Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-04-06
2001-12-25
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C424S142100
Reexamination Certificate
active
06333348
ABSTRACT:
FIELD OF THE INVENTION
This present invention relates to a novel therapeutic and synergistic combination of antineoplastic agents which are useful in the treatment of cancer.
BACKGROUND OF THE INVENTION
The present invention relates more specifically to the use of docetaxel in combination with recombinant humanized anti-HER2 antibody, rhuMAb HER2, for the treatment of cancers.
Selected term definitions are as follows:
“docetaxel” refers to the active ingredient of TAXOTERE® or else TAXOTERE® itself;
“rhuMAb HER2,” or trastuzumab, refers to the active ingredient of HERCEPTIN® or else HERCEPTIN® itself;
“HER2” refers to human epidermal growth factor 2, a 185 kD transmembrane glycoprotein receptor (p185
HER2
); and
“drug” or “drugs” refers to the above-mentioned active ingredients or medicaments or pharmaceutical preparations containing them.
Previous researchers have noted that docetaxel (TAXOTERE®) and its derivatives (such as TAXOL®, paclitaxel) are useful in the treatment of the malignant neoplasms, such as solid tumors and other malignancies. European Patent EP 0 253 738 and International Patent Application WO 92/09589 describe a method of preparation of docetaxel. Generally, the doses, which vary depending on the patient, comprise between 60 and 400 mg/m
2
of docetaxel. Commonly, docetaxel is administered via intravenous route at doses of 60 to 100 mg/m
2
over 1 hour every 3 weeks (
Textbook of Medical Oncology
, Franco Cavelli et al., Martin Dunitz Ltd., p. 4623 (1997)).
Many clinical studies have confirmed the efficacy of docetaxel in treating many types of cancer, particularly breast cancer. Docetaxel's effects are shown in both first and second line therapies. The mechanism of docetaxel's action is thought to be via enhancement of microtubule assembly and inhibition of the depolymerization of tubulin at the cellular level.
The humanized recombinant monoclonal antibody rhuMAb HER2 (Trastuzumab, HERCEPTIN®, Genentech) has also been found to be active in treatment of cancers that express HER2. A gene known as neu, or c-erbB-2, encodes the human epidermal growth factor receptor 2, known as HER2. HER2 is a transmembrane receptor tyrosine kinase with partial homology with the epidermal growth factor receptor, both of which receptors belong to the type 1 tyrosine kinase receptor superfamily. About 30% of human breast tumors overexpress HER2. Such overexpression is associated with a poor prognosis. rhuMAb HER2 inhibits the growth of breast cancer cells overexpressing HER2 and has shown some clinical activity as a single agent.
It has also been described that rhuMAb HER2 enhances the antitumor activity of chemotherapeutic agents against HER2
eu overexpressing human breast cancer xenografts (Baselga et al.,
Cancer Research
, 58, 2825-2831, Jul. 1, 1998), but this result was based solely on preclinical animal models.
Further, both treatments, taxotere and rhuMAb HER2, used alone can have disturbing side effects. All treatments based on taxoid derivatives, including docetaxel, can show serious and troubling toxicities, such as myelosuppression, neutropenia, hypersensitivity, peripheral neuropathy, and fluid retention, among others (Fumoleau et al.,
Bull. Cancer
, (82)8: 629-636 (1995)). While neutropenia, alopecia and mucositis are rarely caused by treatment with rhuMAb HER2, that drug has been shown to be associated with cardiac dysfunction. When such toxicities appear, dosages of the drugs must be limited with a resulting limitation on the efficacy of the treatment.
Consequently, there is an unmet need in the art for pharmaceutical preparations and methods of treating cancer which enhance the activity of docetaxel and rhuMAb HER2 without increasing the amount of the dosages administered and without increasing adverse side effects.
SUMMARY OF THE INVENTION
The present invention embodies methods for treating cancer, comprising administering docetaxel and rhuMAb HER2 in amounts effective to produce a synergistic effect in a patient in need thereof. Among the preferred features of the invention are compositions wherein the ratios of docetaxel and rhuMAb HER2 provide therapeutic synergistic activity. The improved efficacy of this combination has been demonstrated by the determination of resulting therapeutic synergy. Such therapeutic synergy is demonstrated by the showing that the combination is therapeutically superior to one or other of the constituents used as its optimum dose (T. H. Corbett et al.,
Cancer Treatments Reports
, 66: 1187 (1982)). To demonstrate the efficacy of a combination, it may be necessary to compare the maximum tolerated dose of each of the separate constituents in question.
It has also been discovered that the combination of docetaxel and rhuMAb HER2 significantly reduces the development of tumor volume over what would be predicted from administration to tumor-infected mammals of each compound alone.
Another aspect of the invention comprises new pharmaceutical kits and medicaments comprising docetaxel in combination with rhuMAb HER2 for treating cancers.
Yet another aspect of the invention is concerned with new schedules of administration of docetaxel and rhuMAb HER2 for the treatment of cancers wherein rhuMAb HER2 is administered weekly and docetaxel is either administered weekly or triweekly.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The inventors of the present invention have demonstrated via clinical trials, that the combination of docetaxel and rhuMAb HER2 in particular dosages manifests an unexpected and strong synergistic, therapeutic effect on the treatment of neoplastic diseases, particularly breast cancers, and more particularly, in metastatic breast cancers in which the HER2/protooncogene is overexpressed. Generally, according to the invention, docetaxel is administered in a dosage of approximately 20 to 100 mg/m
2
, and rhuMab HER2 is administered in a dosage of 2 to 10 mg/kg. In a specific embodiment of the invention, docetaxel is administered at a dosage of approximately 75 mg/m
2
once every three weeks, and rhuMAb HER2 is administered initially at a dosage of 4 mg/kg and thereafter weekly at a dosage of 2 mg/kg. In another embodiment of the invention, docetaxel is administered in a dosage of 35 mg/m
2
weekly and rhuMab HER2 is administered at an initial dosage of approximately 4 mg/kg, followed by 2 mg/kg weekly. In both of these specific embodiments, the combination exhibits therapeutic synergy.
Therapeutic synergy is demonstrated by the showing that the combination is therapeutically superior to one or other of the constituents used as its optimum dose (T. H. Corbett et al.,
Cancer Treatments Reports
, 66: 1187 (1982)). Therefore, the response rates obtained from the individual components must be considered first.
rhuMAb HER2 administered alone, in two recently published clinical studies, gave complete remission and partial remission data, from which the resulting objective response rates were calculated. The first study reported an overall objective response rate of 11.6% (J. Baselga et al.,
Oncology
, March 1997, Supplement 2: 43-48). The second study, which was multinational, reported two large clinical trials in which the anitbody was administered to patients with a loading dose of 4 mg/kg, followed by weekly administration of 2 mg/kg, which is the dosage and administration used in the instant examples. In this large study, there were eight complete responses (4%) and 26 partial responses (11%) for an objective overall response rate of 15% (M. A. Cobleigh, C. L. Vogel, et al.,
J. Clin. Oncology
, 17: 2639-2648 (1999)).
Docetaxel alone, in several in-house proprietary studies, gave overall response rates of 40 to 43% (in second line therapy at a dose of 100 mg/m
2
), 48% (in first line therapy at a dose of 75 mg/m
2
) and 61% (in first line therapy at a dose of 100 mg/m
2
).
In comparison, in Examples 1 and 2 below, a lower, and therefore less toxic, dose of docetaxel administered in combination with rhuMab HER2 gave an unexpectedly better overall response rate compared to either component alone. Specifically, in these
Bellet Robert E.
Vogel Charles L.
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Goldberg Jerome D.
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