U.S. patent application number 10/808004 was filed with the patent office on 2004-09-30 for treatment for basal cell carcinoma.
This patent application is currently assigned to 3M Innovative Properties Company. Invention is credited to Fox, Terrance L., Ginkel, Angela M., Owens, Mary L..
Application Number | 20040192585 10/808004 |
Document ID | / |
Family ID | 32994823 |
Filed Date | 2004-09-30 |
United States Patent
Application |
20040192585 |
Kind Code |
A1 |
Owens, Mary L. ; et
al. |
September 30, 2004 |
Treatment for basal cell carcinoma
Abstract
The present invention provides a method of treating basal cell
carcinoma in a subject. Generally, the method includes
administering to the subject an amount of IRM compound effective
for treating basal cell carcinoma in a treatment cycle that
includes at least two consecutive days in which the IRM compound is
administered and at least one day in which the IRM compound is not
administered.
Inventors: |
Owens, Mary L.; (Cottage
Grove, MN) ; Fox, Terrance L.; (Oakdale, MN) ;
Ginkel, Angela M.; (St. Paul, MN) |
Correspondence
Address: |
3M INNOVATIVE PROPERTIES COMPANY
PO BOX 33427
ST. PAUL
MN
55133-3427
US
|
Assignee: |
3M Innovative Properties
Company
|
Family ID: |
32994823 |
Appl. No.: |
10/808004 |
Filed: |
March 24, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60457265 |
Mar 25, 2003 |
|
|
|
Current U.S.
Class: |
514/19.3 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 31/44 20130101; A61P 35/00 20180101; A61K 47/12 20130101 |
Class at
Publication: |
514/002 |
International
Class: |
A61K 038/00; A61K
031/44 |
Claims
What is claimed is:
1. A method of treating basal cell carcinoma in a subject, the
method comprising administering to the subject an amount of an IRM
compound effective for treating basal cell carcinoma, wherein the
IRM compound is administered in a treatment cycle that comprises at
least two consecutive days in which the IRM compound is
administered and at least one day in which the IRM compound is not
administered.
2. The method of claim 1 wherein the treatment cycle comprises at
least five days in which the IRM compound is administered.
3. The method of claim 2 wherein the treatment comprises at least
five consecutive days in which the IRM compound is
administered.
4. The method of claim 1 wherein the treatment cycle comprises at
least two consecutive days in which the IRM compound is not
administered.
5. The method of claim 1 wherein the treatment cycle comprises five
days in which the IRM compound is administered and at least two
days in which the IRM compound is not administered.
6. The method of claim 5 wherein the five days are five consecutive
days.
7. The method of claim 1 wherein the method comprises at least two
treatment cycles.
8. The method of claim 7 wherein the method comprises at least six
treatment cycles.
9. The method of claim 1 wherein administering the IRM compound
comprises applying one dose of the IRM compound per day.
10. The method of claim 1 wherein administering the IRM compound
comprises topically applying the IRM compound to a treatment area
that includes a lesion.
11. The method of claim 10 wherein the IRM compound is applied in a
formulation that comprises from about 1% to about 10% IRM
compound.
12. The method of claim 11 wherein the formulation comprises about
5% IRM compound.
13. The method of claim 11 wherein the formulation is applied to
the treatment area for from about two hours to about 24 hours.
14. The method of claim 13 wherein the formulation is applied to
the treatment area for from about six hours to about twelve
hours.
15. The method of claim 11 wherein the formulation is applied to
the treatment area for about eight hours.
16. The method of claim 10 wherein the treatment area further
comprises skin at least 0.5 cm beyond the margin of the lesion.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional
Application Serial No. 60/457,265, filed Mar. 25, 2003.
Background
[0002] Basal cell carcinoma (BCC) is the most common form of skin
cancer and the most common form of cancer of any type in the United
States. It develops in the basal germinative cell layer of the
epidermis, often on sun-exposed areas of the skin. Although BCC
rarely spreads (i.e., metastasizes) to other parts of the body, it
can be very destructive and disfiguring. BCC may cause local tissue
destruction that may lead to disfigurement or functional impairment
of surrounding non-cancerous tissue. Disfigurement may be a
particular concern of BCC patients because many BCC tumors occur on
the sun-exposed--and, therefore, also typically otherwise
exposed--skin of the head and neck. Larger tumors, tumors that have
been present for long periods of time, and tumors that have
recurred after initial therapy may be biologically more aggressive
and especially difficult to cure. While the mortality rate of BCC
is relatively low, its increasing incidence and prolonged morbidity
means that the disease can be very costly to treat.
[0003] A wide variety of surgical and non-surgical therapies are
available for BCC. Nonsurgical therapies include radiation therapy,
chemotherapy, and immunotherapy. These therapies can be useful for
definitive treatment of primary tumors and some recurrent BCC
tumors and for relieving symptoms associated with inoperable
tumors. However, some of these therapies also can have significant
unpleasant side effects. Side effects of radiation therapy and
certain chemotherapies are well documented. One form of
immunotherapy involves intralesional injections of interferon.
While interferon therapy can be effective against BCC, the multiple
intralesional injections can require several clinic visits per week
for many weeks. Also, many patients can be anxious or otherwise
uncomfortable receiving injections. Thus, interferon therapy can
result in significant patient inconvenience and discomfort.
[0004] Interferon therapy also is connected with several side
effects such as, for example, flu-like symptoms such as fever,
chills, aches, drowsiness and nausea; a reduction in the number of
white blood cells; a reduction in the number of red blood cells
(anemia); a reduction in the number of platelets in the blood,
which may give rise to nosebleeds, for example; thinning hair;
liver problems; and heart problems.
[0005] Surgical therapies include excision, curettage and
electrosurgery, cryosurgery, Mohs micrographic surgery, and laser
surgery. Excision is useful for both primary and recurrent tumors
and has the advantage of allowing for histological assessment of
surgical margins. Curettage and electrosurgery involves alternately
removing soft tumor tissue with a curette and then destroying an
extra margin of tissue by electrodesiccation, electrocautery, or
electrocoagulation. The procedure may be repeated as necessary.
Cryosurgery involves freezing the tumor to a temperature that kills
the cells of the tumor. The dead tumor cells can be removed by, for
example, curettage. Mohs micrographic surgery (MMS) involves a
surgeon using a microscope to improve identify the margin of the
tumor more accurately and more precisely than is possible by
unaided visual inspection. MMS can increase the likelihood that the
entire tumor is removed and minimize the amount of normal tissue
that is removed. Laser surgery involves using a laser to vaporize
tumor cells. Alternatively, the laser may be used in lieu of a
scalpel blade for excisional surgery.
SUMMARY
[0006] It has been found that immune response modifier ("IRM")
compounds can provide effective therapeutic treatment for BCC.
Accordingly, the present invention provides a method of treating
basal cell carcinoma in a subject. Generally, the method includes
administering to the subject an amount of an IRM compound effective
for treating basal cell carcinoma, wherein the IRM compound is
administered in a treatment cycle that includes at least two
consecutive days in which the IRM compound is administered and at
least one day in which the IRM compound is not administered.
[0007] In some embodiments, the treatment cycle includes five days
in which the IRM compound is administered and two days in which the
IRM compound is not administered.
[0008] In some embodiments, the treatment of BCC includes at least
six treatment cycles.
[0009] Various other features and advantages of the invention
should become readily apparent with reference to the following
detailed description, examples, claims and appended drawings. In
several places throughout the specification, guidance is provided
through lists of examples. In each instance, the recited list
serves only as a representative group and should not be interpreted
as an exclusive list.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 is a bar graph summarizing data that demonstrate the
efficacy of one embodiment of the method of the invention.
[0011] FIG. 2 is a bar graph summarizing data that demonstrate the
efficacy of one embodiment of the method of the invention.
[0012] FIG. 3 is a bar graph summarizing data related to the
frequency of adverse local skin reactions.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE
INVENTION
[0013] Immune response modifiers ("IRMs") include compounds that
possess potent immunomodulating activity such as, for example,
antiviral and antitumor activity. Certain IRMs modulate the
production and secretion of cytokines. For example, certain IRM
compounds induce the production and secretion of cytokines such as,
e.g., Type I interferons, TNF-.alpha., IL-1, IL-6, IL-8, IL-10,
IL-12, MIP-1, and/or MCP-1. As another example, certain IRM
compounds can inhibit production and secretion of certain T.sub.H2
cytokines, such as IL-4 and IL-5. Additionally, some IRM compounds
are said to suppress IL-1 and TNF (U.S. Pat. No. 6,518,265).
[0014] Certain IRMs are small organic molecules (e.g., molecular
weight under about 1000 Daltons, preferably under about 500
Daltons, as opposed to large biological molecules such as proteins,
peptides, and the like) such as those disclosed in, for example,
U.S. Pat. Nos. 4,689,338; 4,929,624; 4,988,815; 5,037,986;
5,175,296; 5,238,944; 5,266,575; 5,268,376; 5,346,905; 5,352,784;
5,367,076; 5,389,640; 5,395,937; 5,446,153; 5,482,936; 5,693,811;
5,741,908; 5,756,747; 5,939,090; 6,039,969; 6,083,505; 6,110,929;
6,194,425; 6,245,776; 6,331,539; 6,376,669; 6,451,810; 6,525,064;
6,541,485; 6,545,016; 6,545,017; 6,558,951; 6,573,273; 6,656,938;
6,660,735; 6,660,747; 6,664,260; 6,664,264; 6,664,265; 6,667,312;
6,670,372; 6,677,347; 6,677,348; 6,677,349; 6,683,088; European
Patent 0 394 026; U.S. Patent Application Publication Nos.
2002/0016332; 2002/0055517; 2002/0110840; 2003/0133913;
2003/0199538; and 2004/0014779; and International Patent
Publication Nos. WO 01/74343; WO 02/46749 WO 02/102377; WO
03/020889; WO 03/043572; WO 03/045391; and WO 03/103584.
[0015] Additional examples of small molecule IRMs include certain
purine derivatives (such as those described in U.S. Pat. Nos.
6,376,501, and 6,028,076), certain imidazoquinoline amide
derivatives (such as those described in U.S. Pat. No. 6,069,149),
certain imidazopyridine derivatives (such as those described in
U.S. Pat. No. 6,518,265), certain benzimidazole derivatives (such
as those described in U.S. Pat. No. 6,387,938), certain derivatives
of a 4-aminopyrimidine fused to a five membered nitrogen containing
heterocyclic ring (such as adenine derivatives described in U.S.
Pat. Nos. 6,376,501; 6,028,076 and 6,329,381; and in WO 02/08595),
and certain 3-.beta.-D-ribofuranosylthiaz- olo[4,5-d]pyrimidine
derivatives (such as those described in U.S. Patent Application
Publication No. 2003/0199461).
[0016] Other IRMs include large biological molecules such as
oligonucleotide sequences. Some IRM oligonucleotide sequences
contain cytosine-guanine dinucleotides (CpG) and are described, for
example, in U.S. Pat. Nos. 6,194,388; 6,207,646; 6,239,116;
6,339,068; and 6,406,705. Some CpG-containing oligonucleotides can
include synthetic immunomodulatory structural motifs such as those
described, for example, in U.S. Patent Nos. 6,426,334 and
6,476,000. Other IRM nucleotide sequences lack CpG sequences and
are described, for example, in International Patent Publication No.
WO 00/75304.
[0017] Other IRMs include biological molecules such as aminoalkyl
glucosaminide phosphates (AGPs) and are described, for example, in
U.S. Pat. Nos. 6,113,918; 6,303,347; 6,525,028; and 6,649,172.
[0018] By stimulating certain aspects of the immune system, as well
as suppressing other aspects (see, e.g., U.S. Pat. Nos. 6,039,969
and 6,200,592), certain IRMs may be used to treat many diseases and
conditions. For example, some IRMs may be useful for treating viral
diseases, neoplasias, fungal diseases, neoplastic diseases,
parasitic diseases, atopic diseases, and opportunistic infections
and tumors that occur after suppression of cell-mediated immunity.
Certain IRMs may be useful for promoting healing of wounds and
post-surgical scars.
[0019] Certain formulations of imiquimod, as small molecule IRM
compound, have been shown to be useful for the therapeutic
treatment of certain cancerous or pre-cancerous lesions (See, e.g.,
Marks et al., J. Am. Acad. Dermatol., 44(5):807-813 (2001); Geisse
et al., J. Am. Acad. Dermatol., 47(3): 390-398 (2002); Shumack et
al., Arch. Dermatol., 138: 1163-1171 (2002); and U.S. Patent
Application Publication No. 2003/0199538).
[0020] The present invention provides a method of treating basal
cell carcinoma using IRMs generally and imiquimod in particular.
Generally, the method includes applying an amount of an IRM
compound effective for treating basal cell carcinoma, wherein the
IRM compound is administered in a treatment cycle that includes at
least two consecutive days in which the IRM compound is
administered and at least one day in which the IRM compound is not
administered.
[0021] The particular embodiment of the invention selected for
treating basal cell carcinoma can depend, at least in part, on
factors relating to the tumor, the patient, or both. Tumor-related
variables may include, for example, type, size, shape, histological
character, growth character, location, and the like. For example,
variables may include whether the tumor is primary or recurrent;
greater than a particular size; its duration, growth rate, or both;
whether the tumor has indistinct margins, an aggressive
histological pattern, or both; and certain anatomic locations. High
risk histological patterns include infiltrative/desmoplastic,
severe squamous metaplasia, and basosquamous. High-risk locations
may include the nose, eyelids, ears, medial canthus, nasolabial
fold, scalp, lip, fingers, toes, and genitals. Patient-related
variables may include age, medical status, psychological factors,
and concomitant medications. For example, patients who are
immunocompromised may be at greater risk because their tumors may
be more likely to demonstrate very aggressive behavior.
[0022] Any suitable IRM compound may be used to practice of the
invention. In some embodiments, suitable IRM compounds include but
are not limited to the small molecule IRM compounds described
above. Suitable small molecule IRM compounds, having a
2-aminopyridine fused to a five membered nitrogen-containing
heterocyclic ring, include but are not limited to imidazoquinoline
amines such as, for example, amide substituted imidazoquinoline
amines, sulfonamide substituted imidazoquinoline amines, urea
substituted imidazoquinoline amines, aryl ether substituted
imidazoquinoline amines, heterocyclic ether substituted
imidazoquinoline amines, amido ether substituted imidazoquinoline
amines, sulfonamido ether substituted imidazoquinoline amines, urea
substituted imidazoquinoline ethers, thioether substituted
imidazoquinoline amines, and 6-, 7-, 8-, or 9-aryl or heteroaryl
substituted imidazoquinoline amines; tetrahydroimidazoquinoline
amines including, but not limited to, amide substituted
tetrahydroimidazoquinoline amines, sulfonamide substituted
tetrahydroimidazoquinoline amines, urea substituted
tetrahydroimidazoquinoline amines, aryl ether substituted
tetrahydroimidazoquinoline amines, heterocyclic ether substituted
tetrahydroimidazoquinoline amines, amido ether substituted
tetrahydroimidazoquinoline amines, sulfonamido ether substituted
tetrahydroimidazoquinoline amines, urea substituted
tetrahydroimidazoquinoline ethers, and thioether substituted
tetrahydroimidazoquinoline amines; imidazopyridine amines
including, but not limited to, amide substituted imidazopyridine
amines, sulfonamido substituted imidazopyridine amines, urea
substituted imidazopyridine amines, aryl ether substituted
imidazopyridine amines, heterocyclic ether substituted
imidazopyridine amines, amido ether substituted imidazopyridine
amines, sulfonamido ether substituted imidazopyridine amines, urea
substituted imidazopyridine ethers, and thioether substituted
imidazopyridine amines; 1,2-bridged imidazoquinoline amines;
6,7-fused cycloalkylimidazopyridine amines; imidazonaphthyridine
amines; tetrahydroimidazonaphthyridine amines; oxazoloquinoline
amines; thiazoloquinoline amines; oxazolopyridine amines;
thiazolopyridine amines; oxazolonaphthyridine amines;
thiazolonaphthyridine amines; and 1H-imidazo dimers fused to
pyridine amines, quinoline amines, tetrahydroquinoline amines,
naphthyridine amines, or tetrahydronaphthyridine amines.
[0023] In certain embodiments, the IRM compound is an
imidazoquinoline amine such as, for example,
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-- 4-amine.
[0024] The IRM compound may be provided in a formulation suitable
for topical administration. Suitable types of formulations are
described, for example, in U.S. Patent Application Publication No.
2003/0199538. The IRM compound may be provided in any suitable form
including but not limited to a solution, a suspension, an emulsion,
or any form of mixture. The IRM may be delivered in formulation
with any pharmaceutically acceptable excipient, carrier, or
vehicle. The formulation may be delivered in any conventional
dosage form including but not limited to a cream, an ointment, an
aerosol formulation, a non-aerosol spray, a gel, a lotion, a
tablet, a lozenge, an elixir, and the like. The formulation may
further include one or more additives including but not limited to
adjuvants, skin penetration enhancers, colorants, fragrances,
moisturizers, thickeners, and the like.
[0025] The composition of a formulation suitable for practicing the
invention will vary according to factors known in the art including
but not limited to the physical and chemical nature of the IRM
compound, the nature of the carrier, the intended dosing regimen,
the state of the subject's immune system (e.g., suppressed,
compromised, stimulated), the method of administering the IRM
compound, and the species to which the formulation is being
administered. Accordingly, it is not practical to set forth
generally the composition of a formulation effective for treating
BCC for all possible applications. Those of ordinary skill in the
art, however, can readily determine an appropriate formulation with
due consideration of such factors.
[0026] In some embodiments, the invention includes administering
the IRM compound to a subject in a formulation of, for example,
from about 0.001% to about 10% (unless otherwise indicated, all
percentages provided herein are weight/weight with respect to the
total formulation) to the subject, although in some embodiments, a
suitable formulation may include a concentration of IRM compound
that is outside of this range. In certain embodiments, the method
includes administering to a subject a formulation that includes
from about 0.01% to about 5% IRM compound, for example, a
formulation that includes about 5% IRM compound.
[0027] An amount of IRM compound effective for treating basal cell
carcinoma (BCC) is an amount sufficient to reduce the size or
number of BCC lesions, limit or slow the growth of BCC lesions, or
both. The precise amount of IRM compound effective for treating BCC
will vary according to factors known in the art including, but not
limited to, the physical and chemical nature of the particular IRM
compound being administered; the physical and chemical nature of
the formulation; the size, location, and histological type of BCC
being treated; the intended dosing regimen; the state of the
subject's immune system (e.g., suppressed, compromised,
stimulated); and the method of administering the IRM. Accordingly
it is not practical to set forth generally the amount that
constitutes an amount of IRM compound effective for treating BCC
for all possible applications. Those of ordinary skill in the art,
however, can readily determine the appropriate amount with due
consideration of such factors.
[0028] In some embodiments, the invention includes administering
sufficient IRM compound to provide a dose of the IRM compound of,
for example, from about 0.001 mg/cm.sup.2 to about 100 mg/cm.sup.2
to the subject, although in some embodiments the methods may be
performed by administering the IRM compound in amounts outside this
range. In some of these embodiments, the method includes
administering sufficient IRM compound to provide a dose of IRM
compound of from about 0.1 mg/cm.sup.2 to about 5 mg/cm.sup.2 to
the subject, for example, a dose of IRM compound of about 0.5
mg/cm.sup.2 to about 2 mg/cm.sup.2.
[0029] The dosing regimen may depend at least in part on many
factors known in the art including but not limited to the physical
and chemical nature of the IRM compound being administered; the
physical and chemical nature of the formulation; the size,
location, and histological type of the BCC being treated; the
amount of IRM compound being administered; the state of the
subject's immune system (e.g., suppressed, compromised,
stimulated); and the method of administering the IRM compound.
Accordingly, it is not practical to set forth generally the dosing
regimen effective for treating basal cell carcinoma for all
possible applications. Those of ordinary skill in the art, however,
can readily determine an appropriate dosing regimen with due
consideration of such factors.
[0030] An IRM compound can be effective for treating basal cell
carcinoma with a treatment regimen that includes administering the
IRM compound from about once per week to multiple daily doses
(e.g., two doses per day). In certain embodiments of the invention,
treatment of BCC includes administering the IRM compound according
to a treatment cycle that includes at least two consecutive days in
which the IRM compound is administered and at least one day in
which the IRM compound is not administered.
[0031] As used herein, a treatment cycle is a repeated cyclical
pattern of scheduled treatment. A treatment period typically
includes a scheduled number of repeated treatment cycles. A
treatment cycle may call for a specified number and schedule of
days in which treatment is administered (treatment days) as well as
a specified number and schedule of days in which no treatment is
administered (off days). Thus, a treatment cycle specifically
excludes instances in which scheduled treatments are temporarily
interrupted and then subsequently resumed, for example, to allow
one or more adverse reactions to subside. The schedule may be as
specific as necessary for effective treatment. For example, in one
embodiment, a treatment cycle includes five consecutive treatment
days and two consecutive off days per week. In other embodiments,
however, a treatment cycle may specify the number of treatment days
per week (e.g., five) and the number of off days per week (e.g.,
two), but not specify when the off days must occur relative to the
treatment days.
[0032] A treatment cycle that includes at least two consecutive
treatment days and at least one off day can reduce the likelihood
and extent of adverse reactions to the treatment, thereby
minimizing the likelihood that treatment will be interrupted for
one or more rest periods. A treatment cycle that avoids
interrupting treatment can increase the likelihood that the
treatment can be completed as initially scheduled. Such treatment
cycles also can provide treatment that is nearly as, equally, or
even more effective than treatment cycles requiring more frequent
administration or greater total dosages.
[0033] In certain embodiments, the treatment cycle includes five
days of administering the IRM compound and two days in which the
IRM compound is not administered. In one particular embodiment, the
treatment cycle includes five consecutive days of administering the
IRM compound and two consecutive days of not administering the IRM
compound. This treatment cycle can provide efficacy equal to or
better than, and reduced adverse reactions compared to, treatment
cycles that call for administering the same formulation of the IRM
compound more frequently or for a greater number of doses within a
seven-day cycle.
[0034] Treatment periods can range from about two weeks to about 24
weeks. In some embodiments, the treatment period may be a
predetermined fixed length of time. For example, the treatment
period can be at least about two weeks, at least about four weeks,
at least about six weeks, at least about eight weeks, at least
about 12 weeks, or at least about 16 weeks, although in some
embodiments the methods may be performed by administering the IRM
compound for treatment periods outside this range. Alternatively,
the treatment period may terminate upon reaching a particular
milestone. For example, a treatment period of one embodiment of the
method according to the present invention may continue until a
lesion being treated is resolved. Evidence that the lesion is
resolved may be obtained by any medically acceptable means
including but not limited to clinical examination or histological
examination.
[0035] FIG. 1 summarizes data regarding one measure of efficacy for
one embodiment of the invention. Subjects were divided into four
treatment groups: (1) placebo cream, once per day, five days per
week (Vehicle 5.times./week); (2) placebo cream, once per day,
seven days per week (Vehicle 7.times./week); (3) 5% IRM (imiquimod)
cream, once per day for five days per week and two consecutive days
without treatment per week (IRM 5.times./week); and (4) 5% IRM
(imiquimod) cream, once per day, seven days per week (IRM
7.times./week).
[0036] Subjects received treatment for six weeks, then returned
twelve weeks after the end of treatment for a post-treatment visit.
At the post-treatment visit, the entire tumor area--including an
area up to a 3-4 mm around the pre-treatment tumor margin--was
excised. The excised tissue was examined histologically for
evidence of BCC. The proportion of subjects who had no histological
evidence of BCC in the post-treatment excision taken from the
treatment site twelve weeks after the end of treatment were
considered complete histological responders. FIG. 1 shows the
proportion of complete histological responders in each treatment
group. The IRM 5.times./week group exhibited the highest proportion
of complete histological responders.
[0037] FIG. 2 summarizes data regarding a second measure of
efficacy for the embodiment of the invention described above. FIG.
2 shows the proportion of composite complete responders in each
treatment group. Composite complete responders are those who
display both (1) no histological evidence of BCC twelve weeks after
the end of treatment, and (2) no clinical evidence of BCC twelve
weeks after the end of treatment. The IRM 5.times./week treatment
group exhibited the highest proportion of composite complete
responders.
[0038] FIG. 3 summarizes a comparison of moderate and severe
adverse local skin reactions among the treatment groups (the
Vehicle group in FIG. 3 equals the combination of the Vehicle
5.times./week group and Vehicle 7.times./week group). Subjects
completed interval visits 1, 3, and 6 weeks after treatment was
initiated and at twelve weeks after the end of treatment. The
presence of local skin reactions (i.e., erythema, erosion,
ulceration, and scabbing) was assessed at each interval visit and
at the 12-weeks post-treatment visit on a four-point scale (0,
none; 1, mild; 2, moderate; and 3 severe). Reports of local skin
reactions are summarized in FIG. 3, expressed as the percentage of
subjects in each treatment group that reported a moderate or sever
local skin reaction at any time during the study. The incidence of
moderate and severe local skin reactions was less in the IRM
5.times./week treatment group than in the IRM 7.times./week
treatment group for each local skin reaction shown in FIG. 3.
[0039] In some embodiments, administering the IRM compound involves
topical application of a formulation that contains IRM compound.
The formulation may be topically applied to a treatment area
located on the skin of the subject. The treatment area can include
an area of the skin that includes a BCC lesion. The treatment area
also may, in some embodiments, include an area of skin surrounding
the BCC lesion (i.e., extramarginal skin--skin beyond the margin of
the lesion). The treatment area may include extramarginal skin that
is uniform or irregular in shape, and may be of uniform or
irregular width around the margin of the lesion. In some
embodiments, the method includes application of a formulation that
includes an IRM compound to a treatment area that includes a BCC
lesion and skin from about 0.5 cm to about 5.0 cm beyond the margin
of the lesion, for example, 1.0 cm beyond the margin of the
lesion.
[0040] The IRM compound may be left on the treatment area for any
suitable amount of time. The precise duration of time that a
particular application of the IRM compound should remain on the
treatment site may vary according to, for example, the dose of the
IRM compound being administered, the state of the subject's immune
system, the size and character of the tumor, the extent to which
the subject has experienced an adverse reaction, and the like. In
some embodiments, the method includes ensuring that the IRM
compound is applied to the treatment site for from about one hour
to about 48 hours, although certain embodiments of the invention
may be practiced by administering IRM compound to a subject for
periods outside this range. In certain embodiments, the IRM
compound is applied for from about two hours to about 24 hours. In
other embodiments, the IRM compound is applied for from about six
hours to about twelve hours, for example, about eight hours.
EXAMPLES
[0041] The following examples have been selected merely to further
illustrate features, advantages, and other details of the
invention. It is to be expressly understood, however, that while
the examples serve this purpose, the particular materials and
amounts used as well as other conditions and details are not to be
construed in a matter that would unduly limit the scope of this
invention.
[0042] The IRM compound was provided in a 5% cream in a formulation
shown in Table 1, on a percentage weight-by-weight basis. The IRM
compound used to prepare the formulation was imiquimod,
1-(2-methylpropyl)-1H-imidazo[4- ,5-c]quinolin-4-amine. Imiquimod
and methods of synthesizing imiquimod are disclosed in, for
example, U.S. Pat. No. 4,689,338.
1 TABLE 1 Formulation Components (% w/w) IRM 5.0 Isostearic Acid
25.0 Benzyl Alcohol 2.0 Cetyl Alcohol 2.2 Stearyl Alcohol 3.1 White
Petrolatum 3.0 Polysorbate 60 3.4 Sorbitan Monostearate 0.6
Glycerin 2.0 Methyl Paraben 0.2 Propyl Paraben 0.02 Water 52.98
Xanthan Gum 0.5
[0043] The formulation was prepared according to the methods
described in U.S. Pat. No. 5,238,944. The final formulation had a
pH of 5.1, and a viscosity (cps) of 0.33.times.10.sup.5.
Example 1
[0044] Volunteer subjects with superficial basal cell carcinoma
were randomized to either the 5% imiquimod cream formulation
described above or a placebo cream (Vehicle) in one of two
treatment regimens: (1) once daily for seven days per week
(7.times./week), and (2) once daily for five consecutive days per
week and no treatment for the remaining two days (5.times./week).
Subjects in each groups received treatment for six weeks.
[0045] Subjects were instructed to administer a single application
of cream (Vehicle or 5% imiquimod, as assigned) to a target tumor
just prior to normal sleeping hours according to the dosing regimen
to which they were assigned. The subjects were instructed to wash
the tumor lesion prior to applying the cream, and then rub the
cream into the tumor and into extramarginal skin about 1 cm around
the tumor. The subjects were instructed to leave the cream in place
for at least eight hours without occlusion.
[0046] Subjects completed interval visits 1, 3, and 6 weeks after
treatment was initiated and at twelve weeks after the end of
treatment. At the 12-weeks post-treatment visit, the treatment area
was clinically evaluated and the entire tumor area--an area up to a
3-4 mm around the pre-treatment tumor margin--was excised. The
excised tissue was examined histologically for evidence of BCC.
FIG. 1 summarizes the results of the histological assessment,
expressed as the percentage of subjects in each treatment group
that exhibited a complete histological response, i.e., the
proportion of subjects who had no histological evidence of BCC in
the post-treatment excision taken from the treatment site twelve
weeks after the end of treatment. FIG. 2 summarizes the results of
the composite assessment, expressed as the percentage of subjects
having both (a) no clinical evidence of BCC twelve weeks after the
end of treatment, and (b) a complete histological response.
[0047] The presence of local skin reactions (i.e., erythema,
erosion, ulceration, and scabbing) was assessed at each interval
visit and at the 12-weeks post-treatment visit. Reports of local
skin reactions are summarized in FIG. 3, expressed as the
percentage of subjects in each treatment group that reported a
given local skin reaction during the study.
[0048] The complete disclosures of the patents, patent documents
and publications cited herein are incorporated by reference in
their entirety as if each were individually incorporated. In case
of conflict, the present specification, including definitions,
shall control.
[0049] Various modifications and alterations to this invention will
become apparent to those skilled in the art without departing from
the scope and spirit of this invention. Illustrative embodiments
and examples are provided as examples only and are not intended to
limit the scope of the invention. The scope of the invention is
limited only by the claims set forth as follows.
* * * * *