Patent Application: US-20893402-A

Abstract:
this invention provides for a novel schedule and dosage regimen of the combination paclitaxel - estramustine and chemical or surgical androgen depletion to treat patients with advanced prostate cancer who have not received previous therapy and are candidates for hormonal therapy . this invention differs from all current treatment strategies by the intercalation of cytotoxic chemotherapy at a specified interval after initiation of androgen depletion therapy .

Description:
the subject invention is a result of the discovery that a fundamental shortcoming of the prior art treatments for prostate cancer lies in the pattern of treatment scheduling , rather than in the inadequacy of available treatment modalities . in this invention , i have designed a novel pattern of therapy taking into account the two most critical factors , selection of and timing of introduction of cytotoxic chemotherapy . the rationale and the utility of two preferred types of drugs , taxanes ( preferably paclitaxel ) and estramustine , has been amply described ( 1 - 4 , 14 , 15 ). while estramustine is essentially palliative and has limited impact on the course of androgen - independent prostate cancer (“ aipc ”, also can be termed “ hormone - refractory prostate cancer ” or “ hrpc ”), its immediate target is microtubule associated proteins making it a mitotic inhibitor ( 5 - 8 ). these observations have suggested that it might have complementary activity in combination with other mitotic inhibitors like paclitaxel . preclinical ( 9 ) and pilot clinical trials ( 10 ) support this hypothesis . while no evidence of prolongation of survival has of yet been demonstrated , subjective responses as high as 60 % have been reported ( 4 ) and attest to the fact that these two drugs combined may represent the best available synergistic therapeutic combination for prostate cancer . in view of the current state of the art □ s ability to administer any variety of combinations of taxanes and estramustine , this invention is the concept that scheduling of administration is critical in differentiating the combination from a palliative application at failure of hormonal therapy , to a novel prophylactic treatment modality prior to failure as taught herein . in most cases , after induction with androgen ablative agents or procedures , about the eighth week of therapy coincides with maximum decrease in tumor burden ( but this can vary from 2 weeks to 6 months after induction ). according to the teachings herein , it is at this time that cytotoxic chemotherapy , preferably with a combination of paclitaxel and emp , should begin . there follows diminished risk of normal tissue toxicity from the drug combination introduced at this time as well . this means that patients will have responded well enough at this time to tolerate a moderate chemotherapeutic treatment better than when they have relapsed and are in less advantageously positioned clinical states . there is also maximal efficiency in tumor cytotoxic effects because of the minimal tumor burden and increased residual cell cycling activity at this time in the majority of patients . there is the added benefit that androgen - independent tumor cells have enhanced cycling activity , and better vascularity and oxygenation , all of which improve the cytotoxic efficiency of the drugs . the importance of timing is essential as outlined in this discovery in the context of emergence of androgen - independent , or hormonally - refractory , tumor cells . because the population of these cells is at a minimum level at this time , and consequently easier to eliminate , or cytoreduce , the substantial reduction of any tumor cell population reduces the probability of genetic drift or evolution to even hardier tumor phenotypes . accordingly , even if the emergent tumor type is not completely eliminated given the 60 % response rate at relapse , the time to clinically detectible or symptomatic recurrence is substantially prolonged as compared to current standards of care and treatment . thus the novel restructuring of the way patients who have advanced prostate cancer at the time of diagnosis are treated . although combinations of emp and paclitaxel have been tried in various experiments , they have invariably been administered to patients in which hormone therapy has been tried and has failed . the regimen of the subject invention is particularly novel in the requirement that tumor burden be monitored by means known in the art from the outset of hormone therapy , and that the cytotoxic chemotherapy portion of the regimen be initiated at a time of minimal tumor burden , usually 8 weeks but possibly from 2 - 24 weeks after the start of hormone therapy , as determined from the monitoring . hormone therapy in the form of androgen ablation may be by surgical castration , diethylstilbestrol , anti - androgen , ketoconizole and corticosteroids , lhrh analogs such as lupron or zoladex , or any combination of these or other hormonally active agents which may be developed and become available to those skilled in the art . although examples of preferred cytotoxic combinations are provided herein , as those of skill in the art become aware of new effective cytotoxic combinations , those combinations can be substituted into the regimen of the subject invention and be administered at a time of minimal tumor burden as taught herein . the commercial embodiments of the subject invention are articles of manufacture comprising a container ; a pharmaceutically acceptable cytotoxic composition disposed within the container ; and , accompanying the container , instructions for administering the cytotoxic composition to a patient according to the novel scheduling and dosages disclosed herein . the instructions may either be affixed to the container or packaged with the container . all patents and other publications cited or referred to herein are incorporated by reference as if fully set forth herein to the extent that they do not contradict the specific teachings herein . the following examples are provided by way of illustration only and not by way of limitation . those of skill in the art will recognize a variety of non - critical parameters which could be changed or modified to yield essentially similar results without deviating from the subject invention . this strategy is based on the fact that most patients harbor a predominant androgen - dependent tumor and a limited androgen - independent tumor cell population at the time of diagnosis . successful therapy with androgen depletion reduces the androgen - dependent population to a minimum after approximately eight weeks , although variances depending upon the degree of androgen dependence may occur , with minimal disease status ranging from one to six months . this response , if not entirely complete , sets the stage for emergence of an androgen - independent population , based on selection and / or induction , and possible regrowth of androgen - dependent tumor cells if androgen ablation therapy is stopped ( 12 , 12 , 16 ). thus , the eventual relapse of most prostate cancer patients on hormonal treatment . non - hormonal chemotherapy is usually administered after relapse occurs , a period of increasing tumor burden and heterogeneity . although counterintuitive , and not standard - of - care dogma , according to the subject invention the preferred time to add cytotoxic chemotherapy is when there is maximal decrease in the androgen - dependent tumor burden , minimal androgen - independent tumor burden , improved clinical performance status , and motivation on the part of the patient to accept chemotherapy . this time - treatment based strategy assumes a reasonable methodology to estimate minimal tumor burdens . surrogate tumor markers such as prostatic specific antigen ( psa ), or non - specific lactic dehydrogenase ( ldh ) are worthy techniques to determine their status . ( 11 ) since smaller tumors generally respond better to cytotoxic chemotherapy than larger ones , this method extends the duration of disease control compared to most forms of sequentially administered treatments . for purposes of the subject invention , any method which permits an objective evaluation of the level of hormone - sensitive tumor burden can be applied to determine the optimal time to begin the cytotoxic chemotherpy regimen . in cases of prostate cancer , monitoring of psa levels is a preferred method which is well known to those of skill in the art . see , for example , denmead et al . ( 1997 ). as a preferred example , prostate cancer patients who have begun androgen ablation therapy and present a decrease in psa to normal levels can be viewed as having reached minimal tumor burden , and will be ready to begin cytotoxic chemotherapy according to the teachings herein . alternatively , kim et al . ( 1998 ) have reported serum interleukin - 6 ( sil - 6 ) levels as a predictor of early progression in androgen - independent prostate cancer ( aipc ). accordingly , by monitoring the psa / sil - 6 ratio as taught by kim et al ., those of skill in the art can use this as an alternate marker to determine an optimal time to begin the cytotoxic chemotherapy regimen of the subject invention . in a preferred embodiment , this invention is the use of a novel cytotoxic drug combination of paclitaxel given as a one - hour infusion at 45 - 120 mg / m 2 on days 2 , 6 , and 10 of a 21 - day cycle , and estramustine given orally at well - known standard daily dosages of from 280 to 840 mg / m 2 / d , or preferably , for example , 600 mg / m 2 / d , on days 1 - 11 of the 21 - day cycle ( hereinafter , the “ q4dx3 taxol - estramustine combination ”). the first cycle was initiated at minimal tumor burden , approximately 8 weeks after hormonal therapy began on patient “ x ”. after being treated with hormonal therapy and the q4dx3 taxol - estramustine combination as taught herein , patient “ x ” has surprisingly remained free of disease for 1 - ½ years . the combination was extremely well tolerated and the patient continues to receive anti - androgen therapy . additional embodiments of the subject invention include the administration of paclitaxel over alternative schedules which are well known to those of ordinary skill in the art for the administration of paclitaxel . for example , following pre - treatment of the patients to alleviate or minimize hypersensitivity responses , paclitaxel can be infused in dosages of between about 120 mg / m 2 and about 275 mg / m 2 , more preferably between about 135 mg / m 2 and about 175 mg / m 2 , over a duration of about six hours or less , and preferably about one to three hours , on a 21 - day cycle , beginning one day after initiation of oral administration of emp as described in example 1 above . alternatively , paclitaxel dosages of between about 135 mg / m 2 and about 275 mg / m 2 , preferably between about 135 mg / m 2 and about 175 mg / m 2 , can be administered via a 6 - to 24 - hour infusion , preferably a 24 - hour infusion , following premedication and on a a 21 - day cycle , beginning one day after initiation of oral administration of emp as described in example 1 above . such alternative modes of paclitaxel administration are taught by , for example , u . s . pat . no . 5 , 621 , 001 issued to canetta et al . yet another embodiment of a combination of cytotoxic chemicals which can be used in the regimen of the subject invention is disclosed in pienta and smith ( 1997 ). for example , once it is observed that the initial hormone - sensitive tumor burden has been minimized , cytotoxic chemotherapy on a 21 - day cycle can begin by administering estramustine at a dosage of 10 mg / kg / d orally for days 1 - 14 in combination with etoposide at 50 mg / m 2 / d orally for days 1 - 14 , plus paclitaxel at 135 mg / m 2 infused over 1 hour on day 2 . in a preferred variation of this embodiment , the paclitaxel is administered as a 1 - hour infusion at from about 45 - 120 mg / m 2 , most preferably at about 60 mg / m 2 , on days 2 , 6 , and 10 of the 21 - day cycle . this cycle is to be administered at least once , and is preferably repeated from 3 to 6 times , but may be repeated even more as long as cumulative toxic effects are tolerable for the patient . 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