Patent Application: US-83768201-A

Abstract:
the invention relates generally to a method of using paclitaxel in a specific q4d × 3 schedule and dosage for patients with malignant melanoma . the low risk - benefit ratio of this specific schedule provides a method for therapeutic use for all stages of severity of disease ranging from local resectable tumor to diagnosed widespread malignant melanoma .

Description:
by devising alternative schedules and dosages , we have discovered that more effective paclitaxel treatment regimens for melanoma do exist . data from the napro biotherapeutics laboratory utilizing in vitro human tumor cell lines and in vivo experiments with human heterotransplanted tumors in nude mice demonstrated that the therapeutic index and anticancer effects of paclitaxel could be improved . it was discovered that a fractionated schedule and a briefer infusion time is a clinically more effective strategy . because of the smaller fractionated dose , paclitaxel can be given over a 45 - 80 minute infusion time . an added benefit to this regimen includes a reduction in myelosupression . to this end , we devised the q4 day ( q4d )× 3 every 21 - day treatment schedule which has the added value of increasing the dose intensity during each 21 - day treatment period beyond that of the once every 21 - day schedule ( ainsworth s . k ., and helson , l ., u . s . pat . no . 5 , 696 , 153 issued dec . 9 , 1997 ). the safety of this q4d paclitaxel schedule in adult leukemia ( seiter et al 1995 ), solid tumors ( helson et al . 1994 , 1995 ), and pediatric solid tumor patients ( donfrancesco , a . 1995 ) has been published . during these trials an anecdotal twelve - month partial response in a patient with a recurrent large metastatic melanoma was observed . currently , a phase ii trial of the paclitaxel q4d schedule at 90 mg / m 2 / dose in advanced heavily pretreated melanoma patients is being conducted at m d anderson hospital : the 21 - day dose intensity in this schedule is 270 mg / m 2 . interim analysis reveals objective responses of greater than 50 % tumor reduction and 25 - 40 % reductions in hepatic tumor masses sustained over one month in an additional two patients of the first 21 patients accrued and treated . associated toxicity was significantly less than the toxicity associated with lesser dose intensities of 200 mg / m 2 which are observed with the 200 mg / m 2 , q 21 - day schedule . because of the apparent improved efficacy of this schedule , the reduced toxicity associated with brief infusions , and the greater dose intensity permitted with its application , this invention is a novel and important advance in the treatment of melanoma and furthers the understanding of the application of paclitaxel in the clinical setting . because of the reduced associated toxicity , this schedule lends itself to paclitaxel associations with other anticancer modalities such as radiation , cytokines , and chemotherapy . cytokines and therapeutic agents which may be used include , for example , platinum compounds ( e . g ., spiroplatin , cisplatin , and carboplatin ), thalidomide , methotrexate , adriamycin , mitomycin , ansamitocin , bleomycin , cytosine arabinoside , arabinosyl adenine , mercaptopolylysine , vincristine , busulfan , chlorambucil , melphalan ( e . g ., pam , l - pam or phenylalanine mustard ), mercaptopurine , mitotane , carmustine , procarbazine hydrochloride dactinomycin ( actinomycin d ), daunorubicin hydrochloride , doxorubicin hydrochloride , taxol , mitomycin , plicamycin ( mithramycin ), aminoglutethimide , estramustine phosphate sodium , flutamide , leuprolide acetate , megestrol acetate , tamoxifen citrate , testolactone , trilostane , amsacrine ( m - amsa ), asparaginase ( l - asparaginase ) erwina asparaginase , etoposide ( vp - 16 ), interferon α - 2a , interferon α - 2b , teniposide ( vm - 26 ), vinblastine sulfate ( vlb ), vincristine sulfate , bleomycin , bleomycin sulfate , methotrexate , adriamycin , and arabinosyl ; biological response modifiers such as muramyldipeptide , muramyltripeptide , microbial cell wall components , lymphokines ( e . g ., bacterial endotoxin such as lipopolysaccharide , macrophage activation factor ), sub - units of bacteria ( such as mycobacteria , corynebacteria ), the synthetic dipeptide n - acetyl - muramyl - l - alanyl - d - isoglutamine ; hormones such as growth hormone , melanocyte stimulating hormone , estradiol , beclomethasone dipropionate , betamethasone , betamethasone acetate and betamethasone sodium phosphate , vetamethasone disodium phosphate , vetamethasone sodium phosphate , cortisone acetate , dexamethasone , dexamethasone acetate , dexamethasone sodium phosphate , flunisolide , hydrocortisone , hydrocortisone acetate , hydrocortisone cypionate , hydrocortisone sodium phosphate , hydrocortisone sodium succinate , methylprednisolone , methylprednisolone acetate , methylprednisolone sodium succinate , paramethasone acetate , prednisolone , prednisolone acetate , prednisolone sodium phosphate , prednisolone tebutate , prednisone , triamcinolone , triamcinolone acetonide , triamcinolone diacetate , triamcinolone hexacetonide and fludrocortisone acetate ; immunoadjuvants and cytokines may also be employed , including interleukins ( e . g ., il - 1 , il - 2 , il - 3 , il - 6 ), leukemia inhibitory factor , interferons , such as inf - α , tgf - beta , erythropoietin , tnf , lymphotoxin , and thrombopoietin ; thalidomide and / or other agents to inhibit the production and / or action of cytokine / growth factors such as m - α , igf - 1 , egf , tgf α , il - 1β , mgsa and bfgf in different cell types involved in tumor growth and / or angiogenesis of melanoma . radiation therapy can be administered to the mammal according to protocols commonly employed in the art and known to the skilled artisan . such therapy may include cesium , iridium , iodine , or cobalt radiation . the radiation therapy may be whole body irradiation , or may be directed locally to a specific site or tissue in or on the body , such as the lung , bladder , or prostate . typically , radiation therapy is administered in pulses over a period of time from about 1 to about 2 weeks . the radiation therapy may , however , be administered over longer periods of time . for instance , radiation therapy may be administered to mammals having head and neck cancer for about 6 to about 7 weeks . optionally , the radiation therapy may be administered as a single dose or as multiple , sequential doses . as described herein , a range of dosages ( 60 - 175 mg / m 2 and preferably 90 - 120 mg / m 2 ) of paclitaxel and alternative fractionated schedules ( q3 - 6 days ) may be applied depending upon the clinical estimate of the patient &# 39 ; s physiologic fragility consequent to extensive disease status and / or damage from previous treatment ( s ). in the following human studies , all patients had metastatic disease and were previously treated with one or more standard and experimental therapies . hence , they presented with a variety of physiological statuses , and the adverse events following identical paclitaxel dosage and schedules varied according to the patient &# 39 ; s condition at entry to the study . while the examples present the administration of paclitaxel in a specific fractionated schedule , q4d × 3 every 21 days , and dosage of 90 mg / m 2 in patients with malignant melanoma who have been previously treated and failed other therapies , it should be appreciated that a range of dosages ( 60 - 175 mg / m 2 , and preferably 90 - 120 mg / m 2 ) of paclitaxel and alternative fractionated schedules ( q3 - 6 days ) may be applied depending upon the clinical estimate of the patients physiologic fragility consequent to extensive disease status and / or damage from previous treatment ( s ). in the current m d anderson trial , 17 patients with melanoma were given paclitaxel at 90 mg / m 2 q4 days × 3 ( 270 mg / m 2 q 21 days ), and the following toxicities were noted : grade 4 toxicity — 7 times in 3 patients : bun increase ( 1 patient , with greater than 10 times normal values ), granulocytopenia ( 4 patients , less than 0 . 5 × 10 3 / mm 3 ), and leukopenia ( 2 patients , less than 1 . 0 × 10 3 / mm 3 ). grade 3 toxicity — 21 times in 11 patients : the observed toxicities included increased alkaline phosphatase levels ( 2 patients , between 5 . 1 - 20 × n ), anemia ( 2 patients , between 6 . 5 - 7 . 9 grams / 100 ml blood ), diarrhea ( 2 patients , over 7 - 9 stools / day ), edema ( 1 patient , & gt ; 20 % weight gain ), fatigue ( 4 patients , objective weakness with impairment of function ), granulocytopenia ( 6 patients between 0 . 5 - 0 . 9 × 10 3 / mm 3 ), abdominal pain ( 3 patients , sufficient to interfere with function ), and sensory changes ( 1 patient , objective sensory loss or paresthesias interfering with function ). responses obtained in previously treated patients with metastatic melanoma . the patients received paclitaxel at 90 mg / m 2 q4d × 2 - 3 courses . it should be noted that patients with choroidal melanoma are notoriously resistant to any known type of chemotherapy and any responses with single drug chemotherapy are noteworthy ( am . j . ophthalmol 1996 ). patient # 1 . 46 - year - old male with a subungal primary and liver metastases failed interferon and bio - chemotherapy with interleukin - 2 , cisplatin , velban , and ditrioimadazole carbamoxamide ( dtic ). after two courses of paclitaxel at 270 mg / m 2 / course the patient exhibited a 41 % decrease in liver metastases volume . after another two courses , tumor volume decreased 83 %. patient # 2 . 51 - year - old male with a left calf primary diagnosed in 1995 ; in 1998 he developed metastases to femoral and inguinal nodes and lung . patient failed cisplatin , velban , dtic , and melanoma vaccine . patient exhibited a 43 % decrease in lung metastases and a similar decrease in volume of inguinal nodes . tumor control was maintained through eight courses at 270 mg / m 2 / course . the major side effect was paresthesia . patient # 3 . a 49 - year - old male with a scapular primary exhibited a 39 % decrease in tumor volume after 4 courses at 270 mg / m 2 / course . patient # 4 . a 44 - year - old female with a right calf primary exhibited a 15 % decrease in tumor volume after 4 courses at 270 mg / m 2 / course . patient # 5 . a 56 - year - old male with a right heel mass exhibited a 12 % decrease in tumor volume after 2 courses at 270 mg / m 2 / course . patient # 6 . a 79 - year - old male exhibited stable disease during 4 courses of paclitaxel at 270 mg / m 2 / course . patient # 7 . a 37 - year - old female with a ciliochoroidal primary tumor and no previous chemotherapy exhibited stable disease after 3 courses of paclitaxel at 270 mg / m 2 / course . patient # 8 . a 56 - year - old male previously treated with chemotherapy , and with a tumor of the dorsum of the right foot exhibited stable disease during two courses of paclitaxel at 270 mg / m 2 / course . patient # 9 . a 76 - year - old female with no prior chemotherapy and a primary non - choroidal melanoma exhibited stable disease during 6 courses of paclitaxel at 270 mg / m 2 / course . according to the present invention therefore , a method for administration of paclitaxel is provided for patients suffering from malignant melanoma . this method comprises a treatment strategy of infusing an amount of paclitaxel of 60 - 175 mg / m 2 , and preferably 90 - 120 mg / m 2 , over a period of 60 minutes at least 3 times at 3 - 6 day intervals over a 21 - day period . the preferred schedule is every 4 days , and the preferred dosage is 90 mg / m 2 / dose with at least three 21 - day courses . additional 21 - day courses are recommended in the presence of partial clinical responses and tolerable toxicities . the minimum amount of paclitaxel administered over a 63 - day period is 810 mg / m 2 . thus , according to the present invention , dosages surpassing the maximum tolerated dose intensity of 525 mg / m 2 under previous regimens ( three 175 mg / m 2 doses given every 21 days ) exhibit increased efficacy and reduced levels of toxicity as compared to previous regimens . bedikian 1999 , unpublished data from m d anderson study of q4d paclitaxel in malignant melanoma . bedikian , a . y . et al ., “ phase ii trial of docetaxel in patients with advanced cutaneous malignant melanoma previously untreated with chemotherapy ,” j . clin . oncol ., 13 ( 12 ): 2895 - 2899 . donfrancesco , a ., deb , g ., sio , l ., habettswallner , d ., helson , l . “ phase i trial of a q4d taxol regimen in pediatric patients with recurrent solid tumors .” american society of clinical oncology , may 1995 . einzig , a . i ., trump , d . l ., sasloff , j . et al . “ phase ii pilot study of taxol in patients with malignant melanoma .” proc . am . soc . clin . oncol . 7 : 249 , 1988 . hajek , r . et al ., “ paclitaxel ( taxol ): a review of its antitumor activity in clinical studies minireview ,” neoplasma , 43 ( 3 ): 141 - 154 , 1996 . helson , l ., puccio , m . ostrow , s ., mittleman , a ., ahmed , t . “ phase i taxol ; 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