U.S. patent application number 15/030567 was filed with the patent office on 2016-09-01 for treating lymphomas.
The applicant listed for this patent is MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH. Invention is credited to Svetomir N. MARKOVIC, Wendy K. NEVALA.
Application Number | 20160250351 15/030567 |
Document ID | / |
Family ID | 54834378 |
Filed Date | 2016-09-01 |
United States Patent
Application |
20160250351 |
Kind Code |
A1 |
MARKOVIC; Svetomir N. ; et
al. |
September 1, 2016 |
Treating Lymphomas
Abstract
This document provides methods and materials related to treating
lymphomas. For example, methods and materials relating to the use
of a composition containing albumin-containing
nanoparticle/antibody complexes (e.g., ABRAXANE.RTM./anti-CD20
polypeptide antibody complexes) to treat lymphomas are
provided.
Inventors: |
MARKOVIC; Svetomir N.;
(Rochester, MN) ; NEVALA; Wendy K.; (Rochester,
MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MAYO FOUNDATION FOR MEDICAL EDUCATION AND RESEARCH |
Rochester |
MN |
US |
|
|
Family ID: |
54834378 |
Appl. No.: |
15/030567 |
Filed: |
June 12, 2015 |
PCT Filed: |
June 12, 2015 |
PCT NO: |
PCT/US15/35505 |
371 Date: |
April 19, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62012190 |
Jun 13, 2014 |
|
|
|
Current U.S.
Class: |
424/183.1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 31/282 20130101; A61K 2039/505 20130101; C07K 16/2887
20130101; A61K 47/6929 20170801; A61P 35/00 20180101; C07K 2317/24
20130101; A61K 47/6849 20170801; C07K 16/30 20130101; A61K 38/38
20130101; A61K 39/3955 20130101; A61K 47/643 20170801; A61K 2039/54
20130101; A61K 31/337 20130101; A61K 2039/545 20130101; A61K
47/6803 20170801; A61K 39/3955 20130101; A61K 2300/00 20130101;
A61K 38/38 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 47/48 20060101
A61K047/48; A61K 31/337 20060101 A61K031/337; A61K 39/395 20060101
A61K039/395 |
Claims
1-72. (canceled)
73. A method for treating a mammal having lymphoma, said method
comprising administering to said mammal a composition comprising
nanoparticles containing albumin and placitaxel complexed with an
anti-CD20 polypeptide antibody under conditions wherein the length
of progression-free survival is increased.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Ser.
No. 62/012,190 file Jun. 13, 2014. This disclosure of the prior
application is considered part of (and is incorporated by reference
in) the disclosure of this application.
BACKGROUND
[0002] 1. Technical Field
[0003] This document relates to methods and materials involved in
treating lymphomas (e.g., mature B-cell neoplasms, mature T cell
neoplasms, mature natural killer neoplasms,
immunodeficiency-associated lymphoproliferative disorders, Hodgkin
lymphomas, and non-Hodgkin lymphomas. For example, this document
relates to methods and materials involved in using complexes
containing albumin-containing nanoparticies e.g., ABRAXANE.RTM.
nanoparticles) and antibodies (e.g., anti-CD20 polypeptide
antibodies such as Rituximab) to treat lymphomas.
[0004] 2. Background Information
[0005] Lymphomas are blood cancers that occur when B or T
lymphocytes become cancerous. They can develop in the lymph nodes,
spleen, bone marrow, blood, or other organs and eventually form a
tumor.
SUMMARY
[0006] This document provides methods and materials involved in
treating lymphomas (e.g., mature B-cell neoplasms, mature T cell
neoplasms, mature natural killer cell neoplasms,
immunodeficiency-associated lymphoproliferative disorders, Hodgkin
lymphomas, and non-Hodgkin lymphomas). For example, this document
provides methods and materials for using complexes containing
albumin-containing nanoparticles (e.g., ABRAXANE.RTM.
nanoparticles) and antibodies (e.g., anti-CD20 polypeptide
antibodies such as Rituximab) to treat lymphomas.
[0007] ABRAXANE.RTM. is available from Celgene Corp. and is a
nanopartick formulation that combines paclitaxel with human
albumin. Anti-CD20 polypeptide antibodies such as Rituximab are
available from Genentech Inc., Roche, and Aryogen Biopharma under
trade names such as Rituxan.TM., MabThera.TM., and Zytux.TM..
Rituximab is a chimeric monoclonal antibody against CD20
polypeptides presents on surface of lymphocyte cells (see, e.g.,
U.S. Pat. No. 5,736,137).
[0008] As described herein, in vitro mixing of albumin-containing
nanoparticles ABRAXANE.RTM. nanoparticies) and antibodies e.g.,
Rituximab) can result in the formation of macromolecular complexes,
the characteristics of which (e.g., size, antibody content, or
chemotherapeutic drug content) can be customized depending on need.
In some cases, such macromolecular complexes can retain antibody
mediated target binding specificity, can retain or exhibit enhanced
chemotherapeutic tumor cell cytotoxicity, and can exhibit no
additional toxicity beyond that of ABRAXANE.RTM. nanoparticles
alone. As also described herein, contacting ABRAXANE.RTM. with an
anti-CD20 polypeptide antibody (e.g., Rituximab) prior to
administration to a human (e.g., a human lymphoma cancer patient)
can result in a complex that, when administered as a complex, has
an increased ability to treat lymphoma as compared to a treatment
regimen that includes administering ABRAXANE.RTM. and the anti-CD20
polypeptide antibody separately in a manner that does not form
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes.
[0009] The methods and materials provided herein can be used to
increase the progression-free survival rate in lymphoma patients.
Increasing progression-free survival can allow lymphoma cancer
patients to live longer.
[0010] In general, one aspect of this document features a method
for treating a mammal having lymphoma. The method comprises, or
consisting essentially of administering to the mammal a composition
comprising nanoparticles containing albumin and placitaxel
complexed with an anti-CD20 polypeptide antibody under conditions
wherein the length of progression-free survival is increased. The
mammal can be a human. The lymphoma can be a Hodgkin lymphomas. The
composition can comprise Rituximab complexed with the
nanoparticles. The composition can comprise an alkylating agent
complexed with the nanoparticles. The alkylating agent can be a
platinum compound. The platinum compound can be carboplatin. The
anti-CD20 polypeptide antibody can be a humanized antibody. The
anti-CD20 polypeptide antibody can be a chimeric antibody. The
composition can be administered by injection. The progression-free
survival can be increased by 15 percent. The progression-free
survival can be increased by 25 percent. The progression-free
survival can be increased by 50 percent. The progression-free
survival can be increased by 75 percent. The progression-free
survival can be increased by 100 percent. The composition can be
administered under conditions wherein the time to progression is
increased.
[0011] In another aspect, this document features a method for
treating a mammal having lymphoma. The method comprises, or
consists essentially of, administering, to the mammal, a
composition comprising albumin-containing nanoparticle/antibody
complexes, wherein the average diameter of the complexes is between
0.1 and 0.9 .mu.m, and wherein the antibody is an anti-CD20
antibody. The mammal can be a human The lymphoma can be a mature
B-cell neoplasm. The lymphoma can be a mature T neoplasm. The
lymphoma can be a Hodgkin lymphoma. The albumin-containing
nanopartictelantibody complexes can be ABRAXANE.RTM./Rituximab
complexes. The composition or the albumin-containing
nanopartictelantibody complexes can comprise an atkylating agent.
The aikyiating agent can be a platinum compound. The platinum
compound can be carboplatin. The composition can comprise an
anti-inflammatory agent. The anti-CD20 polypeptide antibodies can
be humanized antibodies. The anti-CD20 polypeptide antibodies can
be chimeric antibodies. The composition can be administered by
injection. The administration of the composition can be effective
to increase progression-free survival by 25 percent. The
administration of the composition can be effective to increase
progression-free survival by 50 percent. The administration of the
composition can be effective to increase progression-free survival
by 75 percent. The administration of the composition can be
effective to increase progression-free survival by 100 percent. The
administration of the composition can be under conditions wherein
the median time to progression for a population of mammals with the
lymphoma is at least 150 days. The administration of the
composition can be under conditions wherein the median time to
progression for a population of mammals with the lymphoma is at
least 165 days. The administration of the composition can be under
conditions wherein the median time to progression for a population
of mammals with the lymphoma is at least 170 days. The average
diameter of the complexes can be from 0,1 .mu.m to 0.3 .mu.m. The
average diameter of the complexes can be from 0.15 .mu.m to 0.3
.mu.m. The average diameter of the complexes can be from 0.2 .mu.m
to 0.5 .mu.m. The average diameter of the complexes can be from 0.3
.mu.m to 0.5 .mu.m. The average diameter of the complexes can be
from 0.2 .mu.m to 0.8 .mu.m. The average diameter of the complexes
can be from 0.2 .mu.m to 0.7 .mu.m.
[0012] In another aspect, this document features a method for
treating a mammal having lymphoma. The method comprises, or
consists essentially of, administering, to the mammal, a
composition comprising albumin-containing nanoparticle/antibody
complexes, wherein the average diameter of at least 5 percent of
the complexes of the composition is between 0.1 and 0.9 .mu.m, and
wherein the antibodies are anti-CD20 antibodies. The mammal can be
a human. The lymphoma can be a mature B-cell neoplasm. The lymphoma
can be a mature T neoplasm. The lymphoma can be a Hodgkin lymphoma.
The method of claim 43, wherein the albumin-containing
nanoparticte/antibody complexes can be ABRAXANE.RTM./Rituximab
complexes. The composition or the albumin-containing
nanoparticte/antibody complexes can comprise an alkylating agent.
The alkylating agent can be a platinum compound. The platinum
compound can be carboplatin. The composition can comprise an
anti-inflammatory agent. The anti-CD20 polypeptide antibodies can
be humanized antibodies. The anti-CD20 polypeptide antibodies can
be chimeric antibodies. The composition can be administered by
injection. The administration of the composition can be effective
to increase progression-free survival by 25 percent. The
administration of the composition can be effective to increase
progression-free survival by 50 percent. The administration of the
composition can be effective to increase progression-free survival
by 75 percent. The administration of the composition can be
effective to increase progression-free survival by 100 percent. The
administration of the composition can be under conditions wherein
the median time to progression for a population of mammals with the
lymphoma is at least 150 days. The administration of the
composition can be under conditions wherein the median time to
progression for a population of mammals with the lymphoma is at
least 165 days. The administration of the composition can be under
conditions wherein the median time to progression for a population
of mammals with the lymphoma is at least 170 days. The average
diameter of at least 5 percent of the complexes of the composition
can be from 0.2 .mu.m to 0.9 run. The average diameter of at least
5 percent of the complexes of the composition can be from 0.2 .mu.m
to 0.8 .mu.m. The average diameter of at least 5 percent of the
complexes of the composition can be from 0.2 .mu.m to 0.7 .mu.m.
The average diameter of at least 5 percent of the complexes of the
composition can be from 0.2 .mu.m to 0.6 .mu.m. The average
diameter of at least 5 percent of the complexes of the composition
can be from 0.2 .mu.m to 0.5 .mu.m. The average diameter of at
least 5 percent of the complexes of the composition can be from 0.2
.mu.m to 0.4 .mu.m. The average diameter of at least 10 percent of
the complexes of the composition can be between 0.1 and 0.9 .mu.m.
The average diameter of at least 50 percent of the complexes of the
composition can be between 0.1 and 0.9 .mu.m. The average diameter
of at least 75 percent of the complexes of the composition can be
between 0.1 and 0.9 .mu.m. The average diameter of at least 90
percent of the complexes of the composition can be between and 0.9
.mu.m.
[0013] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used to practice the invention, suitable
methods and materials are described below. All publications, patent
applications, patents, and other references mentioned herein are
incorporated by reference in their entirety. In case of conflict,
the present specification, including definitions, will control. In
addition, the materials, methods, and examples are illustrative
only and not intended to be limiting.
[0014] The details of one or more embodiments of the invention are
set forth in the accompanying drawings and the description below.
Other features, objects, and advantages of the invention will be
apparent from the description and drawings, and from the
claims.
DESCRIPTION OF DRAWINGS
[0015] FIG. 1 is a graph plotting the particle size distribution
for ABRAXANE.RTM. (ABX) dissolved in Rituxan (RIT) as determined
using a Mastersizer 2000E (Malvern Instruments Ltd.,
Worcestershire, England). ABX (10 mg/mL) was reconstituted in 1 mL
of the indicated amount of RIT, and the mixtures were incubated at
room temperature for 30 minutes,
[0016] FIG. 2 is a graph plotting percent change at seven days in
tumor size from baseline of lymphoma (Daudi cell line) tumor
bearing nude mice treated with PBS, Rituxan (RIT; 12 mg/kg) only,
ABRAXANE.RTM. (30 mg/kg) only, Rituxan (RIT; 12 mg/kg) followed by
ABRAXANE.RTM. (30 mg/kg) one day later, or AR160 complexes (0.159
.mu.m; complexes where ABRAXANE.RTM. (10 mg/mL) was premixed with 2
mg/mL Rituxan and incubated for 60 minutes before injection).
[0017] FIG. 3 is a Kaplan Meier graph plotting survival of lymphoma
(Daudi cell line) tumor bearing nude mice treated with PBS, Rituxan
(RIT; 12 mg/kg) only, ABRAXANE.RTM. (30 mg/kg) only, Rituxan (RIT;
12 mg/kg) followed by ABRAXANE.RTM. (30 mg/kg) one day later, or
AR160 complexes (0.159 .beta.m; complexes where ABRAXANE.RTM. (10
mg/mL) was premixed with 2 mg/mL Rituxan and incubated for 60
minutes before injection).
DETAILED DESCRIPTION
[0018] This document provides methods and materials involved in
treating lymphomas (e.g., mature B-cell neoplasms, mature T cell
neoplasms, mature natural killer cell neoplasms,
immunodeficiency-associated lymphoproliferative disorders, Hodgkin
lymphomas, and non-Hodgkin lymphomas). For example, this document
provides methods and materials for using complexes containing
albumin-containing nanoparticles (e.g., ABRAXANE.RTM.
nanoparticles) and antibodies (e.g., anti-CD2( )polypeptide
antibodies such as Rituximab) to treat lymphomas.
[0019] The methods and materials provided herein can be used to
treat any type of lymphoma. For example, the methods and materials
provided herein can be used to treat mature B-cell neoplasms,
mature T cell neoplasms, mature natural killer cell neoplasms,
immunodeficiency-associated lymphoproliferative disorders, Hodgkin
lymphomas, or non-Hodgkin lymphomas. In some cases, the methods and
materials provided herein can be used to treat lymphomas in any
type of mammal including, without limitation, mice, rats, dogs,
cats, horses, cows, pigs, monkeys, and humans.
[0020] In some cases, complexes containing albumin-containing
nanoparticles (e.g., ABRAXANE.RTM. nanoparticles) and antibodies
(e.g., anti-CD20 polypeptide antibodies such as Rituximab) can be
designed to have an average diameter that is greater than 1 .mu.m.
For example, appropriate concentrations of albumin-containing
nanoparticles and antibodies can be used such that complexes having
an average diameter that is greater than 1 .mu.m are formed. In
some cases, manipulations such as centrifugation can be used to
form preparations of albumin-containing nanoparticle/antibody
complexes where the average diameter of those complexes is greater
than 1 .mu.m. In some cases, the preparations of albumin-containing
nanoparticle/antibody complexes provided herein can have an average
diameter that is between 1 .mu.m and 5 .mu.m e.g., between 1.1
.mu.m and 5 .mu.m, between 1.5 .mu.m and 5 .mu.m, between 2 .mu.m
and 5 .mu.m, between 2.5 .mu.m and 5 .mu.m, between 3 .mu.m and 5
.mu.m, between 3.5 .mu.m and 5 .mu.m, between 4 .mu.m and 5 .mu.m,
between 4.5 .mu.m and 5 .mu.m, between 1.1 .mu.m and 4.5 .mu.m,
between 1.1 .mu.m and 4 .mu.m, between 1.1 .mu.m and 3.5 .mu.m,
between 1.1 .mu.m and 3 .mu.m, between 1.1 .mu.m and 2.5 .mu.m,
between 1.1 .mu.m and 2 .mu.m, or between 1.1 .mu.m and 1.5 .mu.m).
Preparations of albumin-containing nanoparticle/antibody complexes
provided herein having an average diameter that is between 1 .mu.m
and 5 .mu.m can be administered systemically (e.g., intravenously)
to treat lymphomas located within a mammal's body. In some cases,
the preparations of albumin-containing nanoparticie/antibody
complexes provided herein can have an average diameter that is
between 5 .mu.m and 50 .mu.m (e.g., between 6 .mu.m and 50 .mu.m,
between 7 .mu.m and 50 .mu.m, ween 10 .mu.m and 50 .mu.m, between
15 .mu.m and 50 .mu.m, between 20 .mu.m and 50 .mu.m, between 25
.mu.m and 50 .mu.m, between 30 .mu.m and 50 .mu.m, between 35 .mu.m
and 50 .mu.m, between 5 .mu.m and 45 .mu.m, between 5 .mu.m and 40
.mu.m, between 5 .mu.m and 35 .mu.m, between 5 .mu.m and 30 .mu.m,
between 5 .mu.m and 25 .mu.m, between 5 .mu.m and 20 .mu.m, between
5 .mu.m and 15 .mu.m, or between 10 .mu.m and 30 .mu.m).
Preparations of albumin-containing nanoparticie/antibody complexes
provided herein having an average diameter that is between 5 .mu.m
and 50 .mu.m can be administered into a tumor (e.g.,
intratumorally) or in a region of a tumor located within a mammal's
body.
[0021] In some cases, a preparation of albumin-containing
nanoparticle/antibody complexes provided herein can have greater
than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99
percent) of the complexes having a diameter that is between 1 .mu.m
and 5 .mu.m (e.g., between 1.1 .mu.m and 5 .mu.m, between 1.5 .mu.m
and 5 .mu.m, between 2 .mu.m and 5 .mu.m, between 2.5 .mu.m and 5
.mu.m, between 3 .mu.m and 5 .mu.m, between 3.5 .mu.m and 5 .mu.m,
between 4 .mu.m and 5 .mu.m, between 4.5 .mu.m and 5 .mu.m, between
1.1 .mu.m and 4.5 .mu.m, between 1.1 .mu.m and 4 .mu.m, between 1.1
.mu.m and 3.5 .mu.m, between 1.1 .mu.m and 3 .mu.m, between 1.1
.mu.m and 2.5 .mu.m, between 1.1 .mu.m and 2 .mu.m, or between 1.1
.mu.m and 1.5 .mu.m). Preparation of albumin-containing
nanoparticle/antibody complexes provided herein having greater than
60 percent (e,g., greater than 65, 70, 75, 80, 90, 95, or 99
percent) of the complexes with a diameter that is between 1 .mu.m
and 5 .mu.m can be administered systemically (e.g., intravenously)
to treat lymphomas located within a mammal's body. In some cases, a
preparation of albumin-containing nanoparticle/antibody complexes
provided herein can have greater than 60 percent (e.g., greater
than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes having
a diameter that is between 5 .mu.m and 50 .mu.m (e.g., between 6
.mu.m and 50 .mu.m, between 7 .mu.m and 50 .mu.m, between 10 .mu.m
and 50 .mu.m, between 15 .mu.m and 50 .mu.m, between 20 .mu.m and
50 .mu.m, between 25 .mu.m and 50 .mu.m, between 30 .mu.m and 50
.mu.m, between 35 .mu.m and 50 .mu.m, between 5 .mu.m and 45 .mu.m,
between 5 .mu.m and 40 .mu.m, between 5 .mu.m and 35 .mu.m, between
5 .mu.m and 30 .mu.m, between 5 .mu.m and 25 .mu.m, between 5 .mu.m
and 20 .mu.m, between 5 .mu.m and 15 .mu.m, or between 10 .mu.m and
30 .mu.m). Preparation of albumin-containing nanoparticle/antibody
complexes provided herein having greater than 60 percent (e.g.,
greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the
complexes with a diameter that is between 5 .mu.m and 50 .mu.m can
be administered into a tumor (e.g., intratumorally) or in a region
of a tumor located within a mammal's body.
[0022] In some cases, complexes containing albumin-containing
nanoparticles (e.g., ABRAXANE.RTM. nanoparticles) and antibodies
(e.g., anti-CD20 polypeptide antibodies such as Rituximab) can be
designed to have an average diameter that is less than 1 .mu.m. For
example, appropriate concentrations of albumin-containing
nanoparticles and antibodies (e.g., Rituximab) can be used such
that complexes having an average diameter that is less than 1 .mu.m
are formed. In some cases, the preparations of albumin-containing
nanoparticle/antibody complexes provided herein can have an average
diameter that is between 0.1 .mu.m and 1 .mu.m (e.g., between 0.1
.mu.m and 0.95 .mu.m, between 0.1 .mu.m and 0.9 .mu.m, between 0.1
.mu.m and 0.8 .mu.m, between 0.1 .mu.m and 0.7 .mu.m, between 0.1
.mu.m and 0.6 .mu.m, between 0.1 .mu.m and 0.5 .mu.m, between 0.1
.mu.m and 0.4 .mu.m, between 0.1 .mu.m and 0.3 .mu.m, between 0.1
.mu.m and 0.2 .mu.m, between 0.2 .mu.m and 1 p,m, between 0.3 .mu.m
and 1 .mu.m, between 0.4 .mu.m and 1 .mu.m, between 0.5 .mu.m and 1
.mu.m, between 0.2 .mu.m and 0.6 .mu.m, between 0.3 .mu.m and 0.6
.mu.m, between 0.2 .mu.m and 0.5 .mu.m, or between 0.3 .mu.m and
0.5 .mu.m). Preparations of albumin-containing
nanoparticle/antibody complexes provided herein having an average
diameter that is between 0.1 .mu.m and 0.9 .mu.m can be
administered systemically (e.g., intravenously) to treat lymphomas
located within a mammal's body.
[0023] In some cases, a preparation of albumin-containing
nanoparticle/antibody complexes provided herein can have greater
than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99
percent) of the complexes having a diameter that is between 0.1
.mu.m and 0.9 .mu.m (e.g., between 0.1 .mu.m and 0.95 .mu.m,
between 0.1 .mu.m and 0.9 .mu.m, between 0.1 .mu.m and 0.8 .mu.m,
between 0.1 .mu.m and 0.7 .mu.m, between 0.1 .mu.m and 0.6 .mu.m,
between 0.1 .mu.m and 0.5 .mu.m, between 0.1 .mu.m and 0.4 .mu.m,
between 0.1 .mu.m and 0.3 .mu.m, between 0.1 .mu.m and 0.2 .mu.m,
between 0.2 .mu.m and 1 .mu.m, between 0.3 .mu.m and 1 .mu.m,
between 0.4 .mu.m and 1 .mu.m, between 0.5 .mu.m and 1 .mu.m,
between 0.2 .mu.m and 0.6 .mu.m, between 0.3 .mu.m and 0.6 .mu.m,
between 0.2 .mu.m and 0.5 .mu.m, or between 0.3 .mu.m and 0.5
.mu.m). Preparation of albumin-containing nanoparticte/antibody
complexes provided herein having greater than 60 percent (e.g.,
greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the
complexes with a diameter that is between 0.1 .mu.m and 0.9 .mu.m
can be administered systemically (e.g., intravenously) to treat
cancers located within a mammal's body.
[0024] In general, albumin-containing nanoparticles such as
ABRAXANE.RTM. can be contacted with an antibody such as an
anti-CD20 polypeptide antibody (e.g., Rituximab) prior to
administration to a human form an albumin-containing
nanoparticle/antibody complex (e.g., an ABRAXANE.RTM./anti-CD20
polypeptide antibody complex). Any appropriate albumin-containing
nanoparticie preparation and any appropriate antibody can be used
as described herein. For example, ABRAXANE.RTM. nanoparticles can
be used as described herein. Examples of antibodies that can be
used to form albumin-containing nanoparticle/antibody complexes as
described herein include, without limitation, Rituximab (e.g.,
Rituxan.TM., MabThera.TM., or Zytux.TM.). For example, an
appropriate dose of ABRAXANE.RTM. and an appropriate dose of
Rituximab can be mixed together in the same container. This mixture
can be incubated at an appropriate temperature (e.g., room
temperature, between 15.degree. C. and 30.degree. C., between
15.degree. C and 25.degree. C., between 20.degree. C. and
30.degree. C., or between 20.degree. C. and 25.degree. C.) for a
period of time (e.g., about 30 minutes, or between about 5 minutes
and about 60 minutes, between about 5 minutes and about 45 minutes,
between about 15 minutes and about 60 minutes, between about 15
minutes and about 45 minutes, between about 20 minutes and about
400 minutes, or between about 25 minutes and about 35 minutes)
before being administered to a cancer patient (e.g., a lymphoma
patient). In some cases, ABRAXANE.RTM. can be contacted with an
anti-CD20 polypeptide antibody by injecting both ABRAXANE.RTM. and
the anti-CD20 polypeptide antibody either individually or as a
pre-mixed combination into an IV bag containing an IV bag solution.
The contents of the IV bag including ABRAXANE.RTM./anti-CD20
polypeptide antibody complexes can be introduced into the patient
to be treated.
[0025] In some cases, albumin-containing nanoparticles such as
ABRAXANE.RTM. can be contacted with an antibody such as an
anti-CD20 polypeptide antibody (e.g., Rituximab) to form
albumin-containing nanoparticle/antibody complexes (e.g.,
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) that are
stored prior to being administered to a cancer patient (e.g., a
lymphoma patient). For example, a composition containing
albumin-containing nanoparticle/antibody complexes can be formed as
described herein and stored for a period of time (e.g., days or
weeks) prior to being administered to a cancer patient.
[0026] Any appropriate method can be used to obtain
albumin-containing nanoparticles such as ABRAXANE.RTM. and an
antibody such as an anti-CD20 polypeptide antibody. For example,
ABRAXANE.RTM. can be obtained from Celgene Corp. or as described
elsewhere (U.S. Pat. No. 6,537,579). Rituximab can be obtained from
Genentech Corp. or Roche Corp. or as described elsewhere (U.S. Pat.
No. 5,736,137).
[0027] In some cases, the combination of an albumin-containing
nanoparticle such as ABRAXANE.RTM. and an antibody such as
anti-CD20 polypeptide antibody can include one or more other agents
such as an alkylating agent (e.g., a platinum compound). Examples
of platinum compounds that can be used as an alkylating agent
include, without carboplatin (PARAPLATIN.RTM.), cisplatin
(PLATINOL.RTM.), oxaliplatin (ELOXATIN.RTM.), and BBR3464. Examples
of other agents that can be included within an albumin-containing
nanoparticle/antibody complex provided herein include, without
limitation, adriamycin, cyclophosphamide, vincristine, prednisone,
dexamethasone, cytarabine, methotrexate, thiotepa, ifosfamide,
chlorambucil, dacarbazine, bleomycin, ibrutinib, campath-B,
gemcitabine, revlimid, sirolimus, temsirolimus, bexxar,
brentuximab, bendamustine, and etoposide. For example, an
albumin-containing nanoparticle/antibody complex provided herein
(e.g., ABRAXANE.RTM./anti-CD20 polypeptide antibody complex) can
include brentuximab, cyclophosphamide, adriamycin, or vincristine
as part of the complex.
[0028] Any appropriate method can be used to administer an
albumin-containing nanoparticle/antibody complex provided herein
(e.g., ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) to a
mammal. For example, a composition containing albumin-containing
nanoparticle/antibody complexes such as ABRAXANE.RTM./anti-CD20
polypeptide antibody complexes can be administered via
injection(e.g., subcutaneous injection, intramuscular injection,
intravenous injection, or intrathecal injection).
[0029] Before administering a composition containing an
albumin-containing nanoparticie/antibody complex provided herein
(e.g.4BRAXANE.RTM./anti-CD20 polypeptide antibody complexes) to a
mammal, the mammal can be assessed to determine whether or not the
mammal has lymphoma. Any appropriate method can be used to
determine whether or not a mammal has lymphoma. For example, a
mammal (e.g., human) can be identified as having lymphoma using
standard diagnostic techniques. In some cases, a tissue biopsy
(e.g., lymph node tissue sample) can be collected and analyzed to
determine whether or not a mammal has lymphoma.
[0030] After identifying a mammal as having lymphoma, the mammal
can be administered a composition containing albumin-containing
nanoparticle/antibody complexes provided herein (e.g.,
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes). For
example, a composition containing ABRAXANE.RTM./anti-CD20
polypeptide antibody complexes can be administered prior to or in
lieu of surgical resection of a tumor. In some cases, a composition
containing albumin-containing nanoparticle/antibody complexes
provided herein (e.g., ABRAXANE.RTM./anti-CD20 polypeptide antibody
complexes can be administered following resection of a tumor.
[0031] A composition containing albumin-containing
nanoparticle/antibody complexes provided herein (e.g.,
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) can be
administered to a mammal in any appropriate amount, at any
appropriate frequency, and for any appropriate duration effective
to achieve a desired outcome (e.g., to increase progression-free
survival). In some cases, a composition containing
albumin-containing nanoparticle/antibody complexes provided herein
e.g., ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) can
be administered to a mammal having lymphoma to reduce the
progression rate of the lymphoma by 5, 10, 25, 50, 75, 100, or more
percent. For example, the progression rate can be reduced such that
no additional cancer progression is detected. Any appropriate
method can be used to determine whether or not the progression rate
of lymphoma is reduced. For example, the progression rate of
lymphoma can be assessed by imaging tissue at different time points
and determining the amount of cancer cells present. The amounts of
cancer cells determined within tissue at different times can be
compared to determine the progression rate. After treatment as
described herein, the progression rate can be determined again over
another time interval. In some cases, the stage of cancer (e,g.,
lymphoma) after treatment can be determined and compared to the
stage before treatment to determine whether or not the progression
rate was reduced.
[0032] In some cases, a composition containing albumin-containing
nanoparticle/antibody complexes provided herein e.g.,
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) can be
administered to a mammal having lymphoma under conditions where
progression-free survival is increased (e.g., by 5, 10, 25, 50, 75,
100, or more percent) as compared to the median progression-free
survival of corresponding mammals having untreated lymphoma or the
median progression-free survival of corresponding mammals having
lymphoma treated with ABRAXANE.RTM. and an antibody (e.g., an
anti-CD20 polypeptide antibody) without forming
ABRAXANE.RTM./antibody complexes (e.g., without forming
ABRAXNE/anti-CD20 polypeptide antibody complexes). In some cases, a
composition containing albumin-containing nanoparticle/antibody
complexes provided herein e.g., ABRAXANE.RTM./anti-CD20 polypeptide
antibody complexes can be administered to a mammal having lymphoma
to increase progression-free survival by 5, 10, 25, 50, 75, 100, or
more percent as compared to the median progression-free survival of
corresponding mammals having lymphoma and having received
ABRAXANE.RTM. or an antibody (e.g., an anti-CD20 polypeptide
antibody) alone, Progression-free survival can be measured over any
length of time (e.g., one month, two months, three months, four
months, five months, six months, or longer),
[0033] In some cases, a composition containing albumin-containing
nanoparticle/antibody complexes provided herein (e.g.,
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) can be
administered to a mammal having lymphoma under conditions where the
8-week progression-free survival rate for a population of mammals
is 65% or greater (e.g., 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%,
74%, 75%, 76%, 77%, 78%, 79%, 80% or greater) than that observed in
a population of comparable mammals not receiving a composition
containing albumin-containing nanoparticie/antibody complexes
provided herein (e.g., ABRAXANE.RTM./anti-CD20 polypeptide antibody
complexes). In some cases, a composition containing
albumin-containing nanoparticle/antibody complexes provided
herein(e.g., ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes
can be administered to a mammal having lymphoma under conditions
where the median time to progression for a population of mammals is
at least 150 days (e.g., at least 155, 160, 163, 165, or 170
days).
[0034] An effective amount of a composition containing
albumin-containing nanoparticle/antibody complexes provided herein
e.g., ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) can
be any amount that reduces the progression rate of lymphoma,
increases the progression-free survival rate, or increases the
median time to progression without producing significant toxicity
to the mammal. Typically, an effective amount of ABRAXANE.RTM. can
be from about 50 mg/m.sup.2 to about 150 mg/m.sup.2 (e.g., about 80
mg/m.sup.2), and an effective amount of an anti-CD20 polypeptide
antibody such as Rituximab can be from about 5 mg/kg to about 20
mg/kg (e.g., about 10 mg/kg or 375 mg/m.sup.2). If a particular
mammal fails to respond to a particular amount, then the amount of
ABRAXANE.RTM. or anti-CD20 polypeptide antibody can be increased
by, for example, two fold. After receiving this higher
concentration, the mammal can be monitored for both responsiveness
to the treatment and toxicity symptoms, and adjustments made
accordingly. The effective amount can remain constant or can be
adjusted as a sliding scale or variable dose depending on the
mammal's response to treatment. Various factors can influence the
actual effective amount used for a particular application. For
example, the frequency of administration, duration of treatment,
use of multiple treatment agents, route of administration, and
severity of the lymphoma may require an increase or decrease in the
actual effective amount administered.
[0035] The frequency of administration can be any frequency that
reduces the progression rate of lymphoma, increases the
progression-free survival rate, or increases the median time to
progression without producing significant toxicity to the mammal.
For example, the frequency of administration can be from about once
a month to about three times a month, or from about twice a month
to about six times a month, or from about once every two months to
about three times every two months. The frequency of administration
can remain constant or can be variable during the duration of
treatment. A course of treatment with a composition containing
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes can include
rest periods. For example, a composition containing
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes can be
administered over a two week period followed by a two week rest
period, and such a regimen can be repeated multiple times. As with
the effective amount, various factors can influence the actual
frequency of administration used for a particular application. For
example, the effective amount, duration of treatment, use of
multiple treatment agents, route of administration, and severity of
the lymphoma may require an increase or decrease in administration
frequency.
[0036] An effective duration for administering a composition
provided herein can be any duration that reduces the progression
rate of lymphoma, increases the progression-free survival rate, or
increases the median time to progression without producing
significant toxicity to the mammal. Thus, the effective duration
can vary from several days to several weeks, months, or years. In
general, the effective duration for the treatment of lymphoma can
range in duration from several weeks to several months. :In some
cases, an effective duration can be for as long as an individual
mammal is alive. Multiple factors can influence the actual
effective duration used for a particular treatment. For example, an
effective duration can vary with the frequency of administration,
effective amount, use of multiple treatment agents, route of
administration, and severity of the lymphoma.
[0037] A composition containing albumin-containing
nanoparticle/antibody complexes provided herein (e.g.,
ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) can be in
any appropriate form. For example, a composition provided herein
can be in the form of a solution or powder with or without a
diluent to make an injectable suspension. A composition also can
contain additional ingredients including, without limitation,
pharmaceutically acceptable vehicles. A pharmaceutically acceptable
vehicle can be, for example, saline, water, lactic acid, mannitol,
or combinations thereof.
[0038] After administering a composition provided herein to a
mammal, the mammal can be monitored to determine whether or not the
lymphoma was treated. For example, a mammal can be assessed after
treatment to determine whether or not the progression rate of
lymphoma was reduced (e.g., stopped). As described herein, any
method can be used to assess progression and survival rates.
[0039] In some cases, a formulation of ABRAXANE.RTM./Rituxan
complexes described in Example 1 can be administered to a human
lymphoma patient as described in the methods set forth in Example
3.
[0040] In some cases, nanoparticles containing albumin (e.g.,
nanoparticles with an albumin shell) and an agent other than
placitaxel can be used as described herein in place of or in
combination with ABRAXANE.RTM.. For example, albumin-containing
nanoparticles designed to carry a cancer chemotherapeutic agent can
be used to form nanoparticle/anti-CD20 polypeptide antibody
complexes that can be used as described herein. An example of such
a cancer chemotherapeutic agent includes, without vinblastine.
[0041] In some cases, a composition can be formulated to include
nanoparticies containing albumin (e,g., nanoparticles with an
albumin shell) that are conjugated to an antibody, agent, or
combination of antibodies and agents to form complexes for treating
lymphoma. For example, albumin nanoparticles can be formulated to
include adriamycin, cyclophosphamide, vincristine, prednisone,
dexamethasone, cytarabine, methotrexate, thiotepa, ifosfamide,
chlorambucil, dacarbazine, bleomycin, ibrutinib, campath-B,
gemcitabine, revlimid, sirolimus, temsirolimus, bexxar,
brentuximab, bendamustine, etoposide, or combinations thereof with
or without including rituximab.
[0042] In some cases, nanoparticles containing albumin (e.g.,
nanoparticles with an albumin shell) or a complex described herein
(e.g., ABRAXANE.RTM./rituximab complexes can be formulated to
include one or more anti-chronic inflammation treatment agents
designed to reduce the global state of immune dysfunction and/or
chronic inflammation present within a cancer patient. For example,
steroidal anti-inflammatory agents (e.g., prednisone),
non-steroidal anti-inflammatory agents (e.g., naproxen),
lympho-depleting cytotoxic agents (e.g., cyclophosphamide), immune
cell and/or cytokine targeting antibodies (e.g., infliximab), or a
combination thereof can be incorporated into nanoparticles
containing albumin or ABRAXANE.RTM./rituximab complexes. In some
cases, anti-IL-4 agents (e.g., anti-IL-4 antibodies), anti-IL-13
agents (e.g., soluble IL-13 receptor), and combinations thereof can
be incorporated into nanoparticles containing albumin or
ABRAXANE.RTM./rituximab complexes.
[0043] Any appropriate method can be used to assess whether or not
the global state of immune dysfunction and/or chronic inflammation
was reduced following an anti-chronic inflammation treatment. For
example, cytokine profiles (e.g., IL-4, IL-13, IL-4, IL-13, IL-5,
IL-10, IL-2, and interferon gamma) present in blood can be assessed
before and after an anti-chronic inflammation treatment to
determine whether or not the global state of immune dysfunction
and/or chronic inflammation was reduced.
[0044] The invention will be further described in the following
examples, which do not limit the scope of the invention described
in the claims.
EXAMPLES
Example 1
Making ABRAXANE.RTM./Rituxan.RTM. Complexes
[0045] ABRAXANE.RTM. was incubated with various increasing
concentrations of Rituxan.RTM. (rituximab) to form
ABRAXANE.RTM./Rituxan.RTM. complexes of increasing diameter. Ten
milligrams of ABRAXANE.RTM. was reconstituted in 1 mL of
Rituxan.RTM. at 0, 2, 4, 6, 8, and 10 mg/mL, and the mixture was
incubated at room temperature for 30 minutes. After incubation, the
distributions of particle sizes were determined with the
Mastersizer 2000. The median particle size ranged from 0.147 .mu.m
to 8.286 .mu.m for 0 and 10 mg/mL Rituxan.RTM., respectively (FIG.
1). These results demonstrate that the antibody concentration in
which ABRAXANE.RTM. is incubated impacts the size of the
nanoparticle. Manipulating the size of the particles can change the
pharmacokinetics of the drug complex as well as its
bio-distribution, which in turn can improve the clinical efficacy
of the drug complex.
Example 2
ABRAXANE.RTM./Rituxan Complexes Inhibit Tumor Growth More Effective
Than ABRAXANE.RTM. Alone, Rituxan Alone, and the Sequential Use of
Rituxan and ABRAXANE.RTM.
[0046] Female athymic nude mice were injected with 1.times.10.sup.6
lymphoma cells (Daudi cell line). Tumors were allowed to grow, and
treatments were administered when tumors were between 800 and 1000
mm.sup.3. Mice were treated with (a) a single dose of 100 .mu.L PBS
on day 0, (b) a single dose of Rituxan (12 mg/kg) on day 0, (c) a
single dose of ABRAXANE.RTM. (30 mg/kg) on day 0, (d) a single dose
of Rituxan (12 mg/kg) on day 0 followed by a single dose of
ABRAXANE.RTM. (30 mg/kg) on day 1, or (e) a single dose of AR160
(equivalent to 30 mg/kg of ABRAXANE.RTM.) on day 0. Tumor volumes
(mm.sup.3) were monitored, and the percent change in tumor volume
seven days after treatment was determined.
[0047] The AR160 complexes were produced as follows. 10 mg
ABRAXANE.RTM. was reconstituted in 2 mg of Rituxan in 500 .mu.L
0.9% saline and incubated for 1 hour at room temperature. After
incubation, AR160 was brought to 1 mL with 0.9% saline. AR160 was
further diluted, and 100 .mu.L was administered to mice at a dose
equivalent to 12 mg/kg Rituxan and 30 mg/kg ABRAXANE.RTM.. Average
particle size for AR160 was 0.159 .mu.m.
[0048] On day 7 post treatment, the mice treated with AR160
exhibited tumors with significantly smaller tumor size as compared
to the other treatment groups (FIG. 2). Survival data also revealed
an improvement for mice treated with ABRAXANE.RTM./Rituxan
complexes (FIG. 3). These results demonstrate that the
albumin-containing nanoparticle/antibody complexes provided herein
(e.g., ABRAXANE.RTM./anti-CD20 polypeptide antibody complexes) can
be used effectively to treat lymphomas,
Example 3
ABRAXANE.RTM./Rituxan Complexes as Targeted Therapy for
Lymphomas
[0049] The treatment schedule for ABRAXANE.RTM./Rituxan complexes
is repeated each month (every 28 days +/-3 days) or until disease
progression, patient refusal, or unacceptable toxicity (Table 1)
with the indicated dose escalation scheme (Table 2) and dose
limiting toxicities (Table 3).
TABLE-US-00001 TABLE 1 Agent Dose Route Days ReRx ABRAXANE .RTM./
assigned IV over 60 minutes 1, 8 Every 28 Rituxan at time of (only
1.sup.st dose; and days* complexes registration subsequent doses 15
infused over 30 minutes) *One treatment cycle = 28 days +/- 3
days
TABLE-US-00002 TABLE 2 Dose Escalation Scheme. Dose Level Dose
(ABX) Dose (RIT) -2 75 mg/m.sup.2 30 mg/m.sup.2 -1 100 mg/m.sup.2
40 mg/m.sup.2 1* 125 mg/m.sup.2 50 mg/m.sup.2 2 150 mg/m.sup.2 60
mg/m.sup.2 3 175 mg/m.sup.2 70 mg/m.sup.2 *Starting dose.
TABLE-US-00003 TABLE 3 Dose Limiting Toxicities (DLT). Toxicity DLT
Definition Hematologic Grade 4 ANC, Grade 4 Hgb, or PLT <25,000
Renal Serum creatinine .gtoreq.2 times baseline Other
nonhematologic .gtoreq.grade 3 as per NCI Common Terminology
Criteria for Adverse Events (CTCAE) version 4.0
Determination of Maximum Tolerated Dose (MTD)
[0050] The maximum tolerated dose is defined as the highest dose
level among those tested where at most one out of six patients
develops a DLT prior to the start of their second cycle of
treatment and the next highest dose level is such that two out of a
maximum of six patients treated at this dose level developed a DLT
prior to the start of their second cycle of treatment.
Enrollment and Determination of MTD
[0051] A minimum of two or a maximum of six patients are accrued to
a given dose level. For dose level 1 (and if accrued to, dose
levels -1 & -2), enrollment is temporarily halted after each
patient has been enrolled in order to gather acute adverse event
data over the first cycle of their treatment. For dose levels 2
& 3, patients are accrued to these dose levels so that at any
given time no more than two patients are receiving their first
cycle of treatment and acute adverse event data over the first
treatment cycle for all other patients treated at the current dose
level is known. If, at any time in the enrollment process, two
patients treated at the current dose level develop a DLT during the
first cycle of treatment, enrollment is closed to that dose level.
Enrollment is re-opened to the next lower dose level if fewer than
six patients have been treated at that dose level. If none of the
first three patients treated at a given dose level develops a DLT
during the first cycle of treatment, enrollment to the dose level
is closed and enrollment is reopen at next higher dose level. If
there are no other higher dose levels to be tested, three
additional patients are enrolled at the current dose level to
confirm MTD. If one of the first three patients treated at a given
dose level develops a DLT during the first cycle of treatment,
three additional patients are enrolled (sequentially) onto the
current dose level. If at any time in the enrollment of these three
additional patients, a patient develops a DLT, enrollment is closed
to this dose level. Enrollment is re-opened to the next lower dose
level if fewer than six patients are treated at that dose level. If
none of these three additional patients develops a DLT during the
first cycle of treatment, enrollment to this dose level is closed
and enrollment is reopened at next higher dose level. If there are
no other higher dose levels to be tooted, this is considered the
MTD.
[0052] For this protocol, the patient returns for evaluation and
retreatment (at least every 28+/-3 days) according to the schedule.
If a patient fails to complete the first cycle of treatment for
reasons other than toxicity, an additional patient is enrolled to
replace this patient.
Dosage Modification Based on Adverse Events
[0053] The modifications in Table 4 are followed until individual
treatment tolerance is ascertained. If multiple adverse events
(Table 5) are seen, dose is administered based on greatest
reduction required for any single adverse event observed. Dose
modifications apply to the treatment given in the preceding cycle
and are based on adverse events observed since the prior dose.
TABLE-US-00004 TABLE 4 Dose Levels Based on Adverse Events.
ABRAXANE .RTM./Rituxan complexes - Both drugs are reduced Dose
Accompanying RIT dose Level ABX dose (40% of ABX dose) 2 175
mg/m.sup.2 70 mg/m.sup.2 -1 150 mg/m.sup.2 60 mg/m.sup.2 1 125
mg/m.sup.2 50 mg/m.sup.2 -2 100 mg/m.sup.2 40 mg/m.sup.2 -2 75
mg/m.sup.2 30 mg/m.sup.2 *Dose level 1 refers to the starting
dose.
TABLE-US-00005 TABLE 5 Use Common Terminology Criteria for Adverse
Events (CTCAE) v. 4.0* unless otherwise specified CTCAE Category
Adverse Event Dose Reduction Investigations ANC <1000 Day 1:
Hold until counts above these levels. or Day 8: Omit dose that day
and retreat at same dose PLT <75,000 level on day 15 if counts
have recovered. Day 15: Omit dose that day. NOTE: if two
consecutive cycles of therapy require omission of a dose,
subsequent treatment cycles should begin (day 1) at next lower
dose. AST or Day 1: Hold until resolved to <Grade 2 then reduce
Alkaline dose by ONE dose level. Phosphatase .gtoreq. If treatment
needs to be held >4 weeks, discontinue Grade 2 study treatment
and go to event monitoring. Neurology Neuropathy disorders
.gtoreq.Grade 2 Day 1: Hold until resolved to <Grade 2 then
reduce dose by ONE dose level. Day 8 OR 15- Omit dose that day. If
resolved to < Grade 2 by next scheduled dose, then dose reduce
by one level If treatment needs to be held >4 weeks, discontinue
study treatment and go to Event Monitoring All other non-
.gtoreq.Grade 3 Day 1: Hold until resolved to .ltoreq.Grade 2 then
reduce hematologic dose by ONE dose level. adverse events Day 8:
Omit dose that day. If resolved to .ltoreq.Grade 2 by day 15, then
dose reduce by one level and retreat. Day 15: Omit dose that day.
NOTE: if two consecutive cycles of therapy require omission of a
dose, subsequent treatment cycles should begin (day 1) at next
lower dose. If treatment needs to be held >4 weeks, discontinue
study treatment and go to Event Monitoring Gastrointestinal Bowel
Discontinue all study treatment and proceed to Disorders
perforation Event Monitoring Bowel Obstruction Grade 1 Continue
patient on study for partial bowel obstruction NOT requiring
medical intervention. Grade 2 Hold for partial obstruction
requiring medical intervention. If resolved to Grade 0 within 4
weeks, treatment may be restarted. If treatment needs to be held
>4 weeks, discontinue all study treatment and go to Event
Monitoring. Grade 3 or 4 For complete bowel obstruction,
discontinue study treatment and proceed to Event Monitoring Cardiac
Disorders Hypertension .gtoreq.Grade 3 Hypertension should be
treated as per general practice. If hypertension (.gtoreq.150/100)
persists despite treatment, hold treatment until blood pressure is
below this level If treatment needs to be held >4 weeks due to
uncontrolled hypertension, discontinue study treatment and go to
Event Monitoring. Left ventricular systolic function- Grade 3 Hold
until resolution to Grade .ltoreq.1. If treatment needs to be held
>4 weeks, discontinue all study treatment and go to Event
Monitoring. Grade 4 Discontinue treatment and proceed to Event
Monitoring Respiratory, Bronchopulmonary thoracic and Hemorrhage
mediastinal .gtoreq.Grade 2 Discontinue all study treatment and
proceed to disorders Event Monitoring Coagulation Hemorrhage Grade
3 Hold until ALL of the following criteria are met: 1. Bleeding has
resolved and Hb is stable. 2. There is no bleeding diathesis that
would increase the risk of therapy. 3. There is no anatomic or
pathologic condition that could increase the risk of hemorrhage
recurrence. If treatment needs to be held >4 weeks, discontinue
study treatment and go to Event Monitoring Patients who experience
a recurrence of Grade 3 hemorrhage are to discontinue all study
treatment and proceed to Event Monitoring. Grade 4 Discontinue
study treatment and proceed to Event Monitoring Bleeding diathesis
Grade 3 or 4 Discontinue study treatment and proceed to Event
Monitoring Vascular disorders Venous thrombosis Grade 3 Hold
treatment. If the planned duration of full- or dose anticoagulation
is <2 weeks, treatment should asymptomatic be held until the
full-dose anticoagulation period Grade 4 is over. If the planned
duration of full-dose anticoagulation is >2 weeks, treatment may
be resumed during the period of full-dose anticoagulation IF all of
the criteria below are met: The subject must have an in-range INR
(usually 2-3) on a stable dose of warfarin, or on stable dose of
heparin prior to restarting treatment. The subject must not have
pathological conditions that carry high risk of bleeding (e.g.
tumor involving major vessels or other conditions) The subject must
not have had hemorrhagic events while on study If thromboemboli
worsen/recur upon resumption of study therapy, discontinue
treatment. Symptomatic Grade 4 Discontinue treatment and proceed to
Event Arterial Monitoring thrombosis Discontinue treatment and
proceed to Event (Angina, Monitoring myocardial infarction,
transient ischemic attack, cerebrovascular accident, or any other
arterial thromboembolic events) ANY Grade
Ancillary Treatment/Supportive Care
[0054] Routine use of colony-stimulating factors (G-CSF or GM-CSF)
is not recommended. Prophylactic use of colony-stimulating factors
during the study is not allowed. Therapeutic use in patients with
serious neutropenic complications such as tissue infection, sepsis
syndrome, fungal infection, etc., may be considered at physician
discretion. Recombinant erythropoietin to maintain adequate
hemoglobin levels and avoid packed red blood cell transfusions is
allowed.
[0055] Patients should receive full supportive care while on this
study. This includes blood product support, antibiotic treatment
and treatment of other newly diagnosed or concurrent medica
conditions. All blood products and concomitant medications such as
antidiarrheals, analgesics, and anti-emetics received from the
first administration of study drugs until 30 days after the final
dose are to be recorded in the medical record. Patients
participating in phase I program clinical trials are not to be
considered for enrollment in any other study involving a
pharmacologic agent-(drugs, biologics, immunotherapy approaches,
gene therapy) whether for symptom control or therapeutic
intent.
Hypersensitivity Reactions
[0056] Patients do not require premedication prior to
administration of ABRAXANE.RTM./Rituxan complexes. In the unlikely
event of a hypersensitivity reaction, treatment with
antihistamines, H2 blockers, and corticosteroids is recommended.
Patients should be pre-medicated with the typical regimen for
paclitaxel regimens for subsequent cycles. In the unlikely event of
a mild hypersensitivity reaction, premedication may be administered
using the premedication regimen the institution typically uses for
solvent-based paclitaxel.
ABRAXANE.RTM./Rituxan Complexes
[0057] ABRAXANE.RTM./Rituxan complexes are prepared as a hazardous
low risk product. ABRAXANE.RTM. is supplied as a white to off-white
lyophilized powder containing 100 mg of paclitaxel and
approximately 900 mg Albumin Human USP (HA) as a stabilizer in a 50
mL, single-use vial. Each vial of the lyophilized product is
reconstituted as set forth below. Unreconstituted ABRAXANE.RTM. is
stored at controlled room temperature in its carton. Reconstituted
ABRAXANE.RTM. is used immediately. Rituxan is classified as an
anti-CD20 monoclonal antibody.
[0058] The dose appropriate number of vials of Rituxan are
obtained, and each vial is further diluted per the following
directions to 4 mg/mL. The dose appropriate number of ABRAXANE.RTM.
(paclitaxel) 100 mg vials is obtained and each vial is
reconstituted per the following directions to a final concentration
containing 10 mg/mL nanoparticle albumin-bound (nab) paclitaxel. It
is not a requirement to use filter needles in the preparation of,
or in-line filters during administration. In addition, filters of
pore-size less than 15 micrometers are to be avoided.
[0059] As with other cytotoxic anticancer drugs, caution is
exercised in handling ABRAXANE.RTM.. The use of gloves is
recommended.
[0060] Using a sterile 3 mL syringe, 1.6 mL (40 mg) of Rituxan 25
mg/mL is withdraw and slowly injected, over a minimum of 1 minute,
onto the inside wall of each of the vials containing 100 mg of
ABRAXANE.RTM.. Unused Rituxan left in the 25 mg/mL vial is
discarded, as the product contains no preservatives. Injecting the
Rituxan solution directly onto the lyophilized cake is avoided as
this will result in foaming. Using a sterile 12 mL sterile syringe,
8.4 mL of 0.9% Sodium Chloride injection, USP, is withdraw and
slowly injected, over a minimum of 1 minute, onto the inside wall
of each vial containing ABRAXANE.RTM. 100 mg and Rituxan 40 mg.
Once the addition of Rituxan 1.6 mL and 0.9% Sodium Chloride
Injection, USP 8.4 mL is complete in each vial, each vial is gently
swirled and/or inverted slowly for at least 2 minutes until
complete dissolution of any cake/powder occurs. The generation of
foam is avoided. The concentration of each vial is 100 mg/10 mL
ABRAXANE.RTM. and 40 mg/10 mL Rituxan. The vials containing the
ABRAXANE.RTM. and Rituxan are allowed to sit for 60 minutes. The
vial(s) are gently swirled and/or inverted every 10 minutes to
continue to mix the complexes. After 60 minutes is elapsed, a
sterile 60- to 100-mL syringe (appropriate size for the volume
being administered) is used to withdraw the calculated dosing
volume of ABRAXANE.RTM. and Rituxan from each vial. A sufficient
quantity of 0.9% Sodium Chloride Injection, USP is added to make
the final concentration of ABRAXANE.RTM. 5 mg/mL and Rituxan 2
mg/mL. The syringe is gently swirled and/or inverted slowly for 1
minute to mix. The storage and stability is for up to 4 hours at
room temperature following final dilution.
Administration
[0061] The IV initial complex dose is infused over 60 minutes via
syringe pump. The infusion may be shortened to 30 minutes if the
initial infusion is well tolerated. Infusion is monitored closely
during the infusion process for signs/symptoms of an infusion
reaction. The patient's line is flushed after administration with
20 mL 0.9% Sodium Chloride. An example calculation and preparation
is as follows:
Dose level 1: ABRAXANE.RTM. 125 mg/m.sup.2/Rituxan 50 mg/m.sup.2
BSA=2 m.sup.2 [0062] Doses required: ABRAXANE.RTM. 250 mg/Rituxan
100 mg [0063] Obtain three 100 mg vials of ABRAXANE.RTM.. [0064]
Obtain one 100 mg vial of Rituxan 25 mg/mL. [0065] Withdraw 1.6 mL
(40 mg) of Rituxan 25 mg/mL and slowly inject over 1 minute onto
the inside wall of one of the 100 mg ABRAXANE.RTM. vials. Repeat
this procedure for each of the remaining two ABRAXANE 100 mg vials.
[0066] Add 8.4 mL 0.9% Sodium Chloride Injection, LISP onto the
inside wall of one of the vials containing .sup.ABRAXANE.RTM. and
Rituxan. Repeat this procedure for each of the remaining two
ABRAXANE.RTM. and Rituxan vials. [0067] Let mixture sit for 60
minutes (swirling every 10 minutes). The final concentration of
each vial should be 100 mg ABRAXANE.RTM./10 mL and 40 mg Rituxan/10
mL. [0068] Withdraw 25 mL from the ABRAXANE.degree. and Rituxan
containing vial and place in a 100 mL sterile syringe. Add 25 mL
0.9% Sodium Chloride Injection, USP for a final ABRAXANE.RTM.
concentration of 5 mg/mL and Rituxan concentration of 2 mg/mL.
Infuse via syringe pump over 60 minutes (first dose; 30 minutes
subsequent doses).
Response to ABRAXANE.RTM./Rituxan Complex Treatment
[0069] Each patient's response to treatment with a
ABRAXANE.RTM./Rituxan complex formulation is monitored.
Other Embodiments
[0070] It is to be understood that while the invention has been
described in conjunction with the detailed description thereof, the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the scope of the following claims.
* * * * *