Surgery – Miscellaneous – Methods
Reexamination Certificate
1998-03-27
2002-01-01
Nguyen, Dinh X. (Department: 3738)
Surgery
Miscellaneous
Methods
Reexamination Certificate
active
06334445
ABSTRACT:
TECHNICAL FIELD
The present invention relates to methods and compositions for treating ovarian cancer in humans. More particularly, the present invention relates to methods for treating ovarian cancer using a taxane composition.
BACKGROUND OF THE INVENTION
Ovarian cancer is the fourth most frequent cause of cancer death in females and in the United States, accounts for approximately 13,000 deaths annually. Moreover, the incidence is rising in industrialized countries. The etiology of the neoplastic transformation remains unknown although there is epidemiological evidence for an association with disordered endocrine function. The incidence of ovarian carcinoma is higher in nulliparous females and in those with early menopause.
Chemotherapy remains the major treatment for patients with advanced ovarian cancer. Alkylating agents induce a response in 33-65% of patients. Such alkylating agents include, but are not limited to chlorambucil, thio-tepa, and cyclophosphamide. Other agents are also known to be effective. Of these, cisplatin and carboplatin are considered to be the single most active cytotoxic agents and the response rate appears to be related to dose. A recent meta-analysis involving most of the major chemotherapy clinical trials of the 1980s in patients with ovarian cancer concluded that platinum-based therapies were the single most effective agents. It was also found that these platinum-based therapies were more effective when given in combination with another agent than when given alone. Cisplatin was also the first cytotoxic agent to demonstrate usefulness as second-line therapy, i.e., treatment for patient whose tumor had relapsed following first-line treatment with alkylating agent therapy.
In the late 1980s, several clinical studies were performed which led to the availability and use of paclitaxel in patients with ovarian cancer. Paclitaxel is now approved for use as a second-line treatment in many countries and is being evaluated as a component of front-line therapy in combination with cisplatin.
Paclitaxel is a novel microtubule stabilizing antitumor agent, originally isolated from the stem bark of
Taxus brevifolia
, the western (Pacific) yew tree. Paclitaxel acts by promoting the formation of unusually stable microtubules, and inhibits the normal dynamic reorganization of the microtubule network required for mitosis and cell proliferation. (See Schiff, P. B., et al (1979)
Nature
277,665; Schiff, P. B., et al (1981)
Biochemistry
20, 3247). In the presence of paclitaxel, the concentration of tubulin required for polymerization is significantly lowered. Microtubule assembly occurs without GTP and at low temperatures, and the microtubules formed are more stable to depolymerization by dilution, calcium, cold, and inhibitory drugs. Paclitaxel reversibly binds to polymerized tubulin, and other tubulin-binding drugs will bind to tubulin in the presence of paclitaxel.
Paclitaxel interacts with the microtubule system of many types of organisms. For example, in mammalian cells a 50 nM paclitaxel concentration usually causes a significant increase in microtubule number, with changes in cell shape and mitotic arrest in actively dividing cells. (Parness, J., et al. (1982)
Biochem. Biophys. Res. Commun
. 105, 1082). These perturbations of microtubule function caused by paclitaxel have a critical impact on the cell because of the role played by microtubules in cell motility, secretion, and cell division.
Paclitaxel has been studied for its effect in combating tumor growth in several clinical trials using a variety of administration schedules. Severe allergic reactions have been observed following administration of paclitaxel. However, it has been demonstrated that the incidence and severity of allergic reactions is affected by the rate of paclitaxel infusion (Weiss, R B., et al (1990)
J. Clin. Oncol
. 8, 1263).
In a study of Taxol®, (trademarked paclitaxel product of Bristol Meyers Squibb), in over 400 patients with ovarian cancer, patients were randomized two ways, (1) between 135 to 175 mg/m
2
and (2) between 3-hour and 24-hour infusions. In this study, minor degrees of flushing were seen in 42% but severe hypersensitivity reactions were seen in only 1-2% without influence of dose or schedule on frequency or severity. Neurosensory symptoms, described as burning paresthesia, occurred more frequently (52%) at the 175 mg/m
2
dose as compared with 36% at the lower dose. A syndrome of arthralgia, with onset 1-2 days after administration and lasting a few days, was common (55-65%) and more frequent at the higher dose.
Myelosuppression (primarily granulocytopenia) occurred frequently but was most common with the 24-hour infusion (71%). Only 18% of patients receiving drug by a 3-hour infusion developed Grade 4 granulocytopenia. Febrile neutropenia was documented only with the 24-hour infusion. Stomatitis occurred in 22-30% of the patients and was severe in less than 2% of the patients. Cardiovascular effects were rare. Asymptomatic bradycardia (pulse<50 beats/min.) was observed in only 1% of cycles (26 of 2354 cycles) and hypotension (systolic <80 mm Hg) in only 13 of 2354 cycles. Nine patients discontinued Taxol® treatment because of nonhematologic toxicity. Of these patients, 4 had neurotoxicity, 3 had hypersensitivity, 1 had mucositis and 1 had idiopathic pulmonary edema.
Infusion times, from 3 hours up to 24 hours, have been used in treatment with paclitaxel to decrease the incidence of toxicity and side effects, including allergic reactions to the drug. Data from these studies indicate that reversible myelosuppression is the dose limiting toxicity, with significant peripheral neuropathy observed at doses of 275 mg/m
2
and greater. Other toxicities include myalgia, mucositis, and alopecia.
Paclitaxel was approved by the FDA in December 1992, for treatment of ovarian cancer after failure of first-line or subsequent chemotherapy. This approval was based on the initial Phase II studies and on the National Cancer Institute compassionate plea program, where paclitaxel was administered over a 24-hour period. More recently, the more convenient 3-hour schedule has been approved for the same indication in many countries.
Studies of paclitaxel in breast cancer treatment has been reported. In single agent studies, response rates have been found to be dose related, with a 13-37% response rate for doses of 135 to 175 mg/m
2
, compared to a 36-71% response rate for doses of 250 mg/m
2
with G-CSF. The highest response rate (79%) has been reported in a 600 patient study using paclitaxel (135 mg/m
2
) in combination with cisplatin (75 mg/m
2
).
In a European-Canadian multi-institutional trial with ovarian cancer patients, 407 patients were randomized to one of two dose levels (135 mg/m
2
or 175 mg/m
2
), given every three weeks, and to either a 3-hour or 24-hour schedule. See Eisenhauer, E.A. et al “European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High dose versus low-dose and long-term versus short infusion.”
J. Clin. Onc
. 1994. 12:2654-66. The response rate was higher at the 175 mglm
2
dose (20%) than the 135 mg/m
2
dose (15%) but the difference was not statistically significant. Time to tumor progression was significantly longer (19 weeks vs 14 weeks) in patients receiving the higher dose. Overall survival based on deaths in about 25% of patients were similar in the different subsets. Thus, the study concluded that the shorter (3-hour) infusion was nearly as efficacious, yet safer and more convenient than the 24-hour infusion.
Paclitaxel, like other chemotherapy agents, has been shown to create drug resistance in tumor cells. Drug resistance by tumor cells is a common response to chemotherapy agents. Two mechanisms of paclitaxel resistance have been identified in vitro. In one cell type, resistance is due to drug efflux, which is the result of increased levels of membrane P-glycoproteins causing increased drug efflux. (Gupta, R. S. (1985)
Cancer Treat. Rep
. 69, 515). These cells are also resistant to the vinca alkaloids, doxorubicin, and o
Baker Norton Pharmaceuticals, Inc.
Nguyen Dinh X.
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