Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1996-02-01
2001-07-17
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S449000
Reexamination Certificate
active
06262054
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a combination therapy of a taxane and edatrexate to treat various cancers, including breast cancer.
BACKGROUND OF THE INVENTION
Breast cancer is the most common malignancy among women and along with lung cancer has the highest fatality rate of all cancers affecting women. The search for new active agents and strategies to improve the prognosis for patients with metastatic breast cancer continues. In spite of the existence of numerous chemotherapeutic agents and regimens found to have antitumor activity, research continues in an effort to find improved treatment modalities, since survival rates in certain cancers remain low. For example, less than one in five patients with Stage IV (advanced) breast cancer survives more than five years after distant metastases are detected.
Methotrexate has been one of the standard anti-tumor agents in the treatment of breast cancer. Edatrexate (10-ethyl-10-deaza-aminopterin) is a relatively new structural analog of methotrexate which was developed at the Memorial Sloan-Kettering Cancer Center in New York in collaboration with SRI International. Like methotrexate, edatrexate inhibits dihydrofolate reductase. However, edatrexate is deemed a promising alternative because in preclinical tests it proved to have a greater antitumor activity than methotrexate against a number of tumors, partly attributed to the fact that this new analog accumulated in sensitive tumor cells to a greater extent than its predecessor methotrexate and was more selectively retained by the tumor cells. See, e.g. Kris et al.,
Cancer Research
48:5573-5579 (1988) and Sirotnak et al.,
NCI Monographs,
No. 5 (1987).
The use of edatrexate as a single agent treatment against various tumors has met with some success. Studies of non-small cell lung cancer patients have reported positive results, with response rates being in the range of 30%. Grant et al.,
Cancer Investigation
11:36-45 (1993). Antitumor activity of edatrexate has also been observed in patients with non-Hodgkin's lymphoma, head and neck carcinoma, and breast cancer. (Vandenberg et al.,
Proc. Am. Soc. Clin. Oncol.
11:51 (1992); Schornagel et al.,
Ann. of Oncology
3:549-552 (1992). No anti-tumor activity was observed in patients with smallcell lung cancer or metastatic colorectal carcinoma. See Grant et al., supra, for a general review of clinical trials with edatrexate.
Edatrexate has also been tested to a certain extent with other various agents in patients with non-small cell lung cancer. For example, positive responses have been reported from the administration of edatrexate with mitomycin and vinblastine (Kris et al.,
Proc. Am. Soc. Clin. Oncol.
9:229 (1990) and with cisplatin and cyclophosphamide (Lee et al.,
Cancer
68:959-964 (1991). See, also, Grant et al., supra.
As with other chemotherapeutic drugs, dosages of edatrexate have been limited because of toxic effects of the drug. The primary toxic effect of edatrexate is mucositis, but leukopenia, thrombocytopenia and myelosuppression also occur. Due to side effects, dosages of edatrexate have been, prior to the invention described below, limited to a range of 80 mg/m
2
body surface area/week, with dosages of up to 120 mg/m
2
/week given occasionally. Grant et al., supra, pages 42-44 and Schornagel et al., supra, p. 551. Fatigue, nausea and vomiting are also side effects of the drug, but severity of these events do not appear to correlate with dosage.
Another agent studied for the control of certain cancers is paclitaxel known as TAXOL®. Paclitaxel was first demonstrated to have activity against refractory ovarian cancer and has subsequently been found to have anti-tumor properties in some breast cancer patients. Seidman,
Annals of Oncology
5 (Suppl. 6):S17-S22 (1994). The primary dose limiting toxic effect of paclitaxel is myelosuppression.
As with the multiple chemotherapeutic drugs available, neither edatrexate nor paclitaxel alone is curative for most metastatic breast cancer patients.
SUMMARY OF THE INVENTION
This invention provides novel combination therapy methods, pharmaceutical combinations and compositions for inducing tumor cell regression in cancer patients, particularly metastatic cancer patients. These methods employ regimens where cancer patients are treated concurrently with edatrexate and a taxane derivative, preferably paclitaxel, either simultaneously or sequentially. In cancer patients, for example, breast cancer patients, high patient response rates are seen with these treatments. The combination treatment of edatrexate with a taxane surprisingly permits the administration of unusually high dosages of edatrexate, i.e. about 180 mg/m
2
up to a dose of about 400 mg/m
2
without the degree of toxicity found when edatrexate is administered alone or with other agents. It was further surprising that such high dosages were effective without dose limiting side effects in light of preclinical test results in mice which indicated that the dosage of edatrexate and taxol should be reduced when the drugs are used together. The mouse data is presented below in Example 1.
Such combination treatments advantageously have application for patients who have chemotherapeutically refractive metastatic breast cancer. The combination treatment described here provides an alternative treatment with a relatively high response rate which will be beneficial to certain breast cancer patients. Further, the increased patient response levels and the lack of serious side effects seen with these combination treatments, will allow many more patients to become eligible for a bone marrow transplant program where they would not have otherwise been eligible. Bone marrow transplants are typically only available for patients showing a major response to therapy that does not markedly compromise normal host tissues, viz. bone marrow. The combination treatments described here will enable patients who have not responded to other treatments an opportunity for this treatment.
DETAILED DESCRIPTION
This invention provides for advantageous combination therapies for cancers, including metastatic breast cancer using regimens which employ administration of a taxane derivative in conjunction with a relatively high dose of edatrexate. The combination described herein provides a better response rate in metastatic breast cancer patients than either drug alone and surprisingly permits the administration of a high dose of edatrexate. The combination results in a surprising synergy which is beneficial to many patients in slowing or stopping tumor cell growth in vivo.
The patients to be treated with the combination therapy provided here are those that have been diagnosed with breast cancer, including metastatic breast cancer. Metastatic breast cancer includes, but is not limited to, those cancers occurring in the breast designated as scirrhous, infiltrative, papillary, ductal, medullary and lobular which have metastasized to other parts of the body, usually by direct extension and via the lymphatics and the bloodstream. Among the most common sites for metastases are the lungs and pleura, the skeleton and the liver. Distant spread of the disease is usually detected by lymph node biopsy or by x-ray surveys of the skeleton and chest or by liver and bone scans using radioactive isotopes.
One element of the combination therapy described is a taxane derivative. The taxanes are a family of terpenes, including, but not limited to paclitaxel and docetaxel (Taxotere), which were derived primarily from the Pacific yew tree,
Taxus brevifolia,
and which have activity against certain tumors, particularly breast and ovarian tumors. Paclitaxel is a preferred taxane. It is considered an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. The term “paclitaxel” includes both naturally d
Fennelly David William
Sirotnak Francis Michael
Goldberg Jerome D.
Maher David W.
Reed Dianne E.
Sloan-Kettering Institute of Cancer Research
Wilson Mark A.
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