Note: Descriptions are shown in the official language in which they were submitted.
CA 02610439 2007-09-25
CL06490 {r ~
UNIT DOSAGE FORMS OF TEMOZOLOMIDE
FIELD OF THE INVENTION
This invention relates to unit dosage forms of temozolomide. These unit
dosage forms are particularly well-suited for decreasing the pill burden and
increasing patient compliance. The invention also relates to methods of
treating
proliferative disorders in a patient with these unit dosage forms. The
invention
additionally relates to kits comprising these unit dosage forms.
BACKGROUND OF THE IIWENTION
Brain tumors comprise approximately 2% of all malignant diseases. Stupp
et al., J. Clin. Onc., 20(5):1375-1382 (2002). More than 17,000 cases are
diagnosed every year in the United States, with approximately 13,000
associated
deaths. The standard protocol for treating a malignant glioma involves
cytoreduction through surgical resection, when feasible, followed by
radiotherapy
(RT) with or without adjuvant chemotherapy. Stupp et al., supra.
A chemotherapeutic agent approved for treating brain tumors is
temozolomide (Schering Corp. under the trade name of Temodar(V in the United
States and Temodal in Europe). The chemical name for temozolomide is 3,4-
dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide (see U.S. Pat.
No. 5,260,291). The cytotoxicity of temozolomide or its metabolite, MTIC (3-
methyl-(triazen-l-yl)imidazole-4-carboxamide), is thought to be primarily due
to
alkylation of DNA. Alkylation (methylation) occurs mainly at the 06 and N7
positions of guanine.
Temodar capsules are currently indicated in the United States for the
treatment of adult patients with newly diagnosed gliobastoma multiforme as
well
as refractory anaplastic astrocytoma, i.e., patients at first relapse who have
experienced disease progression on a drug regimen containing a nitrosourea and
procarbazine. Temodal is currently approved in Europe for the treatment of
patients with malignant glioma, such as glioblastoma multiforme or anaplastic
1
CA 02610439 2007-09-25
astrocytoma for newly diagnosed patients as well as those showing recurrence
or
progression after standard therapy.
A typical regimen for patients with glioma taking temolozomide consists of
two phases, a concomitant phase, followed by a maintenance phase. In the
concomitant phase, the patient receives an oral administration of temozolomide
at
75 mg/m2 (approximately 140 mg for a patient having a Body Surface Area (BSA)
between 1.8 and 1.9 m2) for 42 days concomitant with RT. See Table 1. Four
weeks after completing the concomitant phase, the patient receives 6 cycles of
maintenance treatment. In the first maintenance cycle, temozolomide is
administered at 150 mg/mZ (approximately 280 mg for a patient having a BSA
between 1.8 and 1.9 m2) once daily for five days followed by 23 days without
treatment. The dosage may be escalated to 200 mg/m2 (approximately 360 mg for
a patient having a BSA between 1.8 and 1.9 mZ) for the first 5 days of each
subsequent cycle.
Currently, the capsule formulations of temozolomide contain 5, 20, 100 or
250 mg of temozolomide. Given a therapeutic dose of 150 mg/mg2, a patient
having a BSA of between 1.8 and 1.9 would need to consume 4 capsules per day
to
receive the approximately 280 mg of temozolomide dosage (1 x 250 mg, 1 x 20 mg
and 2 x 5 mg). See Table 2. Such a high pill burden would likely result in
poor
patient compliance with therapies that require self-administration of
temozolomide,
thus producing sub-optimal therapeutic benefit of the drug. Other factors that
may
affect the patient's compliance with self-administering the appropriate number
of
pills is the intensity of the treatment regimens for gliomas, including brain
surgery
and RT. Furthermore, the number of different medications that the patient may
have to take to alleviate the side effects of the surgery or RT or to remedy
or
alleviate other unrelated conditions further exacerbate the already high pill
burden.
In addition, the patient is at risk for cognitive deficits and compromised
neurological status as a result of the intense treatment regimens.
Thus, there is a need to improve the unit dosage form of temozolomide.
Such an improved dosage form would reduce the pill burden and increase patient
compliance.
2
CA 02610439 2007-09-25
~ ~.
Table 1.
Daily Dose Calculations by Body Surface Area (BSA)
Total BSA 75 mg/m 100 mg/m 150 mg/m 200 mg/m
(m) (mg daily) (mg daily)* (mg daily) (mg daily)
1.0 75 100 150 200
1.1 82.5 110 165 220
1.2 90 120 180 240
1.3 97.5 130 195 260
1.4 105 140 210 280
1.5 112.5 150 225 300
1.6 120 160 240 320
1.7 127.5 170 255 340
1.8 135 180 270 360
1.9 142.5 190 285 380
2.0 150 200 300 400
2.1 157.5 210 315 420
2.2 165 220 330 440
2.3 172.5 230 345 460
2.4 180 240 360 480
2.5 187.5 250 375 500
* 100 mg/m daily represents the current minimum dosage for patients on
maintenance dosing.
3
= CA 02610439 2007-09-25
Table 2.
Suggested Currently Available Capsule Combinations Based on Daily Dose in
Adults
Number of Daily Capsules by Strength
Total Daily Dose 250 100 20 5
75 0 0 3 3
82.5 0 0 4 0
90 0 0 4 2
97.5 0 1 0 0
105 0 1 0 1
112.5 0 1 0 2
120 0 1 1 0
127.5 0 1 1 1
135 0 1 1 3
142.5 0 1 2 0
150 0 1 2 2
157.5 0 1 3 0
165 0 1 3 1
172.5 0 1 3 2
180 0 1 4 0
187.5 0 1 4 1
195 0 1 4 3
200 0 2 0 0
210 0 2 0 2
220 0 2 1 0
225 0 2 1 1
240 0 2 2 0
255 1 0 0 1
260 1 0 0 2
270 1 0 1 0
280 1 0 1 2
285 1 0 1 3
300 0 3 0 0
315 0 3 0 3
320 0 3 1 0
330 1 0 4 0
340 0 3 2 0
345 0 3 2 1
360 0 3 3 0
370 1 1 1 0
380 1 1 1 2
400 0 4 0 0
4
CA 02610439 2007-09-25
SUMMARY OF THE INVENTION
The present invention provides an improved unit dosage form of
temozolomide comprising about 140 mg temozolomide. The present invention
also provides an improved unit dosage form of temozolomide comprising about
180 mg of temozolomide. These unit dosage forms reduce the pill burden and
increase patient compliance.
In some embodiments, the unit dosage forms are in the form of a capsule.
In some embodiments, the capsules are color-coded. In some embodiments, the
140 mg temozolomide capsule differs in color from the 180 mg temozolomide
capsule.
The present invention also provides methods of increasing patient
compliance with a regimen by administering these unit dosage forms.
The present invention also provides methods of treating proliferative
disorders with these unit dosage forms. In some embodiments, the proliferative
disorder is selected from a glioma, melanoma, a lung cancer, a lymphoma, a
head
and neck cancer, ovarian cancer, colorectal and/or colon cancer or esophageal
cancer, or other solid tumor or hematologic malignancy.
In some embodiments, the methods of treating proliferative disorders
comprise administering the unit dosage forms according to a dosing regimen. In
some embodiments, the regimen is based upon the methylation state of the
promoter region of the 06-methylguanine-DNA transferase (MGMT) gene in a
sample obtained from the patient. In other embodiments, the regimen is based
upon the presence or absence of the MGMT protein in a sample obtained from the
patient. In other embodiments, the regimen is based upon the level or
enzymatic
activity of the MGMT protein detected in a sample obtained from the patient.
In
other embodiments, the regimen is based upon the presence (or level) of
messenger
RNA of MGMT in a sample obtained from the patient.
The present invention also provides kits comprising these unit dosage
forms. In some embodiments, the kits comprise both unit dosage forms. In some
embodiments, the kits further comprise one or more unit dosage forms
comprising
5
CA 02610439 2007-09-25
about 5, 20 or 100 mg of temozolomide. In some embodiments, the kit is a
blister
pack.
DETAILED DESCRIPTION OF THE INVENTION
In order that the invention herein described may be fully understood, the
following detailed description is set forth.
Unless defined otherwise, all technical and scientific terms used herein
have the same meaning as those commonly understood by one of ordinary skill in
the art to which this invention belongs. Although methods and materials
similar or
equivalent to those described herein can be used in the practice or testing of
the
present invention, suitable methods and materials are described below. The
materials, methods and examples are illustrative only, and are not intended to
be
limiting. All publications, patents and other documents mentioned herein are
incorporated by reference in their entirety.
In order to further define the invention, the following terms and definitions
are provided herein.
The term "pharmaceutically acceptable carrier or adjuvant" refers to a non-
toxic carrier or adjuvant that may be administered to a patient, together with
temolozimide, and that does not destroy the pharmacological activity thereof.
The term "color-coded capsule" refers to a capsule in which any portion or
all of the capsule is colored and the color represents a particular meaning,
e.g. a
given capsule color represents a specific dosage amount of temozolomide.
The term "treating" or "treatment" is intended to mean mitigating or
alleviating the symptoms a cell proliferative disorder in a mammal such as a
human or the improvement of an ascertainable measurement associated with a
cell
proliferative disorder.
The term "patient" refers to an animal including a mammal (e.g., a human).
The tenn "proliferative disorder" may be a neoplasm. Such neoplasms are
either benign or malignant.
The term "neoplasm" refers to a new, abnon-nal growth of cells or a growth
of abnormal cells that reproduce faster than normal. A neoplasm creates an
unstnictured mass (a tumor) which can be either benign or malignant.
6
CA 02610439 2007-09-25
i (Y
The term "benign" refers to a tumor that is noncancerous, e.g., its cells do
not invade surrounding tissues or metastasize to distant sites.
The term "malignant" refers to a tumor that is cancerous, metastastic,
invades contiguous tissue or is no longer under normal cellular growth
control.
The term "brain tumor" includes glioma, glioblastoma multiforme,
ependymoma; astrocytoma, medulloblastoma, neuroglioma, oligodendroglioma
and meningioma.
The term "sample" refers to a specimen that can obtained as or isolated
from normal or tumor tissue, brain tissue, cerebrospinal fluid, blood, plasma,
serum, urine, stool, saliva lymph, lymph nodes, spleen, liver, bone marrow, or
any
other biological specimen containing either MGMT protein or nucleic acid of
the
MGMT gene.
The term "MGMT" refers to 06-methylguanine-DNA methyltransferase.
MGMT is also known as an 06-alkylguanine-DNA-alkyltransferase (AGAT).
The term "GM-CSF" means a protein which (a) has an amino acid sequence
that is substantially identical to the sequence of mature (i.e., lacking a
signal
peptide) human GM-CSF described by Lee et al., Proc. Natl. Acad. Sci. U.S.A.,
82:4360 (1985) and (b) has biological activity that is common to native GM-
CSF.
The term "substantial identity of amino acid sequences" means that the
sequences are identical or differ by one or more amino acid alterations
(deletions,
additions, substitutions) that do not substantially impair biological
activity.
The term "kit" refers to one or more containers for containing the unit
dosage forms of the present invention.
Unit Dosage Forms
The present invention provides a unit dosage form of temozolomide
comprising about 140 mg temozolomide and a pharmaceutically acceptable
carrier.
The present invention also provides a unit dosage form of temozolomide
comprising about 180 mg of temozolomide and a pharmaceutically acceptable
carrier. In some embodiments, the unit dosage form is suitable for oral
administration.
7
CA 02610439 2007-09-25
Pharmaceutically acceptable carriers that may be used in the dosage forms
of the present invention include those well known in the art (see, e.g.,
Remington's
Pharmaceutical Sciences, 16th Ed., Mac Publishing Company (1980)). Such
pharmaceutically acceptable carriers may include other medicinal agents,
carriers,
genetic carriers, adjuvants, excipients, inert diluents, lubricating agents,
etc., such
as human serum albumin or plasma preparations. Non-aqueous vehicles such as
fixed oils and ethyl oleate are also useful herein. Examples of diluents
include
calcium carbonate, potato starch, alginic acid, and lactose. Examples of inert
diluents include lubricating agents, such as magnesium stearate. Preferably,
the
pharmaceutically acceptable carriers are lactate anhydrous, colloidal silicon
dioxide, sodium starch glycolate, tartartic acid and stearic acid.
The unit dosage forms according to the present invention may be prepared
in the form of tablets, pills, granules, dispersible powders or capsules.
Preferably,
the unit dosage forms are in the form of capsules. In some embodiments, the
capsules are color-coded for easy identification. In some embodiments, the 140
mg temozolomide capsule differs in color from the 180 mg temozolomide capsule.
In some embodiments, each capsule strength has a different color, thus
indicating
dosage of temozolomide.
Methods of Increasing Patient Compliance
The unit dosage forms of the present invention may be used to increase
patient compliance by reducing the pill burden. In some embodiments, the
present
invention provides methods of increasing patient compliance by administering
to
the patient one or more unit dosage forms containing about 140 mg or 180 mg of
temozolomide. In some embodiments, the methods further comprise administering
one or more unit dosage forms containing about 5 mg, 20 mg or 100 mg of
temozolomide.
The unit dosage forms may be administered to a patient according to a
dosing regimen and/or dosing schedule. Non-limiting examples of dosing
regimens and schedules are illustrated in Table 3.
8
CA 02610439 2007-09-25
~. ~.
CL06490
Table 3.
T;~IZ Dosing Regimens and Dose Intensity
Regimen Total Dose Dose/wk Dose
No. Dosing Regimen Dosing Schedule (mg/m''/4 Z
(mg/m ) Intensity
wks)
I 5/28 150-200 mg/m2, 5 days/28 day 1000 250 1
cycle (200 mg)
High doses 250 250 mg/m2, 5/28, concomitant
2 mg/mZ for 5/28 w/a growth factor 1250 312 1.2
3 14/28 100 mg/mZ, 14 days/28 day 1400 350 1.4
cycle
4 High doses 300 300 mg/m2, 5/28, concomitant 1500 375 1.5
mg/m' for 5/28 w/a growth factor
21/28 75 mg/mZ, 21 days/28 day 1575 393.75 1.6
cycle
6 42/56 75 mg/mZ, 6 wks/8 wk cycle 3150 393.75 1.6
85 mg/mZ, 21 days/28 day
7 21/28 1785 446.25 1.8
cycle
High doses 350 350 mg/m2, 5/28, concomitant
8 mg/m2 for 5/28 w/a growth factor 1750 437.5 1.8
9 14 on/7 off 100 mg/m2, 14 days/21 day 1400* 467 1.9
cycle
High doses 400 400 mg/m2, 5/28, concomitant
mg/m2 for 5/28 w/a growth factor 2000 500 2.0
150 mg/m2, 7 days/14 day
11 7/7 2100 525 2.1
cycle
12 21/28 100 mg/m2, 21 days/28 day 2100 525 2.1
cycle
150 mg/m2, 14 days/28 day
13 14/28 2100 525 2.1
cycle
14 Continuous 75 mg/mz, daily 2100 525 2.1
dosing
High doses 450 450 mg/m2, 5/28, concomitant 2250 562.5 2.25
mg/m2 for 5/28 w/a growth factor
16 14 on/7 off 150 mg/m2, 14 days/21 day 2100* 700 2.8
cycle
17 Continuous 100 mg/m2, daily 2800 700 2.8
dosing
High doses 250 250 mg/rn', 7/7, conconiitant
18 mg/m'' for 7/7 w/a growth factor 3500 875 3.5
High doses 300 300 mg/m'', 7/7, concomitant
19 mg/m' for 7/7 w/a growth factor 4200 1050 4.2
*Represents total dose received in 3 week cycle
The dosing regimens of Table 3 may be simplified by using the unit dosage
5 forms of the present invention. Suggested capsule combinations using the
unit
dosage forms of the present invention are illustrated in Table 4. In 18 of 29
daily
doses listed in Table 4, the suggested capsule combinations of the present
9
CA 02610439 2007-09-25
invention are lower than the currently available capsule combinations. See
Table
5. Importantly, the suggested capsule combinations of the present invention
increase in only 2 daily doses (see, 255 mg and 370 mg in Table 2 compared to
Table 4). By simplifying the dosing regimens, the pill burden on the patient
is
significantly reduced.
In particular, a patient on a 195 mg of temozolomide per day regimen
would need to consume 8 of the current capsule formulations to achieve the
therapeutic dosage (i.e., I x 100 mg, 4 x 20 mg and 3 x 5 mg). See Tables 2
and S.
However, using the unit dosage forms of the present invention, that patient
would
need to consume only 4 units dosage forms (i.e., 1 x 180 mg and 3 x 5 mg). See
Tables 4 and 5. As another example, a patient on a 280 mg of temozolomide per
day regimen would need to consume 4 of the current capsule formulations to
achieve the therapeutic dosage (i.e., I x 250 mg, 1 x 20 mg and 2 x 5 mg). See
Tables 2 and 5. However, using the unit dosage forms of the present invention,
that patient would need to consume only 2 unit dosage forms (i.e., 2 x 140
mg).
See Tables 4 and 5. As yet another example, a patient on a 380 mg of
temozolomide per day regimen would need to consume 5 of the current capsule
formulations to achieve the therapeutic dosage (i.e., I x 250 mg, 1 x 100 mg,
1 x 20 mg and 2 x 5 mg). See Tables 2 and 5. In contrast, that patient would
need
to consume only 3 unit dosage forms of the present invention (i.e., 2 x 180 mg
and
1 x 20 mg). See Tables 4 and 5.
Table 6 further illustrates how the unit dosage fonms of the present
invention decrease the pill burden on the patient. As shown in Table 6, the
number
of capsules is lower in 28 out of 45 regimens when the patient receives the
unit
dosage forms of the present invention. See Table 6. Importantly, the number
increases in only 8 of the remaining 17 regimens.
CA 02610439 2007-09-25
CL06490
Table 4.
Suggested Capsule Combinations Based on Daily Dose in Adults
Number of Daily Capsules by Strength
Total Daily Dose 180 140 100 20 5
(mg)*
135 0 1 0 0 0
142.5 0 1 0 0 0
150 0 1 0 0 2
157.5 0 1 0 1 0
165 0 1 0 1 1
172.5 0 1 0 1 2
180 1 0 0 0 0
187.5 1 0 0 0 1
195 1 0 0 0 3
200 1 0 0 1 0
210 1 0 0 1 2
220 1 0 0 2 0
225 1 0 0 2 1
240 0 11 0 0
255 0 1 1 0 3
260 0 1 1 1 0
270 1 0 1 0 0
280 1 0 1 0 0
285 1 0 1 0 1
300 0 0 3 0 0
315 0 2 0 1 3
320 1 1 0 0 0
330 1 1 0 0 2
340 0 1 2 0 0
345 0 1 2 0 1
360 2 0 0 0 0
370 2 0 0 0 2
380 2 0 0 1 0
400 0 0 4 0 0
*Assumes rounding
11
CA 02610439 2007-09-25
CL06490
Table 5.
Total Number of Capsules
Total Daily Current Suggested Capsule Suggested Capsule Combinations
Dose Combinations of the Present Invention
(mg)*
135 5 1
142.5 3 1
150 5 3
157.5 4 2
165 5 3
172.5 6 4
180 5 1
187.5 6 2
195 8 4
200 2 2
210 4 4
220 3 3
225 4 4
240 4 2
255 2 5
260 3 3
270 2 -2
280 4 2
285 5 3
300 3 3
315 6 6
320 4 2
330 5 4
340 5 3
345 6 4
360 6 2
370 3 4
380 5 3
400 4 4
12
CA 02610439 2007-09-25
( f.
Table 6.
Dose 75 mg/m 150 mg/m' 200 mg/mZ
BSA/Dose Capsule Current 180/140 BSA/Dose Current 180/140 BSA/Dose Current
180/
140
1.50/113 250 1.50/225 1.50/300 1
180 1
140
100 1 1 2 3
20 1 2 2
3 3 1 1 2
------------ ---------- ----- ----------- ------------- --- ---------- --------
--=- ----- ------
Total 4 4 4 4 5 3
1.55/116 250 1.55/233 1.55/310 1
180 1
140
100 1 1 2 3
20 1 2 3
5 3 3 3 2 ?
--------------- ------- ---------- ---- ---- ------------- ---- --- ----------
------------- ----------- -----
Total 4 4 6 5 4 5
1.60/120 250 1.60/240 1.60/320 1
180 1
140 1 1
100 1 1 2 1
20 1 1 2 3
5 2
-------------=------=--- ----------- ---------- ------------ --------- --------
-- ------------- ----------- --------
Total 2 2 4 2 6 2
1.65/124 250 1.65/248 1 1.65/330 1
180 1
140 1 1
100 1 1 1
20 1 1 4
5 1 1 1 ?
------------ - ------- ---- ------------- --------- ---------- ------------ ---
-------- ------
Total 3 3 1 3 5 4
1.70/128 250 1.70/255 1 1.70/340 1
180
140 1 1
100 1 1 1 2
20 1 1 4
5 2 2 1 3 2
------------------------- - ---=- ----------- ------------- ---------- ------ -
--- ------------- ----------- ---....
Total 4 4 2 5 7
1.75/131 250 1.75/263 1 1.75/350 1
180
140 1 1
100 1 1 1 1 2
20 1 1 1
5 2 2 3 2
-------=--- ---- ------------- -==- ---- ---
Total 4 4 4 3 2 5
13
CA 02610439 2007-09-25
(.. , ~
Dose 75 mg/m2 150 mg/m' 200 mg/mZ
BSA/Dose Capsule Current 180/140 BSA/Dose Current 180/140 BSA/Dose Current
180/
140
1.80/135 250 1.80/270 1 1.80/360 1
180 2
140 1
100 1 1 1 1
20 1 1 1 1
3 3 2 2
------------ --------- ----------- ---------------------- --------- ----------
------------- ----------------
Total 5 5 2 5 4 2
1.85/139 250 1.85/278 1 1.85/370 1
180 1 2
140 1
100 1 1 1
20 2 1 1
5 1 2
------------------------- ----------- ----------- ------------- ---------------
------ ------------- ----------- ------
Total 3 1 4 2 3 4
1.90/143 250 1.90/285 1 1.90/380 1
180 1 2
140 1
100 1 1 1
20 2 1 1 1
5 ------- ---------- ---------- ------------ ---- 3 --- -----1---- ------------
-----?---- ------
Total 3 1 5 3 5 3
1.95/146 250 1.95/293 1 1.95/390 1
180 1 2
140 1
100 1 1 1
20 2 2 2 1
5 -------- ----- 1----- ----- 1------------------------- --- -----3----- ------
------ ----------- ---?
Total 4 2 4 5 4 5
2.00/150 250 2.00/300 2.00/400 1
180
140 1
100 1 3 3 1 4
20 2 2
--------------- 5 ------- --- - 2 ----- --- - 2 ---- ------------- --------- --
-------- ------------ ---- - 2 ----- ------
Total 5 3 3 3 6 4
2.05/154 250 2.05/308 2.05/410 1
180 1
140 1 1
100 1 3 1 4
20 2 2
5 3 3 2 2
------------- --------- ---------- ----------------------- -------- -----------
------------- ---------- -------
Total 6 4 5 2 6 4
2.10/158 250 2.10/315 1 2.10/420 1
180 1 1
140 1 1 1
100 1 1 1
20 3 1 3 3
5 1 2
----------------------------------- -------=--- ------------- ---------- ------
----- ------------- ---------- -------
Total 4 2 5 2 7 3
14
CA 02610439 2007-09-25
Dose 75 mg/m' 150 mg/m' 200 mg/mZ
BSA/Dose Capsule Current 180/140 BSA/Dose Current 180/140 BSA/Dose Current
180/
140
2.15/161 250 2.15/323 1 2.15/430 1
180 1
140 1 1 3
100 1 1
20 3 1 3 4
2 2
Total - -------- ------ 4 ----- ----- 2 ----- ------------ ---- 6 ---- ------
2 ----- ------------ ------ 6 ----- ---- 5--
2.20/165 250 2.20/330 2.20/440 1
180 1
140 1 1
100 1 3 1
20 3 1 1 4
5 1 1 2 2 2 2
----------------------- ----------- ---------- ------------- -------- ---------
- ------------- ---------- ----
Total 5 3 6 4 8 4
Methods of Treating Proliferative Disorders
The unit dosage fonms of the present invention may be used to treat a
proliferative disorder in a patient. Proliferative disorders include, but are
not
5 limited to, benign/malignant tumors such as brain tumors, prostate, lung
cancer,
breast cancer, ovarian, testicular cancer, liver, kidney, spleen, bladder,
colorectal
and/or colon cancer, head and neck, melanoma, carcinoma, sarcoma, lymphoma,
mycosis fungoides as well as leukemia or other hematologic malignancies. In
some embodiments, the methods are used to treat glioma, melanoma, lung cancer,
lymphoma, colorectal and/or colon cancer, head and neck or ovarian cancer. In
some embodiments, the methods are used to treat glioma.
In some embodiments, the unit dosage forms of the present invention are
administered according to one of the dosing regimens presented in Tables 3 and
4.
In some embodiments, the dosing regimen is 150-200 mg/m2 per day for 5 days in
a 28 day cycle. In other embodiments, the dosing regimen is 100 mg/m2 per day
for 14 days in a 21 day cycle. In other embodiments, the dosing regimen is
150 mg/m2 per day for 7 days in a 14 day cycle.
In some embodiments, the unit dosage forms of the present invention are
used to treat glioma. In some embodiments, the unit dosage forms are
administered to a patient having a glioma according to one of the dosing
regimens
presented in Tables 3 and 4. In some embodiments, the dosing regimen is 150-
200
mg/m2 per day for 5 days in a 28 day cycle. In other embodiments, the dosing
CA 02610439 2007-09-25
regimen is 100 mg/mZ per day for 14 days in a 21 day cycle. In other preferred
embodiments, the dosing regimen is 150 mg/m2 per day for 7 days in a 14 day
cycle.
In some embodiments, the unit dosage forms are administered in
combination with a growth factor. Suitable growth factors include, but are not
limited to, GM-CSF, G-CSF, IL-1, IL-3, IL-6, or erythropoietin. Non-limiting
growth factors include Epogen (epoetin alfa), Procrit . (epoetin alfa),
Neupogen (filgrastim, a human G-CSF), Aranesp (hyperglycosylated
recombinant darbepoetin alfa), Neulasta (also branded Neupopeg, pegylated
recombinant filgrastim, pegfilgrastim), AlbupoietinTM (a long-acting
erythropoietin), and AlbugraninTM (albumin G-CSF, a long-acting G-CSF). In
some embodiments, the growth factor is G-CSF.
In some embodiments, the unit dosage forms are administered in a
combination therapy. In some embodiments, the unit dosage forms are
administered in combination with a poly(ADP-ribose) polymerase(s) (PARP)
inhibitor. The PARP inhibitor may be administered either prior to,
concomitantly
with or after administration of the unit dosage forms of the present
invention.
Suitable PARP inhibitors include but are not limited to CEP-6800 (Cephalon;
described in Miknyoczki et al., Mol Cancer Ther, 2(4):371-382 (2003)); 3-
aminobenzamide (also known as 3-AB; Inotek; described in Liaudet et al., Br J
Pharmacol, 133(8):1424-1430 (2001)); PJ34 (Inotek; described in Abdelkarim et
al., Int J Mol Med, 7(3):255-260 (2001)); 5-iodo-6-amino-1,2-benzopyrone (also
known as INH(2)BP; Inotek; described in Mabley et al., Br J Pharmacol,
133(6):909-919 (2001), GPI 15427 (described in Tentori et al., Int J Oncol,
26(2):415-422 (2005)); 1,5-dihydroxyisoquinoline (also known as DIQ; described
in Walisser and Thies, Exp Cell Res, 251(2):401-413 (1999); 5-
aminoisoquinolinone (also known as 5-AIQ; described in Di Paola et al., Eur J
Pharmacol, 492(2-3):203-210 (2004); AG14361 (described in Bryant and
Helleday, Biochem Soc Trans, 32(Pt 6):959-961 (2004); Veuger et al., Cancer
Res,
63(18):6008-6015 (2003); and Veuger et al., Oncogene, 23(44):7322-7329
(2004));
ABT-472 (Abbott); INO-1001 (Inotek); AAI-028 (Novartis); KU-59436 (KuDOS;
described in Farmer et al., "Targeting the DNA repair defect in BRCA mutant
cells
16
CA 02610439 2007-09-25
as a therapeutic strategy," Nature, 434(7035):917-921 (2005)); and those
described
in Jagtap et al., Crit Care Med, 30(5):1071-1082 (2002); Loh et al., Bioorg
Med
Chem Lett, 15(9):2235-2238 (2005); Ferraris et al., J Med Chem, 46(14):3138-
3151 (2003); Ferraris et al., Bioorg Med Chem Lett, 13(15):2513-2518 (2003);
Ferraris et al., Bioorg Med Chem, 11(17):3695-3707 (2003); Li and Zhang
IDrugs,
4(7):804-812 (2001); Steinhagen et al., Bioorg Med Chem Lett, 12(21):3187-3190
(2002)); WO 02/06284 (Novartis); WO 02/06247 (Bayer); PARP inhibitors being
developed by MGI Pharma Inc. (formerly Guildford Pharmaceutical, Inc.)
including PARP inhibitors described in W099/11645 (incorporated herein by
reference in its entirety) including PARP inhibitors designated "1, 1 lb-
dihydro
(1)benzopyrano(4,32-de) isoquinolin-3(2H) one" such as GPI 15427 designated
"10-(4-methyl-piperazin)-1-ylmethyl)-2H-7-oxa-l,2-diazabenzo[de]anthracen-3-
one"; GPI 16539 designated "2-(4-methyl-piperazin-1-yl)-SH-
benzo[c][1,5]napthyridin-6-one";GPI21016, GPI 16346 and GPI 18180, GPI 6.150,
GPI 18078; GPI 6000 as well as 2-phenyl benzimidazole 4-carboxamides
including those described by Agouron/Pfizer in WO/09524379 inclding such as in
16'h NCI-EROTC Symposium New Drugs Cancer Therapy (Amsterdam) 1998 Abs
116; Agouron 91st AACR (San Francisco) 2000, Abs. 5164 including AG-014699,
AG-14361, AG-14073, as well as Kudos's KU59436, KU-0687, etc.
In some embodiments, the unit dosage forms are administered in
combination with an 06-alkylguanine-DNA-alkyltransferase (Atase) inhibitor
such
as 06 -benzylguanine (O6BG) or Lomeguatrib [6-(4-bromo-2-thienyl) methoxy]
purin-2-amine] (a.k.a. PatrinTM or Patrin-2) described in U.S. Pat. No.
6,043,228
(Cancer Research UK) to accentuate hematopoietic toxicity. The Atase inhibitor
such as O6BG can be administered either prior to, concomitantly with or after
administration of the unit dosage forms of the present invention.
In some embodiments, the unit dosage forms are administered in
combination with an anti-emetic agent. Suitable anti-emetic agents include,
but are
not limited to, Palonosetron, Tropisetron, Ondansetron, Granisetron,
Bemesetron
or a combination of at least two of the foregoing. In some embodiments, the
amount of active anti-emetic substance in one dosage unit amounts to 2 to 10
mg,
an amount of 5 to 8 mg active substance in one dosage unit being especially
17
CA 02610439 2007-09-25
~. ~
preferred. A daily dosage comprises generally an amount of active substance of
2
to 20 mg, particularly preferred is an amount of active substance of 5 to 16
mg. In
some embodiments, a neurokinin-1 antagonist (NK-1 antagonist) such as
aprepitant may be administered either alone or in combination with a steroid
such
as dexamethasone in conjunction with an anti-emetic agent. In other
embodiments,
the unit dosage forms are administered in combination with an NK-1 agonist
alone
or with a steroid. In certain embodiments, the NK-1 antagonist is one or more
of
the NK-1 antagonists described in U.S. Pat. No. 7,049,320 alone or in
combination
with one or more of an 5HT3 inhibitor and a steroid.
In some embodiments, the unit dosage forms are administered in
combination with a farnesyl protein transferase inhibitor.
In other embodiments, the unit dosage forms are administered with another
antineoplastic agent. Suitable antineoplastic agents include, but are not
limited to,
Uracil Mustard, Chlormethine, Cyclophosphamide, Ifosfamide, Melphalan,
Chlorambucil, Pipobroman, Tri ethylenemelamine, Triethylenethiophosphoramine,
Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Methotrexate, 5-
Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine,
Fludarabine phosphate, Pentostatine, Gemcitabine, Vinblastine, Vincristine,
Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin,
Idarubicin, Paclitaxel, Mithramycin, Deoxycoformycin, Mitomycin-C, L-
Asparaginase, Interferons, Etoposide, Teniposide 17a-Ethinylestradiol,
Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone
propionate, Testolactone, Megestrolacetate, Tamoxifen, Methylprednisolone,
Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene,
Hydroxyprogesterone, Aminoglutethimide, Estramustine,
Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, Goserelin,
Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane,
Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine,
Reloxafine, Droloxafine, Hexamethylmelamine, Oxaliplatin (Eloxatin0), Iressa
(gefinitib, Zd1839), XELODAO (capecitabine), Tarceva0 (erlotinib), Azacitidine
(5-Azacytidine; 5-AzaC), and mixtures thereof.
18
CA 02610439 2007-09-25
In some embodiments, the unit dosage forms may be administered with
other anti-cancer agents such as the ones disclosed in U.S. Pat. Nos.
5,824,346,
5,939,098, 5,942,247, 6,096,757, 6,251,886, 6,316,462, 6,333,333, 6,346,524,
and
6,703,400, all of which are incorporated by reference.
Methods For Assessing Methylation State Of MGMT Gene
Temozolomide, as an alkylating agent, causes cell death by binding to
DNA which structurally distorts the DNA helical structure preventing DNA
transcription and translation. In normal cells, the damaging action of
alkylating
agents can be repaired by cellular DNA repair enzymes, in particular MGMT. The
level of MGMT varies in tumor cells, even among tumors of the same type. The
gene encoding MGMT is not commonly mutated or deleted. Rather, low levels of
MGMT in tumor cells are due to an epigenetic modification; the MGMT promoter
region is methylated, thus inhibiting transcription of the MGMT gene and
preventing expression of MGMT.
U.S. Publication 20060100188, the entire content of which is incorporated
by reference, discloses methods for treating cancer in a patient comprising
administering temozolomide according to improved dosing regimen and/or
schedules based on the patient's MGMT level.
In some embodiments, the dosing regimen is based upon the methylation
state of the MGMT gene in a sample obtained from the patient. In some
embodiments, the methylation state is assessed by a determination of whether
the
MGMT gene is methylated. In other embodiments, the methylation state is
assessed by a quantitative determination of the level of methylation of the
MGMT
gene. In other embodiments, the methylation state is assessed by determination
of
whether MGMT protein is expressed. In yet other embodiments, the methylation
states is assessed by a determination of the level of MGMT protein expressed
or
measurement of the enzymatic activity of MGMT in the patient sample.
Assessing whether the MGMT gene is methylated may be performed using
any method known to one skilled in the art. Techniques useful for detecting
methylation of a gene or nucleic acid include, but are not limited to, those
described by Ahrendt et al., J. Natl. Cancer Inst., 91:332-339 (1999);
Belsinky et
19
CA 02610439 2007-09-25
al., Proc. Natl. Acad. Sci. U.S.A., 95:11891-11896 (1998), Clark et al.,
Nucleic
Acids Res., 22:2990-2997 (1994); Herman et al., Proc Natl Acad Sci U.S.A.,
93:9821-9826 (1996); Xiong and Laird, Nucleic Acids Res., 25:2532-2534 (1997);
Eads et al., Nuc. Acids. Res., 28:e32 (2002); Cottrell et al., Nucleic Acids
Res.,
32:1-8 (2004).
Methylation-specific PCR (MSP) can rapidly assess the methylation status
of virtually any group of CpG sites within a CpG island, independent of the
use of
methylation-sensitive restriction enzymes. See, MSP; Herman et al., Proc.
Natl.
Acad Sci. USA, 93(18):9821-9826 (1996); Esteller et al., Cancer Res., 59:793-
797
(1999)) see also U.S. Pat. No. 5,786,146, issued Jul. 28, 1998; U.S. Pat. No.
6,017,704, issued Jan. 25, 2000; U.S. Pat. No. 6,200,756, issued Mar. 13,
2001;
and U.S. Pat. No 6,265,171, issued Jul. 24, 2001; U.S. Pat. No. 6,773,897
issued
Aug. 10, 2004; the entire contents of each of which is incorporated herein by
reference. The MSP assay entails initial modification of DNA by sodium
bisulfite,
converting all unmethylated, but not methylated, cytosines to uracil, and
subsequent amplification with primers specific for methylated versus
unmethylated
DNA. MSP requires only small quantities of DNA, is sensitive to 0.1%
methylated alleles of a given CpG island locus, and may be performed on DNA
extracted from paraffin-embedded samples. MSP eliminates the false positive
results inherent to previous PCR-based approaches that relied on differential
restriction enzyme cleavage to distinguish methylated from unmethylated DNA.
This method is very simple and can be used on small amounts of tissue or a few
cells. As would be understood by those skilled in the art, if the gene
encoding
MGMT is not methylated, the MGMT protein is expressed and can be detected
(e.g., by Western blot, immuno-histochemical techniques or enzymatic assays
for
MGMT activity, etc.) as detailed below herein.
An illustrative example of a Western blot assay useful for this embodiment
of the invention to measure the level of MGMT protein in patient samples is
presented in U.S. Pat. No. 5,817,514 by Li et al., the entire disclosure of
which is
incorporated herein by reference. Li et al. described monoclonal antibodies
able to
specifically bind either to native human MGMT protein or to human MGMT
protein having an active site which is alkylated.
CA 02610439 2007-09-25
An illustrative example of an immunohistochemical technique useful for
this embodiment of the invention to measure the level of MGMT protein in
patient
samples is presented in U.S. Pat. No. 5,407,804, the entire disclosure of
which is
incorporated herein by reference. Monoclonal antibodies are disclosed which
are
able to specifically bind to the MGMT protein in single cell preparations
(immunohistochemical staining assays) and in cell-extracts (immunoassays). The
use of fluorescent read out coupled with digitization of the cell image is
described
and allows for quantitative measurement of MGMT levels in patient and control
samples, including but not limited to tumor biopsy samples.
Useful techniques for measuring the enzymatic acitivity of MGMT protein
include but are not limited to methods described by: Myrnes et al.,
Carcinogenesis,
5:1061-1064 (1984); Futscher et al., Cancer Comm., 1: 65-73 (1989); Kreklaw et
al., J. Pharmacol. Exper. Ther., 297(2):524-530 (2001); and Nagel et al.,
Anal.
Biochem., 321(1):38-43 (2003), the entire disclosures of which are
incorporated
herein in their entireties.
The level of MGMT protein expressed in a sample obtained from a patient
may be assessed by measuring MGMT protein, e.g., by Western blot using an
antibody specific to MGMT, see for example, U.S. Pat. No. 5,817,514. The level
of MGMT expressed in a sample may also be assessed by measuring the MGMT
protein using an immunohistochemistry technique on a defined number of patient
cells, e.g., employing a labeled antibody specific for MGMT and comparing the
level with that expressed by the same defined number of normal lymphocytes
known to express MGMT (see, for example, U.S. Pat. No. 5,407,804 by Yarosh for
a description of useful quantitative immunohistochemical assays).
Alternatively,
the level of MGMT may be assessed by enzymatic assay, i.e., the ability to
methylate the 06 or N7 guanine position of DNA. In each of these methods, the
measured level of MGMT protein expressed is compared to that expressed by
normal lymphocytes known to express MGMT. Patient MGMT protein levels are
classified as follows: Low=0-30% of the MGMT expressed by normal
lymphocytes; Moderate=31-70% of the MGMT expressed by normal lymphocytes;
and High=71-300% or higher of the MGMT expressed by normal lymphocytes.
Patient MGMT levels are classified as follows: Low=0-30% of the MGMT
21
CA 02610439 2007-09-25
enzymatic activity of normal lymphocytes; Moderate=31-70% of the MGMT
enzymatic activity of normal lymphocytes; and High=71-300% or higher of the
MGMT enzymatic activity of normal lymphocytes.
The specific activity of MGMT may be assessed and based on a
comparison with cell lines known to express MGMT classified as follows:
Low=less than 20 finol/mg; Moderate=20-60 finol/mg; or High=greater than 60
finol/mg; where the specific activity of MGMT in LOX cells is 6-9 frnol/mg, in
DAOY cells is 60-100 fmol/mg, and in A375 cells is 80-150 finol/mg.
The level of methylation of MGMT may be assessed by quantitative
determination of the methylation of the gene encoding MGMT. The quantitative
technique called COBRA (Xiong et al., Nuc. Acids Res., 25:2532-2534 (1997))
may be used in this determination. The "methyl light" technique of Eads et
al.,
Nuc. Acids Res., 28(8):e32 (2000); U.S. Pat. No. 6,331,393 may also be used.
The
level of methylation of gene encoding MGMT in cells of the patient is compared
to
that of an equivalent number of cells of nonnal lymphocytes known to express
MGMT. As would be understood by those skilled in the art, nonmal lymphocytes
expressing MGMT have a low level of methylation of the MGMT gene;
conversely, cells with high levels of methylation of the MGMT gene express low
levels of the MGMT protein (see for example, Costello et al., J. Biol. Chem.,
269(25):17228-17237 (1994); Qian et al., Carcinogen, 16(6):1385-1390 (1995)).
Patient methylated MGMT gene levels are classified as follows: Low=0-20% of
the CpGs in the promoter region of the MGMT gene are methylated;
Moderate=21-50% of the CpGs in the promoter region of the MGMT gene are
methylated; and High=51-100% of the CpGs in the promoter region of the MGMT
gene are methylated.
COBRA may be used to determine quantitatively DNA methylation levels
at specific gene loci in small amounts of genomic DNA. Restriction enzyme
digestion is used to reveal methylation-dependent sequence differences in PCR
products of sodium bisulfite-treated DNA. (Tano et al., Proc. Natl. Acad. Sci.
USA, 87:686-690 (1990) describe isolation and sequence of the human MGMT
gene). Methylation levels in original DNA sample are represented by the
relative
amounts of digested and undigested PCR product in a linearly quantitative
fashion
22
CA 02610439 2007-09-25
across a wide spectrum of DNA methylation levels. This technique may be
reliably applied to DNA obtained from microdissected paraffin-embedded tissue
samples. COBRA thus combines the powerful features of ease of use,
quantitative
accuracy, and compatibility with paraffin sections.
An illustrative example of a RT-PCR assay useful for assessing the level of
MGMT mRNA is described in Watts et al., Mol. Cell. Biol., 17(9):5612-5619
(1997). In brief, total cellular RNA is isolated by guanidium isothiocyanate
cell
lysis followed by centrifugation through a 5.7 M CsCI gradient for 2.5 hr at
205,000xg. RNA is quantitated in a Beckman TL-100 spectrophotometer by
measurements of absorbance at 260 nm. Total cellular RNA is reverse
transcribed
by incubating a 40 l reaction mixture composed of 200 ng of RNA; 1 xPCR
buffer
(10 mM Tris [pH 8.3], 50 mM KCI, 1.5 mM MgC12); 1 mM each dATP, dCTP,
dGTP, and dTTP; 200 pmol of random hexamer, 40 U of RNasin, and 24 U of
avian myeloblastosis virus reverse transcriptase (Boehringer Mannheim,
Indianapolis, Ind.) at 42 C for 60 min. The reaction is then stopped by
incubation
at 99 C for 10 min. MGMT-specific PCR is performed by adding 80 l of
amplification reaction buffer (lx PCR buffer, 25 pmol of MGMT-specific primers
and/or a control sequence, and 2 U of Taq DNA polymerase) to 20 l of the
reverse transcription reaction mixture followed by incubation at 94 C for 5
min;
30 cycles of 94 C. for 1 min, 60 C for 15 s, and 72 C. for 1 min; a final
extension
at 72 C. for 5 min; and a quick chill to 4 C. For example, the upstream
primer
sequence from exon 4 (nt 665 to 684) of the MGMT gene can be used. Nucleotide
positions can be derived from the cDNA sequence (Tano et al., Proc. Natl.
Acad.
Sci. USA, 87:686-690 (1990)). A control primer sequence can be employed in the
same cDNA reaction (e.g., primers for the histone 3.3 gene). For analysis, 10%
of
the respective PCR products are separated through a 3% agarose gel and
visualized
by ethidium bromide staining.
Methods Of Treating A Patient With A Glioma Based UQon Methylation State Of
MGMT Gene
The unit dosage forms of the present invention are used to treat a patient
having a glioma. In some embodiments, the dosing regimen is based upon the
23
CA 02610439 2007-09-25
~detection of methylated MGMT gene in a sample. When methylation of the
MGMT gene is detected in a sample obtained from a patient having a glioma, the
dosing regimen is 150-200 mg/m2 per day for 5 days in a 28 day cycle. When
methylation is not detected, the dosing regimen is (i) 100 mg/m2 per day for
14
days in a 21 day cycle; (ii) 150 mg/m2 per day for 7 days in a 14 day cycle;
or (iii)
100 mg/m2 per day for 21 days in a 28 day cycle. In some embodiments, the
sample is a tumor biopsy sample. In some embodiments, the MGMT gene is
detected using MSP.
In other embodiments, the dosing regimen is based upon the presence or
absence of MGMT protein. In those embodiments basedupon the presence or
absence of the MGMT protein, when the MGMT protein is not detected in a
sample obtained from a patient having a glioma, the dosing regimen is 150-200
mg/m2 per day for 5 days in a 28 day cycle; when the MGMT protein is detected,
the dosing regimen is selected from (i) 100 mg/m2 per day for 14 days in a 21
day
cycle; 150 mg/m2 per day for 7 days in a 14 day cycle; or (iii) 100 mg/mZ per
day
for 21 days in a 28 day cycle. In some embodiments, the sample is a tumor
biopsy
sample. In some embodiments, the MGMT protein is detected using Western blot
immunoassay, an immunohistochemical technique, or an enzymatic assay for
MGMT protein.
In yet other embodiments, the dosing regimen is based upon the level or
activity of the MGMT protein detected in a sample. When the level or enzymatic
activity of the MGMT protein detected in a sample obtained from the patient is
Low, compared to that of normal lymphocytes, the dosing regimen is (i) 150-200
mg/m2 per day for 5 days in a 28 day cycle; or (ii) 250 mg/mz per day for 5
days in
a 28 day cycle in combination with a growth factor. When the level or
enzymatic
activity of the MGMT protein is Moderate, the dosing regimen is (i) 100 mg/m2
per day for 14 days in a 28 day cycle; (ii) 300 mg/mZ per day for 5 days in a
28 day
cycle in combination with a growth factor; (iii) 75 mg/m2 per day for 21 days
in a
28 day cycle; or (iv) 75 mg/m2 per 42 days in a 56 day cycle. When the level
or
enzymatic activity of the MGMT protein detected in a sample obtained from the
patient is High, the dosing regimen is selected from (i) 100 mg/m2 per day for
14
days in a 21 day cycle; (ii) 150 mg/mz per day for 7 days in a 14 day cycle;
or (iii)
24
CA 02610439 2007-09-25
~ ,.
100 mg/mz per day for 21 days in a 28 day cycle. In some embodiments, the
sample is a tumor biopsy sample.
Methods Of Treating A Patient With Certain Proliferative Disorders Based Upon
Methylation State Of MGMT Gene
In some embodiments, the unit dosage forms are used to treat patients
having a proliferative disorder selected from melanoma, lung cancer, lymphoma,
head cancer, neck cancer, ovarian cancer, colorectal cancer, colon cancer and
esophogeal cancer. In some embodiments, the dosing regimen is based upon the
detection of methylated MGMT gene in a sample. When methylation of the
MGMT gene is not detected in a sample obtained from a patient, the dosing
regimen is (i) 100 mg/m2 per day for 14 days in a 21 day cycle; (ii) 150 mg/m2
per
day for 7 days in a 14 day cycle; or (iii) 100 mg/m2 per day for 21 days in a
28 day
cycle. In some embodiments, the sample is a tumor biopsy sample. In some
embodiments, the MGMT gene is detected using MSP.
In other embodiments, the dosing regimen is based upon the detection of
MGMT protein in a sample. When the MGMT protein is not detected, the dosing
regimen is selected from (i) 100 mg/mz per day for 14 days in a 21 day cycle;
150
mg/mz per day for 7 days in a 14 day cycle; or (iii) 100 mg/mz per day for 21
days
in a 28 day cycle. In some embodiments, the sample is a tumor biopsy sample.
In
some embodiments, the MGMT protein is detected using Western blot
immunoassay, an immunohistochemical technique, or an enzymatic assay for
MGMT protein.
In yet other embodiments, the dosing regimen is based upon the level or
activity of the MGMT protein detected in a sample. When the level or enzymatic
activity of the MGMT protein detected in a sample obtained from the patient is
Low or Moderate, compared to that of normal lymphocytes, the dosing regimen is
(i) 100 mg/mZ per day for 14 days in a 21 day cycle; (ii) 150 mg/m2 per day
for 7
days in a 14 day cycle; or (iii) 100 mg/m2 per day for 21 days in a 28 day
cycle. In
some embodiments, the sample is a tumor biopsy sample.
CA 02610439 2007-09-25
~~ .
Kits Comprising The Unit Dosage Forms Of The Present Invention
The unit dosage forms of the present invention may be included in a kit.
The kit may be in any conventional shape or form as known in the art which is
made of a pharmaceutically acceptable material, for example a paper or
cardboard
box, a glass or plastic bottle or, jar, a re-sealable bag (for example, to
hold a "refill"
of tablets for placement into a different container), or metal or plastic
foil, such as
a blister pack with individual doses for pressing out of the pack or a sachet
or
envelope-like container that may be ripped open to release the unit dosage
form
according to a therapeutic schedule. In some embodiments, the kit is a blister
pack. In other embodiments, the kit may include more than one container to
market a single dosage form. For example, capsules or tablets may be contained
in
a bottle, which is in turn contained within a box. In some embodiments, the
kit is
air-tight. In some embodiments, the kit is made from a light resistant
material.
In some embodiments, the kit comprise one or more unit dosage forms
comprising about 5, 20, 100 140 or 180 mg of temozolomide. In some
embodiments, the kit is a blister pack. The different dosage forms may be
arranged in the form of capsules, tablets or pills in rows lying next to one
another
in the blister pack. At the time indicated by the physician, the patient would
in
each case successively take a capsule, tablet or pill from each row within a
short
length of time (in particular within 5 minutes).
In some embodiments, the kit may be an FDA approved kit. In some
embodiments, the kit is accompanied by instructions for administration. The
kit
may also be accompanied by a notice associated with the container in a form
prescribed by a governmental agency regulating the manufacture, use or sale of
pharmaceuticals, which notice is reflective of approval by the agency of the
form
of the compositions or of human or veterinary administration. Such notice, for
example, may be of the labeling approved by the U.S. Food and Drug
Administration for prescription drugs or of an approved product insert. The
unit
dosage forms may also be prepared, placed in an appropriate container, and
labeled
for treatment of an indicated condition.
26
CA 02610439 2007-09-25
r- (
In order that this invention be more fully understood, the following
example are set forth. This example is for the purpose of illustration only
and is
not to be construed as limiting the scope of the invention in any way.
EXAMPLE
Patients with glioma were enrolled in a clinical trial to receive treatment
with temozolomide. The drug was administered at a dosage of 75 mg/m2, 150
mg/m2 or 200 mg/mZ using only the currently available suggested capsule
combinations of Table 6 ie. 5, 20 and 100 mg capsules. The daily dosage was
determined by the patient's BSA. The majority of the patients enrolled in the
trial
had BSAs ranging from 1.8 to 2.0 (149 out of 284). Upon reviewing the data
regarding the pill burden, the present inventors unexpectedly discovered that
adding unit dosages of about 140 and/or 180 mg of temozolomide would be
beneficial to reduce patient pill burden. See Table 7.
As shown in Table 7, the pill burden would be decreased for patients
receiving the unit dosage fonms of the present invention in 16 of the 24
possible
dosing regimens. The decreased pill burden would be especially significant in
patients having a BSA between 1.8-2Ø For these patients, the pill burden
would
be decreased in 6 of the possible 8 regimens.
27
CA 02610439 2007-09-25
Table 7.
BSA Number of Patients Number of Dosing Regimens
Lower Same Higher
1.4 6 -- -- --
1.5 9 1 2 0
1.6 23 2 1 0
1.7 40 1 1 1
1.8 40 1 1 1
1.9 66 3 0 0
2.0 43 2 1 0
2.1 26 3 0 0
2.2 21 3 0 0
2.3 5 -- -- --
2.4 4 -- -- --
2.5 1 -- -- --
28
