Note: Descriptions are shown in the official language in which they were submitted.
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METHODS AND COMPOSITIONS FOR TREATING
CHEMOTHERAPY-INDUCED DIARRHEA
FIELD OF THE INVENTION
[0001] The present invention is directed to methods of
preventing, ameliorating and/or
treating diarrhea. More specifically, the methods presented herein prevent,
ameliorate or treat
chemotherapy-induced diarrhea (CID) using a proanthocyanidin such as
crofelemer in
combination with a chemotherapy agent.
BACKGROUND
[0002] Diarrhea is a common occurrence in human cancer patients
that can result from
radiotherapy, chemotherapeutic agents, decreased physical performance, graft
versus host
disease and infections or a combination thereof. In particular, chemotherapy-
induced diarrhea
(CID) is common, especially in patients with advanced cancer, and has to be
assessed for
etiologies associated with the chemotherapeutic regimen or not [Gibson, R. and
Stringer, A.,
Curr Opin Support Palliat Care 3: 31-35, 20091 Careful analysis can result in
better
management of the diarrheal symptoms to prevent severe complications that may
be
irreversible [Davila, M. and Bresalier, R., Nat Clin Pract Gastroenterol
Hepatol 5: 682-696,
2008; Vincenzi, B. et al. Nat Clin Pract Oncol 5: 455-465, 20081. Sequelae can
include
dehydration, malnutrition, cardiovascular issues, and even death.
10003] CID is very prevalent depending on the chemotherapy
regime with an estimated
prevalence of between about 50-80% in patients [Benson, A. et al. J Clin Oncol
22: 2918-
2926, 2004; Gibson, R. and Stringer, A., Curr Opin Support Palliat Care 3: 31-
35, 2009]
especially those treated with 5-fluorouracil bolus or some combination
therapies of irinotecan
and fluoropyrimidines (IFL, )(EURO. Regardless of the molecular targeted
approach of
tyrosine kinase inhibitors and antibodies, diarrhea is a common side effect in
up to 60% of
patients with up to 10% having severe diarrhea. Furthermore, the underlying
pathophysiology
is still under investigation.
10004] Therapeutic agents commonly causing diarrhea include 5-
fluorouracil (5-FU),
capecitabine and irinotecan (CPT-11) [Benson, A. et at. J Clin Oncol 22: 2918-
2926, 2004;
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Keefe, D. at al. Semin Oncol Nurs 20: 38 47, 20041. It is often a dose-related
adverse effect
and may be associated with other features of toxicity. CID appears to be a
multifactorial process
whereby acute damage to the intestinal mucosa (including loss of intestinal
epithelium,
superficial necrosis and inflammation of the bowel wall) causes an imbalance
between
absorption and secretion in the small bowel [Keefe, D. et al. Gut 47: 632-637,
2000; Keefe, D.
Support Care Cancer 15: 483-490,2007; Gibson, R. and Stringer, A., Curr Opin
Support Palliat
Care 3: 31-35, 20091.
[0005]
Left untreated, life-threatening gastrointestinal syndrome is recognized by
two
National Cancer Institute-sponsored cooperative group trials as a serious
complication. These
trials reviewed early toxic deaths occurring in irinotecan plus high-dose
fluorouracil and
leucovorin for advanced colorectal cancer and highlighted the need for
vigilant monitoring and
aggressive therapy for this serious complication [Conti, J. et at. J Clin
Oncol 14: 709-715,
1996; Arbuckle, R. et at. Oncologist 5: 250-259, 2000; Saltz L. etal. N Engl J
Med 343: 905-
914, 20001. In addition, diarrhea can hinder chemotherapy and other treatments
for cancer by
causing dosing delays, reductions, or use of alternative agents which may have
an ultimate
impact on survival [Engelking, C. et al., Oncol Nurs Forum 25: 859-860 1998;
Ippoliti, A.,
Am J Health Syst Pharm 55: 1573-1580, 1998].
[0006]
Therefore, drug-related diarrhea in human subjects undergoing chemotherapy
represents an important and unmet clinical need requiring more effective
management.
Currently prescribed therapies are only partially effective or are plagued by
unacceptable side
effects such as constipation and the potential for addiction. The development
of a drug for the
treatment of chemotherapy-associated diarrhea with a low potential for drug-
drug interactions,
effects on drug metabolism, or abuse potential would provide an important
benefit for subjects
undergoing chemotherapy.
SUMMARY
[0007]
Disclosed herein are methods of preventing, ameliorating and/or treating
diarrhea
in human subjects being administered or having been administered a
chemotherapy regimen.
In one embodiment, the methods presented herein prevent, ameliorate or treat
chemotherapy-
induced diarrhea (CID).
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[0008]
In one aspect, provided herein are methods of treating CID in a human
subject
undergoing chemotherapy, particularly for cancer treatment, comprising
administering to a
subject in need thereof a composition comprising an effective amount of a
proanthocyanidin
polymer composition from C. lechleri, preferably crofelemer, to treat,
ameliorate or prevent
CID. In certain embodiments, the crofelemer is an enterically protected
formulation. In certain
embodiments the chemotherapy is administered to treat, ameliorate, manage or
prevent cancer.
[0009]
According to certain embodiments, crofelemer may be administered in
combination with other chemotherapy agents.
[0010]
In one embodiment, the crofelemer is administered at the same time as
administration of chemotherapy to reduce or delay the onset of CID.
[0011]
In certain embodiments, the subject exhibits Grade 1, Grade 2, Grade 3 or
Grade 4
diarrhea in accordance with the Common Toxicity Criteria from the National
Cancer Institute.
[0012]
In one embodiment, the crofelemer is administered before administration of
chemotherapy to reduce or delay the onset of CID.
100131
In one embodiment, the crofelemer is administered after administration of
chemotherapy to reduce the onset of or treat CID.
100141
In certain embodiments, the crofelemer is administered to reduce the risk,
incidence or severity of CID so that the human subject can tolerate a
particular chemotherapy
agent with CID as a side effect or a higher dose of a chemotherapy agent that
has CID as a side
effect.
[0015]
In one embodiment, the chemotherapy agent is selected from alk-ylating
agents,
anthracyclines, cytoskeletal disruptors (taxanes), epothilones, histone
deacetylase inhibitors,
inhibitors of topoisomerase I. inhibitors of topoisomerase II, kinase
inhibitors, nucleotide
analogs and precursor analogs, peptide antibiotics, platinum-based agents and
retinoids.
100161
In one embodiment, the chemotherapy agent comprises one or more tyrosine
kinase
inhibitors. The tyrosine kinase inhibitor (TM) have a target selected from
epithelial growth
factor receptor (EGFR), VEGFR (e.g, VEGFR-1, VEGFR-2, and/or VEGFR-3); AXL,
RET,
TYR03, MER, KIT, TRKB, FLT-3, CSF-1R, anaplastic lymphoma kinase (ALK), ROS-1
(c-
ros); hepatocyte growth factor receptor (HGFR), c-Met, RON, platelet derived
growth factor
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receptor (PDGFR) a and f3, fibroblast growth factor receptor (FGFR1,2,3, or
4), KIT, Lck, Fms,
Itk, BRAF, mutant BRAF, c-CRAF, BRK, EPHRs, and TIE-2, In one embodiment, the
chemotherapy agent comprises one or more EGFR TKIs. In one embodiment, the
chemotherapy agent comprises one or more a pan-ErbB receptor TKIs. In one
embodiment,
the chemotherapy agent comprises EGFR TM and a pan-ErbB receptor TM.
[0017]
In one embodiment, the tyrosine kinase inhibitor is selected from
lapatinib,
sunitinib, sorafenib, erlotinib, gefitinib, axitinib, imatinib, nilotinib,
dasatinib, cabozantinib,
ruxolitinib, neratinib, bosutinib, pazopanib, afatninib, lenvatinib,
tucatinib, vandetanib,
ceritinib, crizotinib, dacomitinib, and valatinib.
[0018]
In one embodiment, the chemotherapy is a phosphoinositide 3-kinase
inhibitor,
such as alpelisib.
[0019]
In one embodiment, the chemotherapy is a CDK (cyclin-dependent kinase) 4/6/
inhibitor, optionally, abemaciclib.
[0020]
In one embodiment, the chemotherapy comprises one or more HER of hEGFR
(Human epidermal growth factor receptor) inhibitors.
[0021]
In one embodiment, the HER inhibitor is selected from RG7116, RG1273
(pertuzumab, Perjetak), RG3502 (trastuzumab emantasine, T-DMI), RG597
(trastuzumab,
HERCEPTIN), RGA201 (RG7160), erlotinib (Tarcevag), dacomitinib (PF-00299804),
PF-
05280014 (Pfizer's biosimilar mAB to RG597).
[0022]
In various embodiments, the chemotherapy regiment comprises two or more HER
inhibitors, such as trastuzumab and pertuzumab, and one or more chemotherapy
agents, such
as, a taxane like docetaxel or paclitaxel. In various embodiments, the
chemotherapy regiment
further comprises a platinum-based antineoplastic such as carboplatin.
[0023]
In various embodiments, the chemotherapy regiment comprises a HER
inhibitors,
such as trastuzumab or pertuzumab, a tyrosine kinase inhibitor, such as
neratinib, and a taxane,
such as, docetaxel or paclitaxel. In various embodiments, the chemotherapy
regiment further
comprises a platinum-based antineoplastic such as carboplatin.
[0024]
In various embodiments, the chemotherapy regiment is administered once
every
three weeks.
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[0025]
In various embodiments, the crofelemer is administered after a subject
begins to
exhibit symptoms of CID.
[0026]
In certain embodiments, the crofelemer is administered for the duration of
treatment with the chemotherapy.
[0027]
In certain embodiments, the subject is undergoing chemotherapy to treat one
or
more forms of cancer, such as breast cancer.
100281
In certain embodiments, the crofelemer is administered until symptoms of
CID are
ameliorated and then crofelemer is discontinued.
[0029]
In various embodiments, the administration comprises: administering about
250
mg to about 1000 mg per day; administering about 250 mg per day; administering
about 500
mg per day; administering about 1000 mg per day; administering about 125 mg
two times per
day; administering about 250 mg two times per day; or administering about 500
mg two times
per day of crofelemer, particularly, enterically protected crofelemer
formulated as a tablet for
oral administration, to a subject in need thereof. in other embodiments, the
crofelemer is
formulated for oral administration but is not enterically protected, e.g.,
does not have an enteric
coating. In other embodiments, the dosage of the proanthocyanidin polymer
composition is
bioequivalent to about 250 mg to about 1000 mg per day; about 250 mg per day;
about 500 mg
per day; about 1000 mg per day; about 125 mg two times per day; about 250 mg
two times per
day; or about 500 mg two times per day of an oral dosage form of crofelemer
that enterically
protected.
[0030]
In one aspect, presented herein are methods of treating stool consistency
in a
subject undergoing chemotherapy, comprising: administering about 250 mg to
about 1000 mg
per day; administering about 250 mg per day; administering about 500 mg per
day;
administering about 1000 mg per day; administering about 125 mg two times per
day;
administering about 250 mg two times per day; or administering about 500 mg
two times per
day of crofelemer, particularly, enterically protected crofelemer formulated
as a tablet for oral
administration, to a subject in need thereof (or is a dosage of a
proanthocyanidin polymer
composition that is bioequivalent to the dosage of an enteric protected
formulation of
crofelemer).
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[0031]
In one aspect, presented herein are methods of improving stool consistency
in a
subject undergoing chemotherapy, comprising: administering about 250 mg to
about 1000 mg
per day; administering about 250 mg per day; administering about 500 mg per
day;
administering about 1000 mg per day; administering about 125 mg two times per
day;
administering about 250 mg two times per day; or administering about 500 mg
two times per
day of crofelemer, particularly, enterically protected crofelemer formulated
as a tablet for oral
administration, to a subject in need thereof (or is a dosage of a
proanthocyanidin polymer
composition that is bioequivalent to the dosage of an enteric protected
formulation of
crofelemer).
[0032]
In one aspect, presented herein are methods of alleviating watery diarrhea
in a
subject undergoing chemotherapy; comprising: administering about 250 mg to
about 1000 mg
per day; administering about 250 mg per day; administering about 500 mg per
day;
administering about 1000 mg per day; administering about 125 mg two times per
day;
administering about 250 mg two times per day; or administering about 500 mg
two times per
day of crofelemer, particularly, enterically protected crofelemer formulated
as a tablet for oral
administration, to a subject in need thereof (or is a dosage of a
proanthocyanidin polymer
composition that is bioequivalent to the dosage of an enteric protected
formulation of
crofelemer).
100331
In one aspect, presented herein are methods of decreasing the number of
bowel
movements per day in a subject undergoing chemotherapy, comprising:
administering about
250 mg to about 1000 mg per day; administering about 250 mg per day;
administering about
500 mg per day; administering about 1000 mg per day; administering about 125
mg two times
per day; administering about 250 mg two times per day; or administering about
500 mg two
times per day of crofelemer, particularly, enterically protected crofelemer
formulated as a tablet
for oral administration, to a subject in need thereof (or is a dosage of a
proanthocyanidin
polymer composition that is bioequivalent to the dosage of an enteric
protected formulation of
crofelemer).
[0034]
The dosages may be the amount of a composition containing a
proanthocyanidin
polymer composition from C. lechleri that is bioequivalent to the dose of an
enteric protected
formulation of crofelemer.
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[0035] In one embodiment, a human subject is considered treated
if the subject
demonstrates one or more of a decrease in the number of bowel movements per
day, a decrease
in the number of watery bowel movements per day, an improvement in the daily
or weekly
abdominal score for pain or discomfort, an improvement in the score for daily
stool
consistency, a decrease in stool consistency score (from watery to formed), a
decrease in the
number of days per week that subjects experienced urgency, a decrease in the
number of days
per week that the subject experienced fecal incontinence.
[0036] In one embodiment, a human subject is considered treated
if the subject
demonstrates an improvement in the score for daily stool consistency.
[0037] In one embodiment, a human subject is considered treated
if the subject
demonstrates a decrease in stool consistency.
[0038] In one embodiment, a human subject is considered treated
if the subject
demonstrates a decrease in the number of watery bowel movements per day.
[0039] In one embodiment, a human subject is considered treated
if the subject
demonstrates a decrease in the number of bowel movements per day.
[0040] In one embodiment, symptoms increased or decreased are
measured from a
baseline.
[0041] In one embodiment, the administering is for the duration
of the chemotherapy.
[0042] In one embodiment, the administering occurs for about I
to about 6 weeks longer
than the chemotherapy cycle.
100431 In one embodiment, the administering occurs for about 3
to 12 weeks.
[0044] Other embodiments are disclosed below.
DETAILED DESCRIPTION
[0045] Certain chemotherapies may cause chemotherapy-induced
diarrhea (CID) is a
human subject that may cause distress, adversely impact the subject's health
and wellbeing,
make the chemotherapy difficult to tolerate such that the subject has to take
a lower dose or go
off of the chemotherapeutic agent or switch to a different treatment regimen
that may be, but
for the CID, more effective for the treatment of cancer. Proanthocyanidin
polymer
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compositions of C. loch/en, particularly, crofelemer, and more particularly,
enteric coated
crofelemer formulated for oral administration, but also SB300, reduce,
ameliorate, prevent or
eliminate the CID symptoms in a subject undergoing chemotherapy. Thus,
administration of
crofelemer, or other proanthocyanidin polymer composition of C. lechleri may
permit subjects
to tolerate either certain chemotherapeutic regimens, or to tolerate higher,
more effective, doses
of certain chemotherapeutic regimens.
[0046]
The methods disclosed herein involved the administration of effective
amounts of
a proanthocyanidin polymer, e.g., crofelemer, to subjects undergoing
chemotherapy having,
for example, chemotherapy-induced diarrhea (CID) or at risk of developing CID.
I. Definitions
[0047]
Where a term is provided in the singular, the inventors also contemplate
aspects of
the invention described by the plural of that term. As used in this
specification and in the
appended claims, the singular forms "a", "an" and "the" include plural
references unless the
context clearly dictates otherwise, e.g., "a compound" includes a plurality of
compounds. Thus,
for example, a reference to "a method" includes one or more methods, and/or
steps of the type
described herein and/or which will become apparent to those persons skilled in
the art upon
reading this disclosure.
[0048]
"Ameliorate,- -amelioration,- "improvement- or the like refers to, for
example, a
detectable improvement or a detectable change consistent with improvement that
occurs in a
subject or in at least a minority of subjects, e.g., in at least about 2%, 5%,
10%, 15%, 20%,
25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 100% or in a range
between about any two of these values. Such improvement or change may be
observed in
treated subjects as compared to subjects not treated with crofelemer, where
the untreated
subjects have, or are subject to developing, the same or similar disease,
condition, symptom or
the like. Amelioration of a disease, condition, symptom or assay parameter may
be determined
subjectively or objectively, e.g., self-assessment by a subject(s), by a
clinician's assessment or
by conducting an appropriate assay or measurement. Amelioration may be
transient, prolonged
or permanent or it may be variable at relevant times during or after
crofelemer is administered
to a subject or is used in an assay or other method described herein or a
cited reference, e.g.,
within timeframes described infra, or about 1 hour after the administration or
use of crofelemer
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to about 7 days, 2 weeks, 28 days. or 1, 3, 6, 9 months or more after a
subject(s) has received
such treatment.
[0049]
The "modulation" of, e.g., a symptom, level or biological activity of a
molecule, or the
like, refers, for example, that the symptom or activity, or the like is
detectably increased or
decreased. Such increase or decrease may be observed in treated subjects as
compared to subjects
not treated with crofelemer, where the untreated subjects have, or are subject
to developing, the
same or similar disease, condition, symptom or the like. Such increases or
decreases may be at
least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%,
85%, 90%,
95%, 98%, 100%, 150%, 200%, 250%, 300%, 400%, 500%, 1000% or more or within
any range
between any two of these values. Modulation may be determined subjectively or
objectively.
Modulation may be transient, prolonged or permanent or it may be variable at
relevant times during
or after crofelemer is administered to a subject or is used in an assay or
other method described
herein or a cited reference, e.g., within times descried infra, or about 1
hour of the administration
or use of crofelemer to about 2 weeks, 28 days, 3, 6, 9 months or more after a
subject(s) has received
crofelemer.
[0050]
As used herein, "subject- includes an animal, including a human, undergoing
chemotherapy and having or being at risk for CID or who could otherwise
benefit from the
administration of crofelemer as described herein, such as a human subject.
[0051]
The language -a therapeutically effective amount- of a compound refers to
an amount
of crofelemer which is effective, upon single or multiple dose administration
to the subject, in
treating, managing, or ameliorating the symptoms of the chemotherapy induced
diarrhea.
[0052]
The language "a prophylactically effective amount" of a compound refers to
an
amount of crofelemer which is effective, upon single or multiple dose
administration to the
subject, in preventing CID.
[0053]
The term "administration" or "administering" includes routes of introducing
crofelemer to a subject to perform its intended function. Examples of routes
of administration that
may be used include injection, oral, inhalation, vaginal, rectal and
transdermal. The pharmaceutical
preparations may be given by forms suitable for each administration route. For
example, these
preparations are administered in tablet or capsule form, by injection,
inhalation, ointment, or
suppository. Administration may also be by injection, infusion or inhalation;
topical by lotion or
ointment; and rectal by suppositories. Oral administration is preferred.
Depending on the route of
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administration, crofelemer can be coated with or disposed in a selected
material to protect it from
natural conditions that may detrimentally affect its ability to perform its
intended function.
Crofelemer can be administered alone, or in conjunction with either another
agent or agents as
described above or with a pharmaceutically-acceptable carrier, or both.
Exemplary enteric coated
forms of crofelemer arc described in, for example, US Patent 7,556,831.
[0054]
Administration "in combination with" one or more further therapeutic agents
includes
simultaneous (concurrent) and consecutive administration in any order.
[0055]
The phrase "pharmaceutically acceptable" refers to crofelemer as described
herein,
compositions containing crofelemer, and/or dosage forms which are, within the
scope of sound
medical judgment, suitable for use in contact with the tissues of human beings
and animals
without excessive toxicity, irritation, allergic response, or other problem or
complication,
commensurate with a reasonable benefit/risk ratio.
[0056]
The phrase -pharmaceutically-acceptable carrier- includes pharmaceutically-
acceptable material, composition or vehicle, such as a liquid or solid filler,
diluent, excipient,
solvent or encapsulating material, involved in carrying or transporting the
subject chemical
from one organ, or portion of the body, to another organ, or portion of the
body.
[0057]
The term "treat- or "treatment- as used herein is intended to include the
reduction
or amelioration of the progression, severity, and/or duration of a condition
or one or more
symptoms caused by chemotherapy or resulting from the administration of one or
more
therapies.
[0058]
For example, treating CID may include an improvement of the following
symptoms of CID, including, for example, a decrease in the number of bowel
movements per
day (frequency), a decrease in the number of watery bowel movements per day, a
decrease in
symptom frequency (urgency, fecal incontinence), a decrease in symptom
severity (abdominal
pain or discomfort), a decrease in daily stool consistency score (watery to
formed), or a
decrease in stool consistency leading to formed stools from watery stools. The
severity of
chemotherapy induced diarrhea may be characterized according to Common
Toxicity Criteria
for diarrhea, adapted from the National Cancer Institute (see, e.g., Stein et
al., Ther. Adv. Med.
Oncol. 2:51-43 (2010). In this criteria, Grade 1 is an increase of greater
than 4 stools per day
over baseline (or mild increase in ostomy output compared to baseline); Grade
2 is an increase
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of 4 to 6 stools per day over baseline (moderate increase in ostomy output
compared to
baseline); Grade 3 is an increase in greater than 7 stools per day over
baseline, with incidences
of incontinence and hospitalization indicated (severe increase in ostomy
output compared to
baseline); and Grade 4 is life-threatening consequences with urgent
intervention indicated.
Thus, treatment may include reduction in one, two or three grades of the
criteria
[0059]
The term -obtaining" as in -obtaining crofelemer" is intended to include
purchasing,
synthesizing, isolating, extracting or otherwise acquiring crofelemer.
[0060]
The term "tolerate- or "tolerance- as in tolerating a particular
chemotherapeutic agent
means that the subject does not suffer side effects so severe that they
compromise the health and
wellbeing of the subject to such an extent that the detriment outweighs the
benefit of the
chemotherapy or the subject is non-compliant with the chemotherapeutic regimen
due to the side
effects.
Active Compounds
A. Proanthocyanidins
[0061]
Proanthocyanidins are a group of condensed tannins. Crude extracts from
medicinal plants, for example, Pycanthus angolenis and Baphia nitida, have
been shown to
have antidiarrheal qualities in animal tests (Onwukaeme and Anuforo, 1993,
Discovery and
Innovation, 5:317; Onwukaeme and Lot, 1991, Phytotherapy Res., 5:254). Crude
extracts
which contain tannins, in particular extracts from carob pods and sweet
chestnut wood, have
been proposed as treatments or prophylactics (U.S. Pat. No. 5,043,160;
European Patent No.
481,396).
[0062]
Proanthocyanidins are comprised of at least two or more monomer units that
may
be of the same or different monomeric structure. The monomer units (generally
termed
"leucoanthocyanidin") are generally monomeric flay onoids which include
catechins,
epicatechins, gallocatechins, galloepicatechins, flavanols, flavonols, and
flavan-3,4-diols,
leucocyanidins and anthocyanidins. Therefore, the polymer chains are based on
different
structural units, which create a wide variation of polymeric proanthocyanidins
and a large
number of possible isomers (Hemingway et al., 1982, J. C. S. Perkin, 1:1217).
Larger polymers
of the flavonoid 3-ol units are predominant in most plants, and are found with
average
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molecular weights above 2.000 daltons, containing 6 or more units (Newman
etal., 1987, Mag.
Res. Chem., 25:118).
[0063]
Proanthocyanidin polymers are found in a wide variety of plants,
particularly those
with a woody habit of growth (e.g., Croton spp. and Calophyllum spp.). A
number of different
Croton tree species, including Croton sakutaris, Croton gossypifolius, Croton
palanostima,
Croton lechleri, Croton erythrochilus and Croton draconoides, found in South
America,
produce a red viscous latex sap called Sangre de Drago or "Dragon's Blood".
U.S. Pat. No.
5,211,944 first described the isolation of an aqueous soluble proanthocyanidin
polymer
composition from Croton spp. and the use of the composition as an antiviral
agent (See also
Ubillas et al., 1994, Phytomedicine, 1:77). The proanthocyanidin polymer
composition was
shown to have antiviral activity against a variety of viruses including,
respiratory syncytial,
influenza, parainfluenza and herpes viruses. U.S. Pat. No. 5,211,944 also
discloses the isolation
of an aqueous soluble proanthocyanidin polymer composition from Calophyllum
inophylum
and the use of this composition as an antiviral agent.
[0064]
Exemplary proanthocyanidin polymer compositions useful in the methods
presented herein are preferably isolated from a Croton spp. or Calophyllum
spp. by any method
known in the art. For example, the proanthocyanidin polymer composition may be
isolated
from a Croton spp. or Calophyllum spp. by the method disclosed in U.S. Pat.
No. 5,211,944 or
in Ubillas etal., 1994, Phytomedicine 1: 77-106.
[0065]
In one specific embodiment, a proanthocyanidin polymer composition useful
in the
methods presented herein is crofelemer.
[0066]
Crofelemer is an oligomeric proanthocyanidin extracted and purified from
the red,
viscous latex of the plant Croton lechleri of the family Euphorbiace. The
plant is widely
distributed throughout tropical Central America and South America and is
widely recognized
by ethnobotanists and local healers for its medicinal properties (McRae 1988),
including for
the treatment of diarrhea. Crofelemer is believed to exert its anti-diarrhea
effect through
luminal blockade of CFTR (cystic fibrosis transmembrane conductance regulator)
chloride (Cl-
) channel. Crofelemer has demonstrated in vitro activity against cholera
toxin, forskolin, E coli
LT and STa toxin-mediated Cl- secretion, and to normalize electrolyte and
fluid accumulation
in CT-treated mice (Gabriel 1999, Fischer 2004, Adam 2005) via its effects on
the CFTR
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channel. Crofelemer also significantly improved the secretory diarrhea in
humans due to
enterotoxigenic E. coli (DiCesare 2002), which is also thought to evoke
secretory diarrhea
through activation of CFTR (Kunzelmann 2002). Blockade of the CFTR channel
could be
anticipated to have negative consequences in man, even mimicking cystic
fibrosis. However,
crofelemer has virtually no systemic bioavailability in humans. When studied,
the results
indicated that there was little or no absorption of crofelemer from the GI
tract, and that
crofelemer was well tolerated by normal male subjects. Thus, the site of
action of crofelemer
is topical in the gastrointestinal tract.
[0067] Crofelemer (CAS 148465-45-6) is an oligomerie
proanthocyanidin of varying
chain lengths derived from the Dragon's Blood Croton lecheri of the family
Euphorbiaceae.
Crofelemer has an average molecular weight of between approximately 1500
daltons and
approximately 2900 daltons. The monomers comprising crofelemer comprise
catechin,
epicatechin, gallocatechin, and epigallocatechin. The chain length of
crofelemer ranges from
about 3 to about 30 units with an average chain length of about 8 units. The
structure of
crofelemer is shown below.
cm_
¨
õ----
- (au
Tro
4 OIL CYR
C.) T.1.
EEO
0 a
R. .14 or ()H.
ri
Wherein the average n=6.
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[0068]
Another method for isolating crofelemer can be found in U.S. Patent
Publication
No. 2005/0019389, the contents of which are expressly incorporated herein.
[0069]
In addition, the proanthocyanidin polymer composition may be SB 300, as
described, for example, by Fischer, H. et al., (2004, 1 Ethnopharmacol., 93 (2-
3) : 351 -357).
SB300 is a natural product extract that is particularly amenable for use in a
non-enterically
coated or protected formulations and compositions. In an embodiment, a
pharmaceutically
acceptable composition comprising a proanthocyanidin polymer from Croton
lechleri and
employed in the treatment methods of the invention can be obtained from C.
lechleri, e.g., as
described in WO 00/47062 to Shaman Pharmaceuticals, Inc., the contents of
which are
incorporated herein, and formulated as a food or dietary supplement or
nutraceutical
formulation, especially in a non-enterically coated formulation.
[0070]
In other embodiments, a raw latex obtained from a Croton species or a
Calophyllum species or an extract obtained from a Croton species or a
Calophyllum species
are useful in the methods presented herein. Exemplary extracts are described
in Persinos et al.,
1979, J. Pharma. Sci. 68:124 and Sethi, 1977, Canadian J. Pharm. Sci. 12:7.
B. Combinations with Chemotherapy Agents
100711
The proanthocyanidins described herein may be combined with cancer
drugs/chemotherapy agents for use in the methods described herein to treat
CID. Cancer Drugs
and Cancer Chemotherapeutic Agents are general terms with a meaning that
includes the terms
cancer drug, cancer chemotherapeutic drugs, cancer agent, cancer chemotherapy,
chemotherapeutic drug, chemotherapeutic agent, chemotherapy, chemotherapy
drug, cancer
compound, cancer compound therapy, chemotherapy compound, and cancer drug
therapies.
Such chemotherapies shall also mean chemical substances that: may inhibit
cancer cellular
pathways; that may be used to kill cancer cells in vitro; that may be used to
kill cancer cells in
vivo, as in cancer tumors; and in some cases may be used to treat a person
suffering cancer to
protect viability of the cancer patient's normal cells or attack the viability
of the cancer patient's
cancer cells.
[0072]
By way of serving only as examples without intending to limit the scope of
the
present invention, and to more particularly point out the practice of the
present invention are
the following examples and combination uses of the chemotherapy agents. A
number of
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cellular pathways that may be targeted by chemotherapy agents are also listed.
Generally a
cancer chemotherapeutic drug is used in the form of a pharmaceutical
composition, for a
pharmaceutical use, or in a method of treatment of as patient.
[0073]
Examples of cellular targets at which a cancer drug may have an effect are
listed
here, but are not limiting. The cellular targets of cancer chemotherapeutic
agents include the
following identified targets: mTORC, RAF kinase, MEK kinase, Phosphoinositol
kinase 3,
Fibroblast growth factor receptor, Multiple tyrosine kinase, Human epidermal
growth factor
receptor, Vascular endothelial growth factor, Other angiogenesis factors, Heat
shock protein;
Smo (smooth) receptor, FMS-like tyrosine kinase 3 receptor, Apoptosis protein
inhibitor,
Cyclin dependent kinases, Deacetylase, ALK tyrosine kinase receptor,
Serine/threonine-
protein kinase Pim-1, Porcupine acyltransferase, Hedgehog pathway, Protein
kinase C,
mDM2, Glypciin 3, ChK1, Hepatocyte growth factor MET receptor, Epidermal
growth factor
domain-like 7, Notch pathway, Src-family kinase, DNA methyltransferase, DNA
intercalators,
Thymidine synthase, Microtubule function disruptor, DNA cross-linkers, DNA
strand
breakers, DNA alkylators, INK-dependent p53 Ser15 phosphorylation inducer, DNA
topoisomerase inhibitors, Bc1-2, and free radical generators.
[0074]
In various embodiments, the chemotherapy agent is selected from alkylating
agents, anthracyclines, cytoskeletal disruptors (taxanes), epothilones,
histone deacetylase
inhibitors, inhibitors of topoisomerase I, inhibitors of topoisomerase II,
kinase inhibitors,
nucleotide analogs and precursor analogs, peptide antibiotics, platinum-based
agents and
retinoids.
100751
In particular embodiments, the chemotherapy agent is a cancer growth
inhibitor.
Cancer growth inhibitors are a type of biological therapy and include tyrosine
kinase inhibitors
and HER2 inhibitors, proteasome inhibitors, mTOR inhibitors, PI3K inhibitors,
histone
deacetvlase inhibitors and hedgehog pathway blockers.
[0076]
In a particular embodiment, the chemotherapeutic agent is one or more
tyrosine
kinase inhibitors (TKI).
[0077]
Tyrosine kinases are enzymes responsible for the activation of many
proteins by
signal transduction cascades. The proteins are activated by adding a phosphate
group to the
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protein (phosphorylation). Tyrosine kinase inhibitors (TM) are typically used
as anti-cancer
drugs. This operate by four different mechanisms: they can compete with
adenosine
triphosphate (ATP), the phosphorylating entity, the substrate or both or can
act in an allosteric
fashion, namely bind to a site outside the active site, affecting its activity
by a conformational
change. TKIs are small molecular weight inhibitors of tyrosine
phosphorylation, which do not
inhibit protein kinases that phosphorylate serine or threonine residues and
can discriminate
between the kinase domains of the EGFR and that of the insulin receptor. It
was further shown
that in spite of the conservation of the tyrosine-kinase domains one can
design and synthesize
TKIs that discriminate between even closely related protein tyrosine kinases
such as EGFR and
its close relative HER2.
[0078]
Specific examples of tyrosine kinase inhibitors include lapatinib,
sunitinib,
sorafenib, erlotinib, gefitinib, axitinib, imatinib, nilotinib, dasatinib,
cabozantinib. ruxolitinib,
neratinib, bosutinib and valatinib.
[0079]
In a particular embodiment, the chemotherapeutic agent is one or more HER
(Human epidermal growth factor receptor) inhibitors.
100801
Signaling pathways activated by HER2 include: mitogen-activated protein
kinase
(MAPK), phosphoinositide 3-kinase (PI3K/Akt), phospholipase C y, protein
kinase C (PKC)
and signal transducer and activator of transcription (STAT). Signaling through
the ErbB family
of receptors promotes cell proliferation and opposes apoptosis, and therefore
must be tightly
regulated to prevent uncontrolled cell growth from occurring. Amplification or
over-expression
of the ERBB2 gene is strongly associated with increased disease recurrence and
a poor
prognosis. Over-expression is also known to occur in breast, ovarian, stomach,
and aggressive
forms of uterine cancer, such as uterine serous endometrial carcinoma. HER2 is
co-localized,
and, most of the time, co-amplified with the gene GRB7, which is a proto-
oncogene associated
with breast, testicular germ cell, gastric, and esophageal tumors. HER2
proteins have been
shown to form clusters in cell membranes that may play a role in
tumorigenesis. Specific
examples of HER (human epidermal growth factor receptor) inhibitors include
RG7116,
RG1273 (pertuzumab, PerjetaX), RG3502 (trastuzumab emantasine, T-DM1), RG597
(trastuzumab, HERCEPTIN), RGA201 (RG7160), erlotinib (Tarcevall)), dacomitinib
(PF-
00299804), PF-05280014 (Pfizer's biosimilar mAB to RG597).
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[0081]
Generic names of cancer chemotherapeutic drugs that have been typically
used in
cancer patients include: doxorubicin, epirubicin; 5-fluorouracil, paclitaxel,
docetaxel, cisplatin,
bleomycin, melphalan, plumbagin, irinotecan, mitomycin-C, and mitoxantrone. By
way of
example, some other cancer chemotherapeutic drugs that may be used and may be
in stages of
clinical trials include: resminostat, tasquinimod, refametinib, lapatinib,
Tyverb, Arenegyr,
pasireotide, Signifor, ticilimumab, tremelimumab, PrevOnco, ABT-869,
linifanib, tivantinib,
Tarceva, erlotinib, Stivarga, regorafenib, fluoro-sorafenib, brivanib,
liposomal doxorubicin,
lenvatinib, ramucirumab, peretinoin, Ruchiko, muparfostat, Teysuno, tegafur,
gimeracil,
oteracil, and orantinib.
[0082]
Examples of FDA approved cancer drugs (by generic name) which can be used
in
the present invention include: sorafenib, regorafenib, imatinib, eribulin,
gemcitabine,
capecitabine, pazopanib, lapatinib, dabrafenib, sunitinib malate, crizotinib,
everolimus,
torisirolimus, sirolimus, axitinib, gefitinib, anastrozole, bicalutamide,
fulvestrant, ralitrexed,
pemetrexed, goserilin acetate, erlotinib, vemurafenib, visiodegib, tamoxifen
citrate, paclitaxel,
docetaxel, cabazitaxel, oxaliplatin, ziv-aflibercept, bevacizumab,
trastuzumab, pertuzumab,
pantiumumab, taxane, bleomycin, melphalan, plumbagin, camptosar, mitomycin-C,
doxorubicin, pegylated doxorubicin, 5-fluoro-uracil, temozolomide,
pasireotide, tegafur,
gimeracil, oteraci, bortezomib, lenalidomide, and romidepsin.
100831
Manufacturer brand names for some cancer drugs that may be used in the
present
invention include: NEXAVAR (sorafenb), STIVARGA (regorafenib), AFINITOR
(everolimus), GLEEVEC (imatinib), HALAVEN (eribulin), ALIMTA (pemetrexed),
GEMZAR (gemcitabine), VOTRIENT (pazopanib), TYKERB (lapatinib), TAFINIAR
(dabrafenib), SUTENT (sutinib malate), XALKORI (crizotinib), TORISEL
(torisirolimus),
INLYTA (axitinib), IRESSA (gefitinib), ARIMIDEX (anastrole), CASODEX
(bicalutamide),
FASLODEX (fulvestrant), TOMUDEX (ralitrexed), ZOLADEX (goserilin acetate),
TARCEVA (erlotininb), XELODA (capecitabine), ZELBROF (vemurafenib), ERIVEDGE
(visiodegib), PERJETA (pertuzumab), HERCEPTIN (trastuzumab), TAXOTERE
(docetaxel),
JEVTANA (cabazitaxel), ELOXATIN (oxaliplatin), ZALTRAP (ziv-aflibercept),
AVASTIN
(bevacizumab) Nolvadex, Istubal, and VALODEX (tamoxifen citrate), TEMODAR
(temozolomide), SIGNIFOR (pasireotide), VECTIBIX (pantiumumab), ADRIAMYCIN
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(doxorubicin). DOXIL (pegylated doxorubicin), ABRAXANE (Paclitaxel), TEYSUNO
(tegafur, gimeracil, oteracil), BORTEZOMIB (Velcade) and with lenalidomide,
ISTODAX
(romidepsin).
[0084]
Cancer drug therapies contemplated for the present invention include Iressa
(gefitinib), Arimidex (anastrole), Casodex (bicalutamide), Faslodex
(fulvestrant), Tomudex
(ralitrexed), Zoladex (goserilin acetate), Nolvadex, Istubal, and Valodex
(tamoxifen citrate),
Erbitux (cetuximab), Sprycel (dasatinib), Ixempra (ixabepilone), Taxol
(paclitaxel), Paraplatin
(carboplatin), and Yervoy (ipilumumab), Vectibix (pantiumumab, rilotumumab,
trebananib,
blinatumumab, Halaven (eribulin), Alimta (pemetrexed), and Gemzar
(gemcitabine), Votrient
(pazopanib), Tykerb (lapatinib), and Tafiniar (dabrafenib). Doxil
(doxorubicin, adriamycin),
Temodar (temozolomide), Afinitor (everolimus), Gleevec (imatinib), and
Signifor
(pasireotide), dovitinib, midostaurin, panobinostat, Teysuno (tegafur,
gimeracil, oteracil),
navitocl ax, velipariban, linifanib, thrombospondin, ilorasertib, elagolix,
atrasentan, Sutent
(sutinib malate), Xalkori (crizotinib), Torisel (torisirolimus), Inlyta
(axitinib), dacomitinib,
bosutinib, Tarceva (erlotininb), Xeloda (capecitabine), Zelbrof (vemurafenib),
Erivedge
(visiodegib), Perj eta (pertuzumab), Herceptin (trastuzumab) Avastin
(bevacizumab), Taxotere
(docetaxel), Jevtana (cabazitaxel), Eloxatin (oxaliplatin), Zaltrap (ziv-
aflibercept), iniparib,
neratini b (1-1K1-272) and ombrabulin.
III. Methods of Treatment
100851
Provided herein are methods of treating, preventing, or alleviating
diarrhea or
gastrointestinal symptoms caused by chemotherapy comprising administering to a
subject in
need thereof an effective amount of crofelemer alone or in combination with a
chemotherapy
agent. Exemplary diarrhea that can be treated or prevented using the methods
presented herein
include CID. The subject is preferably a human.
[0086]
In one embodiment, treating CID includes an improvement of the following
symptoms of CID, including, for example, a decrease in the number of bowel
movements per
day (frequency), a decrease in the number of watery bowel movements per day, a
decrease in
symptom frequency (urgency, fecal incontinence), a decrease in symptom
severity (abdominal
pain or discomfort), a decrease in daily stool consistency score (watery to
formed), or a
decrease in stool consistency leading to formed stools from watery stools. In
certain
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embodiments, the treatment results in a reduction in the Grade of the Common
Toxicity Criteria
for diarrhea, for example, from Grade 4, to Grade 3, Grade 2 or Grade 1; or
from Grade 3, to
Grade 2 or Grade 1; or from Grade 2 to Grade 1. In certain embodiments, the
treatment results
in an improvement such that the subject does not meet any of the Common
Toxicity Criteria
Grades, i.e., is no longer suffering from diarrhea.
[0087]
In other specific embodiments, treatment can also include, for example, one
or
more of a decrease in the number of bowel movements per day, a decrease in the
number of
watery bowel movements per day, an improvement in the daily abdominal score
for pain or
discomfort, an improvement in the score for daily stool consistency, a
decrease in the number
of days per week or per month that subjects experienced urgency, or a decrease
in the number
of days per week or per month that subjects experienced fecal incontinence.
[0088]
In one aspect, provided herein are methods of treating CID in a subject
undergoing
chemotherapy comprising administering to a subject in need thereof a
composition comprising
an effective amount of crofelemer to treat CID. In specific embodiments, the
crofelemer is an
enterically coated oral dosage form. In other embodiments, the crofelemer is
an oral dosage
form that is not enterically protected.
[0089]
In one embodiment, the crofelemer is administered at the same time as
chemotherapy to reduce or delay the onset of CID. In one embodiment, the
crofelemer is
administered before chemotherapy to reduce or delay the onset of CID. In one
embodiment,
the crofelemer is administered after chemotherapy to reduce the onset of or
treat CID.
[0090]
CID can be an adverse side effect of chemotherapy, particularly
chemotherapy for
treatment of cancer. In some embodiments, CID can be severe enough to
interfere with the
chemotherapy regimen of the subject because of lack of tolerance or reduced
tolerance for the
chemotherapy regimen due to the CID. In certain embodiments, therefore,
provided are
methods of increasing the tolerance of a subject for a certain chemotherapy
agent or regimen
such that the subject can tolerate and can be administered a recommended
dosage of a
chemotherapeutic agent or can be administered a chemotherapeutic agent.
100911
In some embodiments, the subject is undergoing chemotherapy to treat one or
more
forms of cancer. The one or more forms of cancer can be selected from breast
cancer, ovarian
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cancer, prostate cancer, bladder cancer, cervical cancer, uterine cancer,
testicular cancer,
kidney cancer, thyroid cancer, oral or oropharyngeal cancer, astrocytoma,
sarcoma,
mesothelioma, meningioma, lymphoma, myeloma, head and neck cancer, lung
cancer,
carcinoma (e.g., squamous cell carcinoma), malignant melanoma, peritoneal
cancer, gastric
cancer, hepatic cancer, colorectal cancer, gallbladder cancer, bone cancer,
pancreatic cancer,
tongue cancer, esophageal cancer, brain tumor, brain stem glioma, a metastases
thereof, and
leukemia.
[0092]
In one embodiment, the chemotherapy comprises one or more tyrosine kinase
inhibitors.
[0093]
In one embodiment, the tyrosine kinase inhibitor is selected from
lapatinib,
sunitinib, sorafenib, erlotinib, gefitinib, axitinib, imatinib, nilotinib,
dasatinib, cabozantinib,
ruxolitinib, neratinib, bosutinib, toceranib, and valatinib.
[0094]
In one embodiment, the chemotherapy comprises one or more HER (Human
epidermal growth factor receptor) inhibitors.
[0095]
In one embodiment, the HER (Human epidermal growth factor receptor)
inhibitor
is selected from RG7116, RG1273 (pertuzumab, Perjeta ), RG3502 (trastuzumab
emantasine,
T-DMI), RG597 (trastuzumab, HERCEPTIN), RGA201 (RG7160), erlotinib (Tarcevag),
dacomitinib (PF-00299804), PF-05280014 (Pfizer's biosimilar mA13 to RG597).
[0096]
In various embodiments, the crofelemer is administered after a subject
begins to
exhibit symptoms of CID. In various embodiments, the crofelemer is
administered prior to the
start of chemotherapy or of a round of chemotherapy to prevent or reduce the
severity of CID
associated with the chemotherapy. In embodiments, the crofelemer is
administered for one
day, three days, or one week prior to chemotherapy or a round of chemotherapy
to prevent or
reduce the risk or incidence of CID upon treatment of chemotherapy.
[0097]
In certain embodiments, the crofelemer is administered for the duration of
treatment with the chemotherapy. The duration of treatment can comprise the
time between
two chemotherapy rounds.
For example, in certain embodiments, chemotherapy is
administered once every three weeks or four weeks or once every 15, 16, 17,
18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 days.
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[0098]
In certain embodiments, the crofelemer is administered until symptoms of
CID are
ameliorated and then crofelemer is discontinued.
[0099]
As will be readily apparent to one skilled in the art, the useful in vivo
dosage to be
administered and the particular mode of administration may vary depending upon
the age, weight
and mammalian species treated, the particular compounds employed, and/or the
specific use for
which these compounds are employed. The determination of effective dosage
levels, that is the
dosage levels necessary to achieve the desired result, can be accomplished by
one skilled in the art
using routine pharmacological methods and in consultation with the data
presented herein.
101001
In one aspect, provided herein are methods of treating stool consistency in
a subject
undergoing chemotherapy, wherein a subject is considered treated if there is
an improvement
in the score for daily stool consistency and/or a decrease in stool
consistency score a measured
throughout the day or days or weeks comprising administering to a subject in
need thereof a
composition comprising an effective amount of crofelemer to treat stool
consistency. This
decrease may be measured from a baseline. The baseline may be determined in
the days to
week prior to treatment with crofelemer. Treatment comprises administering
about 250 mg to
about 1000 mg per day; administering about 250 mg per day; administering 1000
mg per day;
administering about 125 mg two times per day; or administering about 500 mg
two times per
day of crofelemer, preferably an enteric coated oral dosage form, to a subject
in need thereof
or a dosage of a proanthocyanidin polymer composition (including a non-enteric
protected oral
dosage form of crofelemer) that is bioequivalent to 250 mg to about 1000 mg
per day; about
250 mg per day; 1000 mg per day; about 125 mg two times per day; or about 500
mg two times
per day of enteric protected oral dosage form of crofelemer.
[0101]
In one aspect, provided herein are methods of alleviating watery diarrhea
in a
subject undergoing chemotherapy, wherein a subject is considered treated if
the subject
experiences a decrease in the number of watery bowel movements per day and/or
over days, a
week or weeks of administration of crofelemer comprising administering to a
subject in need
thereof a composition comprising an effective amount of crofelemer to
alleviate watery
diarrhea.
[0102]
This decrease may be measured from a baseline. The baseline may be
determined
in the days to week prior to treatment with crofelemer. Treatment comprises
administering
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about 250 mg to about 1000 mg per day; administering about 250 mg per day;
administering
1000 mg per day; administering about 125 mg two times per day; or
administering about 500
mg two times per day of crofelemer, preferably an enteric coated oral dosage
form of
crofelemer, to a subject in need thereof, or, alternatively, a dosage of a
proanthocyanidin
polymer composition (including a non-enteric protected oral dosage form of
crofelemer) that
is bioequivalent to 250 mg to about 1000 mg per day; about 250 mg per day;
1000 mg per day;
about 125 mg two times per day; or about 500 mg two times per day of
enterically protected
oral dosage form of crofelemer.
[0103]
In one aspect, presented herein are methods a decreasing the number of
bowel
movements per day, wherein a subject is considered treated if there is a
decrease in the number
of bowel movements per day as measured from a baseline comprising
administering to a
subject in need thereof a composition comprising an effective amount of
crofelemer to decrease
the number of bowel movements per day.
[0104]
The baseline may be determined in the days to week prior to treatment with
crofelemer. Treatment comprises administering about 250 mg to about 1000 mg
per day;
administering about 250 mg per day; administering 1000 mg per day;
administering about 125
mg two times per day; or administering about 500 mg two times per day of
crofelemer,
preferably an enteric coated oral dosage form of crofelemer, to a subject in
need thereof, or,
alternatively, a dosage of a proanthocyanidin polymer composition (including a
non-enteric
protected oral dosage form of crofelemer) that is bioequivalent to 250 mg to
about 1000 mg
per day; about 250 mg per day; 1000 mg per day; about 125 mg two times per
day; or about
500 mg two times per day of enterically protected oral dosage form of
crofelemer.
[0105]
In certain embodiments, the methods provided result in a decrease in the
Grade of
Common Toxicity Criteria Grades for diarrhea. In addition, the methods
provided result in
increased ability to tolerate the chemotherapeutic regimen such that the
subject remains on and
is compliant with the prescribed chemotherapeutic regimen.
[0106]
Crofelemer may be administered, for example, once a day, twice a day, three
times
a day, or four times or more often as necessary per day. Crofelemer may be
administered in
doses, for example of from about between 25 mg BID to about 3000 mg TID,
preferably
crofelemer is administered from between about 125 mg to about 1000 mg per day.
In another
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embodiment, crofelemer is administered between 125 mg BID to about 500 mg BID
depending
of symptoms. In another embodiment, crofelemer is administered as 125 mg BID.
In another
embodiment, crofelemer is administered as 500 mg BID. Crofelemer may be
administered
orally, for example, in tablet form, powder form, liquid form or in capsules.
In preferred
embodiments, the crofelemer is formulated as an enteric coated oral dosage
form. In other
embodiments, the crofelemer is an oral dosage form that is not enteric coated.
[0107]
In exemplary embodiments, the subject is orally administered 250, 500, or
1000
mg/day of enteric protected crofelemer or is administered a dose of a
proanthocyanidin polymer
composition, including crofelemer, that is bioequivalent to an oral dosage
form of enteric
coated crofelemer administered at 250, 500, or 1000 mg/clay.
[0108]
In specific embodiments, the subject is administered 125, 250 or 500 mg
p.o. b.i.d
(orally twice per day) enteric coated crofelemer or a dosage of a
proanthocyanidin polymer
composition bioequivalent to 125, 250 or 500 mg p.o. b.i.d enteric coated
crofelemer. Other
appropriate dosages for methods may be determined by health care professionals
or by the
subject. The amount of crofelemer administered daily may be increased or
decreased based on
the weight, age, health, sex or medical condition of the subject. One of skill
in the art would
be able to determine the proper dose for a subject based on this disclosure
and the data
presented in the Examples, which follow.
[0109]
In other embodiments, the subject is treated with crofelemer for 2, 4, 6,
8, 10, 12,
14, 16, 18, 20, 22, 24 or more weeks or 26 or more weeks. Length of treatment
may vary
depending on the type and length of disease and the proper length of treatment
may be easily
determined by one of skill in the art having the benefit of this disclosure.
[0110]
Subjects in need thereof include subjects having or that are susceptible to
or who
have CID.
[0111]
In certain embodiments, the subject is administered crofelemer for
treatment of
CID in combination with one or more anti-diarrheals, such as, but not limited
to, loperamide,
octreotide, probiotics and any other agent useful for the treatment of
chemotherapy associated
diarrhea.
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IV. Pharmaceutical Preparations
[0112]
Also provided herein are pharmaceutical compositions, comprising an
effective
amount of a crofelemer described herein and a pharmaceutically acceptable
carrier. In a further
embodiment, the effective amount is effective to treat CID.
[0113]
Examples of the preparation and use of crofelemer have been described in US
Patent 7,556,831, US Patent Publication 20070254050 and US Patent Publication
20080031984, all of which are incorporated herein by reference in their
entirety.
[0114]
One embodiment includes pharmaceutical compositions comprising crofelemer
and a pharmaceutically acceptable carrier. In preferred embodiments, the
pharmaceutical
composition is an enterically protected oral dosage form, such as a tablet or
capsule.
Alternatively, the pharmaceutical composition is an oral dosage form that is
not enterically
protected.
101151
The pharmaceutical compositions described herein may further comprise
excipients, for example, one or more of a diluting agent, binding agent,
lubricating agent,
disintegrating agent, coloring agent, flavoring agent or sweetening agent.
Compositions may
be formulated for selected coated and uncoated tablets, hard and soft gelatin
capsules, sugar-
coated pills, lozenges, wafer sheets, pellets and powders in sealed packet.
For example,
compositions may be formulated for topical use, for example, ointments,
pomades, creams,
gels and lotions.
[0116]
In certain embodiments, these pharmaceutical compositions are suitable for
topical
or oral administration to a subject. In other embodiments, as described in
detail below, the
pharmaceutical compositions may be specially formulated for administration in
solid or liquid
form, including those adapted for the following: (1) oral administration, for
example, drenches
(aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders,
granules, pastes;
(2) parenteral administration, for example, by subcutaneous, intramuscular or
intravenous
injection as, for example, a sterile solution or suspension; (3) topical
application, for example,
as a cream, ointment or spray applied to the skin; (4) intravaginally or
intrarectally, for
example, as a pessary, cream or foam; or (5) aerosol, for example, as an
aqueous aerosol,
liposomal preparation or solid particles containing the compound.
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[0117]
A pharmaceutical carrier must be "acceptable" in the sense of being
compatible
with the other ingredients of the formulation and not injurious to the
patient. Some examples
of materials which can serve as pharmaceutically-acceptable carriers include:
(1) sugars, such
as lactose, glucose and sucrose; (2) starches, such as corn starch and potato
starch; (3) cellulose,
and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose
and cellulose
acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
excipients, such as cocoa
butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
safflower oil, sesame
oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene
glycol; (11) polyols,
such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,
such as ethyl oleate
and ethyl laurate; (13) agar: (14) buffering agents, such as magnesium
hydroxide and aluminum
hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline;
(18) Ringer's
solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other
non-toxic
compatible substances employed in pharmaceutical formulations.
[0118]
Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate
and
magnesium stearate, as well as coloring agents, release agents, coating
agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can also be
present in the
compositions.
[0119]
Examples of pharmaceutically-acceptable antioxidants include: (1) water
soluble
antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate,
sodium
metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such
as ascorbyl
palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
lecithin, propyl
gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such
as citric acid,
ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric
acid, and the like.
[0120]
Compositions containing crofelemer include those suitable for oral, nasal,
topical
(including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral
administration. The
compositions may conveniently be presented in unit dosage form and may be
prepared by any
methods known in the art of pharmacy. The amount of active ingredient which
can be
combined with a carrier material to produce a single dosage form will vary
depending upon the
host being treated, the particular mode of administration. The amount of
active ingredient
which can be combined with a carrier material to produce a single dosage form
will generally
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be that amount of the compound which produces a therapeutic effect. Generally,
out of one
hundred percent, this amount will range from about 0.01% to about 99% of
active ingredient,
for example, from about 5% to about 70%, or from about 10% to about 30%.
[0121]
Liquid dosage forms for oral or rectal administration of crofelemer may
include,
for example, pharmaceutically-acceptable emulsions, microemulsions, solutions,
suspensions,
syrups and elixirs. In addition to the active ingredient, the liquid dosage
forms may contain
inert diluents commonly used in the art, such as, for example, water or other
solvents,
solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol,
ethyl carbonate,
ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene
glycol, oils (in
particular, cottonseed, groundnut, coin, germ, olive, castor and sesame oils),
glycerol,
tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of
sorbitan, and mixtures
thereof
[0122]
Suspensions, in addition to crofelemer may contain suspending agents as,
for
example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, and
mixtures thereof Dosage forms for the topical or transdermal administration of
crofelemer can
include, for example, powders, sprays, ointments, pastes, creams, lotions,
gels, solutions,
patches and inhalants. The ointments, pastes, creams and gels may contain, in
addition to
crofelemer, excipients, such as animal and vegetable fats, oils, waxes,
paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc
and zinc oxide, or mixtures thereof Powders and sprays can contain, in
addition to a
crofelemer, excipients such as lactose, talc, silicic acid, aluminum
hydroxide, calcium silicates
and polyamide powder, or mixtures of these substances. Sprays can additionally
contain
customary propellants, such as chlorofluorohydrocarbons and volatile
unsubstituted
hydrocarbons, such as butane and propane.
[0123]
Examples of suitable aqueous and non-aqueous carriers which may be employed
in the pharmaceutical compositions can include, for example, water, ethanol,
polyols (such as
glycerol, propylene glycol, polyethylene glycol, and the like), and suitable
mixtures thereof,
vegetable oils, such as olive oil, and injectable organic esters, such as
ethyl oleate. Proper
fluidity can be maintained, for example, by the use of coating materials, such
as lecithin, by
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the maintenance of the required particle size in the case of dispersions, and
by the use of
surfactants.
[0124]
In one embodiment, crofelemer is enteric coated so as to protect it from
degradation
by the acidic conditions of the stomach and/or from interactions with
proteins, such as pepsin,
present in the stomach, e.g., an enteric protected formulation. In a specific
embodiment,
crofelemer is in tablet form. In yet another embodiment, the tablet is enteric
coated, e.g.,
Eudragit . In one embodiment, crofelemer is formulated as an enteric coated
bead or granule
in an enteric coated capsule shell. In another embodiment, crofelemer is
formulated in a
delayed release composition.
[0125]
In certain embodiments, the composition is formulated with a compound or
compounds which neutralize stomach acid. Alternatively, the pharmaceutical
composition
containing the composition is administered either concurrent with or
subsequent to or after
administration of a pharmaceutical composition which neutralize stomach acid.
Compounds,
such as antacids, which are useful for neutralizing stomach acid include, but
are not limited to,
aluminum carbonate, aluminum hydroxide, bismuth subnitrate, bismuth
subsalicylate, calcium
carbonate, dihydroxyaluminum sodium carbonate, magaldrate, magnesium
carbonate,
magnesium hydroxide, magnesium oxide, and mixtures thereof Compounds that are
able to
reduce the secretion of stomach acid and/or are able to reduce the acidity of
stomach fluid are
well known in the art and include, but are not limited to, antacids (aluminum
hydroxide,
aluminum carbonate, aluminum glycinate, magnesium oxide, magnesium hydroxide,
magnesium carbonate, calcium carbonate, sodium bicarbonate), stomach acid
blockers and a
combination of any of the foregoing. In general, any drug that has been
approved for sale by
the relevant government agency and is able to reduce the production of stomach
acid and/or
reduce the acidity of stomach fluid can be administered in combination with an
inhibitor
molecule, such as crofelemer, in accordance with the methods presented herein.
[0126]
In a particular embodiment where crofelemer is not enteric coated,
crofelemer is
formulated with one or more compounds that are able to reduce the secretion of
stomach acid
and/or able to reduce the acidity of stomach fluid. In an exemplary
embodiment, crofelemer is
formulated in a controlled release (delayed release) composition, such as
Merck GEM, Alza
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OROS, wax matrix (release is primarily delayed until after the formulation
passes out of the
stomach and into the intestine).
[0127]
Also provided herein are pharmaceutical formulations of crofelemer
comprising
the composition along with a pharmaceutically acceptable carrier, at a dose
which is
therapeutically effective at treating CID. In one embodiment, a directly
compressible
crofelemer (e.g., that can be directly compressed, without excipients, into a
tablet of
pharmaceutically acceptable hardness and friability) compressed into a tablet,
optionally with
a lubricant, such as but not limited to magnesium stearate, is enteric coated.
These formulations
can be prepared by methods known in the art, see, e.g. methods described in
Remington's
Pharmaceutical Sciences, 18th Ed., ed. Alfonso R. Gennaro, Mack Publishing
Co., Easton, Pa.,
1990.
[0128]
In a specific embodiment, the proanthocyanidin polymer composition
comprises
crofelemer (CAS 148465-45-6).
[0129]
In a more another embodiment, a composition is enteric coated. Enteric
coatings
are those coatings that remain intact in the stomach, but will dissolve and
release the contents
of the dosage form once it reaches the small intestine. A large number of
enteric coatings are
prepared with ingredients that have acidic groups such that, at the very low
pH present in the
stomach, i.e. pH 1.5 to 2.5, the acidic groups are not ionized and the coating
remains in an
undissociated, insoluble form. At higher pH levels, such as in the environment
of the intestine,
the enteric coating is converted to an ionized form, which can be dissolved to
release the
inhibitor molecule. Other enteric coatings remain intact until they are
degraded by enzymes in
the small intestine, and others break apart after a defined exposure to
moisture, such that the
coatings remain intact until after passage into the small intestines.
101301
Polymers which are useful for the preparation of enteric coatings include,
but are
not limited to, shellac, starch and amylose acetate phthalates, styrene-maleic
acid copolymers,
cellulose acetate succinate, cellulose acetate phthalate (CAP),
polyvinylacetate phthalate
(PVAP), hydroxypropylmethylcellulose phthalate (grades HP-50 and HP-55),
ethylcellulose,
fats, butyl stearate, and methacrylic acid-methacrylic acid ester copolymers
with acid ionizable
groups. In one embodiment, the pharmaceutical composition contains a polymeric
proanthocyanidin composition and the enteric coating polymer Eudragit L 30D,
an anionic
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copolymer of methacrylic acid and methyl acrylate with a mean molecular weight
of 250,000
Daltons. In another embodiment, the enteric coating polymer is Eudragit L 30D-
55.
Application of the enteric coating to the crofelemer composition can be
accomplished by any
method known in the art for applying enteric coatings. For example, but not by
way of
limitation, the enteric polymers can be applied using organic solvent based
solutions containing
from 5 to 10% w/w polymer for spray applications and up to 30% w/w polymer for
pan
coatings. Solvents that are commonly in use include, but are not limited to,
acetone,
acetone/ethyl acetate mixtures, methylene chloride/methanol mixtures, and
tertiary mixtures
containing these solvents. Some enteric polymers, such as methacrylic acid-
methacrylic acid
ester copolymers can be applied using water as a dispersant. The volatility of
the solvent system
must be tailored to prevent sticking due to tackiness and to prevent high
porosity of the coating
due to premature spray drying or precipitation of the polymer as the solvent
evaporates.
[0131]
In another embodiment, the pharmaceutical composition comprising crofelemer
is
formulated as enteric coated granules or powder (microspheres with a diameter
of 300-5001)
provided in either hard shell gelatin capsules or suspended in an oral
solution for pediatric
administration. The enteric coated powder or granules may also be mixed with
food,
particularly for pediatric administration.
[0132]
The granules and powder can be prepared using any method known in the art,
such
as but not limited to, crystallization, spray-drying or any method of
comminution, for example,
using a high speed mixer/granulator. Exemplary formulations may be found, for
example, in
the following US patents and applications US Patent No. 7,341,744; USSN
11/510,152; and
USSN 12/175,131.
[0133]
Regardless of the route of administration selected, crofelemer is
formulated into
pharmaceutically-acceptable dosage forms by methods known to those of skill in
the art.
[0134]
In combination therapy treatment, both the compounds and the other drug
agent(s)
are administered to mammals (e.g., humans, male or female) by methods known in
the art. The
agents may be administered in a single dosage form or in separate dosage
forms. Effective
amounts of the other therapeutic agents are well known to those skilled in the
art. However, it
is well within the skilled artisan's purview to determine the other
therapeutic agent's optimal
effective-amount range. In one embodiment in which another therapeutic agent
is administered
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to an animal, the effective amount of the compound is less than its effective
amount in case the
other therapeutic agent is not administered. In another embodiment, the
effective amount of
the agent is less than its effective amount in case the compound is not
administered. In this
way, undesired side effects associated with high doses of either agent may be
minimized. Other
potential advantages (including without limitation improved dosing regimens
and/or reduced
drug cost) will be apparent to those skilled in the art.
[0135]
In various embodiments, the therapies (e.g., prophylactic or therapeutic
agents) are
administered less than 5 minutes apart, less than 30 minutes apart, 1 hour
apart, at about 1 hour
apart, at about 1 to about 2 hours apart, at about 2 hours to about 3 hours
apart, at about 3 hours
to about 4 hours apart, at about 4 hours to about 5 hours apart, at about 5
hours to about 6 hours
apart, at about 6 hours to about 7 hours apart, at about 7 hours to about 8
hours apart, at about
8 hours to about 9 hours apart, at about 9 hours to about 10 hours apart, at
about 10 hours to
about 11 hours apart, at about 11 hours to about 12 hours apart, at about 12
hours to 18 hours
apart, 18 hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48
hours apart, 48
hours to 52 hours apart, 52 hours to 60 hours apart, 60 hours to 72 hours
apart, 72 hours to 84
hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hours part. In one
or more
embodiments, two or more therapies are administered within the same patient's
visit.
V. Kits
[0136]
Kits are also provided herein, for example, kits for treating a diarrhea,
e.g., CID in
a subject undergoing chemotherapy. The kits may contain, for example,
crofelemer or a
pharmaceutical composition comprising crofelemer and instructions for use. The
instructions
for use may contain prescribing information, dosage information, storage
information, and the
like.
[0137]
Label instructions include, for example, instructions to take the
crofelemer for at
least 3 days for the treatment of CID. The instructions could also read, for
example, take from
between 125mg BID to 500mg BID of crofelemer until resolution of symptoms or
for the
duration of chemotherapy treatment for treatment of CID. The instructions
could also read, for
example, take 125mg BID of crofelemer until resolution of symptoms or for the
duration of
chemotherapy treatment for treatment of CID. The instructions could also read,
for example,
take 500mg BID of crofelemer until resolution of symptoms of CID.
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EXAMPLE
[0138]
It should be appreciated that the invention should not be construed to be
limited to
the example, which is now described; rather, the invention should be construed
to include any
and all applications provided herein and all equivalent variations within the
skill of the ordinary
artisan.
Example I: A Study of the Safety and Effectiveness of Crofelemer for the
Treatment of
Chemotherapy-Induced Diarrhea in Dogs
[0139]
Toceranib phosphate (Palladia ) is a multi-kinase inhibitor targeting
several receptor
tyrosine kinases (RTK), and is indicated for the treatment of Patnaik grade II
or III, recurrent,
cutaneous mast cell tumors with or without regional lymph node involvement in
dogs. Toceranib
phosphate is currently used more often off-label to treat neoplasias other
than mast cell tumors.
[0140]
Toceranib phosphate is indicated at an initial dosage of 3.25 mg/kg (1.48
mg/lb) body
weight, orally every other day. Dose reduction intervals of 0.5 mg/kg [to a
minimum dose of 2.2
mg/kg (1.0 mg/lb) every other day] and dose interruptions (cessation of
toceranib phosphate for up
to two weeks) may be utilized, if needed, to manage adverse reactions. This
approval was based
upon a randomized, placebo-controlled, double-masked, multicenter clinical
field study showing a
statistically significant advantage for toceranib phosphate over placebo (37%
vs. 8%, p<0.00 I) in
the primary effectiveness endpoint of objective response at the end of the six-
week masked phase
(London CA, et al., Clin. Cancer Res, 15(11), 2009). Toceranib phosphate is
sometimes prescribed
at a lower dose (2.5-3 mg/kg/dose) than the labeled dose; however, adverse
effects of diarrhea are
still observed, although generally with a lower frequency.
[0141]
It is not expected that any increase in adverse reactions would be noted
with the
combination of crofelemer and toceranib phosphate over toceranib phosphate
alone, since
crofelemer is minimally absorbed and has been demonstrated in human studies to
have minimal
interaction on pharmacologic exposure of other drugs.
[0142]
Toceranib phosphate has been associated with severe diarrhea or GI bleeding
that
requires prompt treatment. During the masked phase of the London study, 46%
all grade and 7%
grade 3-4 diarrhea was observed on toceranib phosphate vs. 27% all grade and
3% grade 3-4
diarrhea on placebo. During the masked plus open label phases of the study,
59% any grade and
8% grade 3-4 diarrhea was observed with toceranib phosphate. Dose
interruptions and dose
reductions are considered necessary depending upon the severity of clinical
signs.
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101431
Crofelemer (SP-303) is a proanthocyanidin molecule purified from the tree
Croton
lechleri that has strong anti-secretory properties and a unique mode of action
through modulation
and normalization of hyperactivity of both cAMP-stimulated CFTR channels and
calcium-
activated chloride channels (CaCC). Crofelemer treats diarrhea without
affecting intestinal motility
in several species including dogs and humans. Crofelemer is not absorbed
systemically at the
therapeutic dose, but instead acts locally within the lumen of the
gastrointestinal tract.
[0144]
Crofelemer is approved by the FDA (CDER) for the treatment of non-
infectious
diarrhea in humans with IIIV who are being treated with anti-retrovirals. The
approval supports
chronic administration of crofelemer.
[0145]
Crofelemer is being studied to treat acute diarrhea in dogs. In a proof-of-
concept study
(CANA-001), crofelemer (2 - 4 mg/kg twice daily for three days; n = 29) or
placebo (twice daily
for three days; n = 32) was administered to dogs exhibiting acute diarrhea.
After three 24-hour
treatment periods and one 24-hour observation period, dogs treated with
crofelemer had better
resolution of diarrhea than did placebo-treated dogs. An ongoing randomized,
placebo-controlled
study (CANA-003) is designed to provide substantial evidence of effectiveness
of crofelemer for
acute diarrhea in dogs.
[0146]
A safety and tolerability study of crofelemer dosed at 2 - 4 mg/kg BID for
three days
was performed in eight dogs on chemotherapy (CANA-002). This was a two-site,
open-label, safety
study of crofelemer enteric-coated tablet in client-owned dogs with current
(active) diarrhea or a
history of CID within 90 days prior to screening (either by previously
prescribed medications to
treat diarrhea or by signs noted in their medical chart). No serious adverse
events (SAEs) were
reported during the study, and no subjects withdrew from the study for any
reason including AEs
or subject safety concerns. No clinically significant safety findings were
observed during the study.
All eight dogs had a formed stool at the last reported observation.
Study Design
[0147]
This study is a prospective, double-blinded, multi-site proof-of-concept
study
(Table 1).
Table 1. Summary of C-102 experimental design
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Group N Treatment Do se Route Frequency
Number of
(mg/kg/dose) Doses
IVP >25 Crofelemer 2-54.3 PO BID 6
doses
CP >12 Placebo 0 PO BID 6
doses
Study Overview
[0148]
This study will be conducted on an out-patient basis, sourcing dogs from
referral
and academic veterinary centers. A single protocol will be followed at all
study sites. Only
dogs that have received a minimum of three doses of Palladia brand name
tablets
manufactured by Zoetis will be eligible for this study_ Due to the possibility
that compounded
toceranib phosphate may cause more variation in the induction of diarrhea and
cause more
severe diarrhea, dogs taking compounded toceranib phosphate are not eligible
for this study.
Palladia brand name tablets may be obtained from any source that is agreeable
to the
Investigator and may include the hospital or site pharmacy, a local pharmacy
or an online
pharmacy.
[0149]
Dogs exhibiting diarrhea with a Purina Fecal Score (PFS) of 6 or 7 will be
presented
by their owner for enrollment in the study. Owners may be informed about this
clinical trial at the
time their dog begins Palladia or within approximately 1-12 weeks of starting
Palladia , although
only 20-40% of dogs treated with Palladia will develop clinically significant
diarrhea, depending
upon dosing. if their dog does develop clinically significant diarrhea] signs
while taking Palladia ,
the owner will be instmcted to take a photo of the diarrhea with their cell
phone camera and then
present their dog for a physical exam. If the Investigator assesses the dog as
meeting the enrollment
criteria for the study, enrollment will occur.
[0150]
Baseline information will include the qualifying PFS (and any photos that
the owner
has), the time that diarrhea was first noted, the number of diarrhea episodes
since the diarrhea began
(if known), review of concomitant medications within 72 hours prior to
enrollment, medical and
medication history, physical examination and collection of samples for
clinical pathology testing
(CBC, CHEM, U/A, fecal sample for ova and parasites). Dogs meeting all of the
inclusion criteria
and none of the exclusion criteria will be randomized to receive either the
Investigational
Veterinary Product (IVP) or Control Product (CP) twice daily (12 2 hours
apart) for a total of 6
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doses. The first dose should be administered orally in the hospital by the
hospital staff immediately
following completion of all the screening activities (i.e., the same day).
[0151]
The Study Period (TO ¨ T96hr) is divided into three 24-hour Treatment
Periods (TO ¨
T24hr; T>241u- ¨ T48hr; T>48hr ¨ T72hr) followed by a 24-hour Observation
Period (T>72hr ¨
T96hr), which begins 12 hours following the last treatment (administered at
T60h) and continues
for 24 hours. Therefore, each dog will be assessed by the owner for a total of
96 hours. Dosing for
each dog occurs approximately at TO, T12hr, T24hr, T36hr, T48hr and T6Ohr.
During the Study
Period, dogs live at home, and the safety and health of the dogs will be
monitored by their owner
with daily phone calls between the Investigator or trained designee. These
daily calls assess the
health status of the dog and ensure that the dog is brought to the
Investigator to assess for any
possible adverse events.
[0152]
Fecal Assessments are completed daily by the owner. Owners are asked to
complete a
daily diary in which they record the time, the color and one photo of each
bowel movement (all
elimination within a 15-minute timeframe will be considered a single bowel
movement). This
allows a single blinded person, to select the appropriate Purina Fecal Score
for each bowel
movement. Abnon-nal observations will be reported by the owner which will be
assessed by the
Investigator or trained designee each day for determination of Adverse Events.
Concomitant
medications will be reported by the owner and recorded by the study staff
during the 96-hour Study
Period.
[0153]
At the end of the Study Period or at discontinuation, dogs will undergo a
final
evaluation by the Investigator before completing the study, which will include
another physical
examination and additional clinical pathology testing (CBC, CHEM). A repeat UA
is conducted
only if the baseline results were abnormal.
[0154]
Data is captured on electronic data capture forms, with paper forms used as
a backup.
Study Procedures
Informed Consent
101551
Owners are approached by their dog's treating veterinarian/Investigator
about
participation in this study. Diarrhea associated with Palladia therapy
typically occurs within
the first few weeks of starting therapy. Therefore, owners may be approached
about this study
at the time their dog is started on Palladia treatment of a malignancy, or
within 90 days of
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starting Palladia treatment. This study may be discussed with the dog owner
in anticipation
of the dog potentially developing diarrhea, with the understanding that many
of these dogs will
not develop signs of diarrhea and ultimately will not be enrolled in the
study. Alternatively, an
owner may be presented with this study at the time of first presenting with
their dog that already
has diarrhea! signs. Owners are instructed to take a photo of the diarrhea
with their cellular
telephone or digital camera. The owners are provided with written and oral
information about
the study at that time. If an owner agrees to have their dog participate in
the study, at the time
their dog develops diarrhea per the study requirements, the owner will sign
and date an
informed consent form (ICF) prior to screening activities.
Screening
[0156]
If an owner notes that his/her dog has developed diarrhea after a minimum
of three
doses of Palladia brand name tablets, the owner will bring the dog to the
study site and the
owner and Investigator will discuss the PFS chart and review any photos of
diarrhea that the
owner may have. If the screening PFS is a 6 or 7, an informed consent must be
obtained, and
then the Investigator will determine if the dog meets the study inclusion and
exclusion criteria.
The VCOG-CTCAE v1.1 Grade for diarrhea (See Appendix 4) will also be captured
at
screening. Upon verifying that a dog meets the inclusion criteria and none of
the exclusion
criteria of the study, a medical history, assessment of previous and current
medications,
physical exam and collection of samples for clinical chemistry, hematology,
urinalysis and
fecal analysis will be obtained to establish pre-treatment (baseline) values.
Results of the above
baseline laboratory assessments will not preclude a dog from being enrolled
unless the dog
does not meet the inclusion and exclusion criteria of the protocol. Instead,
pre-treatment values
will be considered baseline findings and recorded on the appropriate CRF.
Time 0
[0157]
After the dog has passed screening it is considered eligible for enrollment
and is
enrolled in the study. The first dose of the study treatment will be
administered orally to the
dog by the study staff while the dog is still at the study site. The time
point for this first dose
administration will be recorded and noted as Time 0 (TO). Since dosing is
intended to occur
approximately every 12 hours, the second dose will be administered at home by
the owner on
the same day if the first dose was administered before 12 noon, or on the
following morning if
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the first dose was administered in the afternoon. All subsequent doses will
follow the twice
daily 12 2 hours apart dosing schedule.
Treatment Period
101581
Study treatments will be administered orally during the Treatment Period
(T0hr ¨
T72hr) twice daily (12 2 hours apart) for three 24-hour Treatment Periods.
However, the
second dose may be administered up to 18 hours after the first dose if the
first dose was
administered at the study site during the afternoon. A vehicle such as a
Greenies Pill
Pocket(TM) may be used for dosing but is not required. Study dogs must remain
on Palladia
brand name tablets and not change to compounded toceranib phosphate while on
study.
101591
For each bowel movement noted, the dog owner or his/her designee will take
a photo
and upload it to a server throughout the subsequent 96 hours from the first
dose. If the
owner/designee finds that a study dog has had an unwitnessed bowel movement, a
photo will be
taken at the time the bowel movement is observed, and entered into the EDC as
an unwitnessed
bowel movement. If multiple bowel movements are noted within a 15-minute time
period, they can
be considered as one bowel movement and the consistency will be determined
based upon the
highest PFS score observed and described.
101601
A daily phone call will be attempted by the study staff to the
owner/designee to
confirm that the data entered into the EDC by the owner is correct. Every
effort will be made by
the site staff to speak to the owner/designee at least once within each 24
hour interval. If the site is
unsuccessful, the site will note this in the EDC; however, this inability to
make telephone contact
will not be considered a protocol deviation.
[0161]
Upon speaking with the owner/designee, any observations noted by the
owner/designee will be assessed by the Investigator as a possible Adverse
Event. Additionally, any
new medications given to the dog by the owner will be entered into the Prior
and Concomitant
Medication page.
Observation Period
[0162]
During the Observation Period (T>72hr ¨ T96hr), the owner will continue to
photograph their dog's bowel movements but no further dosing of test articles
will be done. A
daily phone call will be attempted by the study staff to the owner/designee to
confirm that the
data entered into the EDC by the owner is correct. Any observations noted by
the
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owner/designee will be assessed by the Investigator as a possible Adverse
Event. Additionally,
any new medications given to the dog by the owner will be entered into the
Prior and
Concomitant Medication page. The Observation Period will be used to evaluate
persistence of
effect or recurrence of diarrheal signs upon withdrawal of IVP.
Final Evaluation (End of Study Procedures)
[0163]
A dog will be considered to have completed the study upon successful
completion of
this visit and its procedures. A final physical exam will be conducted at the
end of the Observation
Period, or within 3 business days of the end of the Observation Period or at
discontinuation (if a
dog is discontinued, the site staff will attempt to have the owner bring the
dog in to complete this
visit. If this is not possible, the dog will be considered lost to follow up).
Samples will be collected
for clinical chemistry, hematology and urinalysis (urinalysis will be repeated
only if the initial
sample had clinically significant abnormalities). A final VCOG-CTCAE v1.1
Grade for diarrhea
will also be assessed at the same time. The Investigator or co-Investigator
will meet with the dog
owner to review and confirm for accuracy the data in the daily diary, and ask
about recrudescence
of diarrheal signs with emphasis on the color and the frequency of any bowel
movements following
the completion of IP dosing.
[0164]
The study may be terminated (i.e. not completed) at any time at the
discretion of the
Sponsor. The reason for termination will be documented in the study records.
Study Discontinuation
[0165]
A dog may be discontinued from the study by its owner or by the
Investigator for any
reason and at any time.
[0166]
In the event a dog discontinues the study, the same procedures should be
conducted
that are done at the Final Evaluation. If the reason for discontinuation is
due to an AE, this will be
documented on the AE form.
Adverse Events
[0167]
Any clinically significant changes from the baseline (before treatment with
IPs) in the
dog's signs, behavior and fecal attributes will be reported by the dog's
owner. Any clinically
significant changes from the baseline in the dog's physical exam or laboratory
values will be noted
by the Investigator on the Adverse Event (AE) Form, as appropriate. The
assessment of adverse
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events will also be ascertained via the daily phone calls between the dog
owner and the Investigator
or trained designee. Adverse events will be graded according to the ABON
System.
Number of Animals
[0168] The enrollment target is at least 25 evaluable cases
across all sites on IVP for the
primary evaluation of efficacy. At least 12 additional evaluable cases on CP
will be enrolled to
allow for comparison of efficacy results between IVP and CP. The ratio of IVP
to CP-treated dogs
will be approximately 2:1. The Study will use at least three geographically
diverse sites across the
contiguous United States. The maximum enrollment for any given site is 40% of
the total number
of evaluable cases in the study.
[0169] As this is a pilot study, the sample size estimation is
not based on statistical
considerations. An evaluable sample size of at least 25 evaluable cases on WP
and 12 evaluable
cases on CP is considered sufficient for the purposes of this study.
Blocking Factors
[0170] No blocking factors will be utilized in this study.
Randomization Procedures
[0171] A separate randomization list will be created for each
study site by the Study
Statistician. The Statistician will randomly allocate study treatments at a
ratio of approximately 2:1
IVP:CP.
Blinding Procedures
[0172] This is a randomized, double-blinded study, therefore the
Sponsor, the owner, the
Investigator and all site study staff will be blinded to treatment. Owners
will additionally be blinded
to the previous recordings of their dog's bowel movements in the online data
capture system so as
not to influence their subsequent recording of bowel movements.
INVESTIGATIONAL PRODUCTS (IF)
Investigational Veterinary Product (IVP)
Proprietary Name: Crofelemer (CAS Number: 148465-45-6)
[0173] The IVP formulation will be manufactured according to the
principles of GMP. A
certificate of analysis for each formulation will be included in the final
study report. The
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manufacturing site name and address, percent composition, lot/batch number,
and expiry/retest date
will be documented.
[0174]
In addition to the active pharmaceutical ingredient (API) of crofelemer,
the inactive
ingredients include microcrystalline cellulose, croscarmellose sodium,
colloidal silicon dioxide and
magnesium stearate. The enteric-coating ingredients include ethylacrylate and
methylacrylate
copolymer dispersion, talc, triethyl citrate, xanthan gum, titanium oxide,
propyl paraben and methyl
paraben.
Dosage Form
101751
The IVP will be supplied as unscored enteric-coated white tablets
containing 125 mg
of crofelemer.
Control Product (CP)
[0176]
The CP will be manufactured according to the principles of GMP. A
certificate of
analysis will be included in the final study report. The manufacturing site
name and address, percent
composition, lot/batch number, and expiry/retest date will be documented.
[0177]
The formulation of the CP will match that of the IVP but will not contain
the active
pharmaceutical ingredient (API).
Dosage Form
101781
The CP will be supplied as unscored enteric-coated white tablets of the
same size as
the TVP containing 0 mg crofelemer.
Dose Justification
[0179]
The dose for this study was based on data obtained from a pilot study that
assessed the
clinical effectiveness of crofelemer (SP-303) in alleviating clinical signs
associated with secretory
diarrhea in dogs (CANA-001) and the wide margin of safety established in 30-
day (WIL-288006)
and 9-month (W1L-288022) toxicity studies. Chronic safety of crofelemer in
dogs was studied in a
9-month study during which tablets were administered in capsules once daily, 7
days per week, for
273 or 274 days to three groups of beagle dogs. Dosage levels were 50, 175 and
600 mg/kg/day,
plus a concurrent control group. Based on the results of this study, the no-
observed-adverse-effect
level (NOAEL) for oral (capsule) administration of enteric-coated crofelemer
tablets to dogs for
273 or 274 consecutive days was 50 mg/kg/day. At this dose level, findings
were restricted to
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infrequent gastrointestinal signs. The results at the higher dosages (175 and
600 mg/kg/day)
suggested that the primary adverse effect was gastrointestinal irritation,
which in turn caused a
variety of secondary effects (decreased body weight and food consumption,
diarrhea, emesis,
changes in hematology and serum chemistry parameters, decreased
thyroid/parathyroid weights
and/or macrophage infiltration with the presence of basophilic bodies and the
uptake of pigment in
the lymph nodes, gastrointestinal tract and liver). Thus, the no effect level
is estimated to be
between 50 and 175 mg/kg/day.
Safety Precautions for Study Personnel
[0180]
Standard precautions for the safety of study personnel will be followed
during the
study. There are no special precautions for the dog owner to be aware of when
administering the
IPs. A safety data sheet (SDS) will be provided to the Site with each shipment
of IPs.
INVESTIGATIONAL PRODUCTS ADMINISTRATION
[0181]
A study initiation meeting will be held for each participating study site
(either in-
person or by webinar) to ensure that the Investigator and associated study
personnel have a
thorough understanding of the procedures and can explain such procedures to
the dog owner
regarding administration of IPs and collection of data.
[0182]
At the time of study enrollment for each dog, the dog will be weighed and
the
Investigator will determine the dose from the following table:
Table 2: Dosage based on body weight
Body Weight Dose
to 137 lb. (2.3 to 62 kg) 1 tablet BID
[0183]
The first dose of the study treatment will be administered orally to the
dog by the study
staff while the dog is still at the study site. Dogs will then be dosed at
home orally twice daily (12
2 hours apart) by their owner or designee thr the remainder of the study. The
dog owner will
record the time of dose administration during the study. A vehicle such as a
Greenies Pill PocketTM
may be used or a small ball of food, but is not required. After the dose has
been administered, the
dog will be observed briefly to ensure the tablet(s) have been swallowed and
not spit out.
101841
If a dog vomits within one hour after dosing, this observation will be
recorded by the
owner and the dog should be re-dosed with the same number of new tablets. If a
dog vomits more
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than one hour after dosing, this observation should be recorded by the owner,
but the dog should
not be re-dosed at that time and will be considered dosed for that time point.
If a dog vomits more
than once after dosing, the dog should be discontinued from the study. The
Investigator or designee
will record each vomiting episode on the Adverse Event CRF.
Table 3: Test Animals And Case Identification
CATEGORY DESCRIPTION
Species Canis familiaris (domestic dog)
Source Client-owned animals
Breed Any
Body Weight 5 to 137 lb. (2.3 to 62 kg)
Age >1 year of age
Gender Male or female
Reproductive Status Intact, spayed or neutered. No pregnant of
lactating females
[0185] A unique case number will be assigned to each dog
enrolled in the study but no case
number will be assigned to dogs whose owners sign an ICF but whose dogs are
not formally
screened and enrolled. At each site, case numbers will consist of a two-digit
site identification
number followed by a three-digit dog identification number. IPs will be
dispensed to the owners
based on the sequential numbering of each enrolled dog.
EFFECTIVENESS VARIABLES
Primary Endpoint
Resolution of Diarrhea
[0186] Treatment success (resolution of diarrhea) will be
defined as any dog that develops
formed stool (PFS of 1, 2, 3, 4 or 5) and maintains formed stool (i.e. ¨ no
PFS of 6 or 7) or has no
stool, for at least 24 hours during the Treatment Period (TOlu ¨ T7210.
Therefore, resolution of
diarrhea must occur by T48hr.
[0187] A treatment failure will be defined as any dog that does
not achieve a formed stool
(PFS of 1, 2, 3, 4 or 5) for at least 24 hours during the Treatment Period
(T0hr ¨ T72hr), and/or any
of the following is experienced:
[0188] 1. Withdrawal of Owner Consent due to perceived lack of
efficacy
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101891 2. Adverse event that prevents its continued
participation in the study
Secondary Endpoints
Resolution of Diarrhea over the entire Treatment Period
[0190] Treatment success (resolution of diarrhea) will be
defined as any dog that develops
formed stool (PFS of 1, 2, 3, 4 or 5) and maintains formed stool (i.e. ¨ no
PFS of 6 or 7) or has no
stool, during the Treatment Period (T0hr ¨ T72hr).
101911 A treatment failure will be defined as any dog that does
not achieve a formed stool
(PFS of 1, 2, 3, 4 or 5) during the Treatment Period (T0hr ¨ T72hr), and/or
any of the following is
experienced:
[0192] 1. Withdrawal of Owner Consent due to perceived lack of
efficacy
[0193] 2. Adverse event that prevents its continued
participation in the study
12.2.2 Comparison of Diarrhea VCOG-CTCAE v1.1 Grade at Screening and at Final
Evaluation
[0194] The VCOG-CTCAE v1.1 Grade for diarrhea taken at Screening
for each dog will be
compared to the VCOG-CTCAE v1.1 Grade for diarrhea taken at T72h, T96h and at
Final
Evaluation. The change in Grade between Screening and T72h, T96h and the Final
Evaluation will
be compared between the dogs that received 1VP and the dogs that were given
CP.
Time to Last Unformed Stool
[0195] Time to the last unformed stool (TLUS) will be determined
by the elapsed time
between the first dose (T0hr) and the last unformed stool (PFS of 6 or 7)
during the 72-hour
Treatment Period only (T0hr ¨ T72hr).
Frequency of Loose or Watery Diarrhea
[0196] The frequency of loose or watery diarrhea (PFS of 6 or 7)
will be determined by the
total number of unformed stool episodes (PFS of 6 or 7) occurring during the
Study Period: TOhr -
T96hr. (To be analyzed in 24-hour periods.)
Safety
[0197] Safely assessments will be made on the basis of signs
reported by the owner as well as
physical exam findings made by the Investigator and any abnormalities in
laboratory work
throughout the study.
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Fecal Assessment
Purina Fecal Score (PFS)
[0198]
Using the Purina Fecal Scoring (PFS) Chart, a PFS will be obtained at
screening via
communication with the dog owner and ideally with one or more photos of the
dog's bowel
movements. Each daily evaluation of PFS will be described by the dog owner and
reviewed by
telephone between the dog owner and the Investigator or trained designee.
[0199]
Each fecal assessment will only consider new bowel movements produced since
the
previous fecal assessment. If the dog has experienced two or more bowel
movements during a 15-
minute period, then these bowel movements will be collectively noted and a
single PFS assigned,
with the highest PFS numerical score appropriate for the bowel movements
recorded on the CRF.
Number of Bowel Movements
[0200]
Throughout each day during the Study Period, the dog owner/designee will
record each
episode of bowel movements with a photo uploaded onto the eCRF. If the dog has
experienced two
or more bowel movements during a 15-minute period, then these bowel movements
will be
collectively noted as one event. After each episode of bowel movements and
recording of the time
and photo, the next episode of bowel movement(s) will be considered a separate
event.
STATISTICAL ANALYSIS
[0201]
All statistical tests will be 2-sided. Effectiveness will be evaluated at a
5%
significant level. All tests will be performed using SAS version 9.3 or
higher.
Statistical Analysis Populations
[0202]
As this is a proof-of-concept study, the effectiveness analyses will
include all dogs
that were randomized and received at least one dose of the study medication
(safety
population/Intent-to-Treat (ITT) population).
Effectiveness
Primary Effectiveness Variable: Resolution of Diarrhea
[0203]
The primary effectiveness variable 'resolution of diarrhea' will be
dichotomized
(success vs failure) and the proportion of success between the treatment
groups during the treatment
period (T0hr-72hr) will be compared. Possible differences between treatment
groups will be
assessed by a generalized linear mixed model (using SAS Proc GUMMDC assuming
a binomial
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distribution and logit link). The model will include the fixed effect of
Treatment (WP or CP), Site
and Treatment by Site interaction as random effects with baseline PFS as a
covariate.
[0204]
Treatment effectiveness will be concluded if there is a significant
difference in the
success rates between the two treatment groups and percent success is higher
in the IVP group
compared with the CP group.
Secondary Effectiveness Variables
Resolution of Diarrhea over the entire Treatment Period
[0205]
The effectiveness variable 'resolution of diarrhea over the entire
Treatment Period'
will be dichotomized (success vs failure) and the proportion of success
between the treatment
groups during the treatment period (T0hr-72hr) will be compared. Possible
differences between
treatment groups will be assessed by a generalized linear mixed model (using
SAS Proc
GLIMMIX assuming a binomial distribution and logit link). The model will
include the fixed effect
of Treatment (IVP or CP), Site and Treatment by Site interaction as random
effects with baseline
PFS as a covariate.
[0206]
Treatment effectiveness will be concluded if there is a significant
difference in the
success rates between the two treatment groups and percent success is higher
in the IVP group
compared with the CP group.
Comparison of Diarrhea VCOG-CTCAE v1.1 Grade at Screening and at Final
Evaluation
[0207]
The change in Grade between Screening and the Final Evaluation will be
compared
between the dogs that received IVP and the dogs that were given CP using
analysis of covariance
(ANCOVA) modeling with treatment as a fixed effect, and site and treatment by
site interaction as
random effects with baseline PFS as a covariate.
Time to Last Unformed Stool
102081
Time to last unformed stool (TLUS) will be presented using Kaplan-Meier
methods
and compared using a log-rank test. Dogs without a formed stool (score of 6 or
7) will be censored
at the time of the last unformed stool. For dogs with only formed stool
(scores of 1, 2, 3, 4 or 5) or
no stool, the time of occurrence for TLUS will be set to zero
Frequency of Diarrhea
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102091 ANCOVA modeling with treatment as a fixed effect, and
site and treatment by site
interaction as random effects with baseline PFS as a covariate will be
employed to compare the
frequency of diarrhea between IVP and CP.
Example 2: A Study of Diarrhea Prevention and Prophylaxis With Crofelemer in
HER2
Positive Breast Cancer Patients (Human Subjects)
[0210] Study Design: Chemotherapy induced diarrhea is seen in up
to 40-80% of patients
receiving this treatment for HER2 positive locally advanced or metastatic
breast cancer. This
diarrhea can significantly impact a patient's quality of life and ability to
tolerate chemoianti-
HER2 therapy. This study will look at the efficacy of the drug crofelemer in
preventing diarrhea
in breast cancer patients receiving trastuzumab, pertuzumab, and docetaxel or
paclitaxel with
or without carboplatin (chemotherapeutic regimens referred to as THP and
TCHP).
[0211] Protocol:
[0212] Approximately 46 patients will be randomly assigned to
the treatment arm or the
control. Patients on the treatment arm will take one tablet of crofelemer
twice a day (each
tablet is 125 mg), to be swallowed whole without chewing or crushing, during
cycles 1-2 of
chemotherapy with THP or TCHP. Patient will be monitored off crofelemer during
cycle 3 of
chemotherapy. Patients on the control arm will be on the study for cycles 1-3
of THP or TCHP.
Patients on the control arm will not receive crofelemer at any time on this
study. A cycle can
comprise an infusion of the prescribed THP or TCHP followed by a 21 day
duration. See
Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus Trastuzumab plus Docetaxel
for Metastatic
Breast Cancer. N Engl J Med. 2012;366:109-119).
[0213] Eligibility Criteria:
[0214] Patients eligible for the study much be as follows:
Willing and able to provide
written informed consent; man or woman >18 years of age; pathologically
confirmed diagnosis
of HER2 positive breast cancer of any stage (previous treatment is allowed
without limits on
lines of prior therapy); scheduled to receive at least 3 consecutive cycles of
THP or TCHP;
have a performance status of 0-2 according to the ECOG scale; have a negative
pregnancy test
at time of informed consent for women of childbearing potential; have a Left
Ventricular
Ejection Fraction (LVEF) greater or equal to 50% at baseline as determined by
either ECHO
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or MUGA; and be able to read, understand, follow the study procedure and
complete
crofelemer, rescue medication, and bowel movement diaries. Patients with brain
metastases
(including concurrent steroid treatment) are allowed on this study. Patients
not eligible for the
study include women who are breastfeeding; those with ongoing irritable bowel
syndrome
(IBS) or colitis (including but not limited to ulcerative colitis, Crohn's
disease, microscopic
colitis, etc.); those using investigational drugs within 3 weeks of signing
consent or foreseen
use during the study, chemotherapy, trastuzumab, or pertuzumab within the past
3 weeks,
laxatives within the past 7 days, chronic laxatives (> 30 consecutive days),
or anti-dian-heal
agents (including but not limited to loperamide, octreotide, bismuth, tincture
of opium,
atropine. probiotics in any form other than food) within the past 7 days,
antibiotics within the
past 7 days. Patients are also excluded if they have any of the following: any
type of ostomy;
total colectomy; fecal incontinence; ongoing radiation induced diarrhea or
constipation or
planned radiotherapy to the abdomen or pelvis while on study; active systemic
infection
requiring ongoing intervention, including but not limited to oral and
intravenous antibiotics,
anti-fungals, anti-parasites, anti-virals; major abdominal or pelvic surgery
within the past 6
months; inadequate organ function for starting THP or TCHP, which may include
the following
laboratory results within 28 days prior to signing consent. total bilirubin >
upper limit of normal
(ULN) (unless the patient has documented Gilbert's syndrome); serum creatinine
> 2.0 mgidL
or 177 unaol/L; or AST (SGOT) and ALT (SPGT) >2.5 ULN.
[0215] Effectiveness Variables:
[0216] Primary outcome measures All-grade diarrhea [Time Frame:
29 months]:
Incidence of all grade diarrhea lasting 2 or more consecutive days during
cycles 1 and 2 of
chemotherapy
[0217] Secondary outcome measures as follows:
[0218] Diarrhea any grade [Time Frame: 29 months] Incidence of
diarrhea of any grade,
as measured by CTCAE v4.0, by cycle and by stratum
[0219] Grade 3-4 diarrhea [Time Frame: 29 months] Incidence of
diarrhea of grade 3-4,
as measured by CTCAE v4.0, by cycle and by stratum
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[0220]
Diarrhea onset [Time Frame: 29 months] Time to onset of first episode of
diarrhea
of any grade, overall and by stratum
[0221]
Diarrhea duration [Time Frame: 29 months] Duration (days) of any grade
diarrhea,
defined from day 1 to day 21, by cycle in which the episode started and by
stratum
[0222]
Duration grade 3-4 diarrhea [Time Frame: 29 months] Duration (days) of
grade 3-
4 diarrhea, defined from day 1 to day 21, by cycle in which the episode
started and by stratum
102231
Anti-diarrheal medications iTime Frame: 29 months] Use of anti-diarrheal
medications (other than study drug), by cycle and grade
[0224]
FACIT-D total score [Time Frame: 29 months] Quantitative FACIT-D total
score,
collected day 1 of each cycle and at the time of study completion, by cycle
and by stratum
[0225]
FACIT-D diarrhea score [Time Frame: 29 months] Quantitative FACIT-D
diarrhea
subset (DS) score, by cycle and by stratum
[0226]
Stool frequency and consistency [Time Frame: 29 months] Frequency table of
stool
consistency, as measured by the Bristol Stool scale, by cycle stratum between
treatment groups
[0227]
All publications, patents, and patent applications cited herein are hereby
incorporated herein by reference in their entirety.
Vkainple 3 A 'Study or the Safety and Effeet000.000100Ø100Ø000:WneatWoOtof
Nerafinib-Induced Diarrhea in Beagle DOgs
[0228]
Neratinib (Nerlynxk) is an orally available, 6,7-di-substituted-4-
anilinoquinoline-3-
carbonitrile irreversible inhibitor of the HER-2 receptor tyrosine kinase
(also binds EGFR and
HER4) with potential antineoplastic activity, and is indicated for the
extended adjuvant treatment
of adult patients with early stage HER2-positive (overexpressed/ampli tied)
breast cancer, to follow
adjuvant trastuzumab-based therapy and also for metastatic HER2-positive
breast cancer.
[0229]
The recommended dose for neratinib is 240 mg, orally once daily. Dose
reduction
intervals of 40 mg [to a minimum dose of 120 mg once daily] and dose
interruptions (cessation of
neratinib for up to three weeks) may be utilized, if needed, to manage adverse
reactions.
Antidiarrheal prophylaxis is initiate using loperamide with the first dose of
neratinib and continued
during first 2 cycles (56 days) of treatment. This approval was based upon a
multicenter,
randomized, double-blind, placebo-controlled study (ExteNET).
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102301
It is not expected that any increase in adverse reactions would be noted
with the
combination of crofelemer and neratinib over neratinib alone, since crofelemer
is minimally
absorbed and has been demonstrated in human studies to have minimal
interaction on
pharinacologic exposure of other drugs.
102311
Severe diarrhea and se quelae, such as dehydration, hypotension, and renal
failure, have
been reported during treatment with neratinib. Diarrhea was reported in 95% of
ncratinib-treated
patients in ExteNET. Grade 3 diarrhea occurred in 40% and Grade 4 diarrhea
occurred in 0.1% of
patients. The majority of patients (93%) had diarrhea in the first month of
treatment, the median
time to first onset of Grade > 3 diarrhea was 8 days (range, 1-350), and the
median cumulative
duration of Grade > 3 diarrhea was 5 days (range, 1-139).
Obj ective
102321
The objective of this study was to evaluate the effects of crofelemer in
reducing the
incidence and severity of diarrhea following daily oral neratinib dosing for
28 days in healthy
female dogs, without the concomitant use of loperamide.
Methods
102331
Twenty-four healthy adult female beagle dogs with a mean weight of 7.2 kg
(range
6.4 ¨ 8.5 kg) were randomized into three groups of 8 dogs each. All dogs
received oral neratinib
once daily 40 mg/day for the first 5 days; which was escalated to 80 mg/day
from day 6 for the
remainder of the 28-day period to induce diarrhea as evidenced by the passage
of loose/watery
stools.
102341
Group 1 dogs represented the control group that received daily oral
neratinib tablets
with placebo crofelemer capsules administered orally four times a day (QID)
over the 28 day-
period. Group 2 received daily oral neratinib tablets with daily crofelemer
125 mg delayed-
release tablet (MytesiO) and crofelemer capsules administered orally QID over
the 28 day-
period. Group 3 dogs received daily oral neratinib tablets with daily
crofelemer 125 mg
delayed-release tablet (Mytesik) and crofelemer capsules administered orally
QID over the 28
day-period.
Table 4. Summary of experimental design
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Group N Treatment Dose Route Frequency Duration
(mg/dose)
(days)
1 8 Placebo 0 PO QID 28
2 8 Crofelemer 125 PO QID 28
3 8 Crofelemer 125 PO BID 28
[0235]
Dogs were evaluated twice daily for stool consistency and number of bowel
movements, which were scored according to a 7-Point Purina Fecal Stool Scale
which is
analogous to the human Bristol Stool Form Score. Dogs with mild or moderate
dehydration
were given subcutaneous fluids and/or a single-day neratinib dose reduction or
drug holiday to
ameliorate their diarrhea severity. No dogs in any treatment group received
anti-motility drugs
like I operamide at any time to reduce the diarrhea incidence or severity
during the 28-day
treatment period.
[0236]
The pharmacological effects of crofelemer on reducing diarrhea severity
following
neratinib oral dosing were assessed by: a) Determining the proportion of -
responder" dogs
defined as dogs with <7 watery stool for at least 2 weeks of the 4-week
treatment period; b)
Evaluating the average number of watery stools per week in each treatment
group; c)
Comparing the stool consistency determined by the average fecal scores per
week across all
treatment groups versus placebo; d) Comparing the average number of watery
stools per week
per dose of neratinib across all treatment groups and placebo; e) Comparing
the average fecal
score per week, per dose of neratinib across all treatment groups and placebo;
and f) Evaluating
the changes in body weight, clinical chemistry, and hematologic parameters
across all
treatment groups and placebo.
[0237]
Summary statistics were computed at each week and pair-wise p-values were
computed via t-test to determine differences for the crofelemer-treated groups
from the control
group. Analysis of covariance (ANCOVA) was conducted using baseline fecal
scores as a
covari ate. Least Squares Mean (LSM) results were adjusted for baseline
scores.
Results
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[0238] There was no
significant difference in body weights, clinical chemistry, and
hematologic parameters for any of the treatment groups at any time of the
during the 28-day
treatment period of this study.
[0239] Three of
eight (3/8, 37.5%) control dogs had < 7 watery stools per week for at least
2 of the 4-week period. By contrast, 7 of 8 (87.5%) crofelemer QID-treated
dogs and 6 of 8
(75%) crofelemer BID-treated dogs had <7 watery stools per week for 2 of the 4-
week
treatment period. Logistic regression analysis showed that the control group
was significantly
different from either crofelemer QID (Odds Raio = 17.8, p-value =0.02) and/or
crofelemer BID
(Odds Ratio = 26.8, p-value = 0.03). Dogs receiving crofelemer QID were 26.8
times more
likely to be "responders" than dogs enrolled in the control group.
Table 5. Examples of responder and non-responder dogs
Non-responder: Total watery stools 42
Week 1 Week 2
1;::........., 2 ...........*:..,....., 4 ..........4:::...].....
6 ..........g 8 .:g.:.:.:.:.:. 10 .: 11 . 12
:.:.....:.?...,14: ......... 14
/ W
3 4 .WW.' 7 8 lgri4igi Ii 12 .'izr i y.::: 15 1612::=M. 19 20 iigit::::M
23 24 =]4;C:]26. 27 28 Observe
-"-Mi ----- ''--
g'i]i.:''''-' 2x/day
2 7
4 ]0Ji : ::0 7 4 M 'T 7 7 7::,. V 7 7 '#:': M 7 7 1.7 "Z 7 3 ':t % 7 7
Fecal
Scores
watery stools per week 13 watery stools per week
Week 3 I_ Week 4 --
I 5.,.,.,. 16 ......::Ag.::::.:.. 18 .....,:iM . 20
.,:a,l : 22 ..,:::::A*.,... 24 .. 1 26 .,...:17.......
28 .....
,. ., .... ¨....*, , .. .
29 1]R 31 32 MIIAC: 35 36 10=:0:C 39 40 -.4.k 4 .!-2 . 43 44 :w 0;T 47 48
i.?.0: A 51 52 ,53.54 55 56 Observe
2x/day
.
7 1.:::; '7 7 4::::::::1:: 7 7 1:::
:::::: 5 7 1::: ::1:: : 7 4 M: Z: 2 2 :1::]: ]2: 7 3 4:: .:I 7
5 Fecal
.,.:*:::.::...: == :i:: ::::::% :::*: ::::::::
.:.:.:- =::::: :::.:::
Scores
12 watery stools per week 7 watery stools per
week
Responder: Total watery stools 29
Week 1 Week 2
¨7. ¨
1,,,,:.: 2 :,...:.:.:.ii::...:, 4 .:.:.:.:a:.:....,. 6
,,,,,,i7i::.:.:.:. 8 .:.:...:. 0 : 10 1.õ,.... I I . :.:.:
12 :i:3 14
14
1
W: 3 4-:1W:' 7 8 '''!g!''''''r I I Ir. 14 1 ¨ 1 .:.1 wi'.: I 2
::1.i:.4:=: 2 2 '7.,.r'''' 2¨ 28 Observe
ii1i]i l 2 A 5 6 '0i: 9 0
<,ii 3 4567 2x/day
2 :i:i:i 2 5 :0.:E* 6746 ]* W 7 7 :10]] 7 6 777777 2
Fecal
Scores
6 watery stools per week 12 watery stools per
week
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Week 3 1 Week 4
,
16_ 18 . 20 22 24 ....... 25 .. 26 . .
28
$:.= 3 3 -*TA.. 3 3 -rlf 3 4 4 4 4 4 4 4 4 4 4 A.: 5 5 3 5 5 5 Observe
?r 1 2 gir.!!!A 5 6 7:$!:: 9 0 1 2 3 4 :VP 7 8 W.: V 1 2 :oz,x, 5 6 2v/day
675642777242571 2 1 27 ]k :]2]:
2 2 Fecal
Scores
NNatery stools per week 4 watery stools per week
102401
The average number of watery stools per week for week 1 and at end of
treatment
for the entire 4-week treatment period for placebo and crofelemer-treated BID
and QID groups
are shown in Table 6. The average number of total watery stools over the
entire 28-day period
were significantly lower for crofelemer BID and QID groups when compared to
control dogs
(p<0. 05).
Table 6. Number of watery stools (WS) per week by treatment group
Treatment Group # of WS/wk - p-value 14 of WS/week - p-
value
Weekl Overall
Control 7.54 8.71
QID 4.35 0.048 5.74 0.021
BID 4.36 0.043 5.96 0.028
WS, watery stool; wk, week.
[0241]
Stool consistency as measured by the average fecal scores per week
demonstrated
that crofelemer QID and BID groups had more formed stools while the control
group dogs had
more loose/watery stools. Results by treatment group are shown in Table 7.
There was a trend
toward fewer neratinib dose reductions in the crofelemer BID group when
compared to the
control group (p<0.1). The average number of neratinib dose reduction per week
by treatment
are shown in Table 8.
Table 7. Average fecal scores (FS) per week by treatment group
Treatment group Average fecal scores per p-value
week- Overall
Control 5.09
BID 3.85 0.10
QID 4.12 0.033
Table 8. Number of neratinib dose reductions per week by treatment group
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Treatment group Average number of weekly p-value
dose reductions of neratinib
- Overall
Control 4.87
BID 4.31 0.12
QID 4.26 0.009
102421
There was a significant reduction in the average number of watery stools
per week
per neratinib dose during week 1 as well as over the entire 28-day treatment
period for
crofelemer BID dogs compared to control. Results for week 1 and overall
results are shown in
Table 9.
Table. 9 Average number of watery stools (WS) per week per neratinib dose by
treatment
group
Treatment Group Avg. WS per p-value # of WS/week - p-
value
week per Overall
neratinib dose
¨ Week 1
Control 6.20 7.22
QID 3.44 0.034 4.72 0.052
BID 3.38 0.026 4.68 0.043
[0243]
Stool consistency as measured by the average fecal scores per week per
neratinib
dose showed significantly more formed stools for crofelemer QID and BID groups
over the
entire 28-day treatment period compared to control group. The results are
shown in Table. 10.
Table 10. Average fecal scores per week per neratinib dose by treatment
Treatment group Average fecal scores per p-value
week per neratinib dose -
Overall
Control 5.09
BID 3.85 0.010
QID 4.12 0.033
Conclusions
[0244]
This study demonstrated that crofelemer, a first-class anti-secretory anti
di arrheal
drug, significantly reduced the incidence and severity of diarrhea associated
with daily oral
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administration of neratinib, a kinase inhibitor indicated for adjuvant
treatment of adult patients
with early stage Her-2 positive breast cancer, following trastuzumab-based
therapy. This non-
clinical study in female dogs was conducted without the concomitant
administration of
loperamide (an opiate) and demonstrated that crofelemers' physiological
mechanism of action
of chloride ion channel regulation results in a significant reduction in
diarrhea incidence and
severity following neratinib dosing.
[0245]
Crofelemer also demonstrated significant improvement in the number of
"responders- as defined by a threshold of < 7 watery stools per week for at
least 2 weeks of the
4-week treatment period.
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