U.S. patent application number 16/712148 was filed with the patent office on 2020-12-03 for treatment of gliomas using organonitro compound combination therapy.
The applicant listed for this patent is EpicentRx, Inc.. Invention is credited to Bryan T. Oronsky, Jan Scicinski.
Application Number | 20200375982 16/712148 |
Document ID | / |
Family ID | 1000005021359 |
Filed Date | 2020-12-03 |
![](/patent/app/20200375982/US20200375982A1-20201203-C00001.png)
![](/patent/app/20200375982/US20200375982A1-20201203-C00002.png)
![](/patent/app/20200375982/US20200375982A1-20201203-D00001.png)
![](/patent/app/20200375982/US20200375982A1-20201203-D00002.png)
![](/patent/app/20200375982/US20200375982A1-20201203-D00003.png)
![](/patent/app/20200375982/US20200375982A1-20201203-D00004.png)
![](/patent/app/20200375982/US20200375982A1-20201203-D00005.png)
![](/patent/app/20200375982/US20200375982A1-20201203-D00006.png)
![](/patent/app/20200375982/US20200375982A1-20201203-D00007.png)
![](/patent/app/20200375982/US20200375982A1-20201203-D00008.png)
United States Patent
Application |
20200375982 |
Kind Code |
A1 |
Oronsky; Bryan T. ; et
al. |
December 3, 2020 |
TREATMENT OF GLIOMAS USING ORGANONITRO COMPOUND COMBINATION
THERAPY
Abstract
The invention provides therapeutic methods and kits for treating
a glioma using a particular dosing regimen of the organonitro
compound ABDNAZ, radiation therapy, and one of temozolomide,
irinotecan, or bevacizumab.
Inventors: |
Oronsky; Bryan T.; (Los
Altos Hills, CA) ; Scicinski; Jan; (Saratoga,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
EpicentRx, Inc. |
La Jolla |
CA |
US |
|
|
Family ID: |
1000005021359 |
Appl. No.: |
16/712148 |
Filed: |
December 12, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15989862 |
May 25, 2018 |
10543208 |
|
|
16712148 |
|
|
|
|
15337378 |
Oct 28, 2016 |
9987270 |
|
|
15989862 |
|
|
|
|
62247846 |
Oct 29, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/397 20130101;
A61K 31/4745 20130101; A61K 9/0019 20130101; A61K 9/0053 20130101;
A61N 5/10 20130101; A61K 31/495 20130101 |
International
Class: |
A61K 31/495 20060101
A61K031/495; A61K 31/397 20060101 A61K031/397; A61K 9/00 20060101
A61K009/00; A61K 31/4745 20060101 A61K031/4745 |
Claims
1. A method of treating a glioma in a patient, comprising the steps
of: (a) administering to the patient in need thereof a
therapeutically effective amount of a formulation comprising
temozolomide, and within about 2 days thereafter subjecting the
glioma to radiation therapy; and (b) administering to the patient
at least one dose of a therapeutically effective amount of a
formulation comprising ABDNAZ within about 7 days of administration
of a first dose of the temozolomide; to treat the glioma; wherein
each dose of the formulation comprising ABDNAZ is administered to
the patient by intravenous infusion providing ABDNAZ in an amount
of from about 0.1 mg to about 20 mg.
2. The method of claim 1, wherein the formulation comprising
temozolomide is administered daily for at least 2 weeks.
3.-5. (canceled)
6. The method of claim 1, wherein the patient receives temozolomide
by oral administration at a daily dose of at least 50
mg/m.sup.2.
7.-8. (canceled)
9. The method of claim 1, wherein for a duration of at least 2
weeks following administration of the first dose of temozolomide,
the patient receives at least one dose each week of a
therapeutically effective amount of a formulation comprising
ABDNAZ.
10.-11. (canceled)
12. The method of claim 1, wherein two doses of a therapeutically
effective amount of a formulation comprising ABDNAZ are
administered within about 7 days of administration of the first
dose of temozolomide.
13. The method of claim 1, wherein for a duration of at least 2
weeks following administration of the first dose of temozolomide,
the patient receives two doses each week of a therapeutically
effective amount of a formulation comprising ABDNAZ.
14.-35. (canceled)
36. The method of claim 1, wherein the formulation comprising
ABDNAZ contains dimethylacetamide, water, and a polyethylene
glycol.
37. The method of claim 36, wherein the polyethylene glycol has a
number-average molecular weight of about 400 g/mol.
38. The method of claim 1, wherein the glioma is subjected to
radiation therapy once per day for at least 3 days within a 7 day
period following administration of the first dose of
temozolomide.
39. The method of claim 1, wherein the glioma is subjected to
radiation therapy once per day for at least 5 days within a 7 day
period following administration of the first dose of
temozolomide.
40.-47. (canceled)
48. The method of claim 1, wherein when radiation therapy is
administered to the glioma, the amount of radiation provided to the
glioma on the day of administering the radiation therapy is from
about 1 Gy to about 3 Gy.
49.-52. (canceled)
53. The method of claim 1, wherein after receiving temozolomide for
a duration of 6 weeks, the patient does not receive any of
temozolomide, radiation therapy, or ABDNAZ for a duration of at
least about 2 weeks.
54.-56. (canceled)
57. The method of claim 1, wherein after receiving temozolomide for
a duration of 6 weeks, the patient does not receive any of
temozolomide, radiation therapy, or ABDNAZ for a duration of at
least about 4 weeks.
58.-68. (canceled)
69. A method of treating a glioma in a patient, comprising the
steps of: (a) administering to the patient in need thereof a
therapeutically effective amount of a formulation comprising
irinotecan, and within about 7 days subjecting the glioma to
radiation therapy; and (b) administering to the patient at least
one dose of a therapeutically effective amount of a formulation
comprising ABDNAZ within about 7 days of administration of a first
dose of the irinotecan; to treat the glioma; wherein each dose of
the formulation comprising ABDNAZ is administered to the patient by
intravenous infusion providing ABDNAZ in an amount of from about
0.1 mg to about 20 mg.
70.-107. (canceled)
108. The method of claim 69, wherein the glioma is an
astrocytoma.
109. The method of claim 69, wherein the glioma is a malignant
astrocytoma.
110. The method of claim 69, wherein the glioma is a
glioblastoma.
111.-112. (canceled)
113. The method of claim 69, wherein the patient is an adult
human.
114.-115. (canceled)
116. The method of claim 69, wherein there is at least a 35%
reduction in the size of at least one glioma tumor in the
patient.
117.-118. (canceled)
119. The method of claim 69, wherein there is at least a 35%
reduction in the number of glioma tumors in the patient.
120. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation patent application under
35 U.S.C. .sctn. 120 of U.S. patent application Ser. No.
15/989,862, filed on May 25, 2018, which is a continuation patent
application of U.S. patent application Ser. No. 15/337,378, filed
on Oct. 28, 2016, which claims the benefit of and priority to U.S.
Provisional Patent Application No. 62/247,846, filed on Oct. 29,
2015, the contents of each of which are hereby incorporated by
reference herein, in their entirety.
FIELD OF THE INVENTION
[0002] The invention provides therapeutic methods and kits for
treating a glioma using a particular dosing regimen of the
organonitro compound ABDNAZ, radiation therapy, and one of
temozolomide, irinotecan, or bevacizumab.
BACKGROUND
[0003] Gliomas are tumors that arise from glial tissue of the
brain. Gliomas are often found in the cerebral hemispheres of the
brain, but can be found anywhere in the brain. Because gliomas can
grow rapidly, common symptoms experienced by patients suffering
from a glioma are often associated with an increased pressure in
the brain. The symptoms can include headache, nausea, vomiting, and
drowsiness. In addition, patients suffering from a glioma may
develop other symptoms such as weakness on one side of the body,
memory and/or speech difficulties, and visual changes, often as
function of the location of the glioma tumor.
[0004] Gliomas can be characterized according to grade, where
low-grade gliomas [WHO grade II] are typically well-differentiated
and tend to exhibit benign tendencies. Low-grade gliomas stand in
contrast to high-grade gliomas [WHO grade III or IV] that are
typically undifferentiated and frequently malignant. One example of
a high-grade glioma is glioblastoma multiforme. Glioblastoma
multiforme has been characterized as a World Health Organization
grade IV astrocytoma, with an incidence in North America of 5.0 per
100,000 in the population, representing 15 to 20% of all primary
intracranial neoplasms.
[0005] Currently available therapeutic approaches for treating
patients suffering from a glioma include surgery, radiation
therapy, and treatment with certain anti-cancer agents. A typical
first step in treating a glioblastoma is to surgically remove as
much tumor as possible. This can help alleviate pressure on the
brain. However, glioblastomas often have finger-like tentacles, and
as a result it can be difficult to completely remove all the
glioblastoma. This is particularly true when a glioblastoma appears
near parts of the brain that control important functions, such as
language and coordination. Radiation and chemotherapy may be used
to help slow the growth of glioblastoma tumors that cannot be
removed with surgery. However, survival rates are low using current
standard treatments for glioblastoma. For example, using standard
treatments currently approved by government regulatory agencies,
the median survival time for adults with an anaplastic astrocytoma
has been reported to be about two to three years. For children
suffering from a high-grade glioma tumor (grade III or IV), the
five-year survival rate has been reported to be about twenty-five
percent.
[0006] As a result, there is a need for additional therapies to
treat patients suffering from a glioma. The present invention
addresses this need and provides other related advantages.
SUMMARY
[0007] The invention provides therapeutic methods and kits for
treating a glioma using a particular dosing regimen of the
organonitro compound ABDNAZ, radiation therapy, and one of
temozolomide, irinotecan, or bevacizumab. The compound ABDNAZ has
the following chemical structure:
##STR00001##
[0008] The therapeutic methods and kits provide a solution to the
long unmet need for a more effective treatment for patients
suffering from a glioma. The therapeutic method generally entails
(a) administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising temozolomide,
irinotecan, or bevacizumab, and within a certain amount of time
(e.g., about 7 days) subjecting the glioma to radiation therapy,
and (b) administering to the patient at least one dose of a
therapeutically effective amount of a formulation comprising ABDNAZ
within about 7 days of administration of a first dose of the
temozolomide, irinotecan, or bevacizumab, in order to treat the
glioma. In preferred embodiments, the radiation therapy may be
administered to the patient for a select number of days (e.g., at
least 2, 3, 4, or 5 days) over a two-week period, or longer
duration of time depending on patient response to the therapy. In
preferred embodiments, the formulation comprising ABDNAZ may be
administered to the patient for a select number of days per week
(e.g., at least 2, 3, or 4 days per week) over a two-week period,
or longer duration of time depending on patient response to the
therapy. The therapy may be used to treat various types of gliomas,
such as, for example, a primary glioblastoma or a secondary
glioblastoma. The invention having been generally described is
explained in more detail in the aspects and embodiments below and
in the detailed description.
[0009] Accordingly, one aspect of the invention provides a method
of treating a glioma in a patient. The method comprises the steps
of: (a) administering to the patient in need thereof a
therapeutically effective amount of a formulation comprising
temozolomide, and within about 2 days thereafter subjecting the
glioma to radiation therapy; and (b) administering to the patient
at least one dose of a therapeutically effective amount of a
formulation comprising ABDNAZ within about 7 days of administration
of a first dose of the temozolomide; to treat the glioma.
[0010] Another aspect of the invention provides a method of
treating a glioma in a patient. The method comprises the steps of:
(a) administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising irinotecan, and within
about 7 days subjecting the glioma to radiation therapy; and (b)
administering to the patient at least one dose of a therapeutically
effective amount of a formulation comprising ABDNAZ within about 7
days of administration of a first dose of the irinotecan; to treat
the glioma.
[0011] Another aspect of the invention provides a method of
treating a glioma in a patient. The method comprises the steps of:
(a) administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising bevacizumab, and
within about 7 days subjecting the glioma to radiation therapy; and
(b) administering to the patient at least one dose of a
therapeutically effective amount of a formulation comprising ABDNAZ
within about 7 days of administration of a first dose of the
bevacizumab; to treat the glioma.
[0012] Another aspect of the invention provides a kit for treating
a glioma. In certain embodiments, the kit comprises: (i) a
formulation comprising ABDNAZ, and (ii) instructions for treating a
glioma according to procedures described herein, such as (a)
administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising temozolomide, and
within about 2 days thereafter subjecting the glioma to radiation
therapy; and (b) administering to the patient at least one dose of
a therapeutically effective amount of a formulation comprising
ABDNAZ within about 7 days of administration of a first dose of the
temozolomide; to treat the glioma. In an alternative embodiment,
the kit comprises: (i) a formulation comprising ABDNAZ, and (ii)
instructions for treating a glioma that comprise (a) administering
to the patient in need thereof a therapeutically effective amount
of a formulation comprising irinotecan, and within about 7 days
subjecting the glioma to radiation therapy; and (b) administering
to the patient at least one dose of a therapeutically effective
amount of a formulation comprising ABDNAZ within about 7 days of
administration of a first dose of the irinotecan; to treat the
glioma.
BRIEF DESCRIPTION OF THE FIGURES
[0013] FIG. 1 is a graph showing response observed using a GBM14
TMZ-S patient-derived cell line, as described in Example 3.
[0014] FIG. 2 is a graph showing response observed using a GBM14
TMZ-R patient-derived cell line, as described in Example 3.
[0015] FIG. 3 is a graph showing response observed using cells from
temozolomide-resistant murine EGFRvIII/Arfko neural stem
cell-derived glioma (NSCG) cell line, as described in Example
4.
[0016] FIG. 4 is a graph showing percent survival of subjects over
time, in the experiment in which treatment (i.e., administration of
ABDNAZ (RRx-001), temozolomide (TMZ), or both ABDNAZ and
temozolomide) was started five days after intracranial injection of
NSCG cells, as described in Example 5.
[0017] FIG. 5 is a graph showing percent survival of subjects over
time, in the experiment in which treatment (i.e., administration of
ABDNAZ (RRx-001), temozolomide (TMZ), or both ABDNAZ and
temozolomide) was started ten days after intracranial injection of
NSCG cells, as described in Example 5.
[0018] FIG. 6 is a graph showing the amount of CC3+ cell apoptosis
detected in the assay, as described in Example 6.
[0019] FIG. 7 is a graph showing the amount of TMZ (mg) detected
per gram of tissue analyzed, as described in Example 7.
[0020] FIG. 8 is a graph showing the amount of irinotecan (.mu.g)
detected per milligram of tissue analyzed, as described in Example
8.
DETAILED DESCRIPTION
[0021] The invention provides therapeutic methods and kits for
treating a glioma using a particular dosing regimen of the
organonitro compound ABDNAZ, radiation therapy, and one of
temozolomide, irinotecan, or bevacizumab. The compound ABDNAZ has
the following chemical structure:
##STR00002##
[0022] The therapeutic methods and kits provide a solution to the
long unmet need for a more effective treatment for patients
suffering from a glioma. The therapeutic method generally entails
(a) administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising temozolomide,
irinotecan, or bevacizumab, and within a certain amount of time
(e.g., about 7 days) subjecting the glioma to radiation therapy,
and (b) administering to the patient at least one dose of a
therapeutically effective amount of a formulation comprising ABDNAZ
within about 7 days of administration of a first dose of the
temozolomide, irinotecan, or bevacizumab, in order to treat the
glioma. In preferred embodiments, the radiation therapy may be
administered to the patient for a select number of days (e.g., at
least 2, 3, 4, or 5 days) over a two-week period, or longer
duration of time depending on patient response to the therapy. In
preferred embodiments, the formulation comprising ABDNAZ may be
administered to the patient for a select number of days per week
(e.g., at least 2, 3, or 4 days per week) over a two-week period,
or longer duration of time depending on patient response to the
therapy. The therapy may be used to treat various types of gliomas,
such as, for example, a primary glioblastoma or a secondary
glioblastoma.
[0023] Various aspects of the invention are set forth below in
sections; however, aspects of the invention described in one
particular section are not to be limited to any particular
section.
I. Therapeutic Methods for Treating a Glioma
[0024] The invention provides therapeutic methods for treating a
glioma using a particular dosing regimen of the organonitro
compound ABDNAZ, radiation therapy, and one of temozolomide,
irinotecan, or bevacizumab. The therapeutic methods provide a
solution to the long unmet need for a more effective treatment for
patients suffering from a glioma. The therapeutic method generally
entails (a) administering to the patient in need thereof a
therapeutically effective amount of a formulation comprising
temozolomide, irinotecan, or bevacizumab, and within a certain
amount of time (e.g., about 7 days) subjecting the glioma to
radiation therapy, and (b) administering to the patient at least
one dose of a therapeutically effective amount of a formulation
comprising ABDNAZ within about 7 days of administration of a first
dose of the temozolomide, irinotecan, or bevacizumab, in order to
treat the glioma.
[0025] The invention also provides methods for increasing the
amount of temozolomide, irinotecan, or bevacizumab in a glioma. The
method generally involves administering to a patient having a
glioma (i) a first formulation comprising temozolomide, irinotecan,
or bevacizumab and (ii) an effective amount of a formulation
comprising ABDNAZ so that the ABDNAZ exerts physiological activity
during a time period in which the temozolomide, irinotecan, or
bevacizumab is present in the patient, in order to increase the
amount of the temozolomide, irinotecan, or bevacizumab in the
glioma.
[0026] Various features of the methods are described in sections
below. The sections are arranged for convenience and information in
one section is not limited to that section, but may be applied to
other sections.
First Method--Using Temozolomide
[0027] One aspect of the invention provides a method of treating a
glioma in a patient. The method comprises the steps of: (a)
administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising temozolomide, and
within about 2 days thereafter subjecting the glioma to radiation
therapy; and (b) administering to the patient at least one dose of
a therapeutically effective amount of a formulation comprising
ABDNAZ within about 7 days of administration of a first dose of the
temozolomide; to treat the glioma.
[0028] Temozolomide is a small molecule having the chemical name
3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide,
which is marketed commercially under the tradename
TEMODAR.RTM..
Exemplary Features of the Method
[0029] The above method may be further characterized by additional
features, such as the dosing schedule and amount of temozolomide,
dosing schedule of ABDNAZ, dosing amount for ABDNAZ, features of
the radiation therapy, and the rest period/maintenance period.
Dosing Schedule and Amount of Temozolomide
[0030] The method can be further characterized according to the
dosing schedule and amount of the temozolomide. Accordingly, in
certain embodiments, the formulation comprising temozolomide is
administered daily for at least 2 weeks. In certain embodiments,
the formulation comprising temozolomide is administered daily for
at least 4 weeks. In certain embodiments, the formulation
comprising temozolomide is administered daily for at least 6 weeks.
In certain embodiments, the formulation comprising temozolomide is
administered at the patient's bedtime.
[0031] In certain embodiments, the patient receives temozolomide by
oral administration at a daily dose of at least 50 mg/m.sup.2. In
certain embodiments, the patient receives temozolomide by oral
administration at a daily dose of about 50 mg/m.sup.2 to about 100
mg/m.sup.2. In certain embodiments, the patient receives
temozolomide by oral administration at a daily dose of about 75
mg/m.sup.2.
Dosing Schedule of ABDNAZ
[0032] A formulation comprising ABDNAZ may be administered multiple
times, such as multiple times over a defined period of time.
Further, coordination of the dosing schedule of the temozolomide
and radiation therapy with that of the formulation comprising
ABDNAZ is contemplated to provide therapeutic benefits, such as
superior efficacy.
[0033] In certain embodiments, for a duration of at least 2 weeks
following administration of the first dose of temozolomide, the
patient receives at least one dose each week of a therapeutically
effective amount of a formulation comprising ABDNAZ. In certain
embodiments, for a duration of at least 4 weeks following
administration of the first dose of temozolomide, the patient
receives at least one dose each week of a therapeutically effective
amount of a formulation comprising ABDNAZ. In certain embodiments,
for a duration of at least 6 weeks following administration of the
first dose of temozolomide, the patient receives at least one dose
each week of a therapeutically effective amount of a formulation
comprising ABDNAZ. In certain embodiments, two doses of a
therapeutically effective amount of a formulation comprising ABDNAZ
are administered within about 7 days of administration of the first
dose of temozolomide. In certain embodiments, for a duration of at
least 2 weeks following administration of the first dose of
temozolomide, the patient receives two doses each week of a
therapeutically effective amount of a formulation comprising
ABDNAZ. In certain embodiments, for a duration of at least 4 weeks
following administration of the first dose of temozolomide, the
patient receives two doses each week of a therapeutically effective
amount of a formulation comprising ABDNAZ. In certain embodiments,
for a duration of at least 6 weeks following administration of the
first dose of temozolomide, the patient receives two doses each
week of a therapeutically effective amount of a formulation
comprising ABDNAZ.
[0034] In certain embodiments, for a duration of at least 2 weeks
following administration of the first dose of temozolomide, the
patient receives one dose each week of a therapeutically effective
amount of a formulation comprising ABDNAZ. In certain embodiments,
for a duration of at least 4 weeks following administration of the
first dose of temozolomide, the patient receives one dose each week
of a therapeutically effective amount of a formulation comprising
ABDNAZ. In certain embodiments, for a duration of at least 6 weeks
following administration of the first dose of temozolomide, the
patient receives one dose each week of a therapeutically effective
amount of a formulation comprising ABDNAZ. In certain embodiments,
for a duration of 6 weeks following administration of the first
dose of temozolomide, the patient receives one dose each week of a
therapeutically effective amount of a formulation comprising
ABDNAZ.
[0035] In certain embodiments, any dose of ABDNAZ administered to
the patient within 12 hours of administering temozolomide is
administered at least 3 hours before administering the
temozolomide.
[0036] In certain embodiments, the patient receives ABDNAZ within
about 3 hours prior to subjecting the glioma to radiation therapy.
In certain embodiments, the patient receives ABDNAZ within about 6
hours prior to subjecting the glioma to radiation therapy. In
certain embodiments, the patient receives ABDNAZ within about 24
hours prior to subjecting the glioma to radiation therapy. In
certain embodiments, the patient receives ABDNAZ within about 48
hours prior to subjecting the glioma to radiation therapy.
[0037] In certain embodiments, the formulation comprising ABDNAZ is
administered so that the ABDNAZ exerts physiological activity
during an overlapping time period with one or both of the radiation
therapy and temozolomide.
Dosing Amount of ABDNAZ
[0038] The method may be further a characterized according to the
dose of ABDNAZ administered to the patient. The dose of ABDNAZ
described herein for use in combination with temozolomide and the
radiation therapy has been selected in view of the dosing schedule
and amount of temozolomide and the radiation therapy. Dosing
amounts of ABDNAZ are provided according to the number of
milligrams of ABDNAZ to be administered to the patient based on the
surface area of the patient as measured in m.sup.2.
[0039] In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount ranging from about 2
mg/m.sup.2 to about 20 mg/m.sup.2. In certain embodiments, each
dose of the formulation comprising ABDNAZ is administered to the
patient by intravenous infusion providing ABDNAZ in an amount
ranging from about 2.5 mg/m.sup.2 to about 5 mg/m.sup.2. In certain
embodiments, each dose of the formulation comprising ABDNAZ is
administered to the patient by intravenous infusion providing
ABDNAZ in an amount ranging from about 5 mg/m.sup.2 to about 10
mg/m.sup.2. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount ranging from about 10
mg/m.sup.2 to about 16.5 mg/m.sup.2. In certain embodiments, each
dose of the formulation comprising ABDNAZ is administered to the
patient by intravenous infusion providing ABDNAZ in an amount of
about 2.5 mg/m.sup.2. In certain embodiments, each dose of the
formulation comprising ABDNAZ is administered to the patient by
intravenous infusion providing ABDNAZ in an amount of about 5
mg/m.sup.2. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of about 10 mg/m.sup.2. In
certain embodiments, each dose of the formulation comprising ABDNAZ
is administered to the patient by intravenous infusion providing
ABDNAZ in an amount of about 16.5 mg/m.sup.2.
[0040] In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of from about 0.1 mg to
about 20 mg. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of from about 0.1 mg to
about 10 mg. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of from about 0.5 mg to
about 4.0 mg. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of about 0.5 mg, 1.0 mg, 1.5
mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, or 4.0 mg.
Radiation Therapy Features
[0041] The method can be further characterized according to the
dosing schedule and amount of radiation administered for the
radiation therapy.
[0042] In certain embodiments, the glioma is subjected to radiation
therapy once per day for at least 3 days within a 7 day period
following administration of the first dose of temozolomide. In
certain embodiments, the glioma is subjected to radiation therapy
once per day for at least 5 days within a 7 day period following
administration of the first dose of temozolomide. In certain
embodiments, for a duration of at least 2 weeks following
administration of the first dose of temozolomide, the glioma is
subjected to radiation therapy once per day for at least 3 days of
each week. In certain embodiments, for a duration of at least 4
weeks following administration of the first dose of temozolomide,
the glioma is subjected to radiation therapy once per day for at
least 3 days of each week. In certain embodiments, for a duration
of at least 6 weeks following administration of the first dose of
temozolomide, the glioma is subjected to radiation therapy once per
day for at least 3 days of each week. In certain embodiments, for a
duration of at least 2 weeks following administration of the first
dose of temozolomide, the glioma is subjected to radiation therapy
once per day for at least 5 days of each week. In certain
embodiments, for a duration of at least 4 weeks following
administration of the first dose of temozolomide, the glioma is
subjected to radiation therapy once per day for at least 5 days of
each week. In certain embodiments, for a duration of at least 6
weeks following administration of the first dose of temozolomide,
the glioma is subjected to radiation therapy once per day for at
least 5 days of each week. In certain embodiments, for a duration
of at least 6 weeks following administration of the first dose of
temozolomide, the glioma is subjected to radiation therapy once per
day for 5 days each week. In certain embodiments, for a duration of
6 weeks following administration of the first dose of temozolomide,
the glioma is subjected to radiation therapy once per day for 5
days each week.
[0043] In certain embodiments, when radiation therapy is
administered to the glioma, the amount of radiation provided to the
glioma on the day of administering the radiation therapy is from
about 1 Gy to about 3 Gy. In certain embodiments, when radiation
therapy is administered to the glioma, the amount of radiation
provided to the glioma on the day of administering the radiation
therapy is about 2 Gy. In certain embodiments, the glioma is
exposed to from about 50 Gy to about 70 Gy of radiation by the
radiation therapy over a period of 6 weeks following administration
of the first dose of temozolomide. In certain embodiments, the
glioma is exposed to about 60 Gy of radiation by the radiation
therapy over a period of 6 weeks following administration of the
first dose of temozolomide.
[0044] In certain embodiments, the radiation therapy is (i)
conventional fractionated external beam radiation or (ii)
intensity-modulated radiation therapy. In certain embodiments, the
radiation therapy is conventional fractionated external beam
radiation.
[0045] Various types of radiation therapy are used by those skilled
in the art and have been described in the literature. Exemplary
types of radiation therapy include, for example, radiation therapy
comprising gamma rays, X-rays, electron beams, neutron beams,
particulate radiation, proton beams, or the like. The source of the
radiation is desirably external to the patient, which involves
directing a beam of high-energy radiation to the glioma using a
machine external to the patient. Desirably the target site (i.e.,
site of the glioma) is exposed to the radiation therapy for a short
duration of time, such as less than about 3 hours, 2 hours, 1 hour,
30 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute for each
dose of radiation therapy.
Rest Period/Maintenance Period
[0046] The method may be further characterized according to the
scope of the rest period/maintenance period. For example, in
certain embodiments, after receiving temozolomide for a duration of
6 weeks, the patient does not receive any of temozolomide,
radiation therapy, or ABDNAZ for a duration of at least about 2
weeks.
[0047] In certain embodiments, the patient after having not
received any of temozolomide, radiation therapy, or ABDNAZ for a
duration of at least about 2 weeks, then receives (i) a
therapeutically effective amount of a formulation comprising
temozolomide on at least three days during the first week, and (ii)
a therapeutically effective amount of a formulation comprising
ABDNAZ at least once per week for a duration of at least two weeks.
In certain embodiments, the patient after having not received any
of temozolomide, radiation therapy, or ABDNAZ for a duration of at
least about 2 weeks, then receives (i) a therapeutically effective
amount of a formulation comprising temozolomide on at least five
days during the first week, and (ii) a therapeutically effective
amount of a formulation comprising ABDNAZ at least once per week
for a duration of at least 1 month. In certain embodiments, the
patient after having not received any of temozolomide, radiation
therapy, or ABDNAZ for a duration of at least about 2 weeks, then
receives (i) a therapeutically effective amount of a formulation
comprising temozolomide on at least five consecutive days during
the first week of each 28 day period, and (ii) a therapeutically
effective amount of a formulation comprising ABDNAZ at least once
per week for a duration of at least 4 months. In certain
embodiments, after receiving temozolomide for a duration of 6
weeks, the patient does not receive any of temozolomide, radiation
therapy, or ABDNAZ for a duration of at least about 4 weeks. In
certain embodiments, the patient after having not received any of
temozolomide, radiation therapy, or ABDNAZ for a duration of at
least about 4 weeks, then receives (i) a therapeutically effective
amount of a formulation comprising temozolomide on at least three
days during the first week, and (ii) a therapeutically effective
amount of a formulation comprising ABDNAZ at least once per week
for a duration of at least two weeks. In certain embodiments, the
patient after having not received any of temozolomide, radiation
therapy, or ABDNAZ for a duration of at least about 4 weeks, then
receives (i) a therapeutically effective amount of a formulation
comprising temozolomide on at least five days during the first
week, and (ii) a therapeutically effective amount of a formulation
comprising ABDNAZ at least once per week for a duration of at least
1 month. In certain embodiments, the patient after having not
received any of temozolomide, radiation therapy, or ABDNAZ for a
duration of at least about 4 weeks, then receives (i) a
therapeutically effective amount of a formulation comprising
temozolomide on at least five consecutive days during the first
week of each 28 day period, and (ii) a therapeutically effective
amount of a formulation comprising ABDNAZ at least once per week
for a duration of at least 4 months.
[0048] In certain embodiments, after receiving temozolomide for a
duration of 6 weeks, the patient does not receive any of
temozolomide, radiation therapy, or ABDNAZ for a duration of about
3 weeks to about 6 weeks.
[0049] In certain embodiments, after the duration over which the
patient has not received any of temozolomide, radiation therapy, or
ABDNAZ, the formulation comprising temozolomide is administered
orally to the patient to provide temozolomide in an amount of at
least 150 mg/m.sup.2. In certain embodiments, after the duration
over which the patient has not received any of temozolomide,
radiation therapy, or ABDNAZ, the formulation comprising ABDNAZ is
administered to the patient by intravenous infusion providing
ABDNAZ in an amount of about 5 mg/m.sup.2. In certain embodiments,
after the duration over which the patient has not received any of
temozolomide, radiation therapy, or ABDNAZ, the formulation
comprising temozolomide is administered orally to the patient to
provide temozolomide in an amount of from about 75 mg/m.sup.2 to
about 400 mg/m.sup.2. In certain embodiments, after the duration
over which the patient has not received any of temozolomide,
radiation therapy, or ABDNAZ, the formulation comprising
temozolomide is administered orally to the patient to provide
temozolomide in an amount of from about 150 mg/m.sup.2 to about 350
mg/m.sup.2. In certain embodiments, after the duration over which
the patient has not received any of temozolomide, radiation
therapy, or ABDNAZ, the formulation comprising temozolomide is
administered orally to the patient to provide temozolomide in an
amount of about 150 mg/m.sup.2, 200 mg/m.sup.2, 250 mg/m.sup.2, 300
mg/m.sup.2, or 350 mg/m.sup.2.
[0050] In certain embodiments, after the duration over which the
patient has not received any of temozolomide, radiation therapy, or
ABDNAZ, the formulation comprising ABDNAZ is administered to the
patient by intravenous infusion providing ABDNAZ in an amount of
from about 0.1 mg to about 10 mg. In certain embodiments, after the
duration over which the patient has not received any of
temozolomide, radiation therapy, or ABDNAZ, the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of from about 0.5 mg to
about 4.0 mg. In certain embodiments, after the duration over which
the patient has not received any of temozolomide, radiation
therapy, or ABDNAZ, the formulation comprising ABDNAZ is
administered to the patient by intravenous infusion providing
ABDNAZ in an amount of about 0.5 mg, 1.0 mg, 1.5, mg, 2.0 mg, 2.5
mg, 3.0 mg, or 4.0 mg.
Combinations of Embodiments and Illustration of Exemplary More
Specific Methods
[0051] All combinations of aspects and embodiments described above
are contemplated. For example, a therapeutic method is contemplated
for treating a glioblastoma by administering to a patient in need
thereof (a) for a duration of at least 3 weeks, orally administer
one dose of a formulation comprising temozolimide to the patient
daily, intravenously administer a formulation comprising ABDNAZ at
least once per week, and subject the glioma to radiation therapy at
least 3 days each week, and thereafter (b) do not administer any
temozolimide, ABDNAZ, or radiation therapy to the patient for at
least two weeks, and thereafter (c) orally administer one dose of a
formulation comprising temozolimide to the patient at least 3 days
each month, and intravenously administer a formulation comprising
ABDNAZ at least once per week.
[0052] Exemplary more specific illustrations of the contemplated
dosing methods for treating a glioma (e.g., a glioblastoma) are
provided below in Tables 1, 2, 3, and 4.
TABLE-US-00001 TABLE 1 Step No. Dosing Schedule 1 For a duration of
at least 3 weeks, orally administer one dose of a formulation
comprising temozolimide to the patient daily, intravenously
administer a formulation comprising ABDNAZ at least once per week,
and subject the glioma to radiation therapy at least 3 days each
week. 2 After completing step 1, do not administer any
temozolimide, ABDNAZ, or radiation therapy to the patient for at
least two weeks. 3 After completing step 2, orally administer one
dose of a formulation comprising temozolimide to the patient at
least 3 days each month, and intravenously administer a formulation
comprising ABDNAZ at least once per week.
TABLE-US-00002 TABLE 2 Step No. Dosing Schedule 1 For a duration of
at least 3 weeks, orally administer one dose of a formulation
comprising temozolimide to the patient daily at a daily dosage of
at least 75 mg/m.sup.2, intravenously administer a formulation
comprising ABDNAZ at least once per week, and subject the glioma to
radiation therapy at least 3 days each week. 2 After completing
step 1, do not administer any temozolimide, ABDNAZ, or radiation
therapy to the patient for at least two weeks. 3 After completing
step 2, orally administer one dose of a formulation comprising
temozolimide to the patient at least 3 days each month, and
intravenously administer a formulation comprising ABDNAZ at least
once per week.
TABLE-US-00003 TABLE 3 Step No. Dosing Schedule 1 For a duration of
at least 6 weeks, orally administer one dose of a formulation
comprising temozolimide to the patient daily at a daily dosage of
at least 75 mg/m.sup.2, intravenously administer one dose of a
formulation comprising ABDNAZ at least twice once per week wherein
each dose of the formulation comprising ABDNAZ provides from about
2.5 mg/m.sup.2 to about 16.5 mg/m.sup.2 of ABDNAZ, and subject the
glioma to a dose of radiation therapy at least 5 days each week
wherein each dose of radiation therapy provides from about 1 Gy to
about 3 Gy of radiation. 2 After completing step 1, do not
administer any temozolimide, ABDNAZ, or radiation therapy to the
patient for at least four weeks. 3 After completing step 2, for a
duration of at least two months orally administering one dose of a
formulation comprising temozolimide to the patient at least 5 days
each month wherein each dose of the formulation comprising
temozolimide provides from about 150 mg/m.sup.2 to about 200
mg/m.sup.2 of temozolimide, and intravenously administer a dose of
a formulation comprising ABDNAZ at least once per week where each
dose of the formulation comprising ABDNAZ provides at least 5
mg/m.sup.2 of ABDNAZ.
TABLE-US-00004 TABLE 4 Step No. Dosing Schedule 1 For a duration of
at about 6 weeks, orally administer one dose of a formulation
comprising temozolimide to the patient daily at a daily dosage of
at least 75 mg/m.sup.2, intravenously administer one dose of a
formulation comprising ABDNAZ twice once per week wherein each dose
of the formulation comprising ABDNAZ provides from about 2.5
mg/m.sup.2 to about 16.5 mg/m.sup.2 of ABDNAZ, and subject the
glioma to a dose of radiation therapy 5 days each week wherein each
dose of radiation therapy provides about 2 Gy of radiation. 2 After
completing step 1, do not administer any temozolimide, ABDNAZ, or
radiation therapy to the patient for about four weeks. 3 After
completing step 2, for a duration of at least two months orally
administering one dose of a formulation comprising temozolimide to
the patient about 5 days each month wherein each dose of the
formulation comprising temozolimide provides from about 150
mg/m.sup.2 to about 200 mg/m.sup.2 of temozolimide, and
intravenously administer a dose of a formulation comprising ABDNAZ
once per week where each dose of the formulation comprising ABDNAZ
provides about 5 mg/m.sup.2 of ABDNAZ.
[0053] A further exemplary more specific dosing method for treating
a glioma (e.g., a glioblastoma) is as follows: [0054] Step 1: for a
duration of at about 6 weeks, orally administer one dose of a
formulation comprising temozolimide to the patient daily at a daily
dosage of about 75 mg/m.sup.2, intravenously administer one dose of
a formulation comprising ABDNAZ once per week wherein each dose of
the formulation comprising ABDNAZ provides from about 0.5 mg to
about 4.0 mg of ABDNAZ, and subject the glioma to a dose of
radiation therapy 5 days each week wherein each dose of radiation
therapy provides about 2 Gy of radiation. The ABDNAZ is
administered within 3 hours prior to administering radiation
therapy, and the temozolomide is administered no sooner than 3
hours after administering the ABDNAZ. [0055] Step 2: after
completing step 1, do not administer any temozolimide, ABDNAZ, or
radiation therapy to the patient for about three to six weeks.
[0056] Step 3: after completing step 2, for a duration of at least
five months (preferably for six months) orally administer one dose
of a formulation comprising temozolimide to the patient about 5
days each month (e.g., days 1-5 of each month) wherein each dose of
the formulation comprising temozolimide provides from about 150
mg/m.sup.2 to about 350 mg/m.sup.2 of temozolimide, and
intravenously administer one dose of a formulation comprising
ABDNAZ once per week where each dose of the formulation comprising
ABDNAZ provides about from about 0.5 mg to about 4.0 mg of
ABDNAZ.
Second Method--Using Irinotecan
[0057] Another aspect of the invention provides a method of
treating a glioma in a patient. The method comprises the steps of:
(a) administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising irinotecan, and within
about 7 days subjecting the glioma to radiation therapy; and (b)
administering to the patient at least one dose of a therapeutically
effective amount of a formulation comprising ABDNAZ within about 7
days of administration of a first dose of the irinotecan; to treat
the glioma.
[0058] Irinotecan is commercially available and marketed in the
form of a monohydrochloride trihydrate under the tradename
CAMPTOSAR.RTM..
Exemplary Features of the Method
[0059] The above method may be further characterized by additional
features, such as the dosing schedule and amount of irinotecan,
dosing schedule of ABDNAZ, dosing amount for ABDNAZ, features of
the radiation therapy, and form of irinotecan.
Dosing Schedule and Amount of Irinotecan
[0060] The method can be further characterized according to the
dosing schedule and amount of the irinotecan. Accordingly, in
certain embodiments, the formulation comprising irinotecan is
administered at least once per week for a duration of at least 2
weeks. In certain embodiments, the formulation comprising
irinotecan is administered at least once per week for a duration of
at least 4 weeks.
[0061] In certain embodiments, the patient receives the formulation
comprising irinotecan by (i) intravenous infusion once weekly at a
single dose of at least about 100 mg/m.sup.2 of irinotecan, (ii)
intravenous infusion once every two weeks at a single dose of at
least about 200 mg/m.sup.2 of irinotecan, or (iii) intravenous
infusion once every three weeks at a single dose of at least about
300 mg/m.sup.2 of irinotecan. In certain embodiments, the patient
receives the formulation comprising irinotecan by intravenous
infusion once weekly at a single dose of about 125 mg/m.sup.2 of
irinotecan.
Dosing Schedule for ABDNAZ
[0062] A formulation comprising ABDNAZ may be administered multiple
times, such as multiple times over a defined period of time.
Further, coordination of the dosing schedule of the irinotecan and
radiation therapy with that of the formulation comprising ABDNAZ is
contemplated to provide therapeutic benefits, such as superior
efficacy.
[0063] In certain embodiments, two doses of a therapeutically
effective amount of a formulation comprising ABDNAZ are
administered within about 7 days of administration of the first
dose of irinotecan. In certain embodiments, for a duration of at
least 2 weeks following administration of the first dose of
irinotecan, the patient receives two doses each week of a
therapeutically effective amount of a formulation comprising
ABDNAZ. In certain embodiments, for a duration of at least 4 weeks
following administration of the first dose of irinotecan, the
patient receives two doses each week of a therapeutically effective
amount of a formulation comprising ABDNAZ.
[0064] In certain embodiments, for a duration of at least 2 weeks
following administration of the first dose of irinotecan, the
patient receives one dose each week of a therapeutically effective
amount of a formulation comprising ABDNAZ. In certain embodiments,
for a duration of at least 4 weeks following administration of the
first dose of irinotecan, the patient receives one dose each week
of a therapeutically effective amount of a formulation comprising
ABDNAZ. In certain embodiments, for a duration of at least 6 weeks
following administration of the first dose of irinotecan, the
patient receives one dose each week of a therapeutically effective
amount of a formulation comprising ABDNAZ. In certain embodiments,
for a duration of 6 weeks following administration of the first
dose of irinotecan, the patient receives one dose each week of a
therapeutically effective amount of a formulation comprising
ABDNAZ.
[0065] In certain embodiments, the patient receives ABDNAZ within
about 6 hours prior to subjecting the glioma to radiation therapy.
In certain embodiments, the patient receives ABDNAZ within about 24
hours prior to subjecting the glioma to radiation therapy. In
certain embodiments, the patient receives ABDNAZ within about 48
hours prior to subjecting the glioma to radiation therapy.
[0066] In certain embodiments, the formulation comprising ABDNAZ is
administered so that the ABDNAZ exerts physiological activity
during an overlapping time period with one or both of the radiation
therapy and irinotecan.
Dose of ABDNAZ Administered
[0067] The dose ABDNAZ described herein for use in combination with
irinotecan and radiation therapy has been selected in view of the
dosing amount and dosing schedule of the irinotecan and radiation
therapy. Dosing amounts of ABDNAZ are provided according to the
number of milligrams of ABDNAZ to be administered to the patient
based on the surface area of the patient as measured in
m.sup.2.
[0068] In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount ranging from about 2
mg/m.sup.2 to about 20 mg/m.sup.2. In certain embodiments, each
dose of the formulation comprising ABDNAZ is administered to the
patient by intravenous infusion providing ABDNAZ in an amount
ranging from about 2.5 mg/m.sup.2 to about 5 mg/m.sup.2. In certain
embodiments, each dose of the formulation comprising ABDNAZ is
administered to the patient by intravenous infusion providing
ABDNAZ in an amount ranging from about 5 mg/m.sup.2 to about 10
mg/m.sup.2. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount ranging from about 10
mg/m.sup.2 to about 16.5 mg/m.sup.2. In certain embodiments, each
dose of the formulation comprising ABDNAZ is administered to the
patient by intravenous infusion providing ABDNAZ in an amount of
about 2.5 mg/m.sup.2. In certain embodiments, each dose of the
formulation comprising ABDNAZ is administered to the patient by
intravenous infusion providing ABDNAZ in an amount of about 5
mg/m.sup.2. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of about 10 mg/m.sup.2. In
certain embodiments, each dose of the formulation comprising ABDNAZ
is administered to the patient by intravenous infusion providing
ABDNAZ in an amount of about 16.5 mg/m.sup.2.
[0069] In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of from about 0.1 mg to
about 20 mg. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of from about 0.1 mg to
about 10 mg. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of from about 0.5 mg to
about 4.0 mg. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of about 0.5 mg, 1.0 mg, 1.5
mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, or 4.0 mg.
Radiation Therapy Features
[0070] In certain embodiments, the glioma is subjected to radiation
therapy once per day for at least 3 days within a 7 day period
following administration of the first dose of irinotecan. In
certain embodiments, the glioma is subjected to radiation therapy
once per day for at least 5 days within a 7 day period following
administration of the first dose of irinotecan. In certain
embodiments, for a duration of at least 2 weeks following
administration of the first dose of irinotecan, the glioma is
subjected to radiation therapy once per day for at least 5 days of
each week. In certain embodiments, for a duration of at least 4
weeks following administration of the first dose of irinotecan, the
glioma is subjected to radiation therapy once per day for at least
5 days of each week.
[0071] In certain embodiments, when radiation therapy is
administered to the glioma, the amount of radiation provided to the
glioma on the day of administering the radiation therapy is from
about 1 Gy to about 3 Gy. In certain embodiments, when radiation
therapy is administered to the glioma, the amount of radiation
provided to the glioma on the day of administering the radiation
therapy is about 2 Gy.
[0072] In certain embodiments, the glioma is exposed to from about
50 Gy to about 70 Gy of radiation by the radiation therapy over a
period of 6 weeks following administration of the first dose of
irinotecan. In certain embodiments, the glioma is exposed to about
60 Gy of radiation by the radiation therapy over a period of 6
weeks following administration of the first dose of irinotecan.
[0073] In certain embodiments, the radiation therapy is (i)
conventional fractionated external beam radiation or (ii)
intensity-modulated radiation therapy. In certain embodiments, the
radiation therapy is (i) conventional fractionated external beam
radiation.
[0074] Various types of radiation therapy are used by those skilled
in the art and have been described in the literature. Exemplary
types of radiation therapy include, for example, radiation therapy
comprising gamma rays, X-rays, electron beams, neutron beams,
particulate radiation, proton beams, or the like. The source of the
radiation is desirably external to the patient, which involves
directing a beam of high-energy radiation to the glioma using a
machine external to the patient. Desirably the target site (i.e.,
site of the glioma) is exposed to the radiation therapy for a short
duration of time, such as less than about 3 hours, 2 hours, 1 hour,
30 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute for each
dose of radiation therapy.
Form of Irinotecan
[0075] The method may be further characterized according to the
form of irinotecan used, such as a free base or pharmaceutically
acceptable salt (such an acid addition salt). In certain
embodiments, the formulation comprising irinotecan comprises
irinotecan hydrochloride.
Combinations of Embodiments and Illustration of Exemplary More
Specific Methods
[0076] All combinations of aspects and embodiments described above
are contemplated. For example, a therapeutic method is contemplated
for treating a glioblastoma by administering to a patient in need
thereof (a) for a duration of at least 3 weeks, orally administer
one dose of a formulation comprising irinotecan to the patient
daily, intravenously administer a formulation comprising ABDNAZ at
least once per week, and subject the glioma to radiation therapy at
least 3 days each week, and thereafter (b) do not administer any
irinotecan, ABDNAZ, or radiation therapy to the patient for at
least two weeks, and thereafter (c) orally administer one dose of a
formulation comprising irinotecan to the patient at least 3 days
each month, and intravenously administer a formulation comprising
ABDNAZ at least once per week.
[0077] Exemplary more specific illustrations of the contemplated
dosing methods for treating a glioma (e.g., a glioblastoma) are
provided below in Tables 5, 6, 7, 8, and 9.
TABLE-US-00005 TABLE 5 Step No. Dosing Schedule 1 For a duration of
at least 2 weeks, intravenously administer one dose of a
formulation comprising irinotecan to the patient at least once per
week wherein each dose provides at least 100 mg/m.sup.2 of
irinotecan, intravenously administer a formulation comprising
ABDNAZ at least once per week, and subject the glioma to radiation
therapy at least once per week. 2 After completing step 1, do not
administer any irinotecan to the patient for at least one week.
TABLE-US-00006 TABLE 6 Step No. Dosing Schedule 1 For a duration of
at least 4 weeks, intravenously administer one dose of a
formulation comprising irinotecan to the patient at least once per
week wherein each dose provides at least 100 mg/m.sup.2 of
irinotecan, intravenously administer a formulation comprising
ABDNAZ at least once per week, and subject the glioma to radiation
therapy at least twice per week. 2 After completing step 1, do not
administer any irinotecan to the patient for at least two
weeks.
TABLE-US-00007 TABLE 7 Step No. Dosing Schedule 1 For a duration of
at least 2 weeks, intravenously administer one dose of a
formulation comprising irinotecan to the patient at least once per
week wherein each dose provides at least 125 mg/m.sup.2 of
irinotecan, intravenously administer one dose of a formulation
comprising ABDNAZ at least twice once per week wherein each dose of
the formulation comprising ABDNAZ provides from about 2.5
mg/m.sup.2 to about 16.5 mg/m.sup.2 of ABDNAZ, and subject the
glioma to a dose of radiation therapy at least 2 days each week
wherein each dose of radiation therapy provides from about 1 Gy to
about 3 Gy of radiation. 2 After completing step 1, do not
administer any irinotecan for at least one week.
TABLE-US-00008 TABLE 8 Step No. Dosing Schedule 1 For a duration of
at least 4 weeks, intravenously administer one dose of a
formulation comprising irinotecan to the patient once per week
wherein each dose provides at least 125 mg/m.sup.2 of irinotecan,
intravenously administer one dose of a formulation comprising
ABDNAZ at least twice once per week wherein each dose of the
formulation comprising ABDNAZ provides from about 2.5 mg/m.sup.2 to
about 16.5 mg/m.sup.2 of ABDNAZ, and subject the glioma to a dose
of radiation therapy at least 2 days each week wherein each dose of
radiation therapy provides from about 1 Gy to about 3 Gy of
radiation. 2 After completing step 1, do not administer any
irinotecan for at least one week.
TABLE-US-00009 TABLE 9 Step No. Dosing Schedule 1 For a duration of
at least 3 weeks, intravenously administer one dose of a
formulation comprising irinotecan to the patient once every three
weeks wherein each dose provides at least 350 mg/m.sup.2 of
irinotecan, intravenously administer one dose of a formulation
comprising ABDNAZ at least twice once per week wherein each dose of
the formulation comprising ABDNAZ provides from about 2.5
mg/m.sup.2 to about 16.5 mg/m.sup.2 of ABDNAZ, and subject the
glioma to a dose of radiation therapy at least 2 days each week
wherein each dose of radiation therapy provides from about 1 Gy to
about 3 Gy of radiation. 2 After completing step 1, do not
administer any irinotecan for at least two weeks.
Third Method--Using Bevacizumab
[0078] Another aspect of the invention provides a method of
treating a glioma in a patient. The method comprises the steps of:
(a) administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising bevacizumab, and
within about 7 days subjecting the glioma to radiation therapy; and
(b) administering to the patient at least one dose of a
therapeutically effective amount of a formulation comprising ABDNAZ
within about 7 days of administration of a first dose of the
bevacizumab; to treat the glioma.
[0079] Bevacizumab is a recombinant humanized monoclonal IgG1
antibody that binds to and inhibits the biologic activity of human
vascular endothelial growth factor (VEGF) in in vitro and in vivo
assay systems. Bevacizumab contains human framework regions and the
complementarity-determining regions of a murine antibody that binds
to VEGF. Bevacizumab has an approximate molecular weight of 149 kD
and can be produced in a mammalian cell (Chinese Hamster Ovary)
expression system in a nutrient medium containing the antibiotic
gentamicin. Bevacizumab is marketed commercially as AVASTIN.RTM..
The formulation of bevacizumab marketed commercially as
AVASTIN.RTM. is a clear to slightly opalescent, colorless to pale
brown, sterile, pH 6.2 solution for intravenous infusion. The
formulation is supplied in 100 mg and 400 mg amounts of bevacizumab
in preservative-free, single-use vials. The 100 mg product is
formulated in 240 mg .alpha.,.alpha.-trehalose dihydrate, 23.2 mg
sodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate
(dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for
Injection, USP. The 400 mg product is formulated in 960 mg
.alpha.,.alpha.-trehalose dihydrate, 92.8 mg sodium phosphate
(monobasic, monohydrate), 19.2 mg sodium phosphate (dibasic, a 695
nhydrous), 6.4 mg polysorbate 20, and Water for Injection, USP.
Exemplary Features of the Method
[0080] The above method may be further characterized by additional
features, such as the dosing schedule and amount of bevacizumab,
dosing schedule of ABDNAZ, dosing amount for ABDNAZ, and features
of the radiation therapy.
Dosing Schedule and Amount of Bevacizumab
[0081] The method can be further characterized according to the
dosing schedule and amount of the bevacizumab. Accordingly, in
certain embodiments, the formulation comprising bevacizumab is
administered once every 2 weeks for a duration of at least 4 weeks.
In certain embodiments, the formulation comprising bevacizumab is
administered once every 3 weeks for a duration of at least 6
weeks.
[0082] In certain embodiments, the patient receives the formulation
comprising bevacizumab by (i) intravenous infusion once every 2
weeks at a dose of at least about 5 mg/kg of bevacizumab for a
duration of at least 4, 6, 8, 10, or 12 weeks, (ii) intravenous
infusion once every 2 weeks at a dose of at least about 10 mg/kg of
bevacizumab for a duration of at least 4, 6, 8, 10, or 12 weeks, or
(iii) intravenous infusion once every 3 weeks at a dose of at least
about 15 mg/kg of bevacizumab for a duration of at least 6, 12, 15,
or 18 weeks. In certain embodiments, the patient receives the
formulation comprising bevacizumab by intravenous infusion once
every 2 weeks at a dose of 5-10 mg/kg of bevacizumab for a duration
of at least 4, 6, 8, 10, or 12 weeks.
[0083] In certain other embodiments, the patient receives the
formulation comprising bevacizumab by (i) intravenous infusion once
every 2 weeks at a dose of about 5 mg/kg of bevacizumab for a
duration of at least 4, 6, 8, 10, or 12 weeks, (ii) intravenous
infusion once every 2 weeks at a dose of about 10 mg/kg of
bevacizumab for a duration of at least 4, 6, 8, 10, or 12 weeks, or
(iii) intravenous infusion once every 3 weeks at a dose of about 15
mg/kg of bevacizumab for a duration of at least 6, 12, 15, or 18
weeks. In certain embodiments, the patient receives the formulation
comprising bevacizumab by intravenous infusion once every 2 weeks
at a dose of 5-20 mg/kg of bevacizumab for a duration of at least
4, 6, 8, 10, or 12 weeks.
Dosing Schedule for ABDNAZ
[0084] A formulation comprising ABDNAZ may be administered multiple
times, such as multiple times over a defined period of time.
Further, coordination of the dosing schedule of the bevacizumab and
radiation therapy with that of the formulation comprising ABDNAZ is
contemplated to provide therapeutic benefits, such as superior
efficacy.
[0085] In certain embodiments, two doses of a therapeutically
effective amount of a formulation comprising ABDNAZ are
administered within about 7 days of administration of the first
dose of bevacizumab. In certain embodiments, for a duration of at
least 2 weeks following administration of the first dose of
bevacizumab, the patient receives two doses each week of a
therapeutically effective amount of a formulation comprising
ABDNAZ. In certain embodiments, for a duration of at least 4 weeks
following administration of the first dose of bevacizumab, the
patient receives two doses each week of a therapeutically effective
amount of a formulation comprising ABDNAZ. In certain embodiments,
the patient receives ABDNAZ within about 6 hours prior to
subjecting the glioma to radiation therapy. In certain embodiments,
the patient receives ABDNAZ within about 24 hours prior to
subjecting the glioma to radiation therapy. In certain embodiments,
the patient receives ABDNAZ within about 48 hours prior to
subjecting the glioma to radiation therapy.
[0086] In certain embodiments, the formulation comprising ABDNAZ is
administered so that the ABDNAZ exerts physiological activity
during an overlapping time period with one or both of the radiation
therapy and bevacizumab.
Dose of ABDNAZ Administered
[0087] The dose ABDNAZ described herein for use in combination with
bevacizumab and radiation therapy has been selected in view of the
dosing amount and dosing schedule of the bevacizumab and radiation
therapy. Dosing amounts of ABDNAZ are provided according to the
number of milligrams of ABDNAZ to be administered to the patient
based on the surface area of the patient as measured in
m.sup.2.
[0088] In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount ranging from about 2
mg/m.sup.2 to about 20 mg/m.sup.2. In certain embodiments, each
dose of the formulation comprising ABDNAZ is administered to the
patient by intravenous infusion providing ABDNAZ in an amount
ranging from about 2.5 mg/m.sup.2 to about 5 mg/m.sup.2. In certain
embodiments, each dose of the formulation comprising ABDNAZ is
administered to the patient by intravenous infusion providing
ABDNAZ in an amount ranging from about 5 mg/m.sup.2 to about 10
mg/m.sup.2. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount ranging from about 10
mg/m.sup.2 to about 16.5 mg/m.sup.2. In certain embodiments, each
dose of the formulation comprising ABDNAZ is administered to the
patient by intravenous infusion providing ABDNAZ in an amount of
about 2.5 mg/m.sup.2. In certain embodiments, each dose of the
formulation comprising ABDNAZ is administered to the patient by
intravenous infusion providing ABDNAZ in an amount of about 5
mg/m.sup.2. In certain embodiments, each dose of the formulation
comprising ABDNAZ is administered to the patient by intravenous
infusion providing ABDNAZ in an amount of about 10 mg/m.sup.2. In
certain embodiments, each dose of the formulation comprising ABDNAZ
is administered to the patient by intravenous infusion providing
ABDNAZ in an amount of about 16.5 mg/m.sup.2.
Radiation Therapy Features
[0089] In certain embodiments, the glioma is subjected to radiation
therapy once per day for at least 3 days within a 7 day period
following administration of the first dose of bevacizumab. In
certain embodiments, the glioma is subjected to radiation therapy
once per day for at least 5 days within a 7 day period following
administration of the first dose of bevacizumab. In certain
embodiments, for a duration of at least 2 weeks following
administration of the first dose of bevacizumab, the glioma is
subjected to radiation therapy once per day for at least 5 days of
each week. In certain embodiments, for a duration of at least 4
weeks following administration of the first dose of bevacizumab,
the glioma is subjected to radiation therapy once per day for at
least 5 days of each week.
[0090] In certain embodiments, when radiation therapy is
administered to the glioma, the amount of radiation provided to the
glioma on the day of administering the radiation therapy is from
about 1 Gy to about 3 Gy. In certain embodiments, when radiation
therapy is administered to the glioma, the amount of radiation
provided to the glioma on the day of administering the radiation
therapy is about 2 Gy.
[0091] In certain embodiments, the glioma is exposed to from about
50 Gy to about 70 Gy of radiation by the radiation therapy over a
period of 6 weeks following administration of the first dose of
bevacizumab. In certain embodiments, the glioma is exposed to about
60 Gy of radiation by the radiation therapy over a period of 6
weeks following administration of the first dose of
bevacizumab.
[0092] In certain embodiments, the radiation therapy is (i)
conventional fractionated external beam radiation or (ii)
intensity-modulated radiation therapy. In certain embodiments, the
radiation therapy is (i) conventional fractionated external beam
radiation.
[0093] Various types of radiation therapy are used by those skilled
in the art and have been described in the literature. Exemplary
types of radiation therapy include, for example, radiation therapy
comprising gamma rays, X-rays, electron beams, neutron beams,
particulate radiation, proton beams, or the like. The source of the
radiation is desirably external to the patient, which involves
directing a beam of high-energy radiation to the glioma using a
machine external to the patient. Desirably the target site (i.e.,
site of the glioma) is exposed to the radiation therapy for a short
duration of time, such as less than about 3 hours, 2 hours, 1 hour,
30 minutes, 15 minutes, 10 minutes, 5 minutes, or 1 minute for each
dose of radiation therapy.
Combinations of Embodiments and Illustration of Exemplary More
Specific Methods
[0094] All combinations of aspects and embodiments described above
are contemplated. For example, a therapeutic method is contemplated
for treating a glioblastoma by administering to a patient in need
thereof for a duration of at least 3 weeks, orally administer one
dose of a formulation comprising bevacizumab to the patient daily,
intravenously administer a formulation comprising ABDNAZ at least
once per week, and subject the glioma to radiation therapy at least
3 days each week. Exemplary more specific illustrations of the
contemplated dosing methods for treating a glioma (e.g., a
glioblastoma) using bevacizumab are provided below in Table 10
below describing multiple more specific dosing schedules.
TABLE-US-00010 TABLE 10 Dosing Schedule Description of Dosing
Schedule A For a duration of at least 4 weeks, intravenously
administer one dose of a formulation comprising bevacizumab to the
patient once every two weeks wherein each dose provides at least 5
mg/kg of bevacizumab, intravenously administer a formulation
comprising ABDNAZ at least once per week, and subject the glioma to
radiation therapy at least once per week. B For a duration of at
least 4 weeks, intravenously administer one dose of a formulation
comprising bevacizumab to the patient once every two weeks wherein
each dose provides at least 5 mg/kg of bevacizumab, intravenously
administer a formulation comprising ABDNAZ at least once per week,
and subject the glioma to radiation therapy at least twice per
week. C For a duration of at least 4 weeks, intravenously
administer one dose of a formulation comprising bevacizumab to the
patient once every two weeks wherein each dose provides at least 10
mg/kg of bevacizumab, intravenously administer a formulation
comprising ABDNAZ at least once per week, and subject the glioma to
radiation therapy at least twice per week. D For a duration of at
least 6 weeks, intravenously administer one dose of a formulation
comprising bevacizumab to the patient once every three weeks
wherein each dose provides at least 15 mg/kg of bevacizumab,
intravenously administer a formulation comprising ABDNAZ at least
once per week, and subject the glioma to radiation therapy at least
twice per week. E For a duration of at least 4 weeks, intravenously
administer one dose of a formulation comprising bevacizumab to the
patient once every two weeks wherein each dose provides at least 5
mg/kg of bevacizumab, intravenously administer a formulation
comprising ABDNAZ at least twice per week, and subject the glioma
to radiation therapy at least twice per week. F For a duration of
at least 4 weeks, intravenously administer one dose of a
formulation comprising bevacizumab to the patient once every two
weeks wherein each dose provides at least 10 mg/kg of bevacizumab,
intravenously administer a formulation comprising ABDNAZ at least
twice per week, and subject the glioma to radiation therapy at
least twice per week. G For a duration of at least 4 weeks,
intravenously administer one dose of a formulation comprising
bevacizumab to the patient once every two weeks wherein each dose
provides at least 5 mg/kg of bevacizumab, intravenously administer
a formulation comprising ABDNAZ at least twice per week wherein
each dose of the formulation comprising ABDNAZ provides from about
2.5 mg/m.sup.2 to about 16.5 mg/m.sup.2 of ABDNAZ, and subject the
glioma to radiation therapy at least twice per week wherein each
dose of radiation therapy provides from about 1 Gy to about 3 Gy of
radiation. H For a duration of at least 4 weeks, intravenously
administer one dose of a formulation comprising bevacizumab to the
patient once every two weeks wherein each dose provides at least 10
mg/kg of bevacizumab, intravenously administer a formulation
comprising ABDNAZ at least twice per week wherein each dose of the
formulation comprising ABDNAZ provides from about 2.5 mg/m.sup.2 to
about 16.5 mg/m.sup.2 of ABDNAZ, and subject the glioma to
radiation therapy at least twice per week wherein each dose of
radiation therapy provides from about 1 Gy to about 3 Gy of
radiation. I For a duration of at least 6 weeks, intravenously
administer one dose of a formulation comprising bevacizumab to the
patient once every three weeks wherein each dose provides at least
15 mg/kg of bevacizumab, intravenously administer a formulation
comprising ABDNAZ at least twice per week wherein each dose of the
formulation comprising ABDNAZ provides from about 2.5 mg/m.sup.2 to
about 16.5 mg/m.sup.2 of ABDNAZ, and subject the glioma to
radiation therapy at least twice per week wherein each dose of
radiation therapy provides from about 1 Gy to about 3 Gy of
radiation.
Further Characterization of the First, Second, and Third
Methods
[0095] The methods may be further characterized according to, for
example, the type of glioma, patients for treatment, effects of the
treatment, formulation of ABDNAZ, and form of ABDNAZ.
Type of Glioma
[0096] The methods may be further characterized according to the
nature of the glioma. In certain embodiments, the glioma is an
astrocytoma. In certain embodiments, the glioma is a malignant
astrocytoma. In certain embodiments, the glioma is a glioblastoma.
In certain embodiments, the glioma is a primary glioblastoma. In
certain embodiments, the glioma is a secondary glioblastoma. In
certain embodiments, the glioma is a gliosarcoma. In certain
embodiments, the glioma is an anaplastic glioma with 1p/19q
chromosomes intact. In certain embodiments, the glioma is an
anaplastic oligodendroglioma or anaplastic oligoastrocytoma.
Patients for Treatment
[0097] The therapeutic method may be further characterized
according to the patient to be treated. In certain embodiments, the
patient is an adult human. In certain other embodiments, the
patient is a pediatric human. In certain embodiments, the patient
has previously undergone surgery to remove at least some glioma
tissue. In certain embodiments, the patient has previously
undergone surgery, to remove at least some glioma tissue, within
six weeks prior to receiving the first dose of temozolomide under
the methods described herein using ABDNAZ as part of a combination
therapy treatment.
Characterization of Treatment Effects
[0098] The therapeutic method may be further characterized
according to the effect of the treatment, such as (i) a reduction
in the size of at least one glioma tumors in the patient, and/or
(ii) reduction in the number of glioma tumor in the patient.
[0099] Accordingly, in certain embodiments, the therapeutic method
is characterized by at least a 20% reduction in the size of at
least one glioma tumor in the patient. In certain other
embodiments, there is at least a 35% reduction in the size of at
least one glioma tumor in the patient. In certain other
embodiments, there is at least a 50% reduction in the size of at
least one glioma tumor in the patient.
[0100] In certain embodiments, there is at least a 20% reduction in
the number of glioma tumors in the patient. In certain other
embodiments, there is at least a 35% reduction in the number of
glioma tumors in the patient. In yet other embodiments, there is at
least a 50% reduction in the number of glioma tumors in the
patient.
Exemplary Formulations Comprising ABDNAZ
[0101] The method may be further characterized according to the
formulation comprising ABDNAZ that is administered to the patient.
In certain embodiments, the formulation comprises ABDNAZ,
dimethylacetamide, water, and a polyethylene glycol. In certain
embodiments, the polyethylene glycol has a number-average molecular
weight of about 400 g/mol.
Form of ABDNAZ
[0102] In certain embodiments, the patient may be administered a
pharmaceutically acceptable salt of ABDNAZ.
Methods for Increasing the Amount of Temozolomide, Irinotecan, or
Bevacizumab in a Glioma
[0103] Another aspect of the invention provides a method for
increasing the amount of temozolomide, irinotecan, or bevacizumab
in a glioma. The method generally involves administering to a
patient having a glioma (i) a formulation comprising temozolomide,
irinotecan, or bevacizumab and (ii) an effective amount of a
formulation comprising ABDNAZ so that the ABDNAZ exerts
physiological activity during a time period in which the
temozolomide, irinotecan, or bevacizumab is present in the patient,
in order to increase the amount of the temozolomide, irinotecan, or
bevacizumab in the glioma. The method may be characterized
according to the percent increase in the amount of temozolomide,
irinotecan, or bevacizumab in the glioma relative to the amount of
temozolomide, irinotecan, or bevacizumab in the glioma following an
identical administration procedure but absent administering said
effective amount of a formulation comprising ABDNAZ.
[0104] Accordingly, one aspect of the invention provides a method
of increasing the amount of temozolomide in a glioma, where the
method comprises administering to a patient having a glioma (i) a
formulation comprising temozolomide and (ii) an effective amount of
a formulation comprising ABDNAZ so that the ABDNAZ exerts
physiological activity during a time period in which the
temozolomide is present in the patient, in order to increase the
amount of the temozolomide in the glioma.
[0105] Another aspect of the invention provides a method of
increasing the amount of irinotecan in a glioma, where the method
comprises administering to a patient having a glioma (i) a
formulation comprising irinotecan and (ii) an effective amount of a
formulation comprising ABDNAZ so that the ABDNAZ exerts
physiological activity during a time period in which the irinotecan
is present in the patient, in order to increase the amount of the
irinotecan in the glioma.
[0106] Another aspect of the invention provides a method of
increasing the amount of bevacizumab in a glioma, where the method
comprises administering to a patient having a glioma (i) a
formulation comprising bevacizumab and (ii) an effective amount of
a formulation comprising ABDNAZ so that the ABDNAZ exerts
physiological activity during a time period in which the
bevacizumab is present in the patient, in order to increase the
amount of the bevacizumab in the glioma.
[0107] Each of the foregoing methods may be further characterized
according to features described above in connection with the First,
Second, and Third Methods. Additionally, the foregoing methods may
be further characterized according to the percent increase (e.g.,
at least a 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%,
90%, 100%, 200% or 300% increase) in the amount of temozolomide,
irinotecan, or bevacizumab in the glioma relative to the amount of
temozolomide, irinotecan, or bevacizumab in the glioma following an
identical administration procedure but absent administering said
effective amount of a formulation comprising ABDNAZ.
[0108] In certain embodiments, the formulation comprising ABDNAZ is
administered within about 4, 6, 8, 10, 12, 14, 16, 18, 20 or 24
hours of administration of a formulation comprising one of
temozolomide, irinotecan, or bevacizumab.
Additional Method--Using Temozolomide
[0109] Another aspect of the invention provides a method of
treating a glioma in a patient. The method comprises the steps of:
(a) administering to the patient in need thereof a therapeutically
effective amount of a formulation comprising ABDNAZ, and (b)
thereafter administering to the patient in need thereof a
therapeutically effective amount of a formulation comprising
temozolomide; to treat the glioma. The method may be further
characterized by additional features, such as the dosing schedule
and amount of temozolomide, dosing schedule of ABDNAZ, dosing
amount for ABDNAZ, and/or any rest period/maintenance period, as
described above in connection with the First Method.
IV. Pharmaceutical Compositions
[0110] The invention provides pharmaceutical compositions
comprising an active therapeutic agent and one or more
pharmaceutically acceptable carriers (additives) and/or diluents.
In certain embodiments, the active therapeutic agent is ABDNAZ,
such that the invention provides a pharmaceutical composition
comprising ABDNAZ formulated together with one or more
pharmaceutically acceptable carriers (additives) and/or diluents.
The a pharmaceutical composition may comprise ABDNAZ in a
therapeutically effective amount. As described in detail below, the
pharmaceutical compositions of the present invention may be
specially formulated for administration in liquid form, including
those adapted for the following: (1) oral administration, for
example, drenches (aqueous or non-aqueous solutions or
suspensions); and (2) parenteral administration by, for example,
subcutaneous, intramuscular, intravenous or epidural injection as,
for example, a sterile solution or suspension, or sustained-release
formulation.
[0111] The phrase "therapeutically-effective amount" as used herein
means that amount of a compound, material, or composition
comprising a compound of the present invention which is effective
for producing some desired therapeutic effect in at least a
sub-population of cells in an animal at a reasonable benefit/risk
ratio applicable to any medical treatment.
[0112] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0113] The amount of active ingredient which can be combined with a
carrier material to produce a single dosage form will generally be
that amount of the compound which produces a therapeutic effect.
Generally, out of one hundred percent, this amount will range from
about 0.1 percent to about ninety-nine percent of active
ingredient, preferably from about 5 percent to about 70 percent,
most preferably from about 10 percent to about 30 percent.
[0114] Liquid dosage forms for oral administration of the compounds
of the invention include pharmaceutically acceptable emulsions,
microemulsions, solutions, suspensions, syrups and elixirs. In
addition to the active ingredient, the liquid dosage forms may
contain inert diluents commonly used in the art, such as, for
example, water or other solvents, solubilizing agents and
emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular,
cottonseed, groundnut, corn, germ, olive, castor and sesame oils),
glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty
acid esters of sorbitan, and mixtures thereof.
[0115] Besides inert diluents, the oral compositions can also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, coloring, perfuming and
preservative agents.
[0116] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar and tragacanth, and mixtures thereof.
[0117] Pharmaceutical compositions of this invention suitable for
parenteral administration comprise one or more compounds of the
invention in combination with one or more
pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions, or sterile
powders which may be reconstituted into sterile injectable
solutions or dispersions just prior to use, which may contain
sugars, alcohols, antioxidants, buffers, bacteriostats, solutes
which render the formulation isotonic with the blood of the
intended recipient or suspending or thickening agents.
[0118] Examples of suitable aqueous and nonaqueous carriers which
may be employed in the pharmaceutical compositions of the invention
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained,
for example, by the use of coating materials, such as lecithin, by
the maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0119] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms upon the subject
compounds may be ensured by the inclusion of various antibacterial
and antifungal agents, for example, paraben, chlorobutanol, phenol
sorbic acid, and the like. It may also be desirable to include
isotonic agents, such as sugars, sodium chloride, and the like into
the compositions. In addition, prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
[0120] The preparations of the present invention may be given, for
example, orally or parenterally. The phrases "parenteral
administration" and "administered parenterally" as used herein
means modes of administration other than enteral and topical
administration, usually by injection, and includes, without
limitation, intravenous, intramuscular, intraarterial, intrathecal,
intracapsular, intraorbital, intracardiac, intradermal,
intraperitoneal, transtracheal, subcutaneous, subcuticular,
intraarticulare, subcapsular, subarachnoid, intraspinal and
intrasternal injection and infusion.
[0121] The phrases "systemic administration," "administered
systemically," "peripheral administration" and "administered
peripherally" as used herein mean the administration of a compound,
drug or other material other than directly into the central nervous
system, such that it enters the patient's system and, thus, is
subject to metabolism and other like processes, for example,
subcutaneous administration.
[0122] These compounds may be administered to humans and other
animals for therapy by any suitable route of administration,
including orally, nasally, as by, for example, a spray, rectally,
intravaginally, parenterally, intracisternally and topically, as by
powders, ointments or drops, including buccally and
sublingually.
[0123] Actual dosage levels of the active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition, and mode of administration, without being toxic to the
patient.
[0124] The selected dosage level will depend upon a variety of
factors including the activity of the particular compound of the
present invention employed, or the ester, salt or amide thereof,
the route of administration, the time of administration, the rate
of excretion or metabolism of the particular compound being
employed, the rate and extent of absorption, the duration of the
treatment, other drugs, compounds and/or materials used in
combination with the particular compound employed, the age, sex,
weight, condition, general health and prior medical history of the
patient being treated, and like factors well known in the medical
arts.
[0125] A physician or veterinarian having ordinary skill in the art
can readily determine and prescribe the effective amount of the
pharmaceutical composition required. For example, the physician or
veterinarian could start doses of the compounds of the invention
employed in the pharmaceutical composition at levels lower than
that required in order to achieve the desired therapeutic effect
and gradually increase the dosage until the desired effect is
achieved.
[0126] In general, a suitable daily dose of a compound of the
invention will be that amount of the compound which is the lowest
dose effective to produce a therapeutic effect. Such an effective
dose will generally depend upon the factors described above.
Preferably, the compounds are administered at about 0.01 mg/kg to
about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100
mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
When the compounds described herein are co-administered with
another agent (e.g., as sensitizing agents), the effective amount
may be less than when the agent is used alone.
[0127] If desired, the effective daily dose of the active compound
may be administered as two, three, four, five, six or more
sub-doses administered separately at appropriate intervals
throughout the day, optionally, in unit dosage forms. Preferred
dosing is one administration per day.
[0128] The description above describes multiple aspects and
embodiments of the invention. The patent application specifically
contemplates all combinations and permutations of the aspects and
embodiments.
V. Kits for Use in Medical Applications
[0129] Another aspect of the invention provides a kit for treating
a glioma. The kit comprises: (i) a formulation comprising ABDNAZ,
and (ii) instructions for treating a glioma according to procedures
described herein, such as (a) administering to the patient in need
thereof a therapeutically effective amount of a formulation
comprising temozolomide, and within about 2 days thereafter
subjecting the glioma to radiation therapy; and (b) administering
to the patient at least one dose of a therapeutically effective
amount of a formulation comprising ABDNAZ within about 7 days of
administration of a first dose of the temozolomide; to treat the
glioma. In an alternative embodiment, the kit comprises: (i) a
formulation comprising ABDNAZ, and (ii) instructions for treating a
glioma that comprise (a) administering to the patient in need
thereof a therapeutically effective amount of a formulation
comprising irinotecan, and within about 7 days subjecting the
glioma to radiation therapy; and (b) administering to the patient
at least one dose of a therapeutically effective amount of a
formulation comprising ABDNAZ within about 7 days of administration
of a first dose of the irinotecan; to treat the glioma.
VI. Definitions
[0130] To facilitate an understanding of the present invention, a
number of terms and phrases are defined below.
[0131] The terms "a" and "an" as used herein mean "one or more" and
include the plural unless the context is inappropriate.
[0132] As used herein, the term "patient" refers to organisms to be
treated by the methods of the present invention. Such organisms are
preferably mammals (e.g., murines, simians, equines, bovines,
porcines, canines, felines, and the like), and more preferably
humans.
[0133] As used herein, the term "effective amount" refers to the
amount of a compound (e.g., a compound of the present invention)
sufficient to effect beneficial or desired results. An effective
amount can be administered in one or more administrations,
applications or dosages and is not intended to be limited to a
particular formulation or administration route.
[0134] As used herein, the term "treating" includes any effect,
e.g., lessening, reducing, modulating, ameliorating or eliminating,
that results in the improvement of the condition, disease,
disorder, and the like, or ameliorating a symptom thereof.
[0135] As used herein, the terms "alleviate" and "alleviating"
refer to reducing the severity of the condition, such as reducing
the severity by, for example, at least 10%, 20%, 30%, 40%, 50%,
60%, 70%, 80%, 90%, or 95%.
[0136] As used herein, the term "pharmaceutical composition" refers
to the combination of an active agent with a carrier, inert or
active, making the composition especially suitable for diagnostic
or therapeutic use in vivo or ex vivo.
[0137] As used herein, the term "pharmaceutically acceptable
carrier" refers to any of the standard pharmaceutical carriers,
such as a phosphate buffered saline solution, water, emulsions
(e.g., such as an oil/water or water/oil emulsions), and various
types of wetting agents. The compositions also can include
stabilizers and preservatives. For examples of carriers,
stabilizers and adjuvants, see, for example, Martin, Remington's
Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa.
[1975]).
[0138] As used herein, the term "pharmaceutically acceptable salt"
refers to any pharmaceutically acceptable salt (e.g., acid or base)
of a compound of the present invention which, upon administration
to a subject, is capable of providing a compound of this invention
or an active metabolite or residue thereof. As is known to those of
skill in the art, "salts" of the compounds of the present invention
may be derived from inorganic or organic acids and bases. Examples
of acids include, but are not limited to, hydrochloric,
hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic,
phosphoric, glycolic, lactic, salicylic, succinic,
toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,
ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,
benzenesulfonic acid, and the like. Other acids, such as oxalic,
while not in themselves pharmaceutically acceptable, may be
employed in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their pharmaceutically
acceptable acid addition salts.
[0139] Examples of bases include, but are not limited to, alkali
metal (e.g., sodium) hydroxides, alkaline earth metal (e.g.,
magnesium) hydroxides, ammonia, and compounds of formula NW4.sup.+,
wherein W is C.sub.1-4 alkyl, and the like.
[0140] Examples of salts include, but are not limited to: acetate,
adipate, alginate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, citrate, camphorate, camphorsulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
palmoate, pectinate, persulfate, phenylpropionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate,
undecanoate, and the like. Other examples of salts include anions
of the compounds of the present invention compounded with a
suitable cation such as Na.sup.+, NH4.sup.+, and NW4.sup.+ (wherein
W is a C.sub.1-4 alkyl group), and the like.
[0141] For therapeutic use, salts of the compounds of the present
invention are contemplated as being pharmaceutically acceptable.
However, salts of acids and bases that are non-pharmaceutically
acceptable may also find use, for example, in the preparation or
purification of a pharmaceutically acceptable compound.
[0142] Throughout the description, where compositions are described
as having, including, or comprising specific components, or where
processes and methods are described as having, including, or
comprising specific steps, it is contemplated that, additionally,
there are compositions of the present invention that consist
essentially of, or consist of, the recited components, and that
there are processes and methods according to the present invention
that consist essentially of, or consist of, the recited processing
steps.
[0143] As a general matter, compositions specifying a percentage
are by weight unless otherwise specified. Further, if a variable is
not accompanied by a definition, then the previous definition of
the variable controls.
EXAMPLES
[0144] The invention now being generally described, will be more
readily understood by reference to the following examples, which
are included merely for purposes of illustration of certain aspects
and embodiments of the present invention, and are not intended to
limit the invention.
Example 1--Treatment of Human Patients Suffering from a
Glioblastoma or Malignant Glioma
[0145] Adult human patients having a gliobastoma or malignant
glioma are to be treated using a combination of ABDNAZ,
temozolomide, and radiation therapy (RT) according to the treatment
protocol described below.
Treatment Protocol
Upfront Therapy
[0146] Patients are to receive oral temozolomide 75 mg/m.sup.2
daily for 6 weeks and undergo conformal or intensity-modulated
radiotherapy (60 Gy in 2 Gy fractions) 5 days a week for 6 weeks.
Patients are also to receive ABDNAZ by intravenous administration
twice weekly for 6 weeks administered at one of four dose levels
(2.0 mg/m.sup.2, 8 mg/m.sup.2, 17 mg/m.sup.2, or 29 mg/m.sup.2)
beginning concurrently with temozolomide and radiotherapy. Cohorts
of 3-6 patients will receive escalating doses of ABDNAZ until the
maximum feasible dose (MFD) or maximum tolerated dose (MTD) is
determined. The MTD is defined as the dose preceding that at which
2 of 3 or 2 of 6 subjects experience dose-limiting toxicity.
Maintenance Therapy
[0147] Beginning 28 days after completion of radiotherapy, patients
are to receive oral temozolomide [150 mg/m.sup.2 orally daily for 5
days during cycle 1 (28 days) and 200 mg/m.sup.2 orally daily for 5
days every 28 days for cycles 2-6] and once weekly ABDNAZ at 2
mg/m.sup.2 on days 1-28. Treatment will repeat every 4 weeks for up
to 12 courses in the absence of disease progression or unacceptable
toxicity.
Patient Evaluation Procedure
[0148] Patients are to be evaluated by a radiation oncologist and
medical oncologist prior to the start of any treatment. Efficacy of
the therapy may be evaluated according to procedure described
below.
Pre-Treatment Evaluation (within 14.+-.7 Days Prior to First Dose
of Study Drug)
[0149] Patients may be evaluated using the following criteria prior
to treatment with the therapy to assess nature and extent of the
gliobastoma or malignant glioma: [0150] GAD-enhanced DCE-MRI [0151]
Contrast-enhanced MM and/or CT [0152] Complete history and general
physical exam [0153] Detailed neurological examination [0154]
Safety labs: CBC with differential, comprehensive chemistry panel,
liver function tests [0155] Karnofsky performance status [0156]
Documentation of primary tumor histology [0157] Documentation of
steroid and anticonvulsant doses and any other concomitant
medications. The newer antiepilieptic drugs (levetiracetam,
pregabalin, lamotrigine, lacosamide, topiramate) are generally
preferred over carbamazepine, phenytoin, phenobarbital, or valproic
acid, which stimulate the hepatic cytochrome P450 (CYP) system.
[0158] FACT-BR, Barthel Index of ADLs, and neurocognitive function
(HVLT-R, COWA, and Trail Making A and B) will be evaluated
Evaluation During Radiation Therapy and ABDNAZ Therapy
[0159] Patients may be evaluated using the following criteria
during treatment with the therapy to assess nature and extent of
the gliobastoma or malignant glioma: [0160] Clinical visit once per
week to include neurological examination, history and physical
examination and clinical laboratory testing [0161] GAD-enhanced
DCE-MRI on days 9.+-.1 day and 41.+-.1 day [0162] Collection of
concomitant medications at each clinic visit [0163] Collection of
adverse events (AEs) at each clinic visit [0164] Skin within the
treatment portal shall be examined once per week during radiation
treatment Evaluation after Completion of Radiation Therapy and
ABDNAZ Therapy
[0165] Patients may be evaluated using the following criteria after
treatment with the therapy to assess nature and extent of the
gliobastoma or malignant glioma: [0166] Patients are to be
evaluated 2 weeks after completion of radiation therapy and ABDNAZ
treatment with neurological exam, history and symptom-directed
physical examination, and clinical laboratory testing [0167] During
the maintenance phase, patients are to be evaluated on Day 1.+-.2
days of each 4-week cycle. Each evaluation will consist of
neurological examination, history and symptom-directed physical
examination, ECOG performance status, FACT-BR, Barthel Index of
ADLs, and neurocognitive function [0168] Safety labs every 4 weeks
on Day 1.+-.2 days for Cycles 2+(CBC with differential,
comprehensive chemistry panel, liver function tests). Radiologic
evaluation will occur every 8 weeks as per Standard of Care [0169]
Patients are to be evaluated with contrast-enhanced MRI w/GAD prior
to starting Cycle 1 and at least every 2 months (after every 2
cycles) of ABDNAZ/temozolomide as well as neurocognitive testing at
4 months.+-.7 days (1 month=4 weeks or 28 days) after completion of
radiation therapy/ABDNAZ [0170] Collection of concomitant
medications at each clinic visit [0171] Collection of adverse
events (AEs) at each clinic visit
General Features
[0172] During Upfront Therapy and Maintenance Therapy described
above, temozolomide is to be administered continuously from day 1
of radiotherapy to the last day of radiation at a daily oral dose
of 75 mg/m.sup.2 for a maximum of 49 days (to allow for treatments
interruptions, for example, over holidays). The drug will be
administered at night just before bedtime. The dose will be
determined using actual body surface area (BSA) as defined by the
method of DuBois and DuBois. Capsules of temozolomide are available
in 5, 20, 100, 140, 180, and 250 mg. The daily dose is to be
rounded to the nearest 5 mg. Patients are to be instructed to
swallow the capsules whole, in rapid succession, without chewing
them. If vomiting occurs during the course of treatment, no
re-dosing of the patient is allowed before the next scheduled dose.
The capsules should be taken on an empty stomach, therefore a
minimum of 2 hours after eating and with no food consumption for at
least 1 hour after temozolomide administration. Water is allowed
during the fast period. Administration of the higher dosing regimen
during the maintenance phase of the protocol should also be at
night. However, prophylaxis with a 5-HT3 antagonist is recommended
prior to administration of the first few temozolomide doses and may
be administered orally 30 to 60 minutes before temozolomide
treatment.
[0173] For radiation therapy, 2 Gy of radiation is to be given
daily 5 days per week for a total of 60 Gy over 6 weeks. All fields
shall be treated during each treatment session. Doses are specified
such that at least 95% of the planning treatment volume (PTV) shall
receive 100% of the prescribed dose; Dose Volume Histograms (DVHs)
may be necessary to make this selection. Radiation therapy will be
delivered using standard dose and fractionation as described below:
[0174] Simulation, Immobilization: Patients are to be treated in
the supine position. Adequate immobilization and reproducibility of
position will be ensured using thermoplastic mask. [0175] Target:
The target volume for both the initial volume and the conedown
volume shall be based on CT/MRI. This initial target volume shall
include the contrast-enhancing lesion and surrounding edema (if it
exists) demonstrated on CT/MRI plus a margin. If no surrounding
edema is present, the initial target volume should include the
contrast enhancing lesion plus a margin. The initial target volume
will be treated to 46 Gy in 23 fractions. After 46 Gy, the tumor
volume for the conedown treatment should include the contrast
enhancing lesion (without edema) on the CT/MRI scan plus a margin.
Isodose distributions for the initial target volume and the
conedown target volume are required on all patients, including
those treated with parallel opposed fields. The inhomogeneity
within the target volume shall be kept to 10%. The minimum dose to
the target volume should be kept within 10% of the dose at the
center of the volume. [0176] Dose Limitations: The lens and
cervical spine should be shielded from the direct beam at all
times. When possible to do without shielding gross tumor, attempts
should be made to limit the dose to the optic chiasm to 54 Gy, the
retina of at least one eye (but preferably both) to 50 Gy, and the
brainstem to 60 Gy. When the optic chiasm must be included in the
full dose, then there may be a finite unknown risk of developing
blindness. [0177] Dose Specification: Radiotherapy is to be
delivered with a daily fraction size of 2.0 Gy per fraction given 5
days a week for a total of 60 Gy over 6 weeks. [0178] Technique:
Treatment will be delivered with megavoltage machines with a
minimum energy of 6 MV photons. All fields will be treated during
each treatment session. Treatment plans may include opposed lateral
fields, a wedge pair of fields, rotation, or multiple field
techniques. Intensity-modulated inverse-planned approaches are
permitted. Any of the methods of IMRT (including tomotherapy) may
be used, subject to protocol localization and dosimetry
constraints. CT-based treatment planning is desirable to assure
accuracy in the selection of field arrangements. MRI-fusion for
accurate target delineation is recommended.
Example 2--Treatment of Human Patients Suffering from a
Glioblastoma or Malignant Glioma
[0179] Adult human patients having a gliobastoma or malignant
glioma are to be treated using a combination of ABDNAZ (by
intravenous administration at a dose ranging from 0.5 mg to 4.0
mg), temozolomide, and radiation therapy (RT) according to the
treatment protocol described below.
Treatment Protocol
Upfront Therapy
[0180] Patients are to receive oral temozolomide 75 mg/m.sup.2
daily for 6 weeks and undergo conformal or intensity-modulated
radiotherapy (60 Gy in 2 Gy fractions) 5 days a week for 6 weeks.
Patients are also to receive ABDNAZ by intravenous administration
once weekly for 6 weeks administered at one of four dose levels
(0.5 mg, 1.0 mg, 2.0 mg, or 4.0 mg) beginning concurrently with
temozolomide and radiotherapy. Cohorts of 3-6 patients will receive
escalating doses of ABDNAZ until the maximum feasible dose (MFD) or
maximum tolerated dose (MTD) is determined. The MTD is defined as
the dose preceding that at which 2 of 3 or 2 of 6 subjects
experience dose-limiting toxicity. Administration of temozolomide
is no sooner than 4 hours after administration of ABDNAZ. ABDNAZ is
preferably administered within three hours prior to administration
of radiation therapy.
Maintenance Therapy
[0181] Beginning 4-6 weeks after completion of radiotherapy,
patients are to receive oral temozolomide [150 mg/m.sup.2 orally
daily for on days 1-5 during cycle 1 (28 days) and 200 mg/m.sup.2
orally daily on days 1-5 during cycles 2-6 (where each cycle is 28
days)] and once weekly ABDNAZ by intravenous administration at a
dose ranging from 0.5 mg to 4.0 mg for six months. Administration
of temozolomide is no sooner than 4 hours after administration of
ABDNAZ.
Patient Evaluation Procedure
[0182] Patients are to be evaluated by a neuro-oncologist,
radiation oncologist, or medical oncologist prior to the start of
any treatment. Efficacy of the therapy may be evaluated according
to procedure described below.
Pre-Treatment Evaluation (within 14.+-.7 Days Prior to First Dose
of Study Drug)
[0183] Patients may be evaluated using the following criteria prior
to treatment with the therapy to assess nature and extent of the
gliobastoma or malignant glioma: [0184] Contrast-enhanced MRI
[0185] Complete history and general physical exam [0186] Detailed
neurological examination [0187] Safety labs: CBC with differential,
comprehensive chemistry panel with liver function tests [0188]
Karnofsky performance status [0189] Documentation of primary tumor
histology [0190] Documentation of steroid and anticonvulsant doses
and any other concomitant medications. The newer antiepilieptic
drugs (levetiracetam, pregabalin, lamotrigine, lacosamide,
topiramate) are generally preferred over carbamazepine, phenytoin,
phenobarbital, or valproic acid, which stimulate the hepatic
cytochrome P450 (CYP) system.
Evaluation During Radiation Therapy and ABDNAZ Therapy
[0191] Patients may be evaluated using the following criteria
during treatment with the therapy to assess nature and extent of
the gliobastoma or malignant glioma: [0192] Clinical visit once per
week to include neurological examination, history and physical
examination and clinical laboratory testing [0193] Documentation of
concomitant medications at each clinic visit [0194] Collection of
adverse events (AEs) at each clinic visit [0195] Skin within the
treatment portal shall be examined once per week during radiation
treatment [0196] Serum magnesium test during week 4
Evaluation After Completion of Radiation Therapy and ABDNAZ
Therapy
[0197] Patients may be evaluated using the following criteria after
treatment with the therapy to assess nature and extent of the
gliobastoma or malignant glioma: [0198] Patients are to be
evaluated 3-5 weeks after completion of radiation therapy and
ABDNAZ treatment with neurological exam, history and
symptom-directed physical examination, adverse events, concomitant
medications, and clinical laboratory testing [0199] During the
maintenance phase, patients are to be evaluated on Day 1.+-.2 days
of each 4-week cycle. Each evaluation will consist of neurological
examination, history and symptom-directed physical examination, and
KPS/ECOG performance status [0200] Safety labs every 4 weeks on Day
1.+-.2 days for Cycles 2+(CBC with differential, comprehensive
chemistry panel, liver function tests). Radiologic evaluation will
occur every 8 weeks as per Standard of Care [0201] Patients are to
be evaluated with contrast-enhanced MM w/GAD prior to starting
Cycle 1 and at least every 2 months (after every 2 cycles) of
ABDNAZ/temozolomide as well as neurocognitive testing at 4
months.+-.7 days (1 month=4 weeks or 28 days) after completion of
radiation therapy/ABDNAZ [0202] Collection of concomitant
medications at each clinic visit [0203] Collection of adverse
events (AEs) at each clinic visit
General Features
[0204] During Upfront Therapy and Maintenance Therapy described
above, temozolomide is to be administered continuously from day 1
of radiotherapy to the last day of radiation at a daily oral dose
of 75 mg/m.sup.2 for a maximum of 49 days (to allow for treatments
interruptions, for example, over holidays). The drug will be
administered at night just before bedtime. The dose will be
determined using actual body surface area (BSA) as defined by the
method of DuBois and DuBois. Capsules of temozolomide are available
in 5, 20, 100, 140, 180, and 250 mg. The daily dose is to be
rounded to the nearest 5 mg. Patients are to be instructed to
swallow the capsules whole, in rapid succession, without chewing
them. If vomiting occurs during the course of treatment, no
re-dosing of the patient is allowed before the next scheduled dose.
The capsules should be taken on an empty stomach, therefore a
minimum of 2 hours after eating and with no food consumption for at
least 1 hour after temozolomide administration. Water is allowed
during the fast period. Administration of the higher dosing regimen
during the maintenance phase of the protocol should also be at
night. However, prophylaxis with a 5-HT3 antagonist is recommended
prior to administration of the first few temozolomide doses and may
be administered orally 30 to 60 minutes before temozolomide
treatment.
[0205] For radiation therapy, 2 Gy of radiation is to be given
daily 5 days per week for a total of 60 Gy over 6 weeks. All fields
shall be treated during each treatment session. Doses are specified
such that at least 95% of the planning treatment volume (PTV) shall
receive 100% of the prescribed dose; Dose Volume Histograms (DVHs)
may be necessary to make this selection. Radiation therapy will be
delivered using standard dose and fractionation as described below:
[0206] Simulation, Immobilization: Patients are to be treated in
the supine position. Adequate immobilization and reproducibility of
position will be ensured using thermoplastic mask. [0207] Target:
The target volume for both the initial volume and the conedown
volume shall be based on CT/MRI. This initial target volume shall
include the contrast-enhancing lesion and surrounding edema (if it
exists) demonstrated on CT/MRI plus a margin. If no surrounding
edema is present, the initial target volume should include the
contrast enhancing lesion plus a margin. The initial target volume
will be treated to 46 Gy in 23 fractions. After 46 Gy, the tumor
volume for the conedown treatment should include the contrast
enhancing lesion (without edema) on the CT/MRI scan plus a margin.
Isodose distributions for the initial target volume and the
conedown target volume are required on all patients, including
those treated with parallel opposed fields. The inhomogeneity
within the target volume shall be kept to 10%. The minimum dose to
the target volume should be kept within 10% of the dose at the
center of the volume. [0208] Dose Limitations: The lens and
cervical spine should be shielded from the direct beam at all
times. When possible to do without shielding gross tumor, attempts
should be made to limit the dose to the optic chiasm to 54 Gy, the
retina of at least one eye (but preferably both) to 50 Gy, and the
brainstem to 60 Gy. When the optic chiasm must be included in the
full dose, then there may be a finite unknown risk of developing
blindness. [0209] Dose Specification: Radiotherapy is to be
delivered with a daily fraction size of 2.0 Gy per fraction given 5
days a week for a total of 60 Gy over 6 weeks. [0210] Technique:
Treatment will be delivered with megavoltage machines with a
minimum energy of 6 MV photons. All fields will be treated during
each treatment session. Treatment plans may include opposed lateral
fields, a wedge pair of fields, rotation, or multiple field
techniques. Intensity-modulated inverse-planned approaches are
permitted. Any of the methods of IMRT (including tomotherapy) may
be used, subject to protocol localization and dosimetry
constraints. CT-based treatment planning is desirable to assure
accuracy in the selection of field arrangements. MRI-fusion for
accurate target delineation is recommended.
Example 3--Administration of ABDNAZ and Temozolomide to a GBM14
TMZ-S Patient-Derived Cell Line and a GBM14 TMZ-R Patient-Derived
Cell Line
[0211] Temozolomide-sensitive human GBM14 (GBM14 TMZ-S) patient
derived cell line cells were treated with one of the following (i)
ABDNAZ, (ii) temozolomide, or (iii) ABDNAZ and temozolomide. In a
separate experiment, temozolomide-resistant human GBM14 (GBM14
TMZ-R) patient derived cell line cells were treated with one of the
following (i) ABDNAZ, (ii) temozolomide, or (iii) ABDNAZ and
temozolomide. Experimental procedures and results are provided
below.
Part I--Procedures
[0212] In a first experiment, temozolomide-sensitive human GBM14
(GBM14 TMZ-S) patient derived cell line cells were treated with one
of the following (i) ABDNAZ at a concentration of 2 .mu.M, (ii)
temozolomide at a concentration of 100 .mu.M, or (iii) ABDNAZ (at a
concentration of 2 .mu.M) and temozolomide (at a concentration of
100 .mu.M). WST-1 assay was used to assess the effect of treatment
on cell viability over the time of three days. The presence of live
cells is detected by absorbance at 440 nm in the assay. Data are
presented as the mean.+-.3 standard deviations from three separate
performances of the experiment.
[0213] In a second experiment, temozolomide-resistant human GBM14
(GBM14 TMZ-R) patient derived cell line cells were treated with one
of the following (i) ABDNAZ at a concentration of 2 .mu.M, (ii)
temozolomide at a concentration of 100 .mu.M, or (iii) ABDNAZ (at a
concentration of 2 .mu.M) and temozolomide (at a concentration of
100 .mu.M). The presence of live cells is detected by absorbance at
440 nm in the assay. WST-1 assay was used to assess the effect of
treatment on cell viability over the time of three days. Data are
presented as the mean.+-.3 standard deviations from three separate
performances of the experiment.
Part II--Results
[0214] Results are presented in FIG. 1 showing response from the
GBM14 TMZ-S patient derived cell line and FIG. 2 showing response
from the GBM14 TMZ-R patient derived cell line. As indicated by
data in FIGS. 1 and 2, administration of ABDNAZ and temozolomide
together produced a greater amount of cell death as measured by
lack of absorbance at 440 nm.
Example 4--Administration of ABDNAZ and Temozolomide to NSCG Cells
In Vitro
[0215] Cells from temozolomide-resistant murine EGFRvIII/Arfko
neural stem cell-derived glioma (NSCG) cell line were treated with
one of the following: (i) ABDNAZ (RRx-001), (ii) temozolomide
(TMZ), or (iii) ABDNAZ and temozolomide. Experimental procedures
and results are provided below.
Part I--Procedures
[0216] Cells from temozolomide-resistant murine EGFRvIII/Arfko
neural stem cell-derived glioma (NSCG) cell line were treated with
one of the following (i) ABDNAZ at a concentration of 2 .mu.M, (ii)
temozolomide at a concentration of 100 .mu.M, or (iii) ABDNAZ (at a
concentration of 2 .mu.M) and temozolomide (at a concentration of
100 .mu.M). WST-1 assay was used to assess the effect of treatment
on cell viability over the time of five days. The presence of live
cells is detected by absorbance at 440 nm in the assay. Data are
presented as the mean.+-.3 standard deviations from three separate
performances of the assay.
Part II--Results
[0217] Results are presented in FIG. 3, where the data indicate
that administration of ABDNAZ and temozolomide together produced a
greater amount of cell death as measured by lack of absorbance at
440 nm. Data are presented as the mean.+-.3 standard deviations
from three separate performances of the assay.
Example 5--Administration of ABDNAZ and Temozolomide to Mice
Implanted with NSCG Tumors
[0218] Mice implanted with temozolomide-resistant EGFRvIII/Arfko
GBM (NSCG) cells were treated with (i) ABDNAZ (RRx-001, 10 mg/kg,
intraperitoneal injection), (ii) temozolomide (TMZ)(40 mg/kg, oral
gavage), or (iii) ABDNAZ (10 mg/kg, intraperitoneal injection) and
temozolomide (40 mg/kg, oral gavage). Experimental procedures and
results are provided below.
Part I--Procedures
[0219] NSCG tumors were intracranially injected into FVBN mice.
Mice to be treated were treated with one of the following (i)
ABDNAZ (10 mg/kg, intraperitoneal injection), (ii) temozolomide (40
mg/kg, oral gavage), or (iii) ABDNAZ (10 mg/kg, intraperitoneal
injection) and temozolomide (40 mg/kg, oral gavage). In a first
experiment, treatment (i.e., administration of ABDNAZ (RRx-001),
temozolomide (TMZ), or both ABDNAZ and temozolomide) was started
five days after intracranial injection of NSCG cells. The control
population of mice contained ten mice, the group receiving only
ABDNAZ had twelve mice, the group receiving only temozolomide had
twelve mice, and the group receiving both ABDNAZ and temozolomide
had sixteen mice. Mouse survival was monitored over time.
[0220] In a second experiment, treatment (i.e., administration of
ABDNAZ (RRx-001), temozolomide (TMZ), or both ABDNAZ and
temozolomide) was started ten days after intracranial injection of
NSCG cells. The control population of mice contained three mice,
the group receiving only ABDNAZ had five mice, the group receiving
only temozolomide had four mice, and the group receiving both
ABDNAZ and temozolomide had six mice. Mouse survival was monitored
over time.
Part II--Results
[0221] Results are presented in FIGS. 4 and 5 and Tables 1 and 2
below. FIG. 4 is a graph showing percent survival of subjects over
time, in the experiment in which treatment (i.e., administration of
ABDNAZ (RRx-001), temozolomide (TMZ), or both ABDNAZ and
temozolomide) was started five days after intracranial injection of
NSCG cells. The abbreviation "CTL" in FIG. 4 refers to control
subjects. Table 1 shows median survival time (in days) observed in
the experiment in which treatment (i.e., administration of ABDNAZ
(RRx-001), temozolomide (TMZ), or both ABDNAZ and temozolomide) was
started five days after intracranial injection of NSCG cells.
[0222] FIG. 5 is a graph showing percent survival of subjects over
time, in the experiment in which treatment (i.e., administration of
ABDNAZ (RRx-001), temozolomide (TMZ), or both ABDNAZ and
temozolomide) was started ten days after intracranial injection of
NSCG cells. The abbreviation "CTL" in FIG. 5 refers to control
subjects. Table 2 shows median survival time (in days) observed in
the experiment in which treatment (i.e., administration of ABDNAZ
(RRx-001), temozolomide (TMZ), or both ABDNAZ and temozolomide) was
started ten days after intracranial injection of NSCG cells.
TABLE-US-00011 TABLE 1 Subjects Population Population Population
Receiving Receiving Only Receiving Both Control Only TMZ ABDNAZ
ABDNAZ & TMZ Median 22.2 22.3 25.3 30.4 Survival (ns) (p =
0.072) (p = 0.003) Time (days)
TABLE-US-00012 TABLE 2 Subjects Population Population Population
Receiving Receiving Only Receiving Both Control Only TMZ ABDNAZ
ABDNAZ & TMZ Median 22.1 22.3 22.5 27.2 Survival (ns) (ns) (p =
0.174) Time (days)
Example 6--Administration of ABDNAZ and Temozolomide to Mice
Implanted with NSCG Tumors
[0223] Mice implanted with TMZ-resistant EGFRvIII/Arfko GBM tumors
(NSCG tumors) were treated with ABDNAZ (RRx-001), temozolomide
(TMZ), or both ABDNAZ and temozolomide. Experimental procedures and
results are provided below.
Part I--Procedures
[0224] NSCG tumors were orthotopically implanted in FVBN mice.
Then, the mice were treated with one of the following (i) ABDNAZ
(10 mg/kg, intraperitoneal injection), (ii) temozolomide (40 mg/kg,
oral gavage), or (iii) ABDNAZ (10 mg/kg, intraperitoneal injection)
and temozolomide (40 mg/kg, oral gavage). Percent apoptosis of CC3+
cells was evaluated.
Part II--Results
[0225] The amount of CC3+ cell apoptosis detected in the assay is
shown in FIG. 6. As indicated by data in FIG. 6, administration of
ABDNAZ and temozolomide together produced the highest percentage of
CC3+ cell apoptosis. The abbreviation "CTL" refers to control mice;
the symbol *** refers to p<0.001.
Example 7--Administration of ABDNAZ and Temozolomide to Mice
Implanted with Brain Tumors
[0226] Mice implanted with brain tumors were treated with ABDNAZ,
temozolomide (TMZ), or both ABDNAZ and temozolomide. Experimental
procedures and results are provided below.
Part I--Procedures
[0227] Brain tumors were orthotopically implanted in the brain of
mice. Then, the mice were treated with one of the following (i)
ABDNAZ, (ii) temozolomide, or (iii) ABDNAZ followed by
administration of temozolomide 4 hours later. ABDNAZ (10 mg/kg) was
administered via tail vein 4 hours before any temozolomide (20
mg/kg) via tail vein once weekly for 4 weeks. Twenty-four hours
after temozolomide administration, tumor-bearing mice were
euthanized and brain tumor tissue was collected and dissected.
Temozolomide levels in tumor tissues were measured.
Part II--Results
[0228] The concentration of temozolomide (TMZ) detected in brain
tumor tissue of the mice is shown in FIG. 7. As indicated by data
in FIG. 7, administration of ABDNAZ prior to administration of
temozolomide resulted in a greater concentration of temozolomide in
the brain tumor tissue.
Example 8--Administration of ABDNAZ and Irinotecan to Mice
Implanted with Human Glioblastoma GBM43 Brain Tumors
[0229] Mice implanted with human glioblastoma GBM43 brain tumors
were treated with ABDNAZ, irinotecan, or both ABDNAZ and
irinotecan. Experimental procedures and results are provided
below.
Part I--Procedures
[0230] Human glioblastoma GBM43 tumors were orthotopically
implanted in the brain of immunocompromised mice. Then, the mice
were treated with one of the following (i) ABDNAZ, (ii) irinotecan,
or (iii) ABDNAZ followed by administration of irinotecan 4 hours
later. Twenty-four hours after irinotecan administration,
tumor-bearing mice were euthanized and brain tumor tissue was
collected and dissected. Irinotecan levels in tumor tissues were
measured.
Part II--Results
[0231] The concentration of irinotecan detected in brain tumor
tissue of the mice is shown in FIG. 8. As indicated by data in FIG.
8, administration of ABDNAZ prior to administration of irinotecan
resulted in a greater concentration of irinotecan in the brain
tumor tissue.
INCORPORATION BY REFERENCE
[0232] The entire disclosure of each of the patent documents and
scientific articles referred to herein is incorporated by reference
for all purposes.
EQUIVALENTS
[0233] The invention may be embodied in other specific forms
without departing from the spirit or essential characteristics
thereof. The foregoing embodiments are therefore to be considered
in all respects illustrative rather than limiting the invention
described herein. Scope of the invention is thus indicated by the
appended claims rather than by the foregoing description, and all
changes that come within the meaning and range of equivalency of
the claims are intended to be embraced therein.
* * * * *