Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-27
2002-02-12
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06346524
ABSTRACT:
This invention relates to the treatment of cancer and in particular to the treatment of cancers with Temozolomide.
BACKGROUND OF THE INVENTION
Temozolomide is known for its anti-tumor effects. For example, in one study clinical responses were achieved in 17% of patients having advanced melanoma (Newlands et al. Br. J. Cancer 65 (2) 287-291 (1992)). In another study, a clinical response was achieved in 21% of patients with advanced melanoma (Journal of Clinical Oncology, Vol 13, No. 4 (April), 1995, pp 910-913). Treatment of gliomas in adults with temozolomide is also known (Eur. J. Cancer 1993; 29A:940). Treatment of the following cancers in adults with temozolomide has also been disclosed: metastatic melanoma; high grade glioma, glioblastoma and other brain cancers; lung cancer; breast cancer; testicular cancer; colon and rectal cancers; carcinomas; sarcomas; lymphomas; leukemias; and mycosis fungoides. Prior to the present invention, the generally accepted method for administering temozolomide was to administer it over a 28 day cycle, in which it is administered daily for the first 5 days of the cycle, followed by 23 days of rest, in which it is not administered. Newlands et al., Br. J. Cancer 65 (2) 287-291 (1992). A clinical trial has also been carried out wherein temozolomide was administered continuously as a daily dose for 6-7 weeks in conjunction with radiation treatment. See, e.g., Brock et al., Cancer Research 58, 4363-4367 (1998).
SUMMARY OF THE INVENTION
The present invention provides a method for treating a patient afflicted with cancer, comprising administering temozolomide to said patient for at least two cycles of a cyclical dosing schedule, wherein each cycle comprises a dosing period of 5 to 25 days, in which temozolomide is administered daily, at a dose of 40 to 150 mg/m
2
/day, followed by a rest period of 5 to 14 days in which temozolomide is not administered.
In a further aspect of the present invention, a medical kit for administering temozolomide is provided, comprising printed instructions for administering temozolomide according to the cyclical dosing schedule set forth above, and a supply of temozolomide in dosage units for at least one cycle, wherein each dosage unit comprises 5 to 250 mg of temozolomide and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
The term “temozolomide” is intended to mean a compound having the formula:
One chemical name for temozolomide is 3,4-dihydro-3-methyl-4-oxoimidazo-[5,1-d] 1,2,3,4-tetrazin-8-carboximide. The synthesis of temozolomide is well known. See, for example, Stevens et al., J. Med. Chem, 1984, 27, 196-201 and Wang et al., J. Chem. Soc., Chem. Commun., 1994, pp 1687-1688.
As used herein, the term “mg/m
2
/day” refers to a daily dose measured in milligrams per square meter of body surface area of the patient.
As used herein, the term “patient” refers to a mammal, preferably a human.
Examples of cancers treatable by this invention include, but are not limited to melanoma; high grade glioma, glioblastoma and other brain cancers; lung cancer; breast cancer; testicular cancer; gastro intestinal cancers including colon, rectal, pancreatic, and gastric cancers, hepatocellular carcinoma; head and neck cancers; prostate cancer, renal cell carcinoma; adenocarcinoma; sarcomas; lymphomas; leukemias; and mycosis fungoides. This invention contemplates treating these cancers and other cancers at any stage from the discovery of the cancer to the advanced stage. The invention includes treatment of the primary cancer and metastases thereof.
A person afflicted with cancer may exhibit one or more of the following signs or symptoms:
(a) presence of cancerous tumor,
(b) fatigue,
(c) pain,
(d) decreased performance status from tumor burden, and
(e) the well known symptoms associated with each specific cancer.
The rest period according to the present invention (the portion of the cycle in which temozolomide is not administered) is 5 to 14 days, more preferably, 5 to 10 days, most preferably, 1 week. The dosing period according to the present invention is 5 to 25 days, more preferably, 1, 2, or 3 weeks, most preferably 1 or 3 weeks. The treatment cycles may be continued for as long as needed to cause the cure, remission, or elimination of the cancer that is being treated.
The daily dose during the dosing period of the present invention is 40 to 150 mg/m
2
/day, more preferably 40 to 125 mg/m
2
/day, most preferably 75 to 125 mg/m
2
/day. The daily dose may be administered as a single dose, or as multiple doses adding up to the single dose. For example, a daily dose of 100 mg/m
2
may be administered as two doses of 50 mg/m
2
, or four doses of 25 mg/m
2
. The selected dosage may be decreased, if intolerable side effects or hematologic toxicity are encountered.
A common, but tolerable side effect of temozolomide is nausea and vomiting. This can be alleviated by administering an anti-emetic in conjunction with the temozolomide. It is preferred that the anti-emetic Ondansetron be given p.o. in a dose of about 8 mg about 30 minutes before temozolomide administration. Other anti-emetics such as Hasaldol, Benadryl, and Ativan may also be used as needed.
Temozolomide is preferably administered orally in capsule form wherein it is admixed with conventional pharmaceutical carriers. Preferred temozolomide capsule formulations are:
Ingredient
mg/Capsule
temozolomide
5
20
100
250
Anhydrous Lactose NF
132.8
182.2
175.7
154.3
Sodium Starch Glycolate NF
7.5
11.0
15.0
22.5
Colloidal Silicon Diozide NF
0.2
0.2
0.3
0.7
Tartaric Acid NF
1.5
2.2
3.0
9.0
Steric Acid NF
3.0
4.4
6.0
13.5
Capsule Size*
3
2
1
0
*White opaque, preservative-free, two-piece hard gelatin capsules
Other forms of administration of temozolomide, as they become available, are contemplated, such as by IV injection or infusion, intrathecally, by sustained release dosage form, syrup, suppository, transdermal, nasal spray, etc.. Any form of administration will work so long as the proper dosage is delivered without destroying the temozolomide.
It may be preferable in some instances to administer an initial large oral bolus dose of about 100 to 500 mg/m
2
prior to beginning the cyclical dosing regimen of the present invention.
The medical kit in accordance with the present invention may be in any form suitable for providing a supply of temozolomide for at least one cycle, together with written instructions for administering it according to the cyclical dosing schedule. Examples include, but are not limited to, various containers (e.g., bottles, cartons, blister packs, and ampules) either accompanied by a package insert describing the cyclical dosing instructions, or wherein the cyclical dosing instructions are printed on, or affixed to the container.
REFERENCES:
patent: 2184545 (1998-02-01), None
Dhodapkar et al., Clin. Cancer Res. 3(7), 1093-1100 Abstract Only, 1997.*
Nicholson et al., J. Clin. Oncol., 16(9), 3037-3043 Abstract Only, 1998.*
Newlands et al., Br. J. Cancer 65 (2) 287-291 (1992).
Brock et al., Cancer Research 58, 4363-4367 (1998).
Goldberg Jerome D.
Lee William
Mann Arthur
Schering Corporation
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