U.S. patent application number 12/151760 was filed with the patent office on 2008-09-11 for methods for treating brain cancer using 3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione or 4-(amino)-2-(2,6 dioxo(3-piperidyl))-isoindoline-1,3-dione.
This patent application is currently assigned to Celgene Corporation. Invention is credited to Jerome B. Zeldis.
Application Number | 20080219949 12/151760 |
Document ID | / |
Family ID | 32314544 |
Filed Date | 2008-09-11 |
United States Patent
Application |
20080219949 |
Kind Code |
A1 |
Zeldis; Jerome B. |
September 11, 2008 |
Methods for treating brain cancer using
3-(4-amino-1-oxo-1,3-dihydroisoindol-2-yl)-piperidine-2,6-dione or
4-(amino)-2-(2,6 dioxo(3-piperidyl))-isoindoline-1,3-dione
Abstract
Methods of treating, preventing and/or managing cancer as well
as and diseases and disorders associated with, or characterized by,
undesired angiogenesis are disclosed. Specific methods encompass
the administration of an immunomodulatory compound alone or in
combination with a second active ingredient. The invention further
relates to methods of reducing or avoiding adverse side effects
associated with chemotherapy, radiation therapy, hormonal therapy,
biological therapy or immunotherapy which comprise the
administration of an immunomodulatory compound. Pharmaceutical
compositions, single unit dosage forms, and kits suitable for use
in methods of the invention are also disclosed.
Inventors: |
Zeldis; Jerome B.;
(Princeton, NJ) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Assignee: |
Celgene Corporation
|
Family ID: |
32314544 |
Appl. No.: |
12/151760 |
Filed: |
May 8, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10438213 |
May 15, 2003 |
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12151760 |
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60380842 |
May 17, 2002 |
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60424600 |
Nov 6, 2002 |
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Current U.S.
Class: |
424/85.2 ;
424/85.4; 514/1.1; 514/110; 514/171; 514/180; 514/255.06;
514/263.36; 514/283; 514/323; 514/34; 514/49 |
Current CPC
Class: |
A61P 17/00 20180101;
A61K 9/4858 20130101; A61P 27/14 20180101; A61K 31/675 20130101;
A61P 27/02 20180101; A61K 31/425 20130101; A61K 31/4439 20130101;
A61P 37/06 20180101; A61P 9/00 20180101; A61P 31/00 20180101; A61P
7/06 20180101; A61P 33/02 20180101; A61K 31/573 20130101; A61K
31/40 20130101; A61P 35/00 20180101; A61P 31/12 20180101; A61K
31/515 20130101; A61K 9/4866 20130101; A61P 1/02 20180101; A61K
31/475 20130101; A61K 31/00 20130101; A61K 31/4035 20130101; A61K
31/454 20130101; A61P 35/04 20180101; A61P 43/00 20180101; A61P
29/00 20180101; A61P 37/02 20180101; A61K 31/7048 20130101; A61K
35/12 20130101; A61P 19/08 20180101; A61K 9/0053 20130101; A61K
39/3955 20130101; A61P 31/10 20180101; A61P 31/04 20180101; A61K
31/198 20130101; A61K 31/445 20130101; A61K 31/704 20130101; A61P
19/02 20180101; A61K 2300/00 20130101; A61P 9/10 20180101; A61P
17/02 20180101; A61K 45/06 20130101; A61P 27/06 20180101; A61K
31/40 20130101; A61K 2300/00 20130101; A61K 31/425 20130101; A61K
2300/00 20130101; A61K 31/445 20130101; A61K 2300/00 20130101; A61K
31/515 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/85.2 ;
514/323; 424/85.4; 514/12; 514/283; 514/263.36; 514/180; 514/34;
514/49; 514/171; 514/110; 514/255.06 |
International
Class: |
A61K 31/454 20060101
A61K031/454; A61P 35/00 20060101 A61P035/00; A61K 38/21 20060101
A61K038/21; A61K 38/20 20060101 A61K038/20; A61K 31/4375 20060101
A61K031/4375; A61K 31/522 20060101 A61K031/522; A61K 31/573
20060101 A61K031/573; A61K 31/704 20060101 A61K031/704; A61K
31/7068 20060101 A61K031/7068; A61K 31/675 20060101 A61K031/675;
A61K 31/4965 20060101 A61K031/4965 |
Claims
1-21. (canceled)
22. A method of treating brain cancer, which comprises
administering to a patient having brain cancer a therapeutically
effective amount of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione of
the formula: ##STR00009##
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione of the
formula: ##STR00010## or a pharmaceutically acceptable salt,
solvate or stereoisomer thereof.
23. The method of claim 22, wherein the brain cancer is
neuroblastoma, meningioma, hemangiopericytoma, multiple brain
metastases, glioblastoma, brain stem glioma, poor prognosis
malignant brain tumor, malignant glioma, recurrent malignant
glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,
relapsed brain tumor, progressive brain tumor, recurrent
neuroblastoma, or recurrent glioma.
24. The method of claim 22, wherein the compound is
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione of
the formula: ##STR00011##
25. The method of claim 22, wherein the compound is
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione of the
formula: ##STR00012##
26. The method of claim 22, wherein the compound is a
pharmaceutically acceptable salt.
27. The method of claim 22, wherein the compound is a
pharmaceutically acceptable solvate.
28. The method of claim 22, wherein the compound is a
pharmaceutically acceptable stereoisomer.
29. The method of claim 28, wherein the stereoisomer is an
enantiomerically pure R isomer.
30. The method of claim 28, wherein the stereoisomer is an
enantiomerically pure S isomer.
31. The method of claim 22, which further comprises administering a
therapeutically effective amount of a second active agent.
32. The method of claim 31, wherein the second active agent is
hematopoietic growth factor, a cytokine, or an anti-cancer
agent.
33. The method of claim 31, wherein the second active agent is
granulocyte colony-stimulating factor (G-CSF),
granulocyte-macrophage colony-stimulating factor (GM-CSF),
erythropoietin (EPO), interleukin (IL), interferon (IFN), or a
pharmacologically active mutant or derivative thereof.
34. The method of claim 31, wherein the second active agent is
temozolomide, celecoxib, etoposide, cyclophosphamide, temodar,
irinotecan, carboplatin, procarbazine, carmustine, tamoxifen,
topotecan, or a combination thereof.
35. The method of claim 22, which further comprises administering
radiation therapy, surgery, hormonal therapy, biological therapy or
immunotherapy.
36. The method of claim 22, wherein the brain cancer is relapsed,
refractory or resistant to conventional therapy.
37. The method of claim 22, wherein the compound is administered
orally.
38. The method of claim 37, wherein the compound is administered in
the form of a capsule or tablet.
39. The method of claim 22, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in an amount of from about 5 to about 25 mg per
day.
40. The method of claim 22, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in an amount of about 5, 10, 15, 20, 25, 30, or 50 mg
per day.
41. The method of claim 22, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in an amount of about 25 mg per day.
42. The method of claim 22, wherein
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione is
administered in an amount of from about 0.1 to about 10 mg per
day.
43. The method of claim 22, wherein
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione is
administered in an amount of about 1, 2, or 5 mg per day.
44. The method of claim 22, wherein the compound is administered
cyclically.
45. The method of claim 44, wherein one cycle comprises four to six
weeks.
46. The method of claim 44, wherein one cycle comprises the
administration of the compound for 21 days followed by seven days
rest.
47. The method of claim 44, wherein the compound is administered
for four to twenty-four weeks with one to six weeks of rest.
48. The method of claim 22, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in an amount of from about 5 to about 25 mg per day
for 21 days every 28 days for sixteen to twenty-four weeks.
49. The method of claim 44, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in an amount of about 25 mg per day for 21 days
followed by seven days rest in a 28 day cycle.
50. The method of claim 22, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in an amount of about 5 mg per day.
51. The method of claim 22, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in an amount of 10 mg per day.
52. The method of claim 22, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in an amount of 15 mg per day.
53. The method of claim 22, wherein
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
administered in a capsule of 5 mg, 10 mg, 15 mg or 25 mg.
54. The method of claim 38, wherein the capsule comprises the
compound, lactose anhydrous, microcrystalline cellulose,
croscarmellose sodium and magnesium stearate.
Description
[0001] This application claims the benefit of U.S. provisional
application Nos. 60/380,842, filed May 17, 2002, and 60/424,600,
filed Nov. 6, 2002, the entireties of which are incorporated herein
by reference.
1. FIELD OF THE INVENTION
[0002] This invention relates to methods of treating, preventing
and/or managing specific cancers, and other diseases including, but
not limited to, those associated with, or characterized by,
undesired angiogenesis, by the administration of one or more
immunomodulatory compounds alone or in combination with other
therapeutics. In particular, the invention encompasses the use of
specific combinations, or "cocktails," of drugs and other therapy,
e.g., radiation to treat these specific cancers, including those
refractory to conventional therapy. The invention also relates to
pharmaceutical compositions and dosing regimens.
2. BACKGROUND OF THE INVENTION
2.1 Pathobiology of Cancer and Other Diseases
[0003] Cancer is characterized primarily by an increase in the
number of abnormal cells derived from a given normal tissue,
invasion of adjacent tissues by these abnormal cells, or lymphatic
or blood-borne spread of malignant cells to regional lymph nodes
and to distant sites (metastasis). Clinical data and molecular
biologic studies indicate that cancer is a multistep process that
begins with minor preneoplastic changes, which may under certain
conditions progress to neoplasia. The neoplastic lesion may evolve
clonally and develop an increasing capacity for invasion, growth,
metastasis, and heterogeneity, especially under conditions in which
the neoplastic cells escape the host's immune surveillance. Roitt,
I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed.,
Mosby, St. Louis, Mo., 1993).
[0004] There is an enormous variety of cancers which are described
in detail in the medical literature. Examples includes cancer of
the lung, colon, rectum, prostate, breast, brain, and intestine.
The incidence of cancer continues to climb as the general
population ages, as new cancers develop, and as susceptible
populations (e.g., people infected with AIDS or excessively exposed
to sunlight) grow. A tremendous demand therefore exists for new
methods and compositions that can be used to treat patients with
cancer.
[0005] Many types of cancers are associated with new blood vessel
formation, a process known as angiogenesis. Several of the
mechanisms involved in tumor-induced angiogenesis have been
elucidated. The most direct of these mechanisms is the secretion by
the tumor cells of cytokines with angiogenic properties. Examples
of these cytokines include acidic and basic fibroblastic growth
factor (a,b-FGF), angiogenin, vascular endothelial growth factor
(VEGF), and TNF-.alpha.. Alternatively, tumor cells can release
angiogenic peptides through the production of proteases and the
subsequent breakdown of the extracellular matrix where some
cytokines are stored (e.g., b-FGF). Angiogenesis can also be
induced indirectly through the recruitment of inflammatory cells
(particularly macrophages) and their subsequent release of
angiogenic cytokines (e.g., TNF-.alpha., bFGF).
[0006] A variety of other diseases and disorders are also
associated with, or characterized by, undesired angiogenesis. For
example, enhanced or unregulated angiogenesis has been implicated
in a number of diseases and medical conditions including, but not
limited to, ocular neovascular diseases, choroidal neovascular
diseases, retina neovascular diseases, rubeosis (neovascularization
of the angle), viral diseases, genetic diseases, inflammatory
diseases, allergic diseases, and autoimmune diseases. Examples of
such diseases and conditions include, but are not limited to:
diabetic retinopathy; retinopathy of prematurity; corneal graft
rejection; neovascular glaucoma; retrolental fibroplasia; and
proliferative vitreoretinopathy.
[0007] Accordingly, compounds that can control angiogenesis or
inhibit the production of certain cytokines, including TNF-.alpha.,
may be useful in the treatment and prevention of various diseases
and conditions.
2.2 Methods of Treating Cancer
[0008] Current cancer therapy may involve surgery, chemotherapy,
hormonal therapy and/or radiation treatment to eradicate neoplastic
cells in a patient (see, for example, Stockdale, 1998, Medicine,
vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV).
Recently, cancer therapy could also involve biological therapy or
immunotherapy. All of these approaches pose significant drawbacks
for the patient. Surgery, for example, may be contraindicated due
to the health of a patient or may be unacceptable to the patient.
Additionally, surgery may not completely remove neoplastic tissue.
Radiation therapy is only effective when the neoplastic tissue
exhibits a higher sensitivity to radiation than normal tissue.
Radiation therapy can also often elicit serious side effects.
Hormonal therapy is rarely given as a single agent. Although
hormonal therapy can be effective, it is often used to prevent or
delay recurrence of cancer after other treatments have removed the
majority of cancer cells. Biological therapies and immunotherapies
are limited in number and may produce side effects such as rashes
or swellings, flu-like symptoms, including fever, chills and
fatigue, digestive tract problems or allergic reactions.
[0009] With respect to chemotherapy, there are a variety of
chemotherapeutic agents available for treatment of cancer. A
majority of cancer chemotherapeutics act by inhibiting DNA
synthesis, either directly, or indirectly by inhibiting the
biosynthesis of deoxyribonucleotide triphosphate precursors, to
prevent DNA replication and concomitant cell division. Gilman et
al., Goodman and Gilman's: The Pharmacological Basis of
Therapeutics, Tenth Ed. (McGraw Hill, New York).
[0010] Despite availability of a variety of chemotherapeutic
agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol.
3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost
all chemotherapeutic agents are toxic, and chemotherapy causes
significant, and often dangerous side effects including severe
nausea, bone marrow depression, and immunosuppression.
Additionally, even with administration of combinations of
chemotherapeutic agents, many tumor cells are resistant or develop
resistance to the chemotherapeutic agents. In fact, those cells
resistant to the particular chemotherapeutic agents used in the
treatment protocol often prove to be resistant to other drugs, even
if those agents act by different mechanism from those of the drugs
used in the specific treatment. This phenomenon is referred to as
pleiotropic drug or multidrug resistance. Because of the drug
resistance, many cancers prove refractory to standard
chemotherapeutic treatment protocols.
[0011] Other diseases or conditions associated with, or
characterized by, undesired angiogenesis are also difficult to
treat. However, some compounds such as protamine, hepain and
steroids have been proposed to be useful in the treatment of
certain specific diseases. Taylor et al., Nature 297:307 (1982);
Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos.
5,001,116 and 4,994,443. Thalidomide and certain derivatives of it
have also been proposed for the treatment of such diseases and
conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, 5,712,291,
6,071,948 and 6,114,355 to D'Amato.
[0012] Still, there is a significant need for safe and effective
methods of treating, preventing and managing cancer and other
diseases and conditions, particularly for diseases that are
refractory to standard treatments, such as surgery, radiation
therapy, chemotherapy and hormonal therapy, while reducing or
avoiding the toxicities and/or side effects associated with the
conventional therapies.
2.3 IMIDS.TM.
[0013] A number of studies have been conducted with the aim of
providing compounds that can safely and effectively be used to
treat diseases associated with abnormal production of TNF-.alpha..
See, e.g., Marriott, J. B., et al., Expert Opin. Biol. Ther.
1(4):1-8 (2001); G. W. Muller, et al., Journal of Medicinal
Chemistry 39(17): 3238-3240 (1996); and G. W. Muller, et al.,
Bioorganic & Medicinal Chemistry Letters 8: 2669-2674 (1998).
Some studies have focused on a group of compounds selected for
their capacity to potently inhibit TNF-.alpha. production by LPS
stimulated PBMC. L. G. Corral, et al., Ann. Rheum. Dis. 58:(Suppl
1) 1107-1113 (1999). These compounds, which are referred to as
IMiDs.TM. (Celgene Corporation) or Immunomodulatory Drugs, show not
only potent inhibition of TNF-.alpha. but also marked inhibition of
LPS induced monocyte IL1.beta. and IL12 production. LPS induced IL6
is also inhibited by immunomodulatory compounds, albeit partially.
These compounds are potent stimulators of LPS induced IL10. Id.
Particular examples of IMiD.TM.s include, but are not limited to,
the substituted 2-(2,6-dioxopiperidin-3-yl)phthalimides and
substituted 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles described
in U.S. Pat. Nos. 6,281,230 and 6,316,471, both to G. W. Muller, et
al.
3. SUMMARY OF THE INVENTION
[0014] This invention encompasses methods of treating and
preventing certain types of cancer, including primary and
metastatic cancer, as well as cancers that are refractory or
resistant to conventional chemotherapy. The methods comprise
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of an
immunomodulatory compound, or a pharmaceutically acceptable salt,
solvate, hydrate, stereoisomer, clathrate, or prodrug thereof. The
invention also encompasses methods of managing certain cancers
(e.g., preventing or prolonging their recurrence, or lengthening
the time of remission) which comprise administering to a patient in
need of such management a prophylactically effective amount of an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or
prodrug thereof.
[0015] In particular methods of the invention, an immunomodulatory
compound is administered in combination with a therapy
conventionally used to treat, prevent or manage cancer. Examples of
such conventional therapies include, but are not limited to,
surgery, chemotherapy, radiation therapy, hormonal therapy,
biological therapy and immunotherapy.
[0016] This invention also encompasses methods of treating,
managing or preventing diseases and disorders other than cancer
that are associated with, or characterized by, undesired
angiogenesis, which comprise administering to a patient in need of
such treatment, management or prevention a therapeutically or
prophylactically effective amount of an immunomodulatory compound,
or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof.
[0017] In other methods of the invention, an immunomodulatory
compound is administered in combination with a therapy
conventionally used to treat, prevent or manage diseases or
disorders associated with, or characterized by, undesired
angiogenesis. Examples of such conventional therapies include, but
are not limited to, surgery, chemotherapy, radiation therapy,
hormonal therapy, biological therapy and immunotherapy.
[0018] This invention encompasses pharmaceutical compositions,
single unit dosage forms, dosing regimens and kits which comprise
an immunomodulatory compound, or a pharmaceutically acceptable
salt, solvate, hydrate, stereoisomer, clathrate, or prodrug
thereof, and a second, or additional, active agent. Second active
agents include specific combinations, or "cocktails," of drugs.
4. BRIEF DESCRIPTION OF FIGURE
[0019] FIG. 1 shows a comparison of the effects of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Revimid.TM.) and thalidomide in inhibiting the proliferation of
multiple myeloma (MM) cell lines in an in vitro study. The uptake
of [.sup.3H]-thymidine by different MM cell lines (MM.1S, Hs
Sultan, U266 and RPMI-8226) was measured as an indicator of the
cell proliferation.
5. DETAILED DESCRIPTION OF THE INVENTION
[0020] A first embodiment of the invention encompasses methods of
treating, managing, or preventing cancer which comprises
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or
prodrug thereof.
[0021] In particular methods encompassed by this embodiment, the
immunomodulatory compound is administered in combination with
another drug ("second active agent") or method of treating,
managing, or preventing cancer. Second active agents include small
molecules and large molecules (e.g., proteins and antibodies),
examples of which are provided herein, as well as stem cells.
Methods, or therapies, that can be used in combination with the
administration of the immunomodulatory compound include, but are
not limited to, surgery, blood transfusions, immunotherapy,
biological therapy, radiation therapy, and other non-drug based
therapies presently used to treat, prevent or manage cancer.
[0022] Another embodiment of the invention encompasses methods of
treating, managing or preventing diseases and disorders other than
cancer that are characterized by undesired angiogenesis. These
methods comprise the administration of a therapeutically or
prophylactically effective amount of an immunomodulatory compound,
or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof.
[0023] Examples of diseases and disorders associated with, or
characterized by, undesired angiogenesis include, but are not
limited to, inflammatory diseases, autoimmune diseases, viral
diseases, genetic diseases, allergic diseases, bacterial diseases,
ocular neovascular diseases, choroidal neovascular diseases, retina
neovascular diseases, and rubeosis (neovascularization of the
angle).
[0024] In particular methods encompassed by this embodiment, the
immunomodulatory compound is administer in combination with a
second active agent or method of treating, managing, or preventing
the disease or condition. Second active agents include small
molecules and large molecules (e.g., proteins and antibodies),
examples of which are provided herein, as well as stem cells.
Methods, or therapies, that can be used in combination with the
administration of the immunomodulatory compound include, but are
not limited to, surgery, blood transfusions, immunotherapy,
biological therapy, radiation therapy, and other non-drug based
therapies presently used to treat, prevent or manage disease and
conditions associated with, or characterized by, undesired
angiogenesis.
[0025] The invention also encompasses pharmaceutical compositions
(e.g., single unit dosage forms) that can be used in methods
disclosed herein. Particular pharmaceutical compositions comprise
an immunomodulatory compound of the invention, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof, and a second active agent.
5.1 Immunomodulatory Compounds
[0026] Compounds used in the invention include immunomodulatory
compounds that are racemic, stereomerically enriched or
stereomerically pure, and pharmaceutically acceptable salts,
solvates, hydrates, stereoisomers, clathrates, and prodrugs
thereof. Preferred compounds used in the invention are small
organic molecules having a molecular weight less than about 1,000
g/mol, and are not proteins, peptides, oligonucleotides,
oligosaccharides or other macromolecules.
[0027] As used herein and unless otherwise indicated, the terms
"immunomodulatory compounds" and "IMiDs.TM." (Celgene Corporation)
encompasses small organic molecules that markedly inhibit
TNF-.alpha., LPS induced monocyte IL1.beta. and IL12, and partially
inhibit IL6 production. Specific immunomodulatory compounds are
discussed below.
[0028] TNF-.alpha. is an inflammatory cytokine produced by
macrophages and monocytes during acute inflammation. TNF-.alpha. is
responsible for a diverse range of signaling events within cells.
TNF-.alpha. may play a pathological role in cancer. Without being
limited by theory, one of the biological effects exerted by the
immunomodulatory compounds of the invention is the reduction of
synthesis of TNF-.alpha.. Immunomodulatory compounds of the
invention enhance the degradation of TNF-.alpha. mRNA.
[0029] Further, without being limited by theory, immunomodulatory
compounds used in the invention may also be potent co-stimulators
of T cells and increase cell proliferation dramatically in a dose
dependent manner. Immunomodulatory compounds of the invention may
also have a greater co-stimulatory effect on the CD8+ T cell subset
than on the CD4+ T cell subset. In addition, the compounds
preferably have anti-inflammatory properties, and efficiently
co-stimulate T cells.
[0030] Specific examples of immunomodulatory compounds of the
invention, include, but are not limited to, cyano and carboxy
derivatives of substituted styrenes such as those disclosed in U.S.
Pat. No. 5,929,117;
1-oxo-2-(2,6-dioxo-3-fluoropiperidin-3yl)isoindolines and
1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidine-3-yl)isoindolines such as
those described in U.S. Pat. No. 5,874,448; the tetra substituted
2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines described in U.S. Pat.
No. 5,798,368; 1-oxo and
1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolines (e.g., 4-methyl
derivatives of thalidomide and EM-12), including, but not limited
to, those disclosed in U.S. Pat. No. 5,635,517; and a class of
non-polypeptide cyclic amides disclosed in U.S. Pat. Nos. 5,698,579
and 5,877,200; analogs and derivatives of thalidomide, including
hydrolysis products, metabolites, derivatives and precursors of
thalidomide, such as those described in U.S. Pat. Nos. 5,593,990,
5,629,327, and 6,071,948 to D'Amato; aminothalidomide, as well as
analogs, hydrolysis products, metabolites, derivatives and
precursors of aminothalidomide, and substituted
2-(2,6-dioxopiperidin-3-yl)phthalimides and substituted
2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles such as those described
in U.S. Pat. Nos. 6,281,230 and 6,316,471; isoindole-imide
compounds such as those described in U.S. patent application Ser.
No. 09/972,487 filed on Oct. 5, 2001, U.S. patent application Ser.
No. 10/032,286 filed on Dec. 21, 2001, and International
Application No. PCT/US01/50401 (International Publication No. WO
02/059106). The entireties of each of the patents and patent
applications identified herein are incorporated herein by
reference. Immunomodulatory compounds of the invention do not
include thalidomide.
[0031] Other specific immunomodulatory compounds of the invention
include, but are not limited to, 1-oxo- and 1,3
dioxo-2-(2,6-dioxopiperidin-3-yl)isoindolines substituted with
amino in the benzo ring as described in U.S. Pat. No. 5,635,517
which is incorporated herein by reference. These compounds have the
structure I:
##STR00001##
in which one of X and Y is C.dbd.O, the other of X and Y is C.dbd.O
or CH.sub.2, and R.sup.2 is hydrogen or lower alkyl, in particular
methyl. Specific immunomodulatory compounds include, but are not
limited to: [0032]
1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; [0033]
1-oxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline; [0034]
1-oxo-2-(2,6-dioxopiperidin-3-yl)-6aminoisoindoline; [0035]
1-oxo-2-(2,6-dioxopiperidin-3-yl)-7aminoisoindoline; [0036]
1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline; and
[0037]
1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline.
[0038] Other specific immunomodulatory compounds of the invention
belong to a class of substituted
2-(2,6-dioxopiperidin-3-yl)phthalimides and substituted
2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoles, such as those
described in U.S. Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and
6,476,052, and International Patent Application No. PCT/US97/13375
(International Publication No. WO 98/03502), each of which is
incorporated herein by reference. Compounds representative of this
class are of the formulas:
##STR00002##
wherein R.sup.1 is hydrogen or methyl. In a separate embodiment,
the invention encompasses the use of enantiomerically pure forms
(e.g. optically pure (R) or (S) enantiomers) of these
compounds.
[0039] Still other specific immunomodulatory compounds of the
invention belong to a class of isoindole-imides disclosed in U.S.
patent application Ser. Nos. 10/032,286 and 09/972,487, and
International Application No. PCT/US01/50401 (International
Publication No. WO 02/059106), each of which are incorporated
herein by reference. Representative compounds are of formula
II:
##STR00003##
[0040] and pharmaceutically acceptable salts, hydrates, solvates,
clathrates, enantiomers, diastereomers, racemates, and mixtures of
stereoisomers thereof, wherein:
[0041] one of X and Y is C.dbd.O and the other is CH.sub.2 or
C.dbd.O;
[0042] R.sup.1 is H, (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, benzyl, aryl,
(C.sub.0-C.sub.4)alkyl-(C.sub.1-C.sub.6)heterocycloalkyl,
(C.sub.0-C.sub.4)alkyl-(C.sub.2-C.sub.5)heteroaryl, C(O)R.sup.3,
C(S)R.sup.3, C(O)OR.sup.4, (C.sub.1-C.sub.8)alkyl-N(R.sup.6).sub.2,
(C.sub.1-C.sub.8)alkyl-OR.sup.5,
(C.sub.1-C.sub.8)alkyl-C(O)OR.sup.5, C(O)NHR.sup.3, C(S)NHR.sup.3,
C(O)NR.sup.3R.sup.3', C(S)NR.sup.3R.sup.3' or
(C.sub.1-C.sub.8)alkyl-O(CO)R.sup.5;
[0043] R.sup.2 is H, F, benzyl, (C.sub.1-C.sub.8)alkyl,
(C.sub.2-C.sub.8)alkenyl, or (C.sub.2-C.sub.8)alkynyl;
[0044] R.sup.3 and R.sup.3' are independently
(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, benzyl, aryl,
(C.sub.0-C.sub.4)alkyl-(C.sub.1-C.sub.6)heterocycloalkyl,
(C.sub.0-C.sub.4)alkyl-(C.sub.2-C.sub.5)heteroaryl,
(C.sub.0-C.sub.8)alkyl-N(R.sup.6).sub.2,
(C.sub.1-C.sub.8)alkyl-OR.sup.5,
(C.sub.1-C.sub.8)alkyl-C(O)OR.sup.5,
(C.sub.1-C.sub.8)alkyl-O(CO)R.sup.5, or C(O)OR.sup.5;
[0045] R.sup.4 is (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, (C.sub.1-C.sub.4)alkyl-OR.sup.5, benzyl,
aryl, (C.sub.0-C.sub.4)alkyl-(C.sub.1-C.sub.6)heterocycloalkyl, or
(C.sub.0-C.sub.4)alkyl-(C.sub.2-C.sub.5)heteroaryl;
[0046] R.sup.5 is (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, benzyl, aryl, or
(C.sub.2-C.sub.5)heteroaryl;
[0047] each occurrence of R.sup.6 is independently H,
(C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, benzyl, aryl,
(C.sub.2-C.sub.5)heteroaryl, or
(C.sub.0-C.sub.8)alkyl-C(O)O--R.sup.5 or the R.sup.6 groups can
join to form a heterocycloalkyl group;
[0048] n is 0 or 1; and
[0049] * represents a chiral-carbon center.
[0050] In specific compounds of formula II, when n is 0 then
R.sup.1 is (C.sub.3-C.sub.7)cycloalkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, benzyl, aryl,
(C.sub.0-C.sub.4)alkyl-(C.sub.1-C.sub.6)heterocycloalkyl,
(C.sub.0-C.sub.4)alkyl-(C.sub.2-C.sub.5)heteroaryl, C(O)R.sup.3,
C(O)OR.sup.4, (C.sub.1-C.sub.8)alkyl-N(R.sup.6).sub.2,
(C.sub.1-C.sub.8)alkyl-OR.sup.5,
(C.sub.1-C.sub.8)alkyl-C(O)OR.sup.5, C(S)NHR.sup.3, or
(C.sub.1-C.sub.8)alkyl-O(CO)R.sup.5;
[0051] R.sup.2 is H or (C.sub.1-C.sub.8)alkyl; and
[0052] R.sup.3 is (C.sub.1-C.sub.8)alkyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.2-C.sub.8)alkenyl,
(C.sub.2-C.sub.8)alkynyl, benzyl, aryl,
(C.sub.0-C.sub.4)alkyl-(C.sub.1-C.sub.6)heterocycloalkyl,
(C.sub.0-C.sub.4)alkyl-(C.sub.2-C.sub.5)heteroaryl,
(C.sub.5-C.sub.8)alkyl-N(R.sup.6).sub.2;
(C.sub.0-C.sub.8)alkyl-NH--C(O)O--R.sup.5;
(C.sub.1-C.sub.8)alkyl-OR.sup.5,
(C.sub.1-C.sub.8)alkyl-C(O)OR.sup.5,
(C.sub.1-C.sub.8)alkyl-O(CO)R.sup.5, or C(O)OR.sup.5; and the other
variables have the same definitions.
[0053] In other specific compounds of formula II, R.sup.2 is H or
(C.sub.1-C.sub.4)alkyl.
[0054] In other specific compounds of formula II, R.sup.1 is
(C.sub.1-C.sub.8)alkyl or benzyl.
[0055] In other specific compounds of formula II, R.sup.1 is H,
(C.sub.1-C.sub.8)alkyl, benzyl, CH.sub.2OCH.sub.3,
CH.sub.2CH.sub.2OCH.sub.3, or
##STR00004##
[0056] In another embodiment of the compounds of formula II,
R.sup.1 is
##STR00005##
wherein Q is O or S, and each occurrence of R.sup.7 is
independently H, (C.sub.1-C.sub.8)alkyl, benzyl, CH.sub.2OCH.sub.3,
or CH.sub.2CH.sub.2OCH.sub.3.
[0057] In other specific compounds of formula II, R.sup.1 is
C(O)R.sup.3.
[0058] In other specific compounds of formula II, R.sup.3 is
(C.sub.0 C.sub.4)alkyl-(C.sub.2 C.sub.5)heteroaryl,
(C.sub.1-C.sub.8)alkyl, aryl, or
(C.sub.0-C.sub.4)alkyl-OR.sup.5.
[0059] In other specific compounds of formula II, heteroaryl is
pyridyl, furyl, or thienyl.
[0060] In other specific compounds of formula II, R.sup.1 is
C(O)OR.sup.4.
[0061] In other specific compounds of formula II, the H of
C(O)NHC(O) can be replaced with (C.sub.1-C.sub.4)alkyl, aryl, or
benzyl.
[0062] Still other specific immunomodulatory compounds of the
invention belong to a class of isoindole-imides disclosed in U.S.
patent application Ser. No. 09/781,179, International Publication
No. WO 98/54170, and U.S. Pat. No. 6,395,754, each of which are
incorporated herein by reference. Representative compounds are of
formula III:
##STR00006##
and pharmaceutically acceptable salts, hydrates, solvates,
clathrates, enantiomers, diastereomers, racemates, and mixtures of
stereoisomers thereof, wherein:
[0063] one of X and Y is C.dbd.O and the other is CH.sub.2 or
C.dbd.O;
[0064] R is H or CH.sub.2OCOR';
[0065] (i) each of R.sup.1, R.sup.2, R.sup.3, or R.sup.4,
independently of the others, is halo, alkyl of 1 to 4 carbon atoms,
or alkoxy of 1 to 4 carbon atoms or (ii) one of R.sup.1, R.sup.2,
R.sup.3, or R.sup.4 is nitro or --NHR.sup.5 and the remaining of
R.sup.1, R.sup.2, R.sup.3, or R.sup.4 are hydrogen;
[0066] R.sup.5 is hydrogen or alkyl of 1 to 8 carbons
[0067] R.sup.6 hydrogen, alkyl of 1 to 8 carbon atoms, benzo,
chloro, or fluoro;
[0068] R' is R.sup.7--CHR.sup.10--N(R.sup.8R.sup.9);
[0069] R.sup.7 is m-phenylene or p-phenylene or
--(C.sub.nH.sub.2n)-- in which n has a value of 0 to 4;
[0070] each of R.sup.8 and R.sup.9 taken independently of the other
is hydrogen or alkyl of 1 to 8 carbon atoms, or R.sup.8 and R.sup.9
taken together are tetramethylene, pentamethylene, hexamethylene,
or --CH.sub.2CH.sub.2[X]X.sub.1CH.sub.2CH.sub.2-- in which
[X]X.sub.1 is --O--, --S--, or --NH--;
[0071] R.sup.10 is hydrogen, alkyl of to 8 carbon atoms, or phenyl;
and
[0072] * represents a chiral-carbon center.
[0073] The most preferred immunomodulatory compounds of the
invention are
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione and
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione.
The compounds can be obtained via standard, synthetic methods (see
e.g., U.S. Pat. No. 5,635,517, incorporated herein by reference).
The compounds are available from Celgene Corporation, Warren, N.J.
4-(Amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
(ACTIMID.TM.) has the following chemical structure:
##STR00007##
The compound
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(REVIMID.TM.) has the following chemical structure:
##STR00008##
[0074] Compounds of the invention can either be commercially
purchased or prepared according to the methods described in the
patents or patent publications disclosed herein. Further, optically
pure compounds can be asymmetrically synthesized or resolved using
known resolving agents or chiral columns as well as other standard
synthetic organic chemistry techniques.
[0075] As used herein and unless otherwise indicated, the term
"pharmaceutically acceptable salt" encompasses non-toxic acid and
base addition salts of the compound to which the term refers.
Acceptable non-toxic acid addition salts include those derived from
organic and inorganic acids or bases know in the art, which
include, for example, hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid,
tartaric acid, lactic acid, succinic acid, citric acid, malic acid,
maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic
acid, embolic acid, enanthic acid, and the like.
[0076] Compounds that are acidic in nature are capable of forming
salts with various pharmaceutically acceptable bases. The bases
that can be used to prepare pharmaceutically acceptable base
addition salts of such acidic compounds are those that form
non-toxic base addition salts, i.e., salts containing
pharmacologically acceptable cations such as, but not limited to,
alkali metal or alkaline earth metal salts and the calcium,
magnesium, sodium or potassium salts in particular. Suitable
organic bases include, but are not limited to,
N,N-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumaine (N-methylglucamine),
lysine, and procaine.
[0077] As used herein and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide the compound. Examples of prodrugs include,
but are not limited to, derivatives of immunomodulatory compounds
of the invention that comprise biohydrolyzable moieties such as
biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable
carbamates, biohydrolyzable carbonates, biohydrolyzable ureides,
and biohydrolyzable phosphate analogues. Other examples of prodrugs
include derivatives of immunomodulatory compounds of the invention
that comprise --NO, --NO.sub.2, --ONO, or --ONO.sub.2 moieties.
Prodrugs can typically be prepared using well-known methods, such
as those described in 1 Burger's Medicinal Chemistry and Drug
Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995),
and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York
1985).
[0078] As used herein and unless otherwise indicated, the terms
"biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable
carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide,"
"biohydrolyzable phosphate" mean an amide, ester, carbamate,
carbonate, ureide, or phosphate, respectively, of a compound that
either: 1) does not interfere with the biological activity of the
compound but can confer upon that compound advantageous properties
in vivo, such as uptake, duration of action, or onset of action; or
2) is biologically inactive but is converted in vivo to the
biologically active compound. Examples of biohydrolyzable esters
include, but are not limited to, lower alkyl esters, lower
acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl,
aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl
esters), lactonyl esters (such as phthalidyl and thiophthalidyl
esters), lower alkoxyacyloxyalkyl esters (such as
methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and
isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline
esters, and acylamino alkyl esters (such as acetamidomethyl
esters). Examples of biohydrolyzable amides include, but are not
limited to, lower alkyl amides, .alpha.-amino acid amides,
alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of
biohydrolyzable carbamates include, but are not limited to, lower
alkylamines, substituted ethylenediamines, amino acids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and
polyether amines.
[0079] Various immunomodulatory compounds of the invention contain
one or more chiral centers, and can exist as racemic mixtures of
enantiomers or mixtures of diastereomers. This invention
encompasses the use of stereomerically pure forms of such
compounds, as well as the use of mixtures of those forms. For
example, mixtures comprising equal or unequal amounts of the
enantiomers of a particular immunomodulatory compounds of the
invention may be used in methods and compositions of the invention.
These isomers may be asymmetrically synthesized or resolved using
standard techniques such as chiral columns or chiral resolving
agents. See, e.g., Jacques. J., et al., Enantiomers, Racemates and
Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et
al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of
Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables
of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel,
Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).
[0080] As used herein and unless otherwise indicated, the term
"stereomerically pure" means a composition that comprises one
stereoisomer of a compound and is substantially free of other
stereoisomers of that compound. For example, a stereomerically pure
composition of a compound having one chiral center will be
substantially free of the opposite enantiomer of the compound. A
stereomerically pure composition of a compound having two chiral
centers will be substantially free of other diastereomers of the
compound. A typical stereomerically pure compound comprises greater
than about 80% by weight of one stereoisomer of the compound and
less than about 20% by weight of other stereoisomers of the
compound, more preferably greater than about 90% by weight of one
stereoisomer of the compound and less than about 10% by weight of
the other stereoisomers of the compound, even more preferably
greater than about 95% by weight of one stereoisomer of the
compound and less than about 5% by weight of the other
stereoisomers of the compound, and most preferably greater than
about 97% by weight of one stereoisomer of the compound and less
than about 3% by weight of the other stereoisomers of the compound.
As used herein and unless otherwise indicated, the term
"stereomerically enriched" means a composition that comprises
greater than about 60% by weight of one stereoisomer of a compound,
preferably greater than about 70% by weight, more preferably
greater than about 80% by weight of one stereoisomer of a compound.
As used herein and unless otherwise indicated, the term
"enantiomerically pure" means a stereomerically pure composition of
a compound having one chiral center. Similarly, the term
"stereomerically enriched" means a stereomerically enriched
composition of a compound having one chiral center.
[0081] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of it.
5.2 Second Active Agents
[0082] Immunomodulatory compounds can be combined with other
pharmacologically active compounds ("second active agents") in
methods and compositions of the invention. It is believed that
certain combinations work synergistically in the treatment of
particular types of cancer and certain diseases and conditions
associated with, or characterized by, undesired angiogenesis.
Immunomodulatory compounds can also work to alleviate adverse
effects associated with certain second active agents, and some
second active agents can be used to alleviate adverse effects
associated with immunomodulatory compounds.
[0083] One or more second active ingredients or agents can be used
in the methods and compositions of the invention together with an
immunomodulatory compound. Second active agents can be large
molecules (e.g., proteins) or small molecules (e.g., synthetic
inorganic, organometallic, or organic molecules).
[0084] Examples of large molecule active agents include, but are
not limited to, hematopoietic growth factors, cytokines, and
monoclonal and polyclonal antibodies. Typical large molecule active
agents are biological molecules, such as naturally occurring or
artificially made proteins. Proteins that are particularly useful
in this invention include proteins that stimulate the survival
and/or proliferation of hematopoietic precursor cells and
immunologically active poietic cells in vitro or in vivo. Others
stimulate the division and differentiation of committed erythroid
progenitors in cells in vitro or in vivo. Particular proteins
include, but are not limited to: interleukins, such as IL-2
(including recombinant IL-II ("rIL2") and canarypox IL-2), IL-10,
IL-12, and IL-18; interferons, such as interferon alfa-2a,
interferon alfa-2b, interferon alfa-n1, interferon alfa-n3,
interferon beta-I a, and interferon gamma-I b; GM-CF and GM-CSF;
and EPO.
[0085] Particular proteins that can be used in the methods and
compositions of the invention include, but are not limited to:
filgrastim, which is sold in the United States under the trade name
Neupogen.RTM. (Amgen, Thousand Oaks, Calif.); sargramostim, which
is sold in the United States under the trade name Leukine.RTM.
(Immunex, Seattle, Wash.); and recombinant EPO, which is sold in
the United States under the trade name Epogen.RTM. (Amgen, Thousand
Oaks, Calif.).
[0086] Recombinant and mutated forms of GM-CSF can be prepared as
described in U.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496;
all of which are incorporated herein by reference. Recombinant and
mutated forms of G-CSF can be prepared as described in U.S. Pat.
Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all of which
are incorporated herein by reference.
[0087] This invention encompasses the use of native, naturally
occurring, and recombinant proteins. The invention further
encompasses mutants and derivatives (e.g., modified forms) of
naturally occurring proteins that exhibit, in vivo, at least some
of the pharmacological activity of the proteins upon which they are
based. Examples of mutants include, but are not limited to,
proteins that have one or more amino acid residues that differ from
the corresponding residues in the naturally occurring forms of the
proteins. Also encompassed by the term "mutants" are proteins that
lack carbohydrate moieties normally present in their naturally
occurring forms (e.g., nonglycosylated forms). Examples of
derivatives include, but are not limited to, pegylated derivatives
and fusion proteins, such as proteins formed by fusing IgG1 or IgG3
to the protein or active portion of the protein of interest. See,
e.g., Penichet. M. L. and Morrison, S. L., J. Immunol. Methods
248:91-101 (2001).
[0088] Antibodies that can be used in combination with compounds of
the invention include monoclonal and polyclonal antibodies.
Examples of antibodies include, but are not limited to, trastuzumab
(Herceptin.RTM.), rituximab (Rituxan.RTM.), bevacizumab
(Avastin.TM.), pertuzumab (Omnitarg.TM.), tositumomab
(Bexxar.RTM.), edrecolomab (Panorex.RTM.), and G250. Compounds of
the invention can also be combined with, or used in combination
with, anti-TNF-.alpha. antibodies.
[0089] Large molecule active agents may be administered in the form
of anti-cancer vaccines. For example, vaccines that secrete, or
cause the secretion of, cytokines such as IL-2, G-CSF, and GM-CSF
can be used in the methods, pharmaceutical compositions, and kits
of the invention. See, e.g., Emens, L. A., et al., Curr. Opinion
Mol. Ther. 3(1):77-84 (2001).
[0090] In one embodiment of the invention, the large molecule
active agent reduces, eliminates, or prevents an adverse effect
associated with the administration of an immunomodulatory compound.
Depending on the particular immunomodulatory compound and the
disease or disorder begin treated, adverse effects can include, but
are not limited to, drowsiness and somnolence, dizziness and
orthostatic hypotension, neutropenia, infections that result from
neutropenia, increased HIV-viral load, bradycardia, Stevens-Johnson
Syndrome and toxic epidermal necrolysis, and seizures (e.g., grand
mal convulsions). A specific adverse effect is neutropenia.
[0091] Second active agents that are small molecules can also be
used to alleviate adverse effects associated with the
administration of an immunomodulatory compound. However, like some
large molecules, many are believed to be capable of providing a
synergistic effect when administered with (e.g., before, after or
simultaneously) an immunomodulatory compound. Examples of small
molecule second active agents include, but are not limited to,
anti-cancer agents, antibiotics, immunosuppressive agents, and
steroids.
[0092] Examples of anti-cancer agents include, but are not limited
to: acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; aldesleukin; altretamine; ambomycin; ametantrone
acetate; amsacrine; anastrozole; anthramycin; asparaginase;
asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;
bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;
busulfan; cactinomycin; calusterone; caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin;
cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin;
cisplatin; cladribine; crisnatol mesylate; cyclophosphamide;
cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride;
decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;
diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride;
erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;
fosquidone; fostriecin sodium; gemcitabine; gemcitabine
hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide;
ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride;
lanreotide acetate; letrozole; leuprolide acetate; liarozole
hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; safingol; safingol hydrochloride; semustine; simtrazene;
sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur;
talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone
hydrochloride; temoporfin; teniposide; teroxirone; testolactone;
thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine;
toremifene citrate; trestolone acetate; triciribine phosphate;
trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole
hydrochloride; uracil mustard; uredepa; vapreotide; vertcporfin;
vinblastine sulfate; vincristine sulfate; vindesine; vindesine
sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine
sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine
sulfate; vorozole; zeniplatin; zinostatin; and zorubicin
hydrochloride.
[0093] Other anti-cancer drugs include, but are not limited to:
20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorlns;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxirluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflornithine; elemene;
emitefur; epirubicin; epristeride; estramustine analogue; estrogen
agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim;
finasteride; flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec.RTM.),
imiquimod; immunostimulant peptides; insulin-like growth factor-1
receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF
inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
Erbitux, human chorionic gonadotrophin; monophosphoryl lipid
A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;
mycaperoxide B; mycobacterial cell wall extract; myriaporone;
N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin;
nitric oxide modulators; nitroxide antioxidant; nitrullyn;
oblimersen (Genasense.RTM.); O.sup.6-benzylguanine; octreotide;
okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;
oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel
derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;
peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
plasminogen activator inhibitor; platinum complex; platinum
compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex;
rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stipiamide; stromelysin inhibitors;
sulfinosine; superactive vasoactive intestinal peptide antagonist;
suradista; suramin; swainsonine; tallimustine; tamoxifen
methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin
receptor agonist; thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; velaresol; veramine;
verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0094] Specific second active agents include, but are not limited
to, oblimersen (Genasense.RTM.), remicade, docetaxel, celecoxib,
melphalan, dexamethasone (Decadron.RTM.), steroids, gemcitabine,
cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar,
carboplatin, procarbazine, gliadel, tamoxifen, topotecan,
methotrexate, Arisa.RTM., taxol, taxotere, fluorouracil,
leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated
interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin,
thiotepa, fludarabine, carboplatin, liposomal daunorubicin,
cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,
dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,
busulphan, prednisone, bisphosphonate, arsenic trioxide,
vincristine, doxorubicin (Doxil.RTM.), paclitaxel, ganciclovir,
adriamycin, estramustine sodium phosphate (Emcyt.RTM.), sulindac,
and etoposide.
5.3 Methods of Treatments and Prevention
[0095] Methods of this invention encompass methods of treating,
preventing and/or managing various types of cancer and diseases and
disorders associated with, or characterized by, undesired
angiogenesis. As used herein, unless otherwise specified, the term
"treating" refers to the administration of a compound of the
invention or other additional active agent after the onset of
symptoms of the particular disease or disorder. As used herein,
unless otherwise specified, the term "preventing" refers to the
administration prior to the onset of symptoms, particularly to
patients at risk of cancer, and other diseases and disorders
associated with, or characterized by, undesired angiogenesis. The
term "prevention" includes the inhibition of a symptom of the
particular disease or disorder. Patients with familial history of
cancer and diseases and disorders associated with, or characterized
by, undesired angiogenesis are preferred candidates for preventive
regimens. As used herein and unless otherwise indicated, the term
"managing" encompasses preventing the recurrence of the particular
disease or disorder in a patient who had suffered from it, and/or
lengthening the time a patient who had suffered from the disease or
disorder remains in remission.
[0096] As used herein, the term "cancer" includes, but is not
limited to, solid tumors and blood born tumors. The term "cancer"
refers to disease of skin tissues, organs, blood, and vessels,
including, but not limited to, cancers of the bladder, bone or
blood, brain, breast, cervix, chest, colon, endrometrium,
esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth,
neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat,
and uterus. Specific cancers include, but are not limited to,
advanced malignancy, amyloidosis, neuroblastoma, meningioma,
hemangiopericytoma, multiple brain metastase, glioblastoma
multiforms, glioblastoma, brain stem glioma, poor prognosis
malignant brain tumor, malignant glioma, recurrent malignant
glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,
neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D
colorectal cancer, unresectable colorectal carcinoma, metastatic
hepatocellular carcinoma, Kaposi's sarcoma, karotype acute
myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,
cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large
B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma,
malignant mesothelioma, malignant pleural effusion mesothelioma
syndrome, peritoneal carcinoma, papillary serous carcinoma,
gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous
vasculitis, Langerhans cell histiocytosis, leiomyosarcoma,
fibrodysplasia ossificans progressive, hormone refractory prostate
cancer, resected high-risk soft tissue sarcoma, unrescectable
hepatocellular carcinoma, Waldenstrom's macroglobulinemia,
smoldering myeloma, indolent myeloma, fallopian tube cancer,
androgen independent prostate cancer, androgen dependent stage IV
non-metastatic prostate cancer, hormone-insensitive prostate
cancer, chemotherapy-insensitive prostate cancer, papillary thyroid
carcinoma, follicular thyroid carcinoma, medullary thyroid
carcinoma, and leiomyoma. In a specific embodiment, the cancer is
metastatic. In another embodiment, the cancer is refractory or
resistance to chemotherapy or radiation; in particular, refractory
to thalidomide.
[0097] As used herein to refer to diseases and conditions other
than cancer, the terms "diseases or disorders associated with, or
characterized by, undesired angiogenesis," "diseases or disorders
associated with undesired angiogenesis," and "diseases or disorders
characterized by undesired angiogenesis" refer to diseases,
disorders and conditions that are caused, mediated or attended by
undesired, unwanted or uncontrolled angiogenesis, including, but
not limited to, inflammatory diseases, autoimmune diseases, genetic
diseases, allergic diseases, bacterial diseases, ocular neovascular
diseases, choroidal neovascular diseases, and retina neovascular
diseases.
[0098] Examples of such diseases or disorders associated with
undesired angiogenesis include, but are not limited to, diabetic
retinopathy, retinopathy of prematurity, corneal graft rejection,
neovascular glaucoma, retrolental fibroplasia, proliferative
vitreoretinopathy, trachoma, myopia, optic pits, epidemnic
keratoconjunctivitis, atopic keratitis, superior limbic keratitis,
pterygium keratitis sicca, sjogrens, acne rosacea, phylectenulosis,
syphilis, lipid degeneration, bacterial ulcer, fungal ulcer, Herpes
simplex infection, Herpes zoster infection, protozoan infection,
Kaposi sarcoma, Mooren ulcer, Terrien's marginal degeneration,
mariginal keratolysis, rheumatoid arthritis, systemic lupus,
polyarteritis, trauma, Wegeners sarcoidosis, Scleritis, Steven's
Johnson disease, periphigoid radial keratotomy, sickle cell anemia,
sarcoid, pseudoxanthoma elasticum, Pagets disease, vein occlusion,
artery occlusion, carotid obstructive disease, chronic uveitis,
chronic vitritis, Lyme's disease, Eales disease, Bechets disease,
retinitis, choroiditis, presumed ocular histoplasmosis, Bests
disease, Stargarts disease, pars planitis, chronic retinal
detachment, hyperviscosity syndromes, toxoplasmosis, rubeosis,
sarcodisis, sclerosis, soriatis, psoriasis, primary sclerosing
cholangitis, proctitis, primary biliary srosis, idiopathic
pulmonary fibrosis, and alcoholic hepatitis.
[0099] In specific embodiments of the invention, diseases or
disorders associated with undesired angiogenesis do not include
congestive heart failure, cardiomyopathy, pulmonary edema,
endotoxin-mediated septic shock, acute viral myocarditis, cardiac
allograft rejection, myocardial infarction, HIV, hepatitis, adult
respiratory distress syndrome, bone-resorption disease, chronic
obstructive pulmonary diseases, chronic pulmonary inflammatory
disease, dermatitis, cystic fibrosis, septic shock, sepsis,
endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic
reperfusion injury, meningitis, psoriasis, fibrotic disease,
cachexia, graft rejection, rheumatoid spondylitis, osteoporosis,
Crohn's disease, ulcerative colitis, inflammatory-bowel disease,
multiple sclerosis, systemic lupus erythrematosus, erythema nodosum
leprosum in leprosy, radiation damage, asthma, hyperoxic alveolar
injury, malaria, mycobacterial infection, and opportunistic
infections resulting from HIV.
[0100] This invention encompasses methods of treating patients who
have been previously treated for cancer or diseases or disorders
associated with, or characterized by, undesired angiogenesis, but
are non-responsive to standard therapies, as well as those who have
not previously been treated. The invention also encompasses methods
of treating patients regardless of patient's age, although some
diseases or disorders are more common in certain age groups. The
invention further encompasses methods of treating patients who have
undergone surgery in an attempt to treat the disease or condition
at issue, as well as those who have not. Because patients with
cancer and diseases and disorders characterized by undesired
angiogenesis have heterogenous clinical manifestations and varying
clinical outcomes, the treatment given to a patient may vary,
depending on his/her prognosis. The skilled clinician will be able
to readily determine without undue experimentation specific
secondary agents, types of surgery, and types of non-drug based
standard therapy that can be effectively used to treat an
individual patient with cancer and other diseases or disorders.
[0101] Methods encompassed by this invention comprise administering
one or more immunomodulatory compound of the invention, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof, to a patient (e.g., a human)
suffering, or likely to suffer, from cancer or a disease or
disorder mediated by undesired angiogenesis.
[0102] In one embodiment of the invention, an immunomodulatory
compound of the invention can be administered orally and in single
or divided daily doses in an amount of from about 0.10 to about 150
mg/day. In a particular embodiment,
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
(Actimid.TM.) may be administered in an amount of from about 0.1 to
about 1 mg per day, or alternatively from about 0.1 to about 5 mg
every other day. In a preferred embodiment,
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl-piperidine-2,6-dione
(Revimid.TM.) may be administered in an amount of from about 5 to
25 mg per day, or alternatively from about 10 to about 50 mg every
other day.
[0103] In a specific embodiment,
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
(Actimid.TM.) may be administered in an amount of about 1, 2, or 5
mg per day to patients with relapsed multiple myeloma. In a
particular embodiment,
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Revimid.TM.) may be administered initially in an amount of 5
mg/day and the dose can be escalated every week to 10, 20, 25, 30
and 50 mg/day. In a specific embodiment, Revimid.TM. can be
administered in an amount of up to about 30 mg/day to patients with
solid tumor. In a particular embodiment, Revimid.TM. can be
administered in an amount of up to about 40 mg/day to patients with
glioma.
5.3.1 Combination Therapy with a Second Active Agent
[0104] Specific methods of the invention comprise administering an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or
prodrug thereof, in combination with one or more second active
agents, and/or in combination with radiation therapy, blood
transfusions, or surgery. Examples of immunomodulatory compounds of
the invention are disclosed herein (see, e.g., section 5.1).
Examples of second active agents are also disclosed herein (see,
e.g., section 5.2).
[0105] Administration of the immunomodulatory compounds and the
second active agents to a patient can occur simultaneously or
sequentially by the same or different routes of administration. The
suitability of a particular route of administration employed for a
particular active agent will depend on the active agent itself
(e.g., whether it can be administered orally without decomposing
prior to entering the blood stream) and the disease being treated.
A preferred route of administration for an immunomodulatory
compound of the invention is orally. Preferred routes of
administration for the second active agents or ingredients of the
invention are known to those of ordinary skill in the art. See,
e.g., Physicians' Desk Reference, 1755-1760 (56.sup.th ed.,
2002).
[0106] In one embodiment of the invention, the second active agent
is administered intravenously or subcutaneously and once or twice
daily in an amount of from about 1 to about 1000 mg, from about 5
to about 500 mg, from about 10 to about 350 mg, or from about 50 to
about 200 mg. The specific amount of the second active agent will
depend on the specific agent used, the type of disease being
treated or managed, the severity and stage of disease, and the
amount(s) of immunomodulatory compounds of the invention and any
optional additional active agents concurrently administered to the
patient. In a particular embodiment, the second active agent is
oblimersen (Genasense.RTM.), GM-CSF, G-CSF, EPO, taxotere,
irinotecan, dacarbazine, transretinoic acid, topotecan,
pentoxifylline, ciprofloxacin, dexamethasone, vincristine,
doxorubicin, COX-2 inhibitor, IL2, IL8, IL18, IFN, Ara-C,
vinorelbine, or a combination thereof.
[0107] In a particular embodiment, GM-CSF, G-CSF or EPO is
administered subcutaneously during about five days in a four or six
week cycle in an amount of from about 1 to about 750
mg/m.sup.2/day, preferably in an amount of from about 25 to about
500 mg/m.sup.2/day, more preferably in an amount of from about 50
to about 250 mg/m.sup.2/day, and most preferably in an amount of
from about 50 to about 200 mg/m.sup.2/day. In a certain embodiment,
GM-CSF may be administered in an amount of from about 60 to about
500 mcg/m.sup.2 intravenously over 2 hours, or from about 5 to
about 12 mcg/m.sup.2/day subcutaneously. In a specific embodiment,
G-CSF may be administered subcutaneously in an amount of about 1
mcg/kg/day initially and can be adjusted depending on rise of total
granulocyte counts. The maintenance dose of G-CSF may be
administered in an amount of about 300 (in smaller patients) or 480
meg subcutaneously. In a certain embodiment, EPO may be
administered subcutaneously in an amount of 10,000 Unit 3 times per
week.
[0108] In another embodiment, Revimid.TM. in an amount of about 25
mg/d and dacarbazine in an amount of about from 200 to 1,000
mg/m.sup.2/d are administered to patients with metastatic malignant
melanoma. In a specific embodiment, Revimid.TM. is administered in
an amount of from about 5 to about 25 mg/d to patients with
metastatic malignant melanoma whose disease has progressed on
treatment with dacarbazine, IL-2 or IFN. In a specific embodiment,
Revimid.TM. is administered to patients with relapsed or refractory
multiple myeloma in an amount of about 15 mg/d twice a day or about
30 mg/d four times a day in a combination with dexamethasone.
[0109] In another embodiment, an immunomodulatory compound is
administered with melphalan and dexamethasone to patients with
amyloidosis. In a specific embodiment, an immunomodulatory compound
of the invention and steroids can be administered to patients with
amyloidosis.
[0110] In another embodiment, an immunomodulatory compound is
administered with gemcitabine and cisplatinum to patients with
locally advanced or metastatic transitional cell bladder
cancer.
[0111] In another embodiment, an immunomodulatory compound is
administered in combination with a second active ingredient as
follows: temozolomide to pediatric patients with relapsed or
progressive brain tumors or recurrent neuroblastoma; celecoxib,
etoposide and cyclophosphamide for relapsed or progressive CNS
cancer; temodar to patients with recurrent or progressive
meningioma, malignant meningioma, hemangiopericytoma, multiple
brain metastases, relapased brain tumors, or newly diagnosed
glioblastoma multiforms; irinotecan to patients with recurrent
glioblastoma; carboplatin to pediatric patients with brain stem
glioma; procarbazine to pediatric patients with progressive
malignant gliomas; cyclophosphamide to patients with poor prognosis
malignant brain tumors, newly diagnosed or recurrent glioblastoma
multiforms; Gliadel.RTM. for high grade recurrent malignant
gliomas; temozolomide and tamoxifen for anaplastic astrocytoma; or
topotecan for gliomas, glioblastoma, anaplastic astrocytoma or
anaplastic oligodendroglioma.
[0112] In another embodiment, an immunomodulatory compound is
administered with methotrexate and cyclophosphamide to patients
with metastatic breast cancer.
[0113] In another embodiment, an immunomodulatory compound is
administered with temozolomide to patients with neuroendocrine
tumors.
[0114] In another embodiment, an immunomodulatory compound is
administered with gemcitabine to patients with recurrent or
metastatic head or neck cancer. In another embodiment, an
immunomodulatory compound is administered with gemcitabine to
patients with pancreatic cancer.
[0115] In another embodiment, an immunomodulatory compound is
administered to patients with colon cancer in combination with
Arisa.RTM., taxol and/or taxotere.
[0116] In another embodiment, an immunomodulatory compound is
administered with capecitabine to patients with refractory
colorectal cancer or patients who fail first line therapy or have
poor performance in colon or rectal adenocarcinoma.
[0117] In another embodiment, an immunomodulatory compound is
administered in combination with fluorouracil, leucovorin, and
irinotecan to patients with Dukes C & D colorectal cancer or to
patients who have been previously treated for metastatic colorectal
cancer.
[0118] In another embodiment, an immunomodulatory compound is
administered to patients with refractory colorectal cancer in
combination with capecitabine, xeloda, and/or CPT-11.
[0119] In another embodiment, an immunomodulatory compound of the
invention is administered with capecitabine and irinotecan to
patients with refractory colorectal cancer or to patients with
unresectable or metastatic colorectal carcinoma.
[0120] In another embodiment, an immunomodulatory compound is
administered alone or in combination with interferon alpha or
capecitabine to patients with unresectable or metastatic
hepatocellular carcinoma; or with cisplatin and thiotepa to
patients with primary or metastatic liver cancer.
[0121] In another embodiment, an immunomodulatory compound is
administered in combination with pegylated interferon alpha to
patients with Kaposi's sarcoma.
[0122] In another embodiment, an immunomodulatory compound is
administered in combination with fludarabine, carboplatin, and/or
topotecan to patients with refractory or relapsed or high-risk
acuted myelogenous leukemia.
[0123] In another embodiment, an immunomodulatory compound is
administered in combination with liposomal daunorubicin, topotecan
and/or cytarabine to patients with unfavorable karotype acute
myeloblastic leukemia.
[0124] In another embodiment, an immunomodulatory compound is
administered in combination with gemcitabine and irinotecan to
patients with non-small cell lung cancer. In one embodiment, an
immunomodulatory compound is administered in combination with
carboplatin and irinotecan to patients with non-small cell lung
cancer. In one embodiment, an immunomodulatory compound is
administered with doxetaxol to patients with non-small cell lung
cancer who have been previously treated with carbo/VP 16 and
radiotherapy.
[0125] In another embodiment, an immunomodulatory compound is
administered in combination with carboplatin and/or taxotere, or in
combination with carboplatin, pacilitaxel and/or thoracic
radiotherapy to patients with non-small cell lung cancer. In a
specific embodiment, an immunomodulatory compound is administered
in combination with taxotere to patients with stage IIIB or IV
non-small cell lung cancer.
[0126] In another embodiment, an immunomodulatory compound of the
invention is administered in combination with oblimersen
(Genasense.RTM.) to patients with small cell lung cancer.
[0127] In another embodiment, an immunomodulatory compound is
administered alone or in combination with a second active
ingredient such as vinblastine or fludarabine to patients with
various types of lymphoma, including, but not limited to, Hodgkin's
lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma,
cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or
relapsed or refractory low grade follicular lymphoma.
[0128] In another embodiment, an immunomodulatory compound is
administered in combination with taxotere, IL-2, IFN, GM-CSF,
and/or dacarbazine to patients with various types or stages of
melanoma.
[0129] In another embodiment, an immunomodulatory compound is
administered alone or in combination with vinorelbine to patients
with malignant mesothelioma, or stage IIIB non-small cell lung
cancer with pleural implants or malignant pleural effusion
mesothelioma syndrome.
[0130] In another embodiment, an immunomodulatory compound is
administered to patients with various types or stages of multiple
myeloma in combination with dexamethasone, zoledronic acid,
palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,
cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate,
celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, or a
combination thereof.
[0131] In another embodiment, an immunomodulatory compound is
administered to patients with relapsed or refractory multiple
myeloma in combination with doxorubicin (Doxil.RTM.), vincristine
and/or dexamethasone (Decadron.RTM.).
[0132] In another embodiment, an immunomodulatory compound is
administered to patients with various types or stages of ovarian
cancer such as peritoneal carcinoma, papillary serous carcinoma,
refractory ovarian cancer or recurrent ovarian cancer, in
combination with taxol, carboplatin, doxorubicin, gemcitabine,
cisplatin, xeloda, paclitaxel, dexamethasone, or a combination
thereof.
[0133] In another embodiment, an immunomodulatory compound is
administered to patients with various types or stages of prostate
cancer, in combination with xeloda, 5 FU/LV, gemcitabine,
irinotecan plus gemcitabine, cyclophosphamide, vincristine,
dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir,
paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, or a
combination thereof.
[0134] In another embodiment, an immunomodulatory compound is
administered to patients with various types or stages of renal cell
cancer, in combination with capecitabine, IFN, tamoxifen, IL-2,
GM-CSF, Celebrex.RTM., or a combination thereof.
[0135] In another embodiment, an immunomodulatory compound is
administered to patients with various types or stages of
gynecologic, uterus or soft tissue sarcoma cancer in combination
with IFN, a COX-2 inhibitor such as Celebrex.RTM., and/or
sulindac.
[0136] In another embodiment, an immunomodulatory compound is
administered to patients with various types or stages of solid
tumors in combination with celebrex, etoposide, cyclophosphamide,
docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a
combination thereof.
[0137] In another embodiment, an immunomodulatory compound is
administered to patients with scleroderma or cutaneous vasculitis
in combination with celebrex, etoposide, cyclophosphamide,
docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a
combination thereof.
[0138] This invention also encompasses a method of increasing the
dosage of an anti-cancer drug or agent that can be safely and
effectively administered to a patient, which comprises
administering to a patient (e.g., a human) an immunomodulatory
compound of the invention, or a pharmaceutically acceptable
derivative, salt, solvate, clathrate, hydrate, or prodrug thereof.
Patients that can benefit by this method are those likely to suffer
from an adverse effect associated with anti-cancer drugs for
treating a specific cancer of the skin, subcutaneous tissue, lymph
nodes, brain, lung, liver, bone, intestine, colon, heart, pancreas,
adrenal, kidney, prostate, breast, colorectal, or combinations
thereof. The administration of an immunomodulatory compound of the
invention alleviates or reduces adverse effects which are of such
severity that it would otherwise limit the amount of anti-cancer
drug.
[0139] In one embodiment, an immunomodulatory compound of the
invention can be administered orally and daily in an amount of from
about 0.1 to about 150 mg, and preferably from about 1 to about 50
mg, more preferably from about 2 to about 25 mg prior to, during,
or after the occurrence of the adverse effect associated with the
administration of an anti-cancer drug to a patient. In a particular
embodiment, an immunomodulatory compound of the invention is
administered in combination with specific agents such as heparin,
aspirin, coumadin, or G-CSF to avoid adverse effects that are
associated with anti-cancer drugs such as but not limited to
neutropenia or thrombocytopenia.
[0140] In one embodiment, an immunomodulatory compound of the
invention can be administered to patients with diseases and
disorders associated with, or characterized by, undesired
angiogenesis in combination with additional active ingredients
including but not limited to anti-cancer drugs,
anti-inflammatories, antihistamines, antibiotics, and steroids.
[0141] In another embodiment, this invention encompasses a method
of treating, preventing and/or managing cancer, which comprises
administering an immunomodulatory compound of the invention, or a
pharmaceutically acceptable salt, solvate, hydrate, stereoisomer,
clathrate, or prodrug thereof, in conjunction with (e.g. before,
during, or after) conventional therapy including, but not limited
to, surgery, immunotherapy, biological therapy, radiation therapy,
or other non-drug based therapy presently used to treat, prevent or
manage cancer. The combined use of the immunomodulatory compounds
of the invention and conventional therapy may provide a unique
treatment regimen that is unexpectedly effective in certain
patients. Without being limited by theory, it is believed that
immunomodulatory compounds of the invention may provide additive or
synergistic effects when given concurrently with conventional
therapy.
[0142] As discussed elsewhere herein, the invention encompasses a
method of reducing, treating and/or preventing adverse or undesired
effects associated with conventional therapy including, but not
limited to, surgery, chemotherapy, radiation therapy, hormonal
therapy, biological therapy and immunotherapy. One or more
immunomodulatory compounds of the invention and other active
ingredient can be administered to a patient prior to, during, or
after the occurrence of the adverse effect associated with
conventional therapy.
[0143] In one embodiment, an immunomodulatory compound of the
invention can be administered in an amount of from about 0.1 to
about 150 mg, and preferably from about 1 to about 25 mg, more
preferably from about 2 to about 10 mg orally and daily alone, or
in combination with a second active agent disclosed herein (see,
e.g., section 5.2), prior to, during, or after the use of
conventional therapy.
[0144] In a specific embodiment of this method, an immunomodulatory
compound of the invention and doxetaxol are administered to
patients with non-small cell lung cancer who were previously
treated with carbo/VP 16 and radiotherapy.
5.3.2 Use with Transplantation Therapy
[0145] Compounds of the invention can be used to reduce the risk of
Graft Versus Host Disease (GVHD). Therefore, the invention
encompasses a method of treating, preventing and/or managing
cancer, which comprises administering the immunomodulatory compound
of the invention, or a pharmaceutically acceptable salt, solvate,
hydrate, stereoisomer, clathrate, or prodrug thereof, in
conjunction with transplantation therapy.
[0146] As those of ordinary skill in the art are aware, the
treatment of cancer is often based on the stages and mechanism of
the disease. For example, as inevitable leukemic transformation
develops in certain stages of cancer, transplantation of peripheral
blood stem cells, hematopoietic stem cell preparation or bone
marrow may be necessary. The combined use of the immunomodulatory
compound of the invention and transplantation therapy provides a
unique and unexpected synergism. In particular, an immunomodulatory
compound of the invention exhibits immunomodulatory activity that
may provide additive or synergistic effects when given concurrently
with transplantation therapy in patients with cancer.
[0147] An immunomodulatory compound of the invention can work in
combination with transplantation therapy reducing complications
associated with the invasive procedure of transplantation and risk
of GVHD. This invention encompasses a method of treating,
preventing and/or managing cancer which comprises administering to
a patient (e.g., a human) an immunomodulatory compound of the
invention, or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof, before, during, or
after the transplantation of umbilical cord blood, placental blood,
peripheral blood stem cell, hematopoietic stem cell preparation or
bone marrow. Examples of stem cells suitable for use in the methods
of the invention are disclosed in U.S. provisional patent
application No. 60/372,348, filed Apr. 12, 2002 by R. Hariri et
al., the entirety of which is incorporated herein by reference.
[0148] In one embodiment of this method, an immunomodulatory
compound of the invention is administered to patients with multiple
myeloma before, during, or after the transplantation of autologous
peripheral blood progenitor cell.
[0149] In another embodiment, an immunomodulatory compound is
administered to patients with relapsing multiple myeloma after the
stem cell transplantation.
[0150] In another embodiment, an immunomodulatory compound and
prednisone are administered as maintenance therapy to patients with
multiple myeloma following the transplantation of autologous stem
cell.
[0151] In another embodiment, an immunomodulatory compound and
dexamethasone are administered as salvage therapy for low risk post
transplantation to patients with multiple myeloma.
[0152] In another embodiment, an immunomodulatory compound and
dexamethasone are administered as maintenance therapy to patients
with multiple myeloma following the transplantation of autologous
bone marrow.
[0153] In another embodiment, an immunomodulatory compound is
administered following the administration of high dose of melphalan
and the transplantation of autologous stem cell to patients with
chemotherapy responsive multiple myeloma.
[0154] In another embodiment, an immunomodulatory compound and PEG
INTRO-A are administered as maintenance therapy to patients with
multiple myeloma following the transplantation of autologous
CD34-selected peripheral stem cell.
[0155] In another embodiment, an immunomodulatory compound is
administered with post transplant consolidation chemotherapy to
patients with newly diagnosed multiple myeloma to evaluate
anti-angiogenesis.
[0156] In another embodiment, an immunomodulatory compound and
dexamethasone are administered as maintenance therapy after DCEP
consolidation, following the treatment with high dose of melphalan
and the transplantation of peripheral blood stem cell to 65 years
of age or older patients with multiple myeloma.
5.3.3 Cycling Therapy
[0157] In certain embodiments, the prophylactic or therapeutic
agents of the invention are cyclically administered to a patient.
Cycling therapy involves the administration of an active agent for
a period of time, followed by a rest for a period of time, and
repeating this sequential administration. Cycling therapy can
reduce the development of resistance to one or more of the
therapies, avoid or reduce the side effects of one of the
therapies, and/or improves the efficacy of the treatment.
[0158] Consequently, in one specific embodiment of the invention,
an immunomodulatory compound of the invention is administered daily
in a single or divided doses in a four to six week cycle with a
rest period of about a week or two weeks. The invention further
allows the frequency, number, and length of dosing cycles to be
increased. Thus, another specific embodiment of the invention
encompasses the administration of an immunomodulatory compound of
the invention for more cycles than are typical when it is
administered alone. In yet another specific embodiment of the
invention, an immunomodulatory compound of the invention is
administered for a greater number of cycles that would typically
cause dose-limiting toxicity in a patient to whom a second active
ingredient is not also being administered.
[0159] In one embodiment, an immunomodulatory compound of the
invention is administered daily and continuously for three or four
weeks at a dose of from about 0.1 to about 150 mg/d followed by a
break of one or two weeks. Actimid.TM. is preferably administered
daily and continuously at an initial dose of 0.1 to 5 mg/d with
dose escalation (every week) by 1 to 10 mg/d to a maximum dose of
50 mg/d for as long as therapy is tolerated. In a particular
embodiment, Revimid.TM. is administered in an amount of about 5,
10, or 25 mg/day, preferably in an amount of about 10 mg/day for
three to four weeks, followed by one week or two weeks of rest in a
four or six week cycle.
[0160] In one embodiment of the invention, an immunomodulatory
compound of the invention and a second active ingredient are
administered orally, with administration of an immunomodulatory
compound of the invention occurring 30 to 60 minutes prior to a
second active ingredient, during a cycle of four to six weeks. In
another embodiment of the invention, the combination of an
immunomodulatory compound of the invention and a second active
ingredient is administered by intravenous infusion over about 90
minutes every cycle. In a specific embodiment, one cycle comprises
the administration of from about 10 to about 25 mg/day of
Revimid.TM. and from about 50 to about 200 mg/m.sup.2/day of a
second active ingredient daily for three to four weeks and then one
or two weeks of rest. In another specific embodiment, each cycle
comprises the administration of from about 5 to about 10 mg/day of
Actimid.TM. and from about 50 to about 200 mg/m.sup.2/day of a
second active ingredient for 3 to 4 weeks followed by one or two
weeks of rest. Typically, the number of cycles during which the
combinatorial treatment is administered to a patient will be from
about one to about 24 cycles, more typically from about two to
about 16 cycles, and even more typically from about four to about
three cycles.
5.4 Pharmaceutical Compositions and Dosage Forms
[0161] Pharmaceutical compositions can be used in the preparation
of individual, single unit dosage forms. Pharmaceutical
compositions and dosage forms of the invention comprise an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or
prodrug thereof. Pharmaceutical compositions and dosage forms of
the invention can further comprise one or more excipients.
[0162] Pharmaceutical compositions and dosage forms of the
invention can also comprise one or more additional active
ingredients. Consequently, pharmaceutical compositions and dosage
forms of the invention comprise the active ingredients disclosed
herein (e.g., an immunomodulatory compound and a second active
agent). Examples of optional second, or additional, active
ingredients are disclosed herein (see, e.g., section 5.2).
[0163] Single unit dosage forms of the invention are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), topical (e.g., eye
drops or other ophthalmic preparations), transdermal or
transcutaneous administration to a patient. Examples of dosage
forms include, but are not limited to: tablets; caplets; capsules,
such as soft elastic gelatin capsules; cachets; troches; lozenges;
dispersions; suppositories; powders; aerosols (e.g., nasal sprays
or inhalers); gels; liquid dosage forms suitable for oral or
mucosal administration to a patient, including suspensions (e.g.,
aqueous or non-aqueous liquid suspensions, oil-in-water emulsions,
or a water-in-oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a patient;
eye drops or other ophthalmic preparations suitable for topical
administration; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0164] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form used in the acute treatment of a disease may contain
larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the chronic treatment of the
same disease. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease.
These and other ways in which specific dosage forms encompassed by
this invention will vary from one another will be readily apparent
to those skilled in the art. See, e.g., Remington's Pharmaceutical
Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
[0165] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients are provided herein. Whether a particular
excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which
the dosage form will be administered to a patient. For example,
oral dosage forms such as tablets may contain excipients not suited
for use in parenteral dosage forms. The suitability of a particular
excipient may also depend on the specific active ingredients in the
dosage form. For example, the decomposition of some active
ingredients may be accelerated by some excipients such as lactose,
or when exposed to water. Active ingredients that comprise primary
or secondary amines are particularly susceptible to such
accelerated decomposition. Consequently, this invention encompasses
pharmaceutical compositions and dosage forms that contain little,
if any, lactose other mono- or disaccharides. As used herein, the
term "lactose-free" means that the amount of lactose present, if
any, is insufficient to substantially increase the degradation rate
of an active ingredient.
[0166] Lactose-free compositions of the invention can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general,
lactose-free compositions comprise active ingredients, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free dosage
forms comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0167] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY. N.Y. 1995, pp. 379-80. In effect, water and heat accelerate the
decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0168] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0169] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
[0170] The invention further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0171] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. However, typical dosage
forms of the invention comprise an immunomodulatory compound of the
invention or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof in an amount of from
about 0.10 to about 150 mg. Typical dosage forms comprise an
immunomodulatory compound of the invention or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or
prodrug thereof in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5,
15, 17.5, 20, 25, 50, 100, 150 or 200 mg. In a particular
embodiment, a preferred dosage form comprises
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
(Actimid.TM.) in an amount of about 1, 2, 5, 10, 25 or 50 mg. In a
specific embodiment. a preferred dosage form comprises
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Revimid.TM.) in an amount of about 5, 10, 25 or 50 mg. Typical
dosage forms comprise the second active ingredient in an amount of
1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to
about 350 mg, or from about 50 to about 200 mg. Of course, the
specific amount of the anti-cancer drug will depend on the specific
agent used, the type of cancer being treated or managed, and the
amount(s) of an immunomodulatory compound of the invention and any
optional additional active agents concurrently administered to the
patient.
5.4.1 Oral Dosage Forms
[0172] Pharmaceutical compositions of the invention that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).
[0173] Typical oral dosage forms of the invention are prepared by
combining the active ingredients in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0174] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0175] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0176] Examples of excipients that can be used in oral dosage forms
of the invention include, but are not limited to, binders, fillers,
disintegrates, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0177] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa.), and mixtures thereof. An specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM. and Starch 1500 LM.
[0178] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the invention is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0179] Disintegrants are used in the compositions of the invention
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
invention. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
preferably from about 1 to about 5 weight percent of
disintegrant.
[0180] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums, and mixtures
thereof.
[0181] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the invention include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
[0182] A preferred solid oral dosage form of the invention
comprises an immunomodulatory compound of the invention, anhydrous
lactose, microcrystalline cellulose, polyvinylpyrrolidone, stearic
acid, colloidal anhydrous silica, and gelatin.
5.4.2 Delayed Release Dosage Forms
[0183] Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or control
led-release of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The
invention thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0184] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0185] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
5.4.3 Parenteral Dosage Forms
[0186] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0187] Suitable vehicles that can be used to provide parenteral
dosage forms of the invention are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0188] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the invention. For example,
cyclodextrin and its derivatives can be used to increase the
solubility of an immunomodulatory compound of the invention and its
derivatives. See, e.g., U.S. Pat. No. 5,134,127, which is
incorporated herein by reference.
5.4.4 Topical and Mucosal Dosage Forms
[0189] Topical and mucosal dosage forms of the invention include,
but are not limited to, sprays, aerosols, solutions, emulsions,
suspensions, eye drops or other ophthalmic preparations, or other
forms known to one of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences, 16.sup.th and 18.sup.th eds., Mack
Publishing, Easton Pa. (1980 & 1990); and Introduction to
Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,
Philadelphia (1985). Dosage forms suitable for treating mucosal
tissues within the oral cavity can be formulated as mouthwashes or
as oral gels.
[0190] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide topical and mucosal dosage
forms encompassed by this invention are well known to those skilled
in the pharmaceutical arts, and depend on the particular tissue to
which a given pharmaceutical composition or dosage form will be
applied. With that fact in mind, typical excipients include, but
are not limited to, water, acetone, ethanol, ethylene glycol,
propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl
palmitate, mineral oil, and mixtures thereof to form solutions,
emulsions or gels, which are non-toxic and pharmaceutically
acceptable. Moisturizers or humectants can also be added to
pharmaceutical compositions and dosage forms if desired. Examples
of such additional ingredients are well known in the art. See,
e.g., Remington's Pharmaceutical Sciences, 16.sup.th and 18.sup.th
eds., Mack Publishing, Easton Pa. (1980 & 1990).
[0191] The pH of a pharmaceutical composition or dosage form may
also be adjusted to improve delivery of one or more active
ingredients. Similarly, the polarity of a solvent carrier, its
ionic strength, or tonicity can be adjusted to improve delivery.
Compounds such as stearates can also be added to pharmaceutical
compositions or dosage forms to advantageously alter the
hydrophilicity or lipophilicity of one or more active ingredients
so as to improve delivery. In this regard, stearates can serve as a
lipid vehicle for the formulation, as an emulsifying agent or
surfactant, and as a delivery-enhancing or penetration-enhancing
agent. Different salts, hydrates or solvates of the active
ingredients can be used to further adjust the properties of the
resulting composition.
5.4.5 Kits
[0192] Typically, active ingredients of the invention are
preferably not administered to a patient at the same time or by the
same route of administration. This invention therefore encompasses
kits which, when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
patient.
[0193] A typical kit of the invention comprises a dosage form of an
immunomodulatory compound of the invention, or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, prodrug, or
clathrate thereof. Kits encompassed by this invention can further
comprise additional active ingredients such as oblimersen
(Genasense.RTM.), melphalan, G-CSF, GM-CSF, EPO, topotecan,
dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor,
pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18,
Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or a
pharmacologically active mutant or derivative thereof, or a
combination thereof. Examples of the additional active ingredients
include, but are not limited to, those disclosed herein (see, e.g.,
section 5.2).
[0194] Kits of the invention can further comprise devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, drip bags, patches, and
inhalers.
[0195] Kits of the invention can further comprise cells or blood
for transplantation as well as pharmaceutically acceptable vehicles
that can be used to administer one or more active ingredients. For
example, if an active ingredient is provided in a solid form that
must be reconstituted for parenteral administration, the kit can
comprise a sealed container of a suitable vehicle in which the
active ingredient can be dissolved to form a particulate-free
sterile solution that is suitable for parenteral administration.
Examples of pharmaceutically acceptable vehicles include, but are
not limited to: Water for Injection USP; aqueous vehicles such as,
but not limited to, Sodium Chloride Injection, Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and
Lactated Ringer's Injection; water-miscible vehicles such as, but
not limited to, ethyl alcohol, polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles such as, but not
limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl
oleate, isopropyl myristate, and benzyl benzoate.
6. EXAMPLES
[0196] Certain embodiments of the invention are illustrated by the
following non-limiting examples.
6.1 Modulation of Cytokine Production
[0197] A series of non-clinical pharmacology and toxicology studies
have been performed to support the clinical evaluation of an
immunomodulatory compound of the invention in human subjects. These
studies were performed in accordance with internationally
recognized guidelines for study design and in compliance with the
requirements of Good Laboratory Practice (GLP), unless otherwise
noted.
[0198] Inhibition of TNF-.alpha. production following
LPS-stimulation of human PBMC and human whole blood by
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
(Actimid.TM.),
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
and thalidomide (Revimid.TM.) was investigated in vitro (Muller et
al., Bioorg. Med. Chem. Lett. 9:1625-1630, 1999). The IC.sub.50's
of 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione for
inhibiting production of TNF-.alpha. following LPS-stimulation of
PBMC and human whole blood were .about.24 nM (6.55 ng/mL) and
.about.25 nM (6.83 ng/mL), respectively. In vitro studies suggest a
pharmacological activity profile for
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
that is similar to, but at least 200 times more potent than,
thalidomide. In vitro studies have also demonstrated that
concentrations of
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione of 2.73
to 27.3 ng/mL (0.01 to 0.1 .mu.M) achieved 50% inhibition of the
proliferation of MM.IS and Hs Sultan cells.
[0199] The IC.sub.50's of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
for inhibiting production of TNF-.alpha. following LPS-stimulation
of PBMC and human whole blood were .about.100 nM (25.9 ng/mL) and
.about.480 nM (103.6 ng/mL), respectively. Thalidomide, in
contrast, had an IC.sub.50 of .about.194 .mu.M (50.2 .mu.g/mL) for
inhibiting production of TNF-.alpha. following LPS-stimulation of
PBMC. In vitro studies suggest a pharmacological activity profile
for
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
that is similar to, but 50 to 2000 times more potent than,
thalidomide. It has been shown that the compound is approximately
50-100 times more potent than thalidomide in stimulating the
proliferation of T-cells following primary induction by T-cell
receptor (TCR) activation.
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
also approximately 50 to 100 times more potent than thalidomide in
augmenting the production of IL-2 and IFN-.gamma. following TCR
activation of PBMC (IL-2) or T-cells (IFN-.gamma.). In addition,
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
exhibited dose-dependent inhibition of LPS-stimulated production of
the pro-inflammatory cytokines TNF-.alpha., IL-1.beta., and IL-6 by
PBMC while it increased production of the anti-inflammatory
cytokine IL-10.
6.2 Inhibition of MM Cell Proliferation
[0200] The ability of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Revimid.TM.) and thalidomide for comparison to effect the
proliferation of MM cell lines has been investigated in an in vitro
study. Uptake [.sup.3H]-thymidine by different MM cell lines
(MM.1S, Hs Sultan, U266 and RPMI-8226) was measured as an indicator
of cell proliferation. Cells were incubated in the presence of
compounds for 48 hours; [.sup.3H]-thymidine was included for the
last 8 hours of the incubation period. Addition of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione to
MM.1S and Hs Sultan cells resulted in 50% inhibition of cell
proliferation at concentrations of 0.4 .mu.m and 1 .mu.m,
respectively. In contrast, addition of thalidomide at
concentrations up to 100 .mu.m resulted in only 15% and 20%
inhibition of cell proliferation in MM.1S and Hs Sultan cells,
respectively. These data are summarized in FIG. 1.
6.3 Toxicology Studies
[0201] The effects of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Revimid.TM.) on cardiovascular and respiratory function are
investigated in anesthetized dogs. Two groups of Beagle dogs
(2/sex/group) are used. One group receives three doses of vehicle
only and the other receives three ascending doses of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(2, 10, and 20 mg/kg). In all cases, doses of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione or
vehicle are successively administered via infusion through the
jugular vein separated by intervals of at least 30 minutes.
[0202] The cardiovascular and respiratory changes induced by
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
are minimal at all doses when compared to the vehicle control
group. The only statistically significant difference between the
vehicle and treatment groups is a small increase in arterial blood
pressure (from 94 mmHg to 101 mmHg) following administration of the
low dose of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione.
This effect lasts approximately 15 minutes and is not seen at
higher doses. Deviations in femoral blood flow, respiratory
parameters, and Qtc interval are common to both the control and
treated groups and are not considered treatment-related.
6.4 Cycling Therapy in Patients
[0203] In a specific embodiment, an immunomodulatory compound of
the invention are cyclically administered to patients with cancer.
Cycling therapy involves the administration of a first agent for a
period of time, followed by a rest for a period of time and
repeating this sequential administration. Cycling therapy can
reduce the development of resistance to one or more of the
therapies, avoid or reduce the side effects of one of the
therapies, and/or improves the efficacy of the treatment.
[0204] In a specific embodiment, prophylactic or therapeutic agents
are administered in a cycle of about 4 to 6 weeks, about once or
twice every day. One cycle can comprise the administration of a
therapeutic on prophylactic agent for three to four weeks and at
least a week or two weeks of rest. The number of cycles
administered is from about one to about 24 cycles, more typically
from about two to about 16 cycles, and more typically from about
four to about eight cycles.
[0205] For example, in a cycle of four weeks, on day 1, the
administration of 25 mg/d of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione is
started. On day 22, the administration of the compound is stopped
for a week of rest. On day 29, the administration of 25 mg/d
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidin-2,6-dione is
begun.
6.5 Clinical Studies in Patients
6.5.1 Treatment of Relapsed Multiple Myeloma
[0206] 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
(Actimid.TM.) was administered to patients with relapsed/refractory
multiple myeloma. The study was conducted in compliance with Good
Clinical Practices. Patients were at least 18 years old, had been
diagnosed with multiple myeloma (with paraprotein in serum and/or
urine), and were considered refractory to treatment after at least
two cycles of treatment, or have relapsed after two cycles of
treatment.
[0207] Patients who have progressive disease, according to the
Southwest Oncology Group (SWOG) criteria, on their prior regimen
are considered treatment refractory. Relapse following remission is
defined as >25% increase in M component from baseline levels;
reappearance of the M paraprotein that had previously disappeared;
or a definite increase in the size and number of lytic bone lesions
recognized on radiographs. Patients may have had prior therapy with
thalidomide, provided they were able to tolerate the treatment. A
Zubrod performance status of 0 to 2 is required for all
patients.
[0208] 4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
is administered to patients at doses of 1, 2, 5, or 10 mg/day for
up to four weeks; at each dose level, three patients are initially
enrolled. Dosing occurs at approximately the same time each
morning; all doses are administered in the fasted state (no eating
for at least two hours prior to dosing and two hours after dosing).
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione doses
are administered in an ascending fashion such that patients in the
first cohort receive the lowest dose of
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione (1
mg/day) and escalation to the next higher dose level occurs only
following the establishment of safety and tolerability at the
current dose. If one out of three patients at any dose level
experience dose limiting toxicity (DLT), three additional patients
are enrolled at that dose. If none of the three additional patients
experience DLT, escalation to the next dose level occurs; dose
escalations continue in a similar fashion until the MTD is
established or the maximum daily dose (10 mg/day) is attained.
However, if one of the three additional patients enrolled
experiences DLT, the MTD has been reached. If two or more of the
three additional patients enrolled experience DLT, the MTD is
judged to have been exceeded and three additional patients are
enrolled at the preceding dose level to confirm the MTD. Once the
MTD has been identified, four additional patients are enrolled at
that dose level so that a total of 10 patients is treated at the
MTD.
[0209] Blood sampling for analysis of pharmacokinetic parameters is
performed on Days 1 and 28 according to the following sampling
schedule: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8,
10, 12, 18, and 24 hours post-dose. An additional blood sample is
collected at each weekly visit for the determination of
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione levels.
Total urine collections are also made with urine pooled according
to the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12,
and 12 to 24 hours. Safety assessments are made by monitoring
adverse events, vital signs, ECGs, clinical laboratory evaluations
(blood chemistry, hematology, lymphocyte phenotyping, and
urinalysis), and physical examination at specific times during the
study.
[0210] Results of interim pharmacokinetic analyses obtained
following single- and multiple-dose administration of
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione to
multiple myeloma patients are presented below in Tables 1 and 2.
These data show that
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione was
steadily absorbed at all dose levels in relapsed multiple myeloma
patients. Maximum plasma concentrations occurred at a median
T.sub.max of between 2.5 and 2.8 hours post-dose at Day 1 and
between 3 and 4 hours post-dose at Week 4. At all doses, plasma
concentrations declined in a monophasic manner after reaching
C.sub.max. The start of the elimination phase occurred between 3
and 10 hours post-dose at Day 1 and Week 4, respectively.
[0211] These data also showed that after 4 weeks of dosing,
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione
accumulated to a small extent (mean accumulation ratios .about.1.02
to 1.52 and .about.0.94 to 1.62 for C.sub.max and
AUC.sub.(0-.tau.), respectively). There was almost a dose
proportional increase in AUC.sub.(0-.tau.) and C.sub.max values
with increasing dose. A five-fold higher dose of
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione produced
a 3.2- and 2.2-fold increase in C.sub.max at Day 1 and Week 4,
respectively. Similarly, a 5-fold increase in dose resulted in a
3.6- and 2.3-fold increase in AUC.sub.(0-.tau.), at Day 1 and Week
4, respectively.
TABLE-US-00001 TABLE 1 Pharmacokinetic parameters of Actimid .TM.
in relapsed multiple myeloma patients 1 mg 2 mg 5 mg Parameter (N =
6) (N = 2) (N = 3) Day 1 C.sub.max ng/mL 15.03 (4.04) 24.4* (12.1)
48.56 (14.03) t.sub.max h 3.3 (2.6) 2.7* (0.3) 2.3 (0.3)
AUC.sub.(0-.infin.) ng h/ 152.90 (36.62) 279.18 (51.10) 593.10
(335.23) mL AUC.sub.(0-.tau.) 134.21 (27.14) 249.57 (29.26) 520.94
(267.32) t1/2 h 7.3 (3.4) 6.3 (1.4) 6.5 (2.2) CL/F mL/min 114.75
(29.20) 121.43 (22.22) 182.31 (117.06) Vz/f L 69.55 (44.97) 65.31
(2.80) 87.24 (22.61) t = 24 hours N/A = not available
TABLE-US-00002 TABLE 2 Pharmacokinetic parameters of Actimid .TM.
following multiple oral doses(1, 2, and 5 mg/day) in relapsed
multiple myeloma patients 1 mg 2 mg 5 mg Parameter (N = 5) (N = 2)
(N = 3) Week 4 C.sub.max ng/mL 23.20 (7.48) 30.05* (15.64) 58.07
(38.08) t.sub.max h 3.6 (1.5) 2.8* (0.3) 5.0 (2.6)
AUC.sub.(0-.infin.) ng h/mL N/A N/A N/A AUC.sub.(0-.tau.) 239.31
(122.59) 269.36 (186.34) 597.24 (354.23) t1/2 h 6.2* (0.6) 7.7
(2.8) 7.8 (4.0) CL/F mL/min 87.85 (48.48) 162.68 (112.54) 207.50
(175.41) Vz/f L 41.35* (8.84) 95.04 (35.39) 103.95 (27.25) .tau. =
24 hours N/A = not available *N = 3 patients
6.5.2 Treatment of Relapsed Multiple Myeloma
[0212] Two Phase 1 clinical studies of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Revimid.TM.) have been conducted to identify the maximum tolerated
dose (MTD) in patients with refractory or relapsed multiple
myeloma. These studies have also characterized the safety profile
of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
when ascending doses of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
were given orally for up to 4 weeks. Patients started
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
treatment at 5 mg/day with subsequent escalation to 10, 25, and 50
mg/day. Patients were enrolled for 28 days at their assigned dose,
with the option of extended treatment for those who did not exhibit
disease progression or experience dose limiting toxicity (DLT).
Patients were evaluated for adverse events at each visit and the
severity of these events was graded according to the National
Cancer Institute (NCI) Common Toxicity Criteria. Patients were
discontinued if they experienced DLT (Grade 3 or greater
non-hematological, or Grade 4 hematological toxicity).
[0213] In this study, 27 patients were enrolled. All patients had
relapsed multiple myeloma and 18 (72%) were refractory to salvage
therapy. Among these patients, 15 had undergone prior autologous
stem cell transplantation and 16 patients had received prior
thalidomide treatment. The median number of prior regimens was 3
(range 2 to 6).
[0214] Blood and urine samples were collected for analysis of
pharmacokinetic parameters on Days 1 and 28. Blood samples were
collected according to the following sampling schedule: pre-dose,
0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 18, and 24
hours post-dose. In addition, a blood sample was collected at each
weekly clinic visit for
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
determination. Total urine was collected and pooled according to
the following time intervals post-dose: 0 to 4, 4 to 8, 8 to 12,
and 12 to 24 hours. Response to treatment was assessed by M-protein
quantification (by immunoelectrophoresis) from serum and a 24-hour
urine collection, with creatinine clearance and 24-hour protein
calculations undertaken at screening, baseline, Weeks 2 and 4, and
monthly thereafter (or upon early termination). Bone marrow
aspirations and/or tissue biopsy are also performed at Months 3, 6
and 12 if a patient's paraprotein serum concentration or 24-hour
urine protein excretion declined to the next lower level, based on
best response criteria. Preliminary results for the 28-day
treatment period are summarized below.
[0215] Preliminary pharmacokinetic analyses based on these two
studies indicated that AUC and C.sub.max values increase
proportionally with dose following single and multiple doses in
multiple myeloma patients (as was seen in healthy volunteers).
Further, there was no evidence of accumulation with multiple dosing
as single dose AUC.sub.(0-.tau.) was comparable to multiple dose
AUC.sub.0-.tau. following the same dose of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione.
Similar to healthy volunteer studies, double peaks were observed.
Exposure in multiple myeloma patients appeared to be slightly
higher based on C.sub.max and AUC values as compared to healthy
male volunteers while clearance in multiple myeloma patients was
lower than it was in healthy volunteers, consistent with their
poorer renal function (both as a consequence of their age and their
disease). Finally,
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
half-live in patients was shorter than in healthy volunteers (mean
8 hours, ranging up to 17 hours).
[0216] In this study, the first cohort of 3 patients was treated
for 28 days at 5 mg/day without any dose limiting toxicity (DLT).
The second cohort of 3 patients subsequently commenced therapy at
10 mg/day. Patients in the second 10 mg/day of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
cohort tolerated treatment well.
6.5.3 Treatment of Solid Tumors
[0217] Study with
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Revimid.TM.) was conducted in patients with varying types of solid
tumors, including malignant melanoma (13), carcinoma of the
pancreas (2), carcinoid-unknown primary (1), renal carcinoma (1),
breast carcinoma (1) and NSCLC (2). Patients received 5 mg/day
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
for seven days and are subsequently escalated every seven days to
10 mg/day, 25 mg/day, and 50 mg/day for a total of 4 weeks of
treatment. Patients who, experienced clinical benefit were
permitted to continue on treatment as Named Patients.
[0218] The study initially enrolled 20 patients and was
subsequently amended to enroll 16 additional patients (adrenal
carcinoma, NSCLC, malignant mesothelioma, breast cancer, malignant
melanoma (8), renal cell cancer (4)) at a higher dose. The 16
additional patients were given weekly escalating doses of 25
mg/day, 50 mg/day, 75 mg/day, 100 mg/day, 125 mg/day, and 150
mg/day over a 6-week period with continuing treatment for an
additional six weeks.
[0219] The study of Phase 1 study was designed to determine a
maximum tolerated dose (MTD) of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in
patients with refractory solid tumors and/or lymphoma, as well as
to characterize the pharmacokinetic and side effect profiles of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in
this patient population. The study design dictates that at least 3
patients must be enrolled at a dose level and have completed 28
days of treatment prior to enrollment of patients at the next
higher dose level. Patients in the first cohort began dosing at 5
mg/day of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione.
Patients will be escalated to 10, 20, 25, and 30 mg/day provided
there is no toxicity.
[0220] In this study, the MTD is defined as the highest dose level
in which fewer than two of six patients treated did not experience
Grade 3 or greater non-hematological toxicity or Grade 4 or greater
hematological toxicity. If, at any given dose level in either
study, one out of three patients experiences toxicity, three
additional patients must be treated at that particular dose. If,
however, two out of six patients experience DLT, the MTD is judged
to have been exceeded. No further dose escalations are to occur and
additional patients are to be enrolled at the previous dose level.
The dose of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
administered is escalated until the MTD is achieved or the maximum
daily dose of is reached.
[0221] No DLTs were reported in the initial group of 20 patients
enrolled in the study. Thirteen of the original 20 trial patients,
along with 2 non-trial patients, continued on treatment as named
patients at doses up to 150 mg/day.
6.5.4 Treatment of Gliomas
[0222] This study was performed to find toxicity in patients with
recurrent, high-grade gliomas. The study is designed such that
patients are given increasingly higher doses of
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
until a maximum tolerated dose (MTD) is established. The study also
seeks to obtain preliminary toxicity information and
pharmacokinetic data on
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione,
as well as to develop exploratory data concerning surrogate end
points of angiogenic activity in vivo using functional
neuro-imaging studies, and in vitro assays of serum angiogenic
peptides.
[0223] Patients enrolled in the first cohort receive 2.5
mg/m.sup.2/day for a 4-week cycle. During each 4-week cycle of
therapy,
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
administered once daily for 3 weeks followed by a week of rest.
Patients who complete a treatment cycle may receive another cycle
of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
treatment if two criteria are met. First, the patient must have
stable disease or have experienced a partial response or complete
response, or the patient is benefiting from the therapy with
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as
evidenced by a decrease in tumor-related symptoms such as
neurological deficits. Second, the patient must have recovered from
toxicity related to
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
which occurred in the prior cycle by Day 42 or sooner (28-day cycle
plus limit of 2 weeks to recover) as evidenced by a return to
Grade.ltoreq.1 toxicity level. Patients who experience DLT in the
previous cycle should have their dose modified. DLT is defined as
an non-hematological event Grade.gtoreq.3 toxicity or hematological
event of Grade 4 toxicity thought to be related to the study
medication. Patients who experience DLT in the first cycle and have
no response to therapy are removed from the study.
[0224]
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
doses are subsequently escalated to 5, 8, 11, 15, and 20
mg/m.sup.2/day to a maximum total daily dose of 40 mg. Patients
continue to receive
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione on
a 4-week cycle per dose level until one of the off-study criteria
are met.
[0225] Three patients are enrolled in each cohort. If at least one
DLT occurs, three additional patients are added to the cohort at
that particular dose level. If two DLTs occur, the MTD, defined as
the dose at which fewer than one-third of patients at each dose
level experiences DLT has been exceeded and four more patients are
treated at the previous dose.
[0226] Patients who experience DLT during the first 4-week cycle
are removed from the study, except if they have a response to
therapy. For patients who have completed their first 4-week cycle
of without DLT, but who subsequently experience Grade 3 or 4
hematological and/or nonhematological toxicity, treatment is
suspended for a minimum of a week. If the toxicity resolves to
<Grade 2 within three weeks, the patient is treated at two dose
levels lower than the dose that caused the toxicity (or a 50%
reduction if the patient was treated at the first or second dose
level). Patients in whom Grade 3 or 4 toxicity does not resolve to
<Grade 1 within three weeks, or those who have another Grade 3
toxicity at the reduced dose are removed from the study.
[0227] Pharmacokinetic sampling is performed prior the first dose
of 3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Day 1) and 0.5, 1, 2, 4, 6, 8, 24, and 48 hours thereafter.
Sampling is also conducted pre-dose on Days 7 and 21 and 0.5, 1, 2,
4, 6, 8, and 24 post-dose on Day 21 to evaluate steady-state
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
levels.
6.5.5 Treatment of Metastatic Melanoma
[0228] Patients with metastatic melanoma were started on
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione
(Revmid.TM.) at 5 mg/day for seven days. The dose was then
increased every seven days to 10 mg/day, 25 mg/day, and 50 mg/day,
respectively, for a total of four weeks on therapy. Five of the 13
melanoma patients who were treated under this regimen either showed
disease stabilization or a partial response in the first four weeks
of treatment. Tumor response was seen in cutaneous and subcutaneous
lesions (five patients), lymph nodes (two patients), and liver (one
patient). The duration of response was approximately six months.
The result suggests that the compound appears is a promising new
anti-cancer agent and has both antiangiogenic and immunomodulatory
properties.
6.5.6 Treatment of Relapsed or Refractory Multiple Myeloma
[0229] Patients with relapsed and refractory Dune-Salmon stage III
multiple myeloma, who have either failed at least three previous
regimens or presented with poor performance status, neutropenia or
thrombocytopenia, are treated with up to four cycles of combination
of melphalan (50 mg intravenously), an immunomodulatory compound of
the invention (about 1 to 150 mg orally daily), and dexamethasone
(40 mg/day orally on days 1 to 4) every four to six weeks.
Maintenance treatment consisting of daily an immunomodulatory
compound of the invention and monthly dexamethasone are continued
until the disease progression. The therapy using an
immunomodulatory compound of the invention in combination with
melphalan and dexamethasone is highly active and generally
tolerated in heavily pretreated multiple myeloma patients whose
prognosis is otherwise poor.
[0230] The embodiments of the invention described above are
intended to be merely exemplary, and those skilled in the art will
recognize, or will be able to ascertain using no more than routine
experimentation, numerous equivalents of specific compounds,
materials, and procedures. All such equivalents are considered to
be within the scope of the invention and are encompassed by the
appended claims.
* * * * *