Note: Descriptions are shown in the official language in which they were submitted.
2 ~ 84545
PATENT
CASE OC0626
IMPROVED CANCER TREATMENT
WITH TEMOZOLOMIDE
This invention relates to the treatment of cancer and in particular to the
treatment of cancers with Temozolomide.
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 ES, et al. Br J Cancer 65 (2) 287-2981, 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;
testlcular cancer; colon and rectal cancers; carcinomas; sarcomas; Iymphomas;
leukemias; and mycosis fungoides. This invention is predicated on the
discovery that the effectiveness of temozolomide for treating cancer can be
improved by use of twice, three times, or four times a day dosing, instead of
once a day dosing formerly believed to be the only dosing possible with
temozolomide.
SUMMARY OF THE INVENTION
This invention may be summarized as a method for treating cancer in a
patient in need of such treating comprising administering temozolomide in an
amount sufficient to achieve a clinical response wherein the temozolomide is
administered more than once per day. Preferred aspects of the invention are
administration of temozolomide twice, three times, or four times per day.
DETAILED DESCRIPTION
All references cited herein are incorporated herein by reference.
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The term "temozolomide" is intended to mean a compound having the
formula:
O~NH2
N
/ ~1/ ~N
N ¦
N ~N
O
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.
Cancers treatable by this invention may include melanoma; high grade
glioma, glioblastoma and other brain cancers; lung cancer; breast cancer;
testicular cancer; gastro intestinal cancers including colon, rectal, pancreatic,
15 and gastric cancers, hepatocellular carcinoma; head and neck cancers;
prostate cancer, renal cell carcinoma; adenocarcinoma; sarcomas;
Iymphomas; 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
20 cancer and metastases thereof.
A person suffering from 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
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(e) the well known symptoms associated with each specific cancer.
To practice the invention, temozolomide is administered to the patient exhibiting
one of more of the above signs or symptoms in an amount sufficient to eliminate
5 or at least alleviate one or more of the signs or symptoms. The temozolomide
is administered at more than once per day.
Prior to this invention it was generally believed that administering
temozolomide to a patient having food in his stomach or to a patient who
10 consumed food too soon before or after administering of the temozolomide
would interfere with the bioiavailability of the temozolomide. A fasting of about
8 hours, before administering of temozolomide and 4 hours after receiving
temozolomide was believed necessary. Since two twelve-hour fasting periods
per day would obviously be unacceptable, it was believed that temozolomide
15 could be administered a maximum of once per day. A food effect interaction
study was undertaken and has found that such fasting is not necessary. It was
found that food effects the rate of absorption of the compound, but that the effect
on the extent of absoption was small (Area Under Curve (AUC) for those fed
was about 90~k of AUC for those fasted). Therefore long fasting periods before
20 and after administration of temozolomide are not necessary. Dosing with
temozolomide more than once per day may improve the effectiveness of the
treatment. This is so because increasing the frequency of dosing may deplete
the O6-aklylguanine DNA alkyltransferase more effectively and maintain the
depletion of this repair enzyme, resulting therefore in better effectiveness of the
25 drug.
The preferred dosage of temozolomide for practicing this invention
is a total dose of 500 to 1200 mg/m2 of the patient's body surface area,
administered over a period of from 2 to 28 consecutive days, more preferable
30 over a period of from 4 to 7 consecutive days, and most preferably over a period
5 consecutive days. Thus if the total dose is to be 1000 mg/m2 administered
over a period of 5 days, the daily dose for this period would be 200 mg/m2.
The temozolomide must be administered more than once per day. Preferable
dosing regimens would be twice per day, three times per day or four times per
35 day.
Alternatively the temozolomide may be administered for a much longer
period at reduced dosage. For example, the temozolomide could be
administered more than once daily for up to six weeks at a daily dosage of 50
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to 150 mglm21day, preferably 75 mglm21day. Of course these daily doses are
split about evenly into two or more doses to be administered two or more times
per day.
Regardless of the total amount of the dosage or the length of the
administration period, it may be preferable to administer a larger oral bolus
dose for the first dose to achieve a better depletion of the DNA alkyltransferase,
followed by a maintenance dose to maintain the depletion. The following
examples serve to illustrate, but not limit dosing according to the invention.
Example 1
On day 1 administer 200 mg/m2 as an initial bolus dose and 12 hours
later administer 50 mg/m2. On days 2 to 5 administer 50 mg/m2 every 12 hours.
The total dose is 650 mg/m2 over a five-day period.
Example 2
On day 1 administer 200 mg/m2 as an initial bolus dose and 12 hours
later administer 75 mg/m2. On days 2 to 5 administer 75 mg/m2 every 12 hours.
The total dose is 875 mg/m2 over a five-day period.
Example 3
On day 1 administer 200 mg/m2 as an initial bolus dosage and 12 hours
later 90 mg/m2. On days 2 to 5 administer 90 mg/m2 every 12 hours. The total
dose is 1010 mg/m2 over a five day period.
The oral bolus dose could be anywhere from 100 to 500 mg/m2.
In addition to twice per day dosage, other preferable dosing schedules
include thrice per day and four times per day (with or without an initial oral bolus
dose.
Temozolomide may be administered orally in capsule form wherein it is
admixed with conventional pharmaceutical carriers. Preferred temozolomide
capsule formulations are:
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-
InQredient m~/Capsule
temozolom ide 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
5 * White opaque, preservative-free, two-piece hard gelatin capsules
After a period of about 28 to 42 days, or about 28 to 35 days, or more
preferably 28 days, from the first day of temozolomide administration, another
administration cycle may be performed, with temozolomide being
10 re-administered on day one and on each subsequent day of the administration
period.
The treatment cycles may be continued until a disease progression or
until intolerable side effects are encountered. The dosage may be decreased, if
15 intolerable side effects or hematologic toxicity are encountered.
A common, but tolerable side effect of both 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 given20 p.o. in a dose of about 8 mg about 30 minutes before temozolomide
administration. Of course other anti-emetics such as Hasaldol, Benadryl, and
Ativan may also be used as needed.
Of course, other forms of administration of temozolomide, as they
25 become available, are contemplated, such as by IV injection or infusion,
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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.
The effectiveness of treatment may be determined by controlled clinical
trials. Patients having a cancer treatable by this invention with measurable or
evaluable tumors will be included in the study. A measurable tumor is one that
can be measured in at least two dimensions such as a lung tumor surrounded
by aerated lung, a skin nodule, or a superficial Iymph node. An evaluable tumor
is one that can be measured in one dimension such as a lung tumor not
completely surrounded by aerated lung or a palpable abdominal or soft tissue
mass that can be measured in one dimension. Tumor markers which have
been shown to be highly correlated with extent of disease will also be
considered to measure for the presence of an evaluable disease. Examples of
such tumor markers are PSA for prostate cancer, CA-125 for ovarian cancer,
CA-15-3 for breast cancer, etc.
The tumor will be measured or evaluated before and after treatment by
whatever means provides the most accurate measurement, such as CT scan,
MRI scan, Ultrasonography, etc. New tumors or the lack thereof in previously
irradiated fields can also be used to assess the anti-tumor response. The
criteria for evaluating response will be similar to that of the WHO Handbook of
Reporting Results of Cancer Treatment, WHO Offset Publication 1979, 49-World
Health Organization, Geneva. The following results are defined for uni- and bi-
dimensionally measurable tumors.
Complete response: means complete disappearance of all clinically
detectable malignant disease as determined by two observations not less than
four weeks apart.
Partial Response means the following: (a) for bidimensionally
measurable tumors, a decrease of at least 50% in the sum of the products of the
largest perpendicular diameters of all measurable tumors as determined by two
observations not less than four weeks apart. (b) for unidimensionally
measurable tumors, a decrease by at least 50% in the sum of the largest
diameters of all tumors as determined by two observations not less than four
weeks apart. In cases where the patient has multiple tumors, it is not necessary
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for all tumors to have regressed to achieve a partial response as defined herein,
but no tumor should have progressed and no new tumor should appear.
Stable disease means: (a) for bidimensionally measurable tumors, less
5 than a 50% decrease to less than a 25% increase in the sum of the products of
the largest perpendicular diameters of all measurable tumors. (b) for
unidimensionally measurable tumors, less than a 50% decrease to less than a
25 % increase in the sum of the diameters of all tumors. For (a) and (b) no new
tumors should appear.
Progressive disease is defined as an increase of 25% or greater in the
product of the largest perpendicular diameters for at least one bidimensionally
measurable tumor, or an increase of 25 % or greater at least one
unidimensionally measurable tumor, or appearance of a new lesion.
For patients having both uni- and bi-dimensionally measurable tumors,
the overall response will be determined in accordance with the following table.
Response in Response in
bidimensionally unidimensionally
measurable diseasemeasurable disease Overall Response
PD any PD
Any PD PD
SD SDorPR SD
SD CR PR
PR SD or PR or CR PR
CR SDorPR PR
CR CR CR
~0 Abbreviations: PD: Progressive Disease
CR: Complete Response
PR: Partial Response
SD: Stable Disease
25 Of course elimination or alleviation of other known signs or symptoms of
advanced cancer, especially those listed previously can also be used to
evaluate the effectiveness of this invention.
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The cancers should be evaluated, i.e. tumors measured, etc., no more
than 14 days before the start of the treatment. These cancers should be
reevaluated about 28 days after day 1 of administration of the first dose of
temozolomide. Twenty eight days after this initial administration another
5 administration and evaluation may be performed. The treatment cycles and
evaluations may be continued until disease progression or unacceptable
toxicity is encountered.
