustine binding protein (EMBP) (Eklov, 1996). This was found under normal conditions only in the prostate (Forsgren, 1979, Flucher, 1989). However, a similar protein was also identified in many cancerous tissues, as well as prostate tumors, such as lung, breast glioma, colon, pancreas Bjórk, 1991, Berch 1988, Eklóv 1996, Edgren 1996, Von Shoultz, 1994, Bergenheim , 1993). This protein binds estra- and estro-mustine (EaM and EoM) with a very high affinity and is thought to be responsible for the selective arrest of EoM in the prostate tumor, when a ratio of 1: 6 to 1 has been found: 11 plasma / tumor in patients with prostate cancer treated with estramustine phosphate orally and intravenously, respectively (Norlen 1988, Walz 1988). Recently, a correlation between EMBP levels and EaM and EoM levels in human prostate tumors has been demonstrated after an individual intravenous dose of estramustine phosphate to patients before radical prostatectomy, indicating that EMBP may be the cause of the retention of the drug (Walz, 1996).

BRIEF DESCRIPTION OF THE DRAWINGS A more complete appreciation of the invention and many other advantages thereof will be readily obtained as it is better understood by reference to the detailed description that follows when considered together with the accompanying drawings in which: Figure 1 illustrates the estramustine phosphate concentration after an individual intravenous dose of Estracyt (medium + _ SEM, N = 4 + 4 + 3) given at a dose of 1000 mg (980-1070 mg scale), 1000 mg / m2, and 1500 mg / m2; and Figure 2 illustrates the concentration of estromustine after an individual intravenous dose of Estracyt (medium + SEWI, n = 4 + 4 + 3) given at a dose of 1000 mg (980-1070 mg scale), 1000 mg / m2 , and 1500 mg / m2.

COMPENDIUM OF THE INVENTION The present invention describes methods for enhancing the therapeutic use and efficacy of intravenously administered estramustine phosphate. It is provided for the intravenous administration of estramustine phosphate in doses exceeding 1300 mg. Intravenous administration of estramustine phosphate is also provided at doses exceeding 950 mg / m2 (milligrams per square meter of body surface area). In addition, the administration of intravenous high dose estramustine phosphate is provided as an individual dose, which can also be administered in a weekly or longer program. The present invention allows the optimization of pharmacokinetics in order to maximize the therapeutic advantage, and also allows the use of intravenous estramustine phosphate in combination with other therapies, including other chemotherapies, providing an additional improved therapeutic benefit. The present invention allows the use of intravenous estramustine phosphate as therapy for multiple types of tumors, including prostate, breast, lung cancer, ovarian, colo-rectal, melanoma, pancreatic and brain. Thus, an application of the present invention is to provide a high dose estramustine phosphate therapy intravenously, wherein the dose exceeds 950 mg / m2. Another application is to provide an intravenous administration program, whereby the program activates the optimization of the pharmacokinetics of estramustine phosphate and its metabolites to a minimum toxicity, and in addition said optimization allows convenient and effective regimens of combination therapy. Thus, an application of the present invention allows the use of intravenous estramustine phosphate in combination with other therapeutic regimens, including cytotoxic chemotherapy. Another application of the present invention is to provide a method that increases binding saturation and prolongs the binding duration of estramustine phosphate or its metabolites to the estramustine binding protein or to the estramustine binding protein type protein (EMBP). . Thus, the present invention provides for the application of the treatment of cancers having EMBP, including, but not limited to prostate, breast, lung, ovarian, colorectal, melanoma, pancreatic and brain cancer, through intravenous administration. Another application of the present invention is to provide a method for rapidly mitigating symptoms secondary to cancer, including but not limited to pain induced by cancer and urinary obstruction. In addition, the present invention allows these applications to be used for intravenous estramustine phosphate independent of the formulation. Thus, the present invention provides the infusion of estramustine phosphate as a free drug, as a protein binding drug, or as a drug within liposomes. Thus, the present invention discloses a estramustine phosphate formulation, wherein the estramustine phosphate is administered intravenously together with liposomes. Thus, the method of the present invention wherein doses above 900 mg / m2 (generally greater than 1300 mg per dose) can be administered safely and within an effective program, and it is extremely unexpected. The present invention teaches the advantage of intravenous estramustine in combination with other chemotherapy agents. The present invention further teaches the advantage of high dose intravenous estramustine in combination with other chemotherapeutic agents. In this invention it is taught that intravenous estramustine phosphate can be used to treat tumors by having high EMBP type protein (hereinafter referred to simply as EMBP). The novel and non-obvious applications of the present invention can be recognized from a comparison of pharmacokinetic data after oral administration of estramustine phosphate with those after high-dose intravenous administration of estramustine phosphate. The pharmacokinetic and toxicity data with respect to high dose intravenous estramustine phosphate are not known in the art. The dephosphorylation of estramustine phosphate to estramustine (EM), followed by oxidation at position 17 to estromustine (EoM), the estrone analogue of EM are the major metabolic steps after administration of oral estramustine phosphate in Man. EoM is the predominant metabolite found in plasma when estramustine phosphate is administered in a daily oral program. The relative bioavailability based on stromustine is approximately 44% (Gunnarsson, 1984). After estramustine phosphate intravenously administered initially is found in plasma but is rapidly hydrolyzed to it metabolites thereof where they are after oral administration, the major metabolite estromustine being. Both estramustine and stromustine are further metabolized by cleavage of the carbamic ester to produce approximately 15% estradiol and estrone, respectively (Gunnarsson, 1981, 1984). An unexpected prolonged availability of stromustine from the major metabolite has been demonstrated after high-dose intravenous administration, which leads to unexpected clinical benefits. Previous data from patients treated with an individual intravenous dose of 300 mg showed that the elimination of stromustine had half-lives of 10-20 hours. The main route of elimination was the metabolism of estromustine phosphate to estramustine, estromustine, estradiol and estrone. The data of particular importance for the effectiveness of estramustine phosphate were the half-lives of estramustine phosphate (Figure 1), and the stromustine of the main cytotoxic metabolite (Figure 2). Through the application of the methods of this invention, we now demonstrate the novel finding that after a high intravenous dose of estramustine phosphate of 1000 mg / m2 it was found that the half-life of estromustine was approximately 100 hours (Figure 2). The finding also allows therapeutic applications of high-dose intravenous estramustine phosphate.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The present invention teaches the ability to administer estramustine phosphate at doses above 950 mg / m2 (ie, more than 1300 mg). The method of the present invention is carried out as follows. In the preferred method, estramustine phosphate is administered at an individual infusion dose exceeding 950 mg / m2. Intravenous administration is performed either through a central or peripheral intravenous route. During the preparation of the intended drug, the contents of packaged estramustine phosphate intended for intravenous use are dissolved, wherein the packaged contents may consist of, but not limited to, lyophilized powder of the meglumine salts in estramustine phosphate bottles, or similar freeze-dried estramustine phosphate, which were first dissolved in sterile water such as 5 ml of sterile water per 300 mg estramustine phosphate, or 5% dextrose in water for intravenous administration. In the preferred method, 5% dextrose in water was used as the diluent. In the preferred method, during the preparation of the dissolved drug, the preparation should not be stirred, but rather must be inverted slowly to mix. The solution is then given as an intravenous infusion with the preferred duration of the infusion time being from 30 minutes to 3 hours, so the infusion of 1-2 hours is a safe and convenient method. The saline solution can result in precipitation of the drug and thus its use is not preferred in the infusion. When estramustine phosphate is administered through a peripheral intravenous route, it is preferred that a longer duration of infusion and a larger total infusion volume be used to minimize vascular irritation. Alternatively, the estramustine phosphate solution can be mixed with various amounts, but preferably 3-5% of human albumin or other plasma proteins including synthetic plasma proteins to achieve protein binding of estramustine phosphate and, therefore, , minimize any potential vascular damage. The invention is further carried out using other preparations or formulations of estramustine phosphate. A particularly advantageous preparation of the chemotherapeutic agent, estramustine phosphate, which allows the infusion of estramustine phosphate through a vein either peripheral or central, both at high doses and also doses lower than 1300 mg, involves the infusion of phosphate from estramustine together with liposomes (hereinafter referred to as estramustine phosphate encapsulated in liposomes or liposomal intramustine). In a preferred method for preparing liposomal estramustine, a solution of estramustine phosphate is first prepared in the manner described above and then injected into a vial containing available empty liposomes as a lyophilized powder. After adequate hydration of the liposomes, the bottles are shaken and sound is applied, followed by infusion to the patient. When estramustine phosphate is administered via a central venous route, such administration can be performed through a venous access device either temporary or permanent, including, but not limited to, a triple lumen catheter, Hickman catheter , subclavian line, jugular line, or middle port. Said administration may be, but not necessarily be performed concomitantly with anticoagulant therapy or with the addition of variable amounts, but preferably 3-5% human albumin or other plasma proteins or liposomal estramustine to minimize any potential vascular damage in a given patient. Although the dose of estramustine phosphate in the present invention is greater than 1300 mg, it is preferred that the patient be treated at a dose exceeding 950 mg / m2. In this way, a preferred method is to administer an individual intravenous dose of 1000 mg / m2. Another preferred method is to administer an individual intravenous dose of 1500 mg / m2. In addition, a dose of 2000 mg / m2 can be administered. However, the invention is inclusive of other doses above 950 mg / m2 and the preferred doses are not implying limitation. The most preferred program of administration of estramustine phosphate in the invention is an individual infusion given once a week at a maximum dose of 4000 mg or 3500 mg / m2. Another preferred program is the administration of an individual drug infusion once every two weeks. Another preferred program is the administration of an individual drug infusion once every three weeks. Another preferred program is the administration of an individual drug infusion once every four weeks. One program may be preferred over another in consideration of the programs with another concomitant therapy. These programs can be repeated in a serial or repetitive manner. The invention described herein allows methods for prolonging blood and / or tissue levels at high elevations for estramustine phosphate metabolites, including estromustine, estramustine, estrone and estradiol. In this way, improved synergistic interactions with other therapies are enabled, wherein said therapies include, but are not limited to, chemotherapy, radiotherapy, monoclonal antibodies and biological therapies. The present invention provides for the maximization of therapeutic benefit through the prolongation of elevated levels of estramustine phosphate in the blood and tissues and their metabolites. In this way, maximization of therapeutic benefit is achieved when estramustine phosphate is administered intravenously at doses exceeding 950 mg / m2, which are administered in combination with other cancer therapies, including, but not limited to, radiation therapy, chemotherapy, monoclonal antibodies and biological therapies. In the preferred method, the therapeutic benefit is enhanced by administering intravenous estramustine phosphate at individual doses exceeding 950 mg / m2, with other cytotoxic therapies. In the preferred method, said combination is achieved by administering intravenous estramustine phosphate in three days of the other chemotherapeutic agents, preferably on the day of, or the day before administration of the other chemotherapeutic agents. A particularly preferred method is achieved when the other chemotherapeutic agents consist of anti-mitotic agents or anti-microtubule agents, including, but not limited to, taxanes, including taxol and taxotere, and agents including vinblastine, vincristine, etoposide, navelbine, toxorubisin. , irinotecan (CPT-11), and chemotherapeutic agents encapsulated in liposome, including taxanes encapsulated in liposome such as paclitaxel encapsulated in liposome. It may also be beneficial if a combination with a monoclonal therapy is used, that monoclonal agent includes a radionucleotide or a factor-against-growth agent.

Stromustine levels in plasma or serum are also maintained when estramustine phosphate is administered intravenously as an individual infusion at a dose exceeding 950 mg / m2. The infusion can optionally be repeated in a serial or repetitive manner to maintain high levels of stromustine phosphate metabolites in the blood. The sustained levels of estramustine phosphate and its metabolites in this way allow for sustained therapeutic benefit. The present invention thus provides a method for increasing the binding saturation of estramustine or its metabolites to the estramustine binding protein or similar protein by administering estramustine phosphate intravenously at an individual infusion dose exceeding 950 mg / m2. Similarly, the binding duration of the estramustine phosphate or its metabolites to the estramustine binding protein or estramustine binding protein type protein (EMBP) was increased in the invention by administering the drug at intravenous doses exceeding 950 mg / m2. In this manner, all cancers that have either a estramustine binding protein or a estramustine binding protein type protein can be treated through intravenous estramustine phosphate. It is particularly preferred to treat prostate cancer in said form. It is also preferred to treat breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer, and brain cancers in such a manner. It is particularly preferred that the estramustine phosphate is administered intravenously, wherein the individual dose exceeds 950 mg / m2 when treating cancers that have either a estramustine binding protein or a protein of the estramustine binding protein type, including , but not limited to the group of cancers including prostate cancer, breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer and brain cancers. These cancers can also be treated using liposomal estramustine, either as an individual agent or in combination with other chemotherapies. Said administrations are preferably repeated in series or in a repetitive manner to the programs of the invention, with or without the combination of other therapies. In this way, such programs may include the combination treatment of intravenous estramustine phosphate with other chemotherapeutic therapies given once a week, and once every two weeks, once every three weeks, or once every four weeks, as a program , and variations in them.

It is particularly preferred that the intravenously administered estramustine phosphate be administered in combination with other cytotoxic chemotherapeutic agents when used in the treatment of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, cancer of the ovary and the brain. It is further particularly preferred that intravenously administered estramustine phosphate be administered in combination with radiation when used in the treatment of prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer and brain cancers. It is also preferred that they treat cancers having estramustine binding protein or a protein of estramustine binding protein type, including prostate cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and Brain cancers, estramustine phosphate is administered at intravenous doses exceeding 950 mg / m2 when used in combination with other cancer therapies. The present invention allows both objective and subjective therapeutic benefit. The benefit obtained can be related to the reduction of the size of the tumor, the improved quality of life, the reduction of tumor obstruction, such as urinary obstruction, reduction of cancer-induced pain, improved survival, reduction in time to cancer recurrence, or other evidence of improvement. In particular, a rapid objective or subjective therapeutic benefit is achieved by administering the estramustine phosphate intravenously at a dose exceeding 950 mg / m2, either as a single agent or preferably in combination with other cancer therapies. In this way, the invention allows rapid relief of urinary obstruction induced by cancer and rapid relief of pain induced by cancer. Other aspects of the invention will be apparent in the course of the following descriptions of the illustrative embodiments given for the illustration of the invention and are not intended to limit the same.

EXAMPLES The following clinical cases are provided by way of example and not limitation.

EXAMPLE 1 Two patients with advanced metastatic prostate cancer with estramustine phosphate intravenously given through a central line were treated. The patients received a dose of estramustine phosphate of 2500 mg / m2. Estramustine phosphate was administered as an individual infusion in a weekly schedule in a repetitive manner. Each infusional dose was administered during a 90-minute infusion. The infusions were well tolerated without serious toxicity and both patients demonstrated a response (reduction) in their prostate-specific antigen (PSA).

EXAMPLE 2 Three patients with advanced metastatic prostate cancer were treated with estramustine phosphate intravenously given through a central line at a dose of 2000 mg / m2. Estramustine phosphate was administered as an individual infusion in a weekly schedule in a repetitive manner. Each infusional dose was administered in a 30-minute infusion. The infusions were well tolerated with several patients demonstrating PSA response.

EXAMPLE 3 Three patients with advanced metastatic prostate cancer were treated with estramustine phosphate administered intravenously through a central line at a dose of 1500 mg / m2. Estramustine phosphate was administered as an individual infusion in a weekly schedule in a repetitive manner. The infusional dose was administered either for 30 minutes or for 1 hour. The infusions were well tolerated with a patient demonstrating a response in bulky tumor adenopathy.

EXAMPLE 4 Three patients with advanced metastatic prostate cancer with estramustine phosphate intravenously given through a central line were treated. The patients received a dose of estramustine phosphate of 2000 mg / m2. Estramustine phosphate was administered as an individual infusion in a weekly schedule in a repetitive manner. Each infusional dose was administered during a 60-minute infusion. An antithrombotic agent was additionally administered for prophylaxis of venous thrombosis. The estramustine phosphate infusions were well tolerated without serious toxicity, and with evidence of PSA response.

REFERENCES Anderson SB, Lundgren R. Svensson L: gas chromatographic determination of four metabolites of estramustine phosphate in plasma. Acta Pharm Suec 19: 1-10, 1982. Batra S. Karlsson R. Witt L: Potentiation through estramustine of the cytotoxic effect of vinblastine and doxorubicin on prostatic tumor cells. Int. J. Cancer 68: 1-6, 1996. Bergenheim AT, Gunnarsson PO, Edman K, von Schoultz E, Hariz Ml Henriksson R: Consumption and retention of estramustine and the presence of estramustine binding proteins in malignant tumors of the brain in humans. Br J. Cancer 67: 358-361, 1993. Bergh J, Bjork P. Westlin J-E, Nilsson S: expression of an associated estramustine binding protein in human lung cancer cell lines. Cancer Res 48: 4615-4619, 1988. Bjórk P. Borg A. Fernó M. Nilsson S: Expression and partial characterization of the estramustine binding protein (EMBP) in human breast cancer and malignant melanoma. Anticancer Res 11 (3): 1173-1182, 1991. Bjork P. Jónsson U. Andrén-Sandberg A: binding sites for the cytotoxic metabolites of estramustine phosphate (Estracyt®) in rat and human pancreas which are different from the pancreatic estrogen binding protein. Pancreas 6: 1: 77-89, 1991. Dahllóf B. Hartley-Asp B. Billstrom A. Cabral F: estramustine depolymerizes microtubules through tubulin binding. Cancer Res 53: 4573-4581, 1993. Edgren M. Westlin JE, Letocha H and others: estramustine binding protein (EMBP) in immunohistochemistry of renal cell carcinoma, immunoscintigraphy and effects of estramustine in vitro. Acta Oncol 35 (4): 483-488, 1996. Eklov S et al .: evidence for a non-estrogenic cytostatic effect of estramustine on human prostate carcinoma cells in vivo. The Prostate 20: 43-50, 1992. Eklov S, Mahdy E, Wester K and others: content of estramustine-binding protein (EMBP) in four different cell lines and its correlation with metaphase arrest induced by estramustine. Anticancer Res 16 (4A): 1819-1922, 1996. Flüchter S. Nelde HJ, Bjórk P. and others: Effect of treatment on the expression of estramustine binding protein (EMBP) in patients with prostate cancer: an immunohistochemical study. The Prostate 14: 27-43, 1989. Forsgren B, Bjork P. Carlstrom K, Gustafsson JA, Pousette A.

Hógberg B: purification and distribution of a major protein in rat prostate that binds estramustine, a nitrogen mustard derivative of estradiol-17β. Proc. Nati Acad. Sci. USA: 76: 3149- 3153, 1979. Gunnarsson PO, Andersson S-B. Johansson S-Á and others: pharmacokinetics of estramustine phosphate (Estracyt®) in patients with prostate cancer. Eur J. Clin Pharmacol 26: 113-119, 1984.

Gunnarsson PO, Plym Forshell G. Fritjofsson A. Norlen BJ: plasma concentration of estramustine phosphate and its main metabolites in patients with prostatic carcinoma treated with different doses of estramustine phosphate (Estracyt®). Scand J Urol Nephrol 15: 201-206, 1981. Hartley-Asp B: mitotic arrest induced by estramustine in two cell lines of human prostatic carcinoma DU 145 and PC-3. The Prostate 5: 93-100, 1984. Hartley-Asp B. Gunnarsson PO: cell growth and survival after treatment with estramustine, non-nitrogen mustard, estradiol and testosterone from a human prostate cancer cell line (DU 145 ). J Urology 127: 818-822, 1982. Hudes G. Obasaju C. Chapman A. Gallo J. McAleer C. Greenberg R: Phase I study of Paclitaxel and Estramustine: preliminary activity in hormone refractory prostate cancer. Sem Oncol, Vol. 22: 3, Suppl. 6: 6-11, 1995. Hudes GR, Greenberg R. Krigel RL. Fox S. et al .: Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J. Clin. Oncol 10: 1754-1761, 1992. Keren-Rosenberg, S. Muggia, FM: response to estramustine phosphate and paclitaxel in patients with advanced breast cancer: A phase I Study Seminars in Oncology 24: 5 S3-26-S3- 29, 1997. Lindberg B: treatment of rapid prostate carcinoma progression with Estracyt. Journal of Urol 108: 303-305, 1972. Maier U. Hienert G. Simak R: estramustine phosphate in carcinoma resistant to secondary hormone of the prostate. Eur Urol 17: 216-218, 1990. Mareel MM, Storme GA, Dragonetti CH, De Bruyne GK, Hartley-Asp B., Segers JL, Rabaey ML: anti-invasive activity of estramustine in malignant MO4 mouse cells and human prostate carcinoma DU 145 in vitro. Cancer Res 48: 1842-1849, 1988. Murphy GP, Slack NH, Mittleman A: Experiments with estramustine phosphate (Estracyt, Emycit) in prostate cancer. Seminars in oncology 10 (3) Sppl 3, 34-42, 1983. Nagel R. Kólln C-P: treatment of advanced carcinoma of the prostate with estramustine phosphate. British Journal of Urol 49: 73-79, 1977. Norlen, B.J., Andersson S.B. Bjork P., Gunnarsson P.O. Fritjofsson A: Consumption of estramustine phosphate metabolites (Estracyt) in prostate cancer. Journal of Urol 140: 1058-1062, 1988. Petrylak DP, Shelton GB, Mac Arthur RB and others: Phase I analysis of docetaxel-estramustine in androgen-insensitive prostate cancer. Cancer Investigation 16. Supp I p. 62, 1997. Pienta KJ, Lehr JE: inhibition of the growth of prostate cancer through estramustine and etoposide: evidence for interaction in the nuclear matrix. Journal of Urol 149: 1622-1625, 1993. Pienta KJ, Redman B. Hussain M, Cummings G and others: Phase II evaluation of oral estramustine and oral etoposide in refractory prostate hormone adenocarcinoma. J. Clin Oncol 12: 2005-2012, 1994. Seidman AD, Scher Hl, Petrylak D, Dershaw DD, Curley T: Estramustine and vinblastine: use of specific antigen in prostate as a final point of clinical analysis for hormone refractory prostate cancer . J. Urol 147: 931-934, 1992. Speicher LA, Barone L, Tew KD: Combined anti-microtubule activity of estramustine and taxol in human prostatic carcinoma cell lines. Cancer Res 52: 4433-4440, 1992. Stearns M. Tew KD: estramustine binds to MAP-2 to inhibit microtubule assembly in vitro. J. Cell Science 89: 331-342, 1988. Von Schoultz E, Carlstrom K. Henriksson R. and others: estramustine binding protein in primary tumors and malignant melanoma metastasis. Melanoma Res 4 (6): 401-405, 1994. Walz PH, Bjork P, Edman K, Gunnarsson PO, Hartley-Asp B: Consumption and distribution of estramustine-estramustine phosphate metabolite after injection of single dose in patients with prostate cancer. Akt Urol 27: 92-93, 1996. Lundgren, R. Estracyt intravenost for behaving av hormonreftraktarprostatacancer: Svenska Lakaresallskapets Rikstamma, 1995.

This request is based on the provisional application of E. U. A. Series No. 60 / 079,542, which was filed on March 27, 1998, which is hereby incorporated by reference in its entirety. Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. Therefore, it should be understood that within the scope of the appended claims, the invention may be practiced in a manner different from that specifically described herein.

Claims (90)

1. - A method to administer estramustine phosphate as an intravenous dose, whereby the dose of an individual infusion exceeds 1300 mg.

2. A method to administer estramustine phosphate as an intravenous dose, so that the dose of an individual infusion exceeds 950 mg / m2.

3. The method according to claim 1 or 2, wherein the estramustine phosphate is administered as an individual infusion in a once a week program.

4. The method according to claim 1 or 2, wherein the estramustine phosphate is administered as an individual infusion in a program once every two weeks.

5. The method according to claim 1 or 2, wherein the estramustine phosphate is administered as an individual infusion in a program once every three weeks.

6. The method according to claim 1 or 2, wherein the estramustine phosphate is administered as an individual infusion in a program once every four weeks.

7. The method according to claim 1 or 2, wherein the estramustine phosphate is administered in combination with other anti-cancer therapies.

8. The method according to claim 7, wherein the estramustine phosphate is administered intravenously in combination with other chemotherapeutic agents.

9. A method to enhance the therapeutic benefit of a multiple drug chemotherapeutic regimen, wherein one of the drugs in the regimen comprises estramustine, administering estramustine phosphate as an intravenous formulation.

10. The method according to claim 9, wherein the intravenous formulation comprises estramustine phosphate given at a high dose.

11. The method according to claim 9, wherein the other drug in the regimen comprises an anti-mitotic agent or an anti-microtubule agent.

12. The method according to claim 10, wherein the dose of an individual infusion of estramustine phosphate exceeds 1300 mg.

13. The method according to claim 10, wherein the dose of an individual infusion of estramustine phosphate exceeds 950 mg / m2.

14. A method to produce prolonged elevated levels of estramustine in the plasma to promote the synergistic interaction between estramustine and a second chemotherapeutic agent wherein: estramustine is administered as an intravenous formulation; and estramustine is administered on the day of, or after, three days of the administration of said second chemotherapeutic agent.

15. - The method according to claim 14, wherein the second chemotherapeutic agent comprises an antimitotic agent or an anti-microtubule agent.

16. The method according to claim 14, wherein the intravenous formulation comprises estramustine phosphate.

17. The method according to claim 16, wherein the dose of an individual infusion of estramustine phosphate exceeds 1300 mg.

18. The method according to claim 16, wherein the dose of an individual infusion of estramustine phosphate exceeds 950 mg / m2.

19. A method to produce high levels in the estramustine plasma of estramustine metabolite, to promote the synergistic interaction between estromustine and a second chemotherapeutic agent wherein: estrastine is administered as an intravenous formulation; and estramustine is administered on the day of, or after, three days of the administration of the second therapeutic agent.

20. The method according to claim 19, wherein the second chemotherapeutic agent comprises an antimitotic agent or an anti-microtubule agent.

21. The method according to claim 19, wherein the intravenous formulation comprises estramustine phosphate.

22. The method according to claim 21, wherein the dose of an individual infusion of estramustine phosphate exceeds 1300 mg.

23. The method according to claim 21, wherein the dose of an individual infusion of estramustine phosphate exceeds 950 mg / m2.

24. A method according to claim 14, to enhance a therapeutic benefit.

25. A method according to claim 19, to enhance a therapeutic benefit.

26.- A method to sustain estramustine and stromustine levels in plasma, where estramustine phosphate is administered intravenously as an individual infusion at a dose exceeding 1300 mg; optionally repeating the infusion in a series form.

27.- A method to sustain the levels of estramustine and stromustine in the plasma, where the estramustine phosphate is administered intravenously as an individual infusion at a dose exceeding 950 mg / m2; optionally repeating the infusion in a series form.

28. A method according to claim 26, wherein the therapeutic benefit is sustained.

29. A method according to claim 27, wherein the therapeutic benefit is sustained.

30.- A method to increase the saturation of estramustine binding to the estramustine binding protein or similar protein, wherein: estramustine is administered as an intravenous formulation such as estramustine phosphate at an individual infusion dose exceeding 1300 mg; and in this way the binding saturation of the estramustine binding protein is increased.

31.- A method to increase the binding saturation of estramustine or its metabolites to the estramustine binding protein or similar protein, where: estramustine is administered as an intravenous formulation such as estramustine phosphate at an individual infusion dose that exceeds 950 mg / m2; and in this way the binding saturation of the estramustine binding protein is improved.

32.- A method to prolong the duration of binding of estramustine or its metabolites to the estramustine binding protein or similar protein, where: estramustine is administered as an intravenous formulation such as estramustine phosphate at an individual infusion dose that exceeds 1300 mg; and in this way the binding duration of the estramustine binding protein is prolonged.

33.- A method to prolong the duration of binding of estramustine or its metabolites to the estramustine binding protein or similar protein, where: estramustine is administered as an intravenous formulation such as estramustine phosphate at an individual infusion dose that exceeds 950 mg / m2; and in this way the binding duration of the estramustine binding protein is prolonged.

34. The method according to claim 30, wherein the method is used to treat a cancer having estramustine binding protein, or a protein of the estramustine binding protein type.

35.- The method according to claim 34, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and cancers. of the brain.

36. The method according to claim 31, wherein the method is used to treat a cancer having estramustine binding protein, or similar protein.

37.- The method according to claim 36, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and cancers. of the brain.

38.- The method according to claim 32, wherein the method is used to treat a cancer having estramustine binding protein, or similar protein.

39. The method according to claim 38, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and brain cancers .

40. The method according to claim 33, wherein the method is used to treat a cancer having estramustine binding protein, or similar protein.

41.- The method according to claim 40, wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and cancers of the brain.

42.- A method to treat breast cancer where estramustine phosphate is administered intravenously.

43.- A method to treat lung cancer in which estramustine phosphate is administered intravenously.

44.- A method to treat pancreatic cancer in which estramustine phosphate is administered intravenously.

45.- A method to treat colorectal cancer in which the estramustine phosphate is administered intravenously.

46.- A method to treat ovarian cancer where the estramustine phosphate is administered intravenously.

47.- A method to treat brain cancer wherein the estramustine phosphate is administered intravenously.

48. - The method according to claim 1, wherein the infusion is given for 30 minutes to 3 hours.

49. The method according to claim 2, wherein the infusion is given for 30 minutes to 3 hours.

50. The method according to claim 1, wherein the relief of urinary obstruction induced by cancer is achieved.

51. The method according to claim 2, wherein the relief of urinary obstruction induced by cancer is achieved.

52. The method according to claim 1, wherein a rapid relief of pain induced by cancer is achieved.

53. The method according to claim 2, wherein a rapid relief of pain induced by cancer is achieved.

54. The method according to claim 42, wherein the estramustine phosphate is administered in combination with one or more other chemotherapeutic agents.

55. The method according to claim 43, wherein the estramustine phosphate is administered in combination with one or more other chemotherapeutic agents.

56. The method according to claim 44, wherein the estramustine phosphate is administered in combination with one or more other chemotherapeutic agents.

57. The method according to claim 45, wherein the estramustine phosphate is administered in combination with one or more other chemotherapeutic agents.

58. The method according to claim 46, wherein the estramustine phosphate is administered in combination with one or more other chemotherapeutic agents.

59. The method according to claim 47, wherein the estramustine phosphate is administered in combination with one or more other chemotherapeutic agents.

60.- A method for the treatment of melanoma in which estramustine phosphate is administered intravenously.

61.- The method according to claim 60, wherein the estramustine phosphate is administered in combination with one or more other chemotherapeutic agents.

62. The method according to claim 11, wherein the anti-microtubule agent is a taxane.

63. The method according to claim 11, wherein the anti-microtubule agent is a taxane encapsulated in liposome.

64.- The method according to claim 63, wherein the taxane encapsulated in liposome is paclitaxel encapsulated in liposome.

65. The method according to claim 9, wherein another drug in the regimen is CPT-11.

66. The method according to claim 9, wherein another drug in said regimen is doxorubicin.

67. The method according to claim 9, wherein another drug in said regimen is etoposide.

68. The method according to claim 9, wherein another drug in said regimen is navelbine.

69. - The method according to claim 9, wherein another drug in said regimen is vinblastine.

70.- A method for enhancing the therapeutic effect of a multiple drug chemotherapeutic regimen, wherein a drug in the regimen comprises a taxane, and wherein another drug in the regimen comprises estramustine phosphate, and wherein the estramustine phosphate is administered intravenously at a dose exceeding 950 mg / m2.

71. The method according to claim 15, wherein the anti-microtubule agent is a taxane.

72. The method according to claim 20, wherein the anti-microtubule agent is a taxane.

73. A method for administering estramustine phosphate, wherein the estramustine phosphate is first encapsulated within liposomes, and then administered intravenously.

74.- A estramustine phosphate formulation, where estramustine is encapsulated within liposomes.

75.- A method to treat cancer, where the estramustine phosphate encapsulated in liposomes is administered.

76.- A chemotherapeutic agent consisting of estramustine phosphate encapsulated within a liposome.

77.- A method for the treatment of prostate cancer, where the estramustine phosphate encapsulated in a liposome is administered.

78.- A method for the treatment of breast cancer, wherein the estramustine phosphate encapsulated in a liposome is administered.

79. A method for the treatment of lung cancer, wherein the estramustine phosphate encapsulated in a liposome is administered.

80.- A method for the treatment of pancreatic cancer, where the estramustine phosphate encapsulated in a liposome is administered.

81.- A method for the treatment of colorectal cancer, where the estramustine phosphate encapsulated in a liposome is administered.

82.- A method for the treatment of ovarian cancer, where the estramustine phosphate encapsulated in a liposome is administered.

83.- A method for the treatment of melanoma, where the estramustine phosphate encapsulated in a liposome is administered.

84.- A formulation according to claim 74, intended for intravenous administration.

85.- A product comprising estramustine phosphate suitable for intravenous administration and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anti-cancer therapy.

86. A product according to claim 85, wherein one or more of the chemotherapeutic agents are selected from the group consisting of CPT-11, doxorubicin, etoposide, navelbine, and a taxane derivative.

87. A method according to claim 85, wherein the estramustine phosphate suitable for intravenous administration is used as an individual dose infusion exceeding 1300 mg.

88. A method according to claim 85, wherein the estramustine phosphate suitable for intravenous administration is used as an individual dose infusion exceeding 950 mg / m2.

89. A product according to any of claims 85 to 88 for the treatment of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer or brain cancers. 90.- A method for the treatment of prostate cancer, breast cancer, melanoma, lung cancer, pancreatic cancer, colorectal cancer, ovarian cancer and brain cancers, which includes the administration of a product according to any of claims 85 to 88.