Patent Application: US-27674199-A

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 administered 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:
the present invention teaches the ability to administer estramustine phosphate at doses above 950 mg / m 2 ( i . e ., greater than 1300 mg ). the method of the present invention is performed as follows . in the preferred method , estramustine phosphate is administered at a single infusion dosage exceeding 950 mg / m 2 . intravenous administration is performed either through a central or peripheral intravenous route . during preparation of the intended drug , the contents of packaged estramustine phosphate intended for intravenous usage are dissolved , wherein the packaged contents may consist of but are not limited to a lyophilized powder of the meglumine salts in vials of estramustine phosphate , or similar freeze - dried estramustine phosphate which are first dissolved in sterile water such as 5 ml sterile water per 300 mg estramustine phosphate , or in 5 % dextrose in water for intravenous administration . in the preferred method , 5 % dextrose in water is used as the diluent . in the preferred method , during preparation of the dissolved drug the preparation should not be shaken , but should be slowly inverted to mix . the solution is then given as an intravenous infusion with the preferred duration of infusion time being 30 minutes to 3 hours , whereby infusion over 1 - 2 hours is a safe and convenient method . saline solution may result in drug precipitation and thereby 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 greater total infusional volume be utilized to minimize vascular irritation . alternatively , the estramustine phosphate solution can be mixed with various amounts but preferably 3 - 5 % human albumin or other plasma proteins including synthetic plasma proteins to achieve protein binding of the estramustine phosphate and therefore minimize any potential vascular damage . the invention may be further realized using other preparations or formulations of estramustine phosphate . one particularly advantageous preparation of the chemotherapeutic agent estramustine phosphate which enables infusion of estramustine phosphate through either a peripheral or central vein , both at high doses and also doses less than 1300 mg , involves the infusion of estramustine phosphate in conjunction with liposomes ( herein referred to as liposome encapsulated estramustine phosphate or liposomal estramustine ). in one preferred method of preparing liposomal estramustine , estramustine phosphate solution is first prepared in the manner described above and then injected into a vial containing empty liposomes available as a lyophilized powder . following adequate hydration of the liposomes , the vials are vortexed and sonicated , followed by infusion into the patient . when estramustine phosphate is administered through a central venous route , said administration may be performed through either a temporary or permanent venous access device , including but not limited to a triple lumen catheter , hickman catheter , subclavian line , jugular line , or medi - port . said administration may be but is not necessarily performed concomitant with anticoagulant therapy or with the addition of varying amounts but preferably 3 - 5 % human albumin or other plasma proteins or liposomal estramustine to minimize any potential vascular damage in a given patient . while the dosage 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 / m 2 . thereby , one preferred method is to administer a single intravenous dosage of 1000 mg / m 2 . another preferred method is to administer a single intravenous dosage of 1500 mg / m 2 . furthermore , a dosage of 2000 mg / m 2 may be administered . however , the invention is inclusive of other dosages above 950 mg / m 2 and the preferred dosages are not to imply limitation . the most preferred schedule of estramustine phosphate administration in the invention is a single infusion given once weekly to a maximal dose of 4000 mg or 3500 mg / m 2 . another preferred schedule is administration of a single drug infusion once every two weeks . another preferred schedule is administration of a single drug infusion once every three weeks . another preferred schedule is administration of a single drug infusion once every four weeks . one schedule may be preferred over another in consideration of schedules with other concomitant therapy . these schedules may repeat in a serial or repetitive fashion . the invention described herein enables methods to prolong blood and / or tissue levels at high elevations for estramustine phosphate metabolites , including estromustine , estramustine , estrone and estradiol . thereby , enhanced synergistic interactions with other therapies is enabled , wherein such other therapies include but are not limited to chemotherapy , radiotherapy , monoclonal antibodies , and biologic herapies . the present invention provides maximization of therapeutic benefit by rolongation of elevated blood and tissue levels of estramustine phosphate and its etabolites . thereby , maximization of therapeutic benefit is achieved wherein estramustine phosphate is administered intravenously at dosages exceeding 950 mg / m 2 , which are administered in combination with other cancer therapies , inclusive but not limited to radiotherapy , chemotherapy , monoclonal antibodies , and biologic therapies . in the preferred method , therapeutic benefit is potentiated by administering intravenous estramustine phosphate at single dosages exceeding 950 mg / m 2 , with other cytotoxic chemotherapies . in the preferred method said combination is achieved by administering intravenous estramustine phosphate within 3 days of the other chemotherapeutic agents , preferably on the day of , or the day prior to administration of the other chemotherapeutic agents . a particularly preferred method is achieved when the other chemotherapeutic agents consist of anti - mitotic agents or antimicrotubule agents , inclusive of but not limited to taxanes , including taxol and taxotere , and agents including vinblastine , vincristine , etoposide , navelbine , doxorubicin , irinotecan ( cpt - 11 ), and liposome encapsulated chemotherapeutic agents , including liposome encapsulated taxanes such as liposome encapsulated paclitaxel . it may be further beneficial if a combination with a monoclonal therapy is utilized , that the monoclonal agent include a radionucleotide or an anti - growth factor agent . plasma or serum levels of estromustine are further sustained when estramustine phosphate is administered intravenously as a single infusion at a dosage exceeding 950 mg / m 2 the infusion may optionally be repeated in a serial or repetitive manner to maintain elevated blood levels of the estromustine phosphate metabolites . sustained levels of estramustine phosphate and its metabolites thereby enable sustained therapeutic benefit . the present invention thereby provides a method to increase the binding saturation of estramustine or its metabolites to estramustine binding protein or likeprotein protein by administering estramustine phosphate intravenously at a single infusion dose exceeding 950 mg / m 2 . similarly , the binding duration of estramustine phosphate or its metabolites to estramustine binding protein or estramustine binding protein - like protein ( embp ) is increased in the invention by administering the drug at intravenous dosages exceeding 950 mg / m 2 . thereby , all cancers having either estramustine binding protein or estramustine binding protein like - protein may be treated by intravenous estramustine phosphate . it is particularly preferred to treat prostate cancer in such manner . it is further preferred to treat breast cancer , melanoma , lung cancer . pancreatic cancer , colorectal cancer , ovarian cancer , and cancers of the brain in such manner . it is particularly preferred that estramustine phosphate be administered intravenously wherein the single dosage exceeds 950 mg / m 2 when treating cancers having either estramustine binding protein or estramustine binding protein likeprotein , inclusive of but not limited to the group of cancers including prostate cancer , breast cancer , ovarian cancer , pancreatic cancer , melanoma , lung cancer , and cancers of the brain . said cancers may further be treated using liposomal estramustine , either as a single agent or in combination with other chemotherapies . said administrations are preferably repeated in serial or repetitive fashion at schedules of the invention , with or without combination of other therapies . thus , said schedules may include combinational treatment of intravenous estramustine phosphate with other chemotherapeutic therapies given on a once weekly , a once every two week , a once every three week , or a once every four week schedule , and variations therein . it is particularly preferred that intravenously administered estramustine phosphate be administered in combination with other chemotherapeutic cytotoxic agents when used in the treatment of prostate cancer , breast cancer , melanoma , lung cancer , pancreatic cancer , colorectal cancer , ovarian , and cancers of 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 cancers of the brain . it is further preferred that in treating cancers having estramustine binding protein or estramustine binding protein like - protein , including prostate cancer , breast cancer , lung cancer , pancreatic cancer , colorectal cancer , ovarian cancer , and cancers of the brain , estramustine phosphate be administered at intravenous dosages exceeding 950 mg / m 2 when used in combination with other cancer therapies . the present invention enables both objective and subjective therapeutic benefit . benefit achieved may relate to reduction of tumor size , improved quality of life , 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 , rapid objective or subjective therapeutic benefit is achieved by administering estramustine phosphate intravenously at a dosage exceeding 950 mg / m 2 , either as a single agent or preferably in combination with other cancer therapies . thereby the invention enables rapid relief of cancer - induced urinary obstruction , and rapid relief of cancer - induced pain . other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof . the following clinical cases are provided by way of example and not limitation . two patients with advanced metastatic prostate cancer were treated with estramustine phosphate intravenously given through a central line . the patients received an estramustine phosphate dosage of 2500 mg / m 2 . estramustine phosphate was administered as a single infusion on a weekly schedule in a repetitive fashion . each infusional dose was administered over 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 ). three patients with advanced metastatic prostate cancer were treated with estramustine phosphate administered intravenously through a central line at a dosage of 1000 mg / m 2 . estramustine phosphate was administered as a single infusion on a weekly schedule in a repetitive fashion . each infusional dose was administered over a 30 minute infusion . the infusions were well tolerated with several patients demonstrating psa response . three patients with advanced metastatic prostate cancer were treated with estramustine phosphate administered intravenously through a central line at a dosage of 1500 mg / m 2 . estramustine phosphate was administered as a single infusion on a weekly schedule in a repetitive fashion . the infusional dose was administered either over 30 minutes or over 1 hour . the infusions were well tolerated with one patient demonstrating a response in bulky tumor adenopathy . three patients with advanced metastatic prostate cancer were treated with estramustine phosphate intravenously given through a central line . the patients received an estramustine phosphate dosage of 2000 mg / m 2 . estramustine phosphate was administered as a single infusion on a weekly schedule in a repetitive fashion . each infusional dose was administered over a 60 minute infusion . an anti - thrombotic agent was additionally administered for venous thrombosis prophylaxis . the estramustine phosphate infusions were well tolerated without serious toxicity , and with evidence of psa response . andersson s b , lundgren r , svensson l : gas chromatographic determination of four metabolites of estramustine phosphate on plasma . acta pharm suec 19 : 1 - 10 , 1982 batra s , karlsson r , witt l : potentiation by estramustine of the cytotoxic effect of vinblastine and doxorubicin in prostatic tumor cells . int j cancer 68 : 1 - 6 , 1996 bergenheim a t , gunnarsson p o , edman k , von schoultz e , hariz m i henriksson r : uptake and retention of estramustine and the presence of estramustine binding protein in malignant brain tumors in humans . br j cancer 67 : 358 - 361 , 1993 bergh j , björk p , westlin j - e , nilsson s : expression of an estramustine - binding associated protein in human lung cancer cell lines . cancer res 48 : 4615 - 4619 , 1988 björk p , borg a , fernöm , nilsson s : expression and partial characterization of estramustine - 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1625 , 1993 pienta k j , redman b , hussain m , cummings g et al . : phase ii evaluation of oral estramustine and oral etoposide in hormone - refractory adenocarcinoma of the prostate . j clin oncol 12 : 2005 - 2012 , 1994 seidman a d , scher h i , petrylak d , dershaw d d , curley t : estramustine and vinblastine : use of prostate specific antigen as a clinical trial end point for hormone refractory prostatic cancer . j urol 147 : 931 - 934 , 1992 speicher l a , barone l , tew k d : combined antimicrotubule activity of estramustine and taxol in human prostatic carcinoma cell lines . cancer res 52 : 4433 - 4440 , 1992 stearns m , tew k d : estramustine binds map - 2 to inhibit microtubule assembly in vitro . j cell science 89 : 331 - 342 , 1988 von schoultz e , carlstrom k , henriksson r et al . : estrarnustine binding protein in primary tumors and metastases of malignant melanoma . melanoma res 4 ( 6 ): 401 - 405 , 1994 walz p h , björk p , edman k , gunnarsson p o , hartley - asp b : uptake and distribution of the estramustine - phosphate metabolite estramustine after single - dose injection in patients with prostatic cancer . akt urol 27 : 92 - 93 , 1996 lundgren , r . estracyt intravenost for behandling av hormonreftraktarprostatacancer : svenska lakaresallskapets rikstamma , 1995 this application is based on u . s . provisional application ser . no . 60 / 079 , 542 , which was filed on mar . 27 , 1998 , which is incorporated herein by reference in its entirety . obviously , numerous modifications and variations of the present invention are possible in light of the above teachings . it is therefore to be understood that , within the scope of the appended claims , the invention may be practiced otherwise than as specifically described herein .