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Cancer Patent Abstract
There is disclosed a method for treating advanced cancer in patients
in need of such treating. Temozolomide and alpha interferon are
administered in combination in amounts sufficient to achieve a clinical
response.
Cancer Patent Claims
The invention claimed is:
1. A method for treating a malignant melanoma in a patient in need
of such treating comprising administering temozolomide and interferon
alpha 2b in amounts sufficient to eliminate or at least alleviate
one or more of the signs or symptoms of the malignant melanoma.
2. The method of claim 1 wherein the amount of temozolomide administered
is from 50 to 400 mg per m.sup.2 of the patient'1s body surface
area per day for a period of from 2 to 10 days and the amount of
interferon alpha 2b administered is from 1 million to 25 million
IU per m.sup.2 of the patient's body surface area administered intraveneously
or subcutaneously 1 to 7 times per week.
3. The method of claim 2 wherein beginning 28 to 42 days after
the first day of the temozolomide administration period, the temozolomide
administrations are repeated.
4. The method of claim 2 wherein the amount of temozolomide administered
is from 75 to 300 mg per m.sup.2 of the patient's body surface area
per day for a period of from 3 to 8 days and the amount of interferon
alpha 2b administered is from 5 million to 15 million IU per m.sup.2
of the patient's body surface area administered intravenously or
subcutaneously.
5. The method of claim 4 wherein beginning about 28 to 35 days
after the first day of the temozolomide administration period, the
temozolomide administrations are repeated.
6. The method of claim 4 wherein the amount of temozolomide administered
is from 100 to 200 mg per m.sup.2 of the patient's body surface
area per day for a period of 5 days and the amount of interferon
alpha 2b administered is from 7.5 million to 12.5 million IU per
m.sup.2 of the patient's body surface area administered intravenously
or subcutaneously.
7. The method of claim 6 wherein beginning 28 days after the first
day of the temozolomide administration period, the temozolomide
administrations are repeated.
8. The method of claim 1 wherein the temozolomide is administered
orally after the patient has fasted from food and liquids other
than water for 4 hours before temozolomide administration and for
2 hours after temozolomide administration.
9. The method of claim 2 wherein the temozolomide is administered
orally after the patient has fasted from food and liquids other
than water for 4 hours before temozolomide administration and for
2 hours after temozolomide administration.
10. The method of claim 3 wherein the temozolomide is administered
orally after the patient has fasted from food and liquids other
than water for 4 hours before temozolomide administration and for
2 hours after temozolomide administration.
11. The method of claim 4 wherein the temozolomide is administered
orally after the patient has fasted from food and liquids other
than water for 4 hours before temozolomide administration and for
2 hours after temozolomide administration.
12. The method of claim 4 wherein the temozolomide is administered
orally after the patient has fasted from food and liquids other
than water for 4 hours before temozolomide administration and for
2 hours after temozolomide administration.
13. The method of claim 6 wherein the temozolomide is administered
orally after the patient has fasted from food and liquids other
than water for 4 hours before temozolomide administration and for
2 hours after temozolomide administration.
14. The method of claim 7 wherein the temozolomide is administered
orally after the patient has fasted from food and liquids other
than water for 4 hours before temozolomide administration and for
2 hours after temozolomide administration.
15. The method of claim 1 wherein the temozolomide is administered
orally for a period of from 6 days to 6 weeks.
16. The method of claim 1 wherein the malignant melanoma is a malignant
metastasized melanoma.
Cancer Patent Description
Despite the numerous advances in cancer treatment, the well-known
life style changes that can greatly reduce the risk of cancer, and
the early warning signs that some cancers provide, many patients
still develop advanced cancer for which no conventional therapies
are available that offer any reasonable hope of cure or significant
palliation. This invention is the use of two known anti-tumor agents
in combination therapy to provide a positive effect on such advanced
cancers. It is also expected that the combination therapy will allow
the administration of the two anti-tumor agents in quantities that
will not result in intolerable side effects.
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). However, temozolomide
is not always effective and has dose-limiting side effects, such
as hematologic toxicity, myelosuppression, anemia, leukopenia, etc.
Alpha interferon is also known to have anti-cancer effects. See,
for example, Ernstoff et al., Intravenous (IV) Recombinant .alpha.-2
Interferon in Metastatic Melanoma, Proc ASCO 2:57 (C-222), 1983.
However this treatment is not always effective and sometimes results
in intolerable side effects related to the dosage and duration of
therapy.
There is a need for a method for treating advanced cancers with
higher response rates or reduced side effects, or both.
SUMMARY OF THE INVENTION
This invention may be summarized as a method for treating advanced
cancer in patients in need of such treating comprising administering
temozolomide and alpha interferon in amounts sufficient to achieve
a clinical response. The temozolomide is administered to the patient
in combination with the alpha interferon, that is, the temozolomide
and alpha interferon doses are administered during the same period
of time. Preferred specific dosing schedules are given below.
DETAILED DESCRIPTION
All references cited herein are incorporated herein by reference.
The term "temozolomide" is intended to mean a compound
having the formula.
##STR00001## 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.
The term "alpha interferon" as used herein means the
family of highly homologous species-specific proteins that inhibit
viral replication and cellular proliferation and modulate immune
response. Typical suitable alpha interferons include but are not
limited to recombinant interferon alpha-2b such as Intron-A interferon
available form Schering Corporation, Kenilworth, N.J., recombinant
interferon alpha-2a such as Roferon A interferon available from
Hoffmann-La Roche, Nutley, N.J., recombinant interferon alpha-2C
such as Berofor alpha 2 interferon available from Boehringer lngelheim
Pharmaceutical, Inc., Ridgefield, Conn., interferon alpha-n1, a
purified blend of natural alpha interferons such as Sumiferon available
from Sumitomo, Japan or as Wellferon interferon alpha-n1 (INS) available
from the Glaxo-Wellcome Ltd., London, Great Britain. or a consensus
alpha interferon available from Amgen, Inc., Newbury Park, Calif.,
or interferon alpba-n3 a mixture of natural alpha interferons made
by Interferon Sciences and available from the Purdue Frederick Co.,
Norwalk, Conn., under the Alferon Tradename. The use of interferon
alpba-2a or alpha 2b is preferred. interferon alpha 2b is most preferred.
The manufacture of interferon alpha 2b is described in U.S. Patent
No. 4,530,901.
Advanced cancers treatable by this invention include malignant
melanoma, malignant metastasized melanoma, cancer of the lung, cancer
of the breast, brain cancer, ovarian cancer, cancer of the head
and/or neck, sarcoma, prostate cancer, and other cancers known to
be at least partially responsive to alpha interferon or temozolomide
treatment, that have advanced to a stage where conventional therapy
is unlikely to provide a cure.
A person suffering from advanced 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.
To practice the invention, temozolomide and alpha interferon are
administered to the patient exhibiting one of more of the above
signs or symptoms in amounts sufficient to eliminate or at least
alleviate one or more of the signs or symptoms.
The preferred dosage of temozolomide for practicing the combination
therapy of this invention is 50 to 400 mg per m.sup.2 of the patient's
body surface area per day, more preferably 75 to 300 mg/m.sup.2
and most preferably 100 to 200 mg/m.sup.2/day. It is preferred that
the daily dosage of temozolomide be administered once per day for
a 2 to 10 day period, more preferably for a 3 to 8 day period and
most preferably for a 5 day period. The temozolomide dosing periods
may be repeated in cycles of 28 to 42 days, more perferably 28 to
35 days, and most preferably 28 days. That is, 28 to 42 days after
the first day of temozolomide administration, another temozolomide
administration period may be started.
Alternatively the temozolomide may be administered for a much longer
period at reduced dosage. For example, the temozolomide could be
administered daily for 11 days to six weeks at a dosage of 50 to
150 mg/m.sup.2/day.
Temozolomide may be administered orally in capsule form wherein
it is admixed with conventional pharmaceutical carriers. Preferred
temozolomide capsule formulations are:
TABLE-US-00001 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
It is especially preferred that the patient fast from all food
or drink, except water, for four hours before temozolomide administration
and for two hours after.
The alpha interferon is preferably administered by intravenous
or subcutantous injection beginning on day one of the first temozolomide
administration period. However, unlike the temozolomide, the alpha
interferon is administered more or less regularly throughout the
combination therapy. The alpha interferon may be administered 1
to 7 times per week, more preferably 2 to 5 times per week, and
most preferably three times per week or every other day. The amount
of alpha interferon per dose may be 1 million to 25 million international
units (IU) per m.sup.2 of patient's body surface area, more preferably
5 million to 15 million IU/m.sup.2 and most preferably 7.5 million
to 12.5 million IU/m.sup.2.
The treatment may be continued until a clinical response is achieved
or until intolerable side effects are encountered. The dosages of
temozolomide and/or alpha interferon may be increased with each
new treatment cycle, provided intolerable side effects are not encountered.
The dosages may also be decreased, if intolerable side effects 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. Of course other anti-emetics
such as Haldol, Benadryl, and Ativan may also be used as needed.
A common, but usually tolerable, side effect of alpha interferon
is flu-like symptoms. These can usually be alleviated with acetaminophen
and other common aspirin-like medicines.
Of course, other forms of administration of both active ingredients,
as they become available, are contemplated, such as by nasal spray,
transdermally, by suppository, by sustained release dosage form,
by IV injection, etc. Any form of administration will work so long
as the proper dosages are delivered without destroying the active
ingredient.
The effectiveness of treatment may be determined by controlled
clinical trials. Patients having advanced cancer 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 lymph node. An evaluable tumor in 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 provide an evaluable disease, such as 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: Complete disappearance of all clinically detectable
malignant disease determined by two observations not less than four
weeks apart.
Partial Response: (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 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: (a) for bidimensionally measurable tumors, less
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.
No clinical response, i.e. progressive disease in defined as an
increase of more than 50% in the product of the largest perpendicular
diameters for at least one bidimensionally measurable tumor, or
an increase of more than 25% in measurable dimension of at least
one unidimensionally measurable tumor.
For patients having both uni- and bi-dimensionally measurable tumors,
the overall response will be determined in accordance with the following
table.
TABLE-US-00002 Response in Response in bidimensionally unidimensionally
measurable disease measurable disease Overall Response PD any PD
Any PD PD SD SD or PR SD SD CR PR PR SD or PR or CR PR CR SD or
PR PR CR CR CR Abbreviations: PD: Progressive Disease CR: Complete
Response PR: Partial Response SD: Stable Disease
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.
The advanced 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 doses of temozolomide and alpha interferon. Twenty
eight days after this initial administration another administration
period may be performed, and evaluations performed 28 days after
the start of this second cycle. The treatment cycles may be continued
until a clinical response is achieved or unacceptable toxicity is
encountered.
Another aspect of this invention is the treatment of advanced cancer
with reduced side effects normally associated with temozolomide
and alpha interferon. It is believed that this objective can be
achieved by administration of lower doses of the two active ingredients
or by shorter duration of dosing brought about by the synergistic
effect of the combination.
The most serious side effect of temozolomide is hematologic toxicity.
Dose limiting toxicity for temozolomide is defined herein as
CTC Grade 4 neutropenia (absolute neutrophil count, including bands,
of less than 0.5.times.10.sup.3/mm.sup.3) which is not resolved
in five days or
CTC Grade 4 anemia (hemoglobin of less than 6.5 g/dl), or
CTC Grade 3 thrombocytopenia (platelet count of less than 50.times.10.sup.3/mm.sup.3)
or
CTC Grade 4 thrombocytopenia(platelet count of less than 25.times.10.sup.3/mm.sup.3).
The most common side effects of alpha interferon are:
flu-like syndrone Neurotoxicity, including neuropsychiatric, neurosensory,
and neuromotor, Cardiopulmonary Gastrointestinal, including nausea,
vomiting, and/or diarreha Hepatotoxicity, including elevations of
bilirubin, transaminases, or alkaline phosphatase Nephrotoxicity.
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