U.S. patent application number 15/178299 was filed with the patent office on 2016-10-06 for methods of treating a bruton's tyrosine kinase disease or disorder.
The applicant listed for this patent is Celgene Avilomics Research, Inc.. Invention is credited to Heather Lounsbury, Jay M. Mei, Bruce A. Silver, Kathryn Stiede, William Frederick Westlin, III, Steven Richard Witowski.
Application Number | 20160287588 15/178299 |
Document ID | / |
Family ID | 48168552 |
Filed Date | 2016-10-06 |
United States Patent
Application |
20160287588 |
Kind Code |
A1 |
Witowski; Steven Richard ;
et al. |
October 6, 2016 |
METHODS OF TREATING A BRUTON'S TYROSINE KINASE DISEASE OR
DISORDER
Abstract
The present invention provides methods of treating, stabilizing
or lessening the severity or progression of a disease or disorder
associated with BTK.
Inventors: |
Witowski; Steven Richard;
(Cumming, GA) ; Westlin, III; William Frederick;
(Boxborough, MA) ; Lounsbury; Heather;
(Framingham, MA) ; Stiede; Kathryn; (Hollis,
NH) ; Silver; Bruce A.; (Dunkirk, MD) ; Mei;
Jay M.; (North Wales, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Celgene Avilomics Research, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
48168552 |
Appl. No.: |
15/178299 |
Filed: |
June 9, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13661678 |
Oct 26, 2012 |
9364476 |
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15178299 |
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61660319 |
Jun 15, 2012 |
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61649450 |
May 21, 2012 |
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61618347 |
Mar 30, 2012 |
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61604780 |
Feb 29, 2012 |
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61593056 |
Jan 31, 2012 |
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61592351 |
Jan 30, 2012 |
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61569475 |
Dec 12, 2011 |
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61552936 |
Oct 28, 2011 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/505 20130101;
A61K 9/4866 20130101; A61P 35/02 20180101; A61K 9/0053 20130101;
A61K 31/506 20130101; A61P 43/00 20180101; A61P 35/00 20180101 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61K 9/48 20060101 A61K009/48; A61K 9/00 20060101
A61K009/00 |
Claims
1. A method of treating, stabilizing or lessening the severity or
progression of a disease or disorder selected from the group
consisting of B-cell non-Hodgkin's lymphoma, chronic lymphocytic
leukemia and Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutically
acceptable composition comprising
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide (1): ##STR00003##
2. The method according to claim 1, wherein the B-cell
non-Hodgkin's lymphoma is indolent.
3. The method according to claim 2, wherein the B-cell
non-Hodgkin's lymphoma is selected from follicular lymphoma and
marginal zone lymphoma.
4. The method according to claim 1, wherein the B-cell
non-Hodgkin's lymphoma is aggressive.
5. The method according to claim 4, wherein the B-cell
non-Hodgkin's lymphoma is selected from diffuse large B-cell
lymphoma and mantle cell lymphoma.
6. The method according to claim 1, wherein the pharmaceutically
acceptable composition is formulated as an oral dosage form.
7. The method according to claim 6, wherein the pharmaceutically
acceptable composition is administered once a day.
8. The method according to claim 6, wherein the pharmaceutically
acceptable composition is administered twice a day.
9. The method according to claim 7 or 8, wherein the
pharmaceutically acceptable composition is administered for at
least one 28-day cycle.
10. The method according to claim 9, wherein the patient has failed
at least one prior therapy.
11. The method according to claim 1, wherein Compound 1 is in the
form of a benzenesulfonic acid salt.
12. The method according to claim 11, wherein the composition
comprises from about 10% to about 50%
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate.
13. The method according to claim 12, wherein the composition
comprises about 10%
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-yl-
amino)phenyl)acrylamide besylate.
14. The method according to claim 12, wherein the composition
comprises about 42%
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-yl-
amino)phenyl)acrylamide besylate.
15. The method according to claim 1, wherein the composition
comprises from about 5% to about 15% by weight of wetting
agent.
16. The method according to claim 12, wherein the composition
comprises about 10% by weight of wetting agent.
17. The method according to claim 15 or 16, wherein the wetting
agent is selected from poloxamer, polyoxyethylene ethers,
polyoxyethylene sorbitan fatty acid esters polyoxyethylene fatty
acid esters, polyethylene glycol fatty acid esters, polyoxyethylene
hydrogenated castor oil, polyoxyethylene alkyl ether, polysorbates,
cetyl alcohol, glycerol fatty acid esters, polyoxymethylene
stearate, sodium lauryl sulfate, sorbitan fatty acid esters,
sucrose fatty acid esters, benzalkonium chloride, polyethoxylated
castor oil, and docusate sodium.
18. The method according to claim 17, wherein the wetting agent is
a poloxamer.
19. The method according to claim 18, wherein the poloxamer is
poloxamer 407.
20. A method of preventing, treating, stabilizing or lessening the
severity or progression of a disease or disorder selected from the
group consisting of B-cell non-Hodgkin's lymphoma, chronic
lymphocytic leukemia and Waldenstrom's macroglobulinemia, the
method comprising administering to a patient in need thereof a
composition comprising a therapeutically effective amount of
Compound 1, wherein the therapeutically effective amount is about
125 mg to about 1250 mg.
21. The method of claim 20, wherein the therapeutically effective
amount is about 125 mg to about 1000 mg.
22. The method of claim 20, wherein the therapeutically effective
amount is about 125 mg to about 750 mg.
23. The method of claim 20, wherein the therapeutically effective
amount is about 125 mg to about 625 mg.
24. The method of claim 20, wherein the therapeutically effective
amount is about 250 mg to about 1250 mg.
25. The method of claim 20, wherein the therapeutically effective
amount is about 250 mg to about 1000 mg.
26. The method of claim 20, wherein the therapeutically effective
amount is about 250 mg to about 750 mg.
27. The method of claim 20, wherein the therapeutically effective
amount is about 250 mg to about 625 mg.
28. The method of claim 20, wherein the therapeutically effective
amount is about 250 mg to about 400 mg.
29. The method of claim 20, wherein the therapeutically effective
amount is about 400 mg to about 1250 mg.
30. The method of claim 20, wherein the therapeutically effective
amount is about 400 mg to about 1000 mg.
31. The method of claim 20, wherein the therapeutically effective
amount is about 400 mg to about 750 mg.
32. The method of claim 20, wherein the therapeutically effective
amount is about 400 mg to about 625 mg.
33. The method of claim 20, wherein the therapeutically effective
amount is about 625 mg to about 1250 mg.
34. The method of claim 20, wherein the therapeutically effective
amount is about 625 mg to about 1000 mg.
35. The method of claim 20, wherein the therapeutically effective
amount is about 625 mg to about 750 mg.
36. The method of claim 20, wherein the therapeutically effective
amount is about 750 mg to about 1250 mg.
37. The method of claim 20, wherein the therapeutically effective
amount is about 750 mg to about 1000 mg.
38. The method of claim 20, wherein the therapeutically effective
amount is about 1000 mg to about 1250 mg.
39. The method of claim 20, wherein the therapeutically effective
amount is about 375 mg BID.
40. The method of claim 20, wherein the therapeutically effective
amount is about 500 mg BID.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims priority to U.S. provisional
application Ser. No. 61/552,936, filed Oct. 28, 2011; 61/569,475,
filed Dec. 12, 2011; 61/592,351, filed Jan. 30, 2012; 61/593,056,
filed Jan. 31, 2012; 61/604,780, filed Feb. 29, 2012; 61/618,347,
filed Mar. 30, 2012; 61/649,450, filed May 21, 2012; and
61/660,319, filed Jun. 15, 2012, the entirety of each of which is
hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention provides methods of treating,
stabilizing or lessening the severity or progression of a disease
or disorder associated with Bruton's Tyrosine Kinase ("BTK")
inhibitor.
BACKGROUND OF THE INVENTION
[0003] The search for new therapeutic agents has been greatly aided
in recent years by a better understanding of the structure of
enzymes and other biomolecules associated with diseases. One
important class of enzymes that has been the subject of extensive
study is protein kinases.
[0004] Protein kinases constitute a large family of structurally
related enzymes that are responsible for the control of a variety
of signal transduction processes within the cell. Protein kinases
are thought to have evolved from a common ancestral gene due to the
conservation of their structure and catalytic function. Almost all
kinases contain a similar 250-300 amino acid catalytic domain. The
kinases may be categorized into families by the substrates they
phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,
lipids, etc.).
[0005] In general, protein kinases mediate intracellular signaling
by effecting a phosphoryl transfer from a nucleoside triphosphate
to a protein acceptor that is involved in a signaling pathway.
These phosphorylation events act as molecular on/off switches that
can modulate or regulate the target protein biological function.
These phosphorylation events are ultimately triggered in response
to a variety of extracellular and other stimuli. Examples of such
stimuli include environmental and chemical stress signals (e.g.,
osmotic shock, heat shock, ultraviolet radiation, bacterial
endotoxin, and H.sub.2O.sub.2), cytokines (e.g., interleukin-1
(IL-1) and tumor necrosis factor .alpha. (TNF-.alpha.)), and growth
factors (e.g., granulocyte macrophage-colony-stimulating factor
(GM-CSF), and fibroblast growth factor (FGF)). An extracellular
stimulus may affect one or more cellular responses related to cell
growth, migration, differentiation, secretion of hormones,
activation of transcription factors, muscle contraction, glucose
metabolism, control of protein synthesis, and regulation of the
cell cycle.
[0006] Many diseases are associated with abnormal cellular
responses triggered by protein kinase-mediated events as described
above. These diseases include, but are not limited to, autoimmune
diseases, inflammatory diseases, bone diseases, metabolic diseases,
neurological and neurodegenerative diseases, cancer, cardiovascular
diseases, allergies and asthma, Alzheimer's disease, and
hormone-related diseases. Accordingly, there remains a need to find
protein kinase inhibitors useful as therapeutic agents.
SUMMARY OF THE INVENTION
[0007] The present invention provides methods of treating,
stabilizing or lessening the severity or progression of one or more
diseases and conditions associated with BTK. In some aspects, the
present invention provides methods of treating, stabilizing or
lessening the severity or progression of one or more diseases and
conditions associated with BTK comprising administering to a
patient in need thereof a pharmaceutically acceptable composition
comprising
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide (1):
##STR00001##
[0008] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of one or more diseases and conditions associated with BTK selected
from group consisting of B-cell non-Hodgkin's lymphoma, chronic
lymphocytic leukemia and Waldenstrom's macroglobulinemia, wherein
the method comprises administering to a patient in need thereof a
pharmaceutically acceptable composition comprising Compound 1.
[0009] In some embodiments, provided methods comprise orally
administering to a patient compositions comprising Compound 1. In
some embodiments, such compositions are capsule formulations. In
general, provided methods comprise administering a composition
which comprises Compound 1 and one or more pharmaceutically
acceptable excipients, such as, for example, binders, diluents,
disintegrants, wetting agents, lubricants and adsorbents.
[0010] In some embodiments, the present invention also provides
dosing regimens and protocols for the administration of Compound 1
to patients in need thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 depicts the treatment duration for cohorts 1, 2, 3, 4
and 5 through Sep. 11, 2012. Each subject was administered the
respective milligram dose as a continuous daily oral dose. Dotted
bars indicate subjects still on treatment as of Sep. 11, 2012.
Hashed bars indicate subjects off treatment.
[0012] FIG. 2 depicts the treatment duration for cohorts 6A and 6B
through Sep. 11, 2012. Each subject was administered the respective
milligram dose as an oral dose (1000 mg once daily or 375 mg twice
daily). Dotted bars indicate subjects still on treatment as of Sep.
11, 2012.
[0013] FIG. 3 depicts the treatment duration for the CLL expansion
cohort C through Sep. 11, 2012. Each subject was administered the
respective milligram dose as a continuous daily oral dose. Dotted
bars indicate subjects still on treatment as of Sep. 11, 2012.
Hashed bars indicate subjects off treatment.
[0014] FIG. 4 depicts Btk Occupancy with .gtoreq.250 mg
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate for cohorts 2, 3 and 4.
[0015] FIG. 5 depicts the adverse events reported for cohorts 1, 2,
3, 4 and 5 through May 22, 2012.
[0016] FIG. 6 depicts the change in lymph node size in CLL patients
during treatment through Sep. 11, 2012.
[0017] FIG. 7 depicts the change in absolute lymphocyte count (ALC)
in CLL patients during treatment through Sep. 11, 2012.
[0018] FIG. 8 depicts the lymph node size percent change in B-NHL
patients during treatment through Sep. 11, 2012.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0019] As used herein, a "disease or disorder associated with BTK"
means any disease or other deleterious condition in which BTK, or a
mutant thereof, is known or suspected to play a role. Accordingly,
another embodiment of the present invention relates to preventing,
treating, stabilizing or lessening the severity or progression of
one or more diseases in which BTK, or a mutant thereof, is known or
suspected to play a role. Specifically, the present invention
relates to a method of treating or lessening the severity of a
proliferative disorder, wherein said method comprises administering
to a patient in need thereof Compound 1 or a pharmaceutically
acceptable composition thereof.
[0020] As used herein, a "therapeutically effective amount" means
an amount of a substance (e.g., a therapeutic agent, composition,
and/or formulation) that elicits a desired biological response. In
some embodiments, a therapeutically effective amount of a substance
is an amount that is sufficient, when administered as part of a
dosing regimen to a subject suffering from or susceptible to a
disease, disorder, and/or condition, to treat, diagnose, prevent,
and/or delay the onset of the disease, disorder, and/or condition.
As will be appreciated by those of ordinary skill in this art, the
effective amount of a substance may vary depending on such factors
as the desired biological endpoint, the substance to be delivered,
the target cell or tissue, etc. For example, the effective amount
of compound in a formulation to treat a disease, disorder, and/or
condition is the amount that alleviates, ameliorates, relieves,
inhibits, prevents, delays onset of, reduces severity of and/or
reduces incidence of one or more symptoms or features of the
disease, disorder, and/or condition. In some embodiments, a
"therapeutically effective amount" is at least a minimal amount of
a compound, or composition containing a compound, which is
sufficient for treating one or more symptoms of a disorder or
condition associated with Bruton's tyrosine kinase.
[0021] The term "subject", as used herein, means a mammal and
includes human and animal subjects, such as domestic animals (e.g.,
horses, dogs, cats, etc.).
[0022] The terms "treat" or "treating," as used herein, refers to
partially or completely alleviating, inhibiting, delaying onset of,
preventing, ameliorating and/or relieving a disorder or condition,
or one or more symptoms of the disorder or condition. As used
herein, the terms "treatment," "treat," and "treating" refer to
partially or completely alleviating, inhibiting, delaying onset of,
preventing, ameliorating and/or relieving a disorder or condition,
or one or more symptoms of the disorder or condition, as described
herein. In some embodiments, treatment may be administered after
one or more symptoms have developed. In some embodiments, the term
"treating" includes preventing or halting the progression of a
disease or disorder. In other embodiments, treatment may be
administered in the absence of symptoms. For example, treatment may
be administered to a susceptible individual prior to the onset of
symptoms (e.g., in light of a history of symptoms and/or in light
of genetic or other susceptibility factors). Treatment may also be
continued after symptoms have resolved, for example to prevent or
delay their recurrence. Thus, in some embodiments, the term
"treating" includes preventing relapse or recurrence of a disease
or disorder.
[0023] The expression "unit dosage form" as used herein refers to a
physically discrete unit of inventive formulation appropriate for
the subject to be treated. It will be understood, however, that the
total daily usage of the compositions of the present invention will
be decided by the attending physician within the scope of sound
medical judgment. The specific effective dose level for any
particular subject or organism will depend upon a variety of
factors including the disorder being treated and the severity of
the disorder; activity of specific active agent employed; specific
composition employed; age, body weight, general health, sex and
diet of the subject; time of administration, and rate of excretion
of the specific active agent employed; duration of the treatment;
drugs and/or additional therapies used in combination or
coincidental with specific compound(s) employed, and like factors
well known in the medical arts.
Compound 1 is an Irreversible BTK Inhibitor
[0024] United States published patent application number US
2010/0029610, published Feb. 4, 2010 ("the '610 publication," the
entirety of which is hereby incorporated herein by reference),
describes certain 2,4-disubstituted pyrimidine compounds which
covalently and irreversibly inhibit activity of one or more protein
kinases, including BTK, a member of TEC-kinases. Such compounds
include Compound 1, which is designated as compound number I-182 in
the '610 publication. The synthesis of Compound 1 is described in
detail at Example 20. Compound 1 is active in a variety of assays
and therapeutic models demonstrating covalent, irreversible
inhibition of BTK (in enzymatic and cellular assays). Notably,
Compound 1 was found to inhibit B-cell proliferation and
activation. Accordingly, Compound 1 is useful for treating one or
more disorders associated with activity of BTK.
[0025] The present invention provides methods of treating,
stabilizing or lessening the severity or progression of one or more
diseases and conditions associated with BTK comprising
administering to a patient in need thereof a pharmaceutically
acceptable composition comprising Compound 1, wherein the
pharmaceutically acceptable composition is an oral dosage form. In
some such embodiments, the pharmaceutically acceptable composition
is formulated as a capsule. Such methods, dosing regimens and
protocols for the administration of pharmaceutically acceptable
compositions comprising Compound 1 are described in further detail,
below.
I. General Dosing Protocol
[0026] As described above, the present invention provides methods
of treating, stabilizing or lessening the severity or progression
of one or more diseases or conditions associated with BTK, wherein
the method comprises administering to a patient in need thereof a
pharmaceutically acceptable composition comprising Compound 1. In
some embodiments, the present invention provides a method of
preventing the progression of a disease or disorder associated with
BTK.
[0027] In some embodiments, provided methods comprise administering
to a patient in need thereof a pharmaceutically acceptable
composition comprising from about 5% to about 60% of Compound 1,
based upon total weight of the formulation. In some embodiments,
provided methods comprise administering to a patient in need
thereof a pharmaceutically acceptable composition comprising from
about 5% to about 15% or about 7% to about 15% or about 7% to about
10% or about 9% to about 12% of Compound 1, based upon total weight
of the composition. In some embodiments, provided methods comprise
administering to a patient in need thereof a pharmaceutically
acceptable composition comprising from about 25% to about 75% or
about 30% to about 60% or about 40% to about 50% or about 40% to
about 45% of Compound 1, based upon total weight of the
formulation. In certain embodiments, provided methods comprise
administering to a patient in need thereof a pharmaceutically
acceptable composition comprising from about 6%, about 7%, about
8%, about 9%, about 10%, about 11%, about 12%, about 13%, about
20%, about 30%, about 40%, about 41%, about 42%, about 43%, about
44%, about 45%, about 50%, about 60%, about 70%, or about 75% of
Compound 1, based upon total weight of given composition or
formulation.
[0028] In some embodiments, provided methods comprise administering
a pharmaceutically acceptable composition comprising Compound 1
one, two, three, or four times a day. In some embodiments, a
pharmaceutically acceptable composition comprising Compound 1 is
administered once daily ("QD"). In some embodiments, a
pharmaceutically acceptable composition comprising Compound 1 is
administered twice daily ("BID"). In some embodiments, a
pharmaceutically acceptable composition comprising Compound 1 is
administered three times a day ("TID"). In some embodiments, a
pharmaceutically acceptable composition comprising Compound 1 is
administered four times a day ("QID"). For example, administration
of a 375 mg dose of Compound 1 "BID" means that the patient is
administered two separate doses of 375 mg in one day.
[0029] In some embodiments, provided methods comprise administering
a pharmaceutically acceptable composition comprising Compound 1
once a day ("QD"). In some embodiments, a pharmaceutically
acceptable composition comprising Compound 1 is administered once
daily for a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 days.
In some embodiments, a pharmaceutically acceptable composition
comprising Compound 1 is administered once daily for 28 consecutive
days ("a 28-day cycle"). In some embodiments, a pharmaceutically
acceptable composition comprising Compound 1 is administered once
daily for at least one 28-day cycle. In some embodiments, a
pharmaceutically acceptable composition comprising Compound 1 is
administered once daily for at least two, at least three, at least
four, at least five or at least six 28-day cycles. In some
embodiments, a pharmaceutically acceptable composition comprising
Compound 1 is administered once daily for at least seven, at least
eight, at least nine, at least ten, at least eleven or at least
twelve 28-day cycles. In some embodiments, a pharmaceutically
acceptable composition comprising Compound 1 is administered once
daily for at least thirteen, at least fourteen, at least fifteen,
at least sixteen, at least seventeen, at least eighteen, at least
nineteen or at least twenty 28-day cycles. In some embodiments, a
pharmaceutically acceptable composition comprising Compound 1 is
administered to a patient for the duration of the patient's
life.
[0030] In some embodiments, two adjacent 28-day cycles may be
separated by a rest period. Such a rest period may be one, two,
three, four, five, six, seven or more days during which the patient
is not administered a unit dose of Compound 1. In a preferred
embodiment, two adjacent 28-day cycles are continuous.
[0031] In some embodiments, provided methods comprise administering
to a patient in need thereof a pharmaceutically acceptable
composition comprising Compound 1, wherein the patient has failed
at least one prior therapy.
Unit Dosage Forms
[0032] Pharmaceutical compositions for use in the present invention
may be prepared as a unit dosage form. A person of ordinary skill
will appreciate that the unit dosage forms described herein refer
to an amount of Compound 1 as a free base. A person skilled in the
art will further appreciate that, when a pharmaceutical composition
comprises a salt form of Compound 1, for example a besylate salt
form, the amount of the salt form present in the composition is an
amount that is equivalent to a unit dose of the free base of
Compound 1. For example, a pharmaceutical composition comprising a
besylate salt of Compound 1 would contain 34.97 mg of the besylate
salt form necessary to deliver an equivalent 25 mg unit dose of the
free base of Compound 1.
[0033] In some embodiments, provided methods comprise administering
to a patient in need thereof a composition comprising a
therapeutically effective amount of Compound 1, wherein the
therapeutically effective amount is about 125 mg to about 625 mg.
In some embodiments, provided methods comprise administering to a
patient in need thereof a composition comprising a therapeutically
effective amount of Compound 1, wherein the therapeutically
effective amount is about 125 mg to about 750 mg. In some
embodiments, provided methods comprise administering to a patient
in need thereof a composition comprising a therapeutically
effective amount of Compound 1, wherein the therapeutically
effective amount is about 125 mg to about 1000 mg. In some
embodiments, provided methods comprise administering to a patient
in need thereof a composition comprising a therapeutically
effective amount of Compound 1, wherein the therapeutically
effective amount is about 125 mg to about 1250 mg.
[0034] In some embodiments, the therapeutically effective amount of
Compound 1 is about 125 mg to about 500 mg, or about 125 mg to
about 400 mg, or about 125 mg to about 325 mg, or about 125 mg to
about 250 mg, or about 250 mg to about 1250 mg, or about 250 mg to
about 1000 mg, or about 250 mg to about 750 mg, or about 250 mg to
about 625 mg, or about 250 mg to about 500 mg, or about 250 mg to
about 400 mg, or about 250 mg to about 325 mg, or about 325 mg to
about 1250 mg, or about 325 mg to about 1000 mg, or about 325 mg to
about 750 mg, or about 325 mg to about 625 mg, or about 325 mg to
about 500 mg, or about 325 mg to about 400 mg, or about 400 mg to
about 1250 mg, or about 400 mg to about 1000 mg, or about 400 mg to
about 750 mg, or about 400 mg to about 625 mg, or about 400 mg to
about 500 mg, or about 500 mg to about 1250 mg, or about 500 mg to
about 1000 mg, or about 500 mg to about 750 mg, or about 500 mg to
about 625 mg, or about 625 mg to about 1250 mg, or about 625 mg to
about 1000 mg, or about 625 mg to about 750 mg.
[0035] In some embodiments, the therapeutically effective amount of
Compound 1 is about 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg,
155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195
mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg,
240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280
mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg,
325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365
mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg,
410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450
mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg,
495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535
mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg,
580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620
mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg,
665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705
mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg,
750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790
mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg,
835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875
mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg,
920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960
mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, 1000
mg, 1005 mg, 1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg,
1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075
mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1100 mg, 1105 mg, 1110 mg,
1115 mg, 1120 mg, 1125 mg, 1130 mg, 1135 mg, 1140 mg, 1145 mg, 1150
mg, 1155 mg, 1160 mg, 1165 mg, 1170 mg, 1175 mg, 1180 mg, 1185 mg,
1190 mg, 1195 mg, 1200 mg, 1205 mg, 1210 mg, 1215 mg, 1220 mg, 1225
mg, 1230 mg, 1235 mg, 1240 mg, 1245 mg or 1250 mg.
[0036] In some embodiments, provided methods comprise administering
to a patient in need thereof a pharmaceutical composition
comprising a unit dose of Compound 1. In some such embodiments, the
unit dose is about 25 mg, about 50 mg, about 75 mg, about 100 mg,
about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225
mg or about 250 mg.
II. Uses of Compounds and Pharmaceutically Acceptable
Compositions
[0037] Compound 1 and compositions described herein are generally
useful for the inhibition of protein kinase activity of one or more
enzymes. Examples of kinases that are inhibited by Compound 1 and
compositions described herein and against which the methods
described herein are useful include BTK and other TEC-kinases,
including ITK, TEC, BMX and RLK, or a mutant thereof.
[0038] Bruton's tyrosine kinase ("BTK"), a member of TEC-kinases,
is a key signaling enzyme expressed in most hematopoietic cell
types except T lymphocytes. BTK plays an essential role in the
B-cell signaling pathway linking cell surface B-cell receptor (BCR)
stimulation to downstream intracellular responses.
[0039] BTK is a key regulator of B-cell development, activation,
signaling, and survival (Kurosaki, Curr. Op. Imm., 2000, 276-281;
Schaeffer and Schwartzberg, Curr. Op. Imm. 2000, 282-288). In
addition, BTK plays a role in a number of other hematopoietic cell
signaling pathways, e.g., Toll like receptor (TLR) and cytokine
receptor-mediated TNF-.alpha. production in macrophages, IgE
receptor (Fc_epsilon_RI) signaling in mast cells, inhibition of
Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and
collagen-stimulated platelet aggregation. See, e.g., C. A.
Jeffries, et al., (2003), Journal of Biological Chemistry
278:26258-26264; N. J. Horwood, et al., (2003), The Journal of
Experimental Medicine 197: 1603-1611; Iwaki et al. (2005), Journal
of Biological Chemistry 280(48):40261-40270; Vassilev et al.
(1999), Journal of Biological Chemistry 274(3): 1646-1656, and Quek
et al. (1998), Current Biology 8(20): 1137-1140.
[0040] Patients with mutations in BTK have a profound block in
B-cell development, resulting in the almost complete absence of
mature B lymphocytes and plasma cells, severely reduced Ig levels
and a profound inhibition of humoral response to recall antigens
(reviewed in Vihinen et al Frontiers in Bioscience 5: d917-928).
Mice deficient in BTK also have a reduced number of peripheral
B-cells and greatly decreased serum levels of IgM and IgG3. BTK
deletion in mice has a profound effect on B-cell proliferation
induced by anti-IgM, and inhibits immune responses to
thymus-independent type II antigens (Ellmeier et al, J Exp Med 192:
1611-1623 (2000)). BTK also plays a crucial role in mast cell
activation through the high-affinity IgE receptor (Fc_epsilon_RI).
BTK deficient murine mast cells have reduced degranulation and
decreased production of proinflammatory cytokines following
Fc_epsilon_RI cross-linking (Kawakami et al. Journal of Leukocyte
Biology 65: 286-290).
[0041] Compound 1 is an inhibitor of BTK and therefore useful for
treating one or more disorders associated with activity of BTK.
Thus, in some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of a BTK-mediated disorder comprising the step of administering to
a patient in need thereof
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylam-
ino)phenyl)acrylamide, or pharmaceutically acceptable compositions
thereof.
[0042] As used herein, the term "BTK-mediated" disorders or
conditions as used herein means any disease or other deleterious
condition in which BTK, or a mutant thereof, is known or suspected
to play a role. Accordingly, another embodiment of the present
invention relates to treating, stabilizing or lessening the
severity or progression of one or more diseases in which BTK, or a
mutant thereof, is known or suspected to play a role. Specifically,
the present invention relates to a method of treating, stabilizing
or lessening the severity or progression of a proliferative
disorder, wherein said method comprises administering to a patient
in need thereof Compound 1 or a composition according to the
present invention.
[0043] Non-Hodgkin's lymphomas (NHL), most of which are classified
as B-cell in origin, and chronic lymphocytic leukemia (CLL)
comprise a substantial proportion of the overall cancer burden in
the United States. For NHL, approximately 65,500 new cases and
20,200 deaths were expected in 2010; while for CLL, approximately
15,000 new cases and 4,400 deaths were predicted. NHL accounts for
approximately 4% of incident cancer and cancer deaths in the United
States.
[0044] 1. B-Cell Non-Hodgkin's Lymphomas
[0045] The B-cell non-Hodgkin's lymphomas (B-NHL) exhibit variable
clinical behavior and are principally classified on the basis of
morphologic criteria. Although many specific entities are
recognized, the two most prevalent categories comprise diffuse
large B-cell lymphomas (DLBCL), approximately 33% of non-Hodgkin's
lymphoma, and the follicular B-cell lymphomas, comprising 20-25%.
Other clinically relevant categories include mantle cell, marginal
zone (including the extranodal marginal zone lymphoma of
mucosa-associated lymphoid tissue, [MALT]), primary mediastinal
large B-cell, and Burkitt lymphomas.
[0046] Diffuse large B-cell lymphoma typically presents as an
aggressive neoplasm with median survival of less than 1 year if
left untreated. For several decades, multi-agent chemotherapy with
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
was the front-line standard treatment. This regimen produced 41%
disease-free and 54% overall survival (OS) at 3 years, and was
demonstrated to be as effective as more complicated and toxic
chemotherapy regimens. Compared to CHOP alone, the current
front-line treatment standard of the anti-CD20 monoclonal antibody
rituximab administered concurrently with CHOP (R-CHOP) results in
superior event-free survival (EFS) and OS in both poor risk older
patients (60-80 years of age; 7 year follow-up: EFS 25% (CHOP) vs.
42% (R-CHOP); OS 35% vs. 53%), as well as in good risk younger
patients (18-60 years of age; 3 year follow-up: EFS 59% (CHOP) vs.
79% (R-CHOP); OS 84% vs. 93%). A clinical scoring index, the
International Prognostic Index (IPI), was developed to stratify
patients by prognosis. More recently, gene expression profiling was
utilized to distinguish 3 prognostic groups of patients with DLBCL:
germinal center B-cell like, activated B-cell like, and a diffuse
type 3 group. These 3 molecular subgroups were not strictly related
to any specific histologic sub-type of DLBCL, and they predicted
survival following anthracycline-based chemotherapy independently
of the IPI. Five year OS following anthracycline-based chemotherapy
for the germinal center B-cell-like group was 60% compared with 39%
for the diffuse type 3 group, and 35% for the activated B-cell-like
group.
[0047] Despite the success of R-CHOP in treating DLBCL, some
patients relapse. Based largely on the PARMA study, the standard
treatment approach to fit patients with relapsed disease is to
employ salvage chemotherapy and consolidation with autologous stem
cell transplant (ASCT). In the PARMA trial, the use of
transplantation following salvage chemotherapy versus continued
salvage chemotherapy alone resulted in improved 5 year EFS (46% vs.
12%) and OS (53% vs. 32%).
[0048] The follicular NHLs are characterized by a relatively
indolent clinical course and high response rates to various
chemotherapies, immunotherapies, radioimmunotherapies, and
radiation therapy. Not all cases require immediate treatment and
"watch and wait" remains an option for some. Nonetheless, most
patients eventually require treatment for clinical complications of
progressively bulky tumor and undergo multiple courses of treatment
characterized by variable degrees of remission followed by
successive progressions at shorter and shorter intervals. Median OS
from diagnosis in the pre-rituximab era was 8-10 years, although
various clinical prognostic and molecular classifications have
identified subsets with distinctly poorer outcomes, including some
with only 4-5 year median survival. Monotherapy with rituximab
produced clinically meaningful responses in both front-line and
relapsed follicular lymphoma; and in randomized studies comparing
combinations of alkylator and/or anthracycline-based chemotherapies
alone versus with rituximab, the addition of rituximab resulted in
improved median progression-free and short-term (3-4 year
follow-up) OS. However, despite the introduction of rituximab and
other advances in the management of advanced stage follicular
lymphomas, these diseases remain largely incurable for the majority
of those afflicted.
[0049] Indolent NHL is a slow-growing or low-grade form of NHL.
Indolent NHL types have a relatively good prognosis with a median
survival as long as 10 years, but they usually are not curable in
advanced clinical stages. Early stage indolent NHL (stages I and
II) has traditionally been treated with radiation therapy. However,
a continuous rate of relapse is usually seen in advanced stages of
indolent NHL. Accordingly, there remains a need for improved
therapies for the treatment of indolent NHL. The present invention
provides a method of treating, stabilizing or lessening the
severity or progression of indolent Non-Hodgkin's lymphoma, wherein
said method comprises administering to a patient in need thereof
Compound 1 or a pharmaceutically acceptable composition
thereof.
[0050] A person of ordinary skill will appreciate that diseases
characterized as "B-cell lymphoma" exist as a continuum of diseases
or disorders. While the continuum of B-cell lymphomas is sometimes
discussed in terms of "aggressive" B-cell lymphomas or "indolent"
B-cell lymphomas, a person of ordinary skill will appreciate that a
B-cell lymphoma characterized as indolent may progress and become
an aggressive B-cell lymphoma. Conversely, an aggressive form of
B-cell lymphoma may be downgraded to an indolent or stable form of
B-cell lymphoma. Reference is made to indolent and aggressive
B-cell lymphomas as generally understood by a person skilled in the
art with the recognition that such characterizations are inherently
dynamic and depend on the particular circumstances of the
individual.
[0051] In some embodiments, the B-cell lymphoma is a B-cell
non-Hodgkin's lymphoma selected from diffuse large B-cell lymphoma,
Burkitt's lymphoma/leukemia, mantle cell lymphoma, mediastinal
(thymic) large B-cell lymphoma, follicular lymphoma, marginal zone
lymphoma (including extranodal marginal zone B-cell lymphoma and
nodal marginal zone B-cell lymphoma), lymphoplasmacytic
lymphoma/Waldenstrom macroglobulinemia. In some embodiments, the
B-cell lymphoma is chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL). In some embodiments, the B-cell lymphoma is
Waldenstrom macroglobulinemia.
[0052] Aggressive B-cell non-Hodgkin's lymphomas include diffuse
large B-cell lymphoma (DLBCL), Burkitt's lymphoma/leukemia, mantle
cell lymphoma and mediastinal lymphoma.
[0053] Indolent or slow-growing B-cell non-Hodgkin's lymphomas
include follicular lymphoma, marginal zone lymphoma and
lymphoblastic lymphoma/Waldenstrom macroglobulinemia.
[0054] 2. Chronic Lymphocytic Leukemia
[0055] The B-cell disorders chronic lymphocytic leukemia/small
lymphocytic lymphoma (CLL/SLL) represent 2 ends of a spectrum of
the same disease process differing in the degree of blood/marrow
involvement (CLL) versus lymph node involvement (SLL). Chronic
lymphocytic leukemia is the most common leukemia in the U.S. and is
typically characterized immunophenotypically as CD5+, CD23+, CD10-,
CD19+, CD20 dim, sIg dim, and cyclin D1--(the latter point a
distinguishing feature from mantle cell lymphoma). Chronic
lymphocytic leukemia must also be distinguished from monoclonal B
lymphocytosis (absolute monoclonal B-cell count <5000/.mu.L and
absence of adenopathy or other clinical features of
lymphoproliferative disorder). The understanding of CLL/SLL biology
and prognostic factors, and advances in formulating a
risk-stratified approach to treatment of CLL/SLL have been recently
reviewed by Lanasa, Furman, and the National Comprehensive Cancer
Network NHL panel.
[0056] Allogeneic stem cell transplant is the only potentially
curative treatment for CLL, but 70% of affected patients are
.gtoreq.65 years of age at the time of diagnosis; have co-morbid
conditions limiting eligibility for such therapy; and may exhibit a
prolonged natural history with or without specific treatment. The
actual prognosis of CLL is variable and dependent principally on
clinical stage and certain genetic and molecular features. Both the
Rai and Binet clinical staging systems are able to distinguish
patient prognostic groups with median OSs ranging from 19 months in
the most advanced stage (thrombocytopenia) to >150 months in the
earliest stage (blood and marrow lymphocytosis without adenopathy,
organomegaly, or defined anemia/thrombocytopenia). Classification
by the presence or absence of immunoglobulin heavy gene somatic
mutation (IgVH) and by interphase fluorescent in situ hybridization
(iFISH) analysis for probed-for acquired chromosomal abnormalities
adds additional prognostic discrimination to clinical staging, with
unmutated IgVH and del(11q) and del(17p) cytogenetics predicting
poorer outcome.
[0057] The CLL treatment algorithm is complex and requires first
the decision to treat (e.g., presence of symptoms such as fatigue
or night sweats; bulky adenopathy/organomegaly; progressive
anemia/thrombocytopenia); and second, choice of the treatment
regimen, usually involving one or more: purine nucleosides
(fludarabine), alkylating agents (cyclophosphamide, chlorambucil,
bendamustine), corticosteroids, anti-CD20 monoclonal antibodies
(rituximab/ofatumumab), or anti-CD52 monoclonal antibodies
(alemtuzumab). The choice of specific therapies depends on the
patient's age, disease pattern (eg, primarily nodal versus
non-nodal), anticipated drug tolerance and contraindications, and
presence or absence of adverse prognostic features such as del(11q)
or del(17p). Despite numerous therapies to choose from, treatment
options are eventually limited by drug toxicities and resistance,
and patients who do not succumb to other maladies endure
progressive complications relating to cytopenias, the effects of
lymphadenopathy and organomegaly, systemic symptoms, and infectious
complications. Given the often elderly character of the patient
population, an orally available, well tolerated treatment that
exploits a novel weakness of CLL would be welcome.
[0058] 3. Waldenstrom's Macroglobulinemia
[0059] Waldenstrom's Macroglobulinemia (WM) is a malignant B-cell
lymphoplasmoproliferative disorder characterized by production of
monoclonal pentameric Immunoglobulin M (IgM). Approximately
1000-1500 new cases occur annually in the United States, with an
excess in white males. Clinical symptoms relate to tumor
infiltration (anemia, thrombocytopenia secondary to marrow
infiltration; lymphadenopathy and organomegaly); serum
hyperviscosity from the monoclonal IgM excess (bleeding, ocular,
neurologic, and cardiovascular symptoms); deposition of IgM in
tissues (glomeruli--proteinuria, intestine--diarrhea,
skin--papules/nodules); and autoantibody activity of the IgM
(chronic immune hemolytic anemia associated with cold agglutinins,
peripheral neuropathies). The characteristic lymphoplasmacytic
infiltrate in the bone marrow is most often surface IgM positive
(sIgM+), CD19+, CD20+, CD22+, and CD79+; although some cases of WM
may express CD5, CD10, or CD23. The differential diagnosis includes
CLL and mantle cell lymphoma.
[0060] Criteria for the initiation of treatment in WM have been
defined by a consensus panel of experts, and several recent reviews
have summarized treatment recommendations. Initiation of therapy is
not based on the IgM level per se but rather on clinical
manifestations such as constitutional symptoms,
lymphadenopathy/organomegaly, anemia, thrombocytopenia,
manifestations of serum hyperviscosity, etc. Recommended first line
therapies include rituximab, alkylators (chlorambucil), nucleoside
analogs (fludarabine, cladribine), and various combinations of
these agents with rituximab. Combinations of rituximab with
cyclophosphamide or nucleoside analogs produce overall response
rates of 70-80% and complete responses in 10%. Combinations of
rituximab with bortezomib and dexamethasone have demonstrated
overall response rates of 96%, including 22% with complete
response. Consequently, regimens such as rituximab with bortezomib
have been recommended as salvage regimens as well as for first line
management for patients in need of immediate disease control, since
the median time to response with this regimen was only 1.1 months.
Other salvage approaches include recycling previously effective
first line regimens, thalidomide with rituximab, alemtuzumab, and
autologous stem cell and reduced-intensity conditioning allogeneic
stem cell transplant.
[0061] Rituximab, particularly when administered as monotherapy to
patients with high IgM levels >3 g/L, may be associated with an
IgM flare that can lead to symptomatic hyperviscosity and other
signs and symptoms. The elevated IgM levels may persist for months
and do not necessarily portend treatment failure, as evidenced by
concurrent reduction in marrow lymphoplasmacytic infiltrate.
Conversely, treatment with bortezomib may be associated with rapid
reduction in serum IgM levels without significant reduction in bone
marrow lymphoplasmacytic infiltrates, suggesting inhibition of IgM
secretion without overt cell killing. Indeed, it has been
demonstrated that treatment may induce delayed reductions in serum
M protein despite prompt reductions in marrow clonal B-cells; while
leaving, however, readily identifiable residual CD138+ monoclonal
plasma cells in the marrow, explaining the persistent production of
the Mprotein. The discordant response between the serum IgM levels
and degree of marrow infiltration observed with rituximab and
bortezomib based therapies have resulted in the recommendation that
in situations where the serum IgM levels may appear out of clinical
context, a bone marrow examination be considered to clarify the
underlying disease burden.
[0062] Despite therapeutic progress and a variety of available
treatment options for WM, therapies are limited by adverse
tolerance and eventual resistance. WM generally remains incurable
and most patients die of disease. A 1999 review reported median
survival of 5 years. Ten years later, in 2009, an International
Prognostic Scoring System for Waldenstrom's Macroglobulinemia
(ISSWM) was reported which analyzed 587 WM patients meeting
consensus panel criteria for treatment and reported median
survivals from initiation of treatment in risk classified
sub-groups ranging from less than 4 years to 12 years, with an
overall median of 7 years. In some embodiments, Compound 1
mitigates and/or is effective in treating the rituximab-induced IgM
flare in Waldenstrom's macroglobulinemia.
[0063] Rationale for Targeting Btk in B-NHL, CLL, and WM
[0064] Mechanisms of B-cell lymphoma pathogenesis have recently
been reviewed. Most B-cell lymphomas depend on expression of the
B-cell receptor for survival, and antigen activation signaling
through the BCR seems to be an important factor for lymphoma
pathogenesis. An RNA interference genetic screen revealed that the
BCR signaling component Btk is essential for survival of activated
B-cell like (ABC) DLBCLs with wild type Caspase Recruitment Domain
Family Member 11 (CARD11). Small hairpin RNAs (shRNA) targeting Btk
were toxic for ABC cell lines with downstream wild type CARD11 but
not for cell lines with mutant CARD11 capable of constitutively
signaling through the NF-kB pathway, suggesting that further
molecular pathway dissection and clinical correlation may open
avenues for kinase inhibition strategies that are personalized to
the tumor phenotype.
[0065] The importance of BCR signaling in CLL has also been
studied, in which it has been reported that half of all CLL retain
BCR signaling in vitro and that IgVH is an important determinant of
BCR responsiveness. Two groups have reported that mutated and
unmutated CLL cells respond differentially to IgM ligation of the
BCR, with unmutated, but not mutated, CLL cells responding to BCR
stimulation with increased global tyrosine phosphorylation and by
up-regulating several genes associated with cell cycle regulation
and allowing cell growth and expansion. These data highlight the
differential role that BCR signaling plays in CLL physiology
depending on IgVH mutational status and may suggest a possible
differential responsiveness of CLL to inhibitors of BCR signaling.
Other in vitro studies have reported that specific Btk inhibition
with the investigational agent PCI-32765 produced substantially
more apoptosis and cytotoxicity in CLL cells relative to normal
B-cells; as well as inducing apoptosis in the face of
anti-apoptotic micro-environmental signals, reduction of secretion
of chemokines CCL3 and CCL4, and reduction of chemotaxis towards
the chemokines CXCL12 and CXCL13. Detailed studies of the
pathophysiologic role of Btk in the origin and/or maintenance of WM
have not yet been reported. However, a recent report investigating
transgenic mouse models demonstrated that constitutively active Btk
expression resulted in selective expansion or survival of B-1 cells
that were driven into germinal center independent plasma cell
differentiation, as evidenced by increased numbers of IgM+ plasma
cells in spleen and bone marrow and significantly elevated serum
IgM. Anti-nucleosome autoantibodies and glomerular IgM deposition
were also observed. However, one study of sequence analysis in 19
WM patients with hypogammaglobulinemia G and/or A failed to find
any novel variants in the promoter, flanking introns, or exons of
Btk.
[0066] Strategies specifically targeting B-cells, for example the
B-cell depleting anti-CD20 monoclonal antibodies rituximab and
ofatumumab, have demonstrated clinical efficacy in B-cell lymphoma
and CLL. Spleen tyrosine kinase (Syk) is a kinase in the BCR
signaling pathway proximal to Btk. Inhibition of Syk with the
orally available Syk inhibitor fostamatinib disodium produced
clinical responses in DLBCL, CLL, and mantle cell lymphoma. Most
tellingly, clinical proof of concept for Btk inhibition has been
demonstrated by clinical investigations of the orally available Btk
inhibitor PCI-32765, which have reported objective anti-tumor
responses in patients with DLBCL; mantle cell, marginal
zone/mucosa-associated lymphoid tissue (MALT), and follicular
lymphoma; Waldenstrom's macroglobulinemia; and CLL/SLL, with good
tolerability.
[0067] Thus, based on the critical importance of BCR signaling
mediated through Btk for the survival and proliferation of various
malignant B-cells; Btk's limited cellular expression in B-cells,
macrophages, and monocytes; and demonstrated pre-clinical and early
clinical proofs of concept that Btk inhibition produces salutary
anti-lymphoma, CLL, and WM effects with acceptable clinical
tolerability, targeting Btk with a selective Btk inhibitor is a
promising and appropriate therapeutic strategy to investigate
further in the clinic.
[0068] Compound 1 is a potent, selective, orally administered small
molecule inhibitor of Bruton's tyrosine kinase (Btk), a major
component of the BCR signaling complex. The expression of Btk is
limited primarily to B lymphocytes, mast cells, monocytes, and
basophils. Compound 1 inhibits Btk activity by binding with high
affinity to the ATP binding site of Btk and forming a covalent bond
with the target Btk protein, providing rapid, complete, and
prolonged inhibition of Btk activity, both in vitro and in
vivo.
[0069] Both tonic and activated BCR signaling have been implicated
in the growth and survival of distinct subtypes of B-cell lymphomas
as well as CLL. Reducing the expression of the Immunoglobulin
.alpha. (Ig.alpha.) or Immunoglobulin .beta. (Ig.beta.) subunits of
the BCR by siRNA knockdown reduced proliferation of B-cell lymphoma
cell lines. Additionally, the mutational status of the BCR in CLL
is one of the strongest predictors of disease progression, as
aggressive disease typically displays BCR encoded by unmutated
immunoglobulin variable heavy chains.
III. Methods of Treating Diseases or Disorders Associated with
BTK
[0070] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of a disease or disorder selected from the group consisting of
B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of a pharmaceutically acceptable composition
comprising Compound 1, wherein the pharmaceutically acceptable
composition is administered as an oral dosage form. In some such
embodiments, the oral dosage form is a capsule.
[0071] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of a disease or disorder selected from the group consisting of
B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a solid oral dosage form
comprising a unit dose of Compound 1, wherein the unit dose is
about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg,
about 150 mg, about 175 mg, about 200 mg, about 225 mg or about 250
mg.
[0072] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of a disease or disorder selected from the group consisting of
B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutical
composition comprising Compound 1, wherein the patient has failed
at least one prior therapy. In some embodiments, the present
invention provides a method of preventing the progression of a
disease or disorder selected from the group consisting of B-cell
non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutical
composition comprising Compound 1, wherein the patient has failed
at least one prior therapy.
[0073] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of indolent non-Hodgkin's lymphoma, wherein said method comprises
administering to a patient in need thereof Compound 1 or a
pharmaceutically acceptable composition thereof. In some
embodiments, the indolent non-Hodgkin's lymphoma is selected from
follicular lymphoma, marginal zone lymphoma and lymphoblastic
lymphoma/Waldenstrom macroglobulinemia. In some embodiments, the
indolent non-Hodgkin's lymphoma is selected from follicular
lymphoma and marginal zone lymphoma.
[0074] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of aggressive non-Hodgkin's lymphoma, wherein said method comprises
administering to a patient in need thereof Compound 1 or a
pharmaceutically acceptable composition thereof. In some
embodiments, the aggressive non-Hodgkin's lymphoma is selected from
diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma/leukemia,
mantle cell lymphoma and mediastinal lymphoma.
[0075] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of a disease or disorder selected from the group consisting of
B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutical
composition comprising about 125 mg to about 625 mg of Compound 1.
In some embodiments, the present invention provides a method of
treating, stabilizing or lessening the severity or progression of a
disease or disorder selected from the group consisting of B-cell
non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutical
composition comprising about 125 mg to about 750 mg of Compound 1.
In some embodiments, the present invention provides a method of
treating, stabilizing or lessening the severity or progression of a
disease or disorder selected from the group consisting of B-cell
non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutical
composition comprising about 125 mg to about 1000 mg of Compound 1.
In some embodiments, the present invention provides a method of
treating, stabilizing or lessening the severity or progression of a
disease or disorder selected from the group consisting of B-cell
non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutical
composition comprising about 125 mg to about 1250 mg of Compound
1.
[0076] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of a disease or disorder selected from the group consisting of
B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a therapeutically
effective amount of Compound 1, wherein the therapeutically
effective amount comprises about 125 mg, 130 mg, 135 mg, 140 mg,
145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185
mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg,
230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270
mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg,
315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355
mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg,
400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440
mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg,
485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525
mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg,
570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610
mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg,
655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695
mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg,
740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780
mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg,
825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865
mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg,
910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950
mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg,
995 mg, 1000 mg, 1005 mg, 1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030
mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg,
1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1100 mg, 1105
mg, 1110 mg, 1115 mg, 1120 mg, 1125 mg, 1130 mg, 1135 mg, 1140 mg,
1145 mg, 1150 mg, 1155 mg, 1160 mg, 1165 mg, 1170 mg, 1175 mg, 1180
mg, 1185 mg, 1190 mg, 1195 mg, 1200 mg, 1205 mg, 1210 mg, 1215 mg,
1220 mg, 1225 mg, 1230 mg, 1235 mg, 1240 mg, 1245 mg or 1250 mg of
Compound 1.
[0077] In some embodiments, a therapeutically effective amount of
Compound 1 is administered one, two, three, or four times daily. In
some embodiments, a therapeutically effective amount of Compound 1
is administered once daily ("QD"). In some embodiments, a
therapeutically effective amount of Compound 1 is administered
twice daily ("BID"). In some embodiments, a therapeutically
effective amount of Compound 1 is administered three times a day
("TID"). In some embodiments, a therapeutically effective amount of
Compound 1 is administered four times a day ("QID"). In some
embodiments, a therapeutically effective amount of Compound 1 is
administered once daily (QD), wherein the therapeutically effective
amount is 125 mg, 250 mg, 400 mg, 625 mg, 750 mg, 1000 mg or 1250
mg. In some embodiments, a therapeutically effective amount of
Compound 1 is administered twice daily (BID), wherein the
therapeutically effective amount is 125 mg, 250 mg, 375 mg or 500
mg. In some embodiments, Compound 1 is administered 375 mg BID. In
some embodiments, Compound 1 is administered 500 mg BID.
[0078] In some embodiments, a therapeutically effective amount of
Compound 1 is administered over a period of 28 consecutive days ("a
28-day cycle"). In some embodiments, a therapeutically effective
amount of Compound 1 is administered for two, three, four, five or
six 28-day cycles. In some embodiments, a therapeutically effective
amount of Compound 1 is administered for seven, eight, nine, ten,
eleven, twelve or more 28-day cycles. In some embodiments, a
pharmaceutically acceptable composition comprising Compound 1 is
administered once daily for at least thirteen, at least fourteen,
at least fifteen, at least sixteen, at least seventeen, at least
eighteen, at least nineteen or at least twenty 28-day cycles. In
some embodiments, a therapeutically effective amount of Compound 1
is administered to a patient for the duration of the patient's
life.
[0079] In some embodiments, two adjacent 28-day cycles may be
separated by a rest period. Such a rest period may be one, two,
three, four, five, six, seven or more days during which the patient
is not administered a unit dose of Compound 1. In a preferred
embodiment, two adjacent 28-day cycles are continuous.
[0080] In some embodiments, the therapeutically effective amount of
Compound 1 is administered to a patient who has failed at least one
prior therapy.
IV. Formulations Comprising Compound 1
[0081] As described above, provided methods comprise administering
to a patient in need thereof a pharmaceutically acceptable
composition comprising Compound 1, wherein the pharmaceutically
acceptable composition is an oral dosage form. In some embodiments,
the pharmaceutically acceptable composition is formulated as a
capsule.
[0082] In certain embodiments, provided methods comprise
administering to a patient in need thereof a pharmaceutically
acceptable composition which comprises Compound 1, and one or more
pharmaceutically acceptable excipients, such as, for example,
binders, film coatings, diluents, disintegrants, wetting agents,
lubricants and adsorbents, or combinations thereof. One skilled in
the art will readily appreciate that the category under which a
particular component is listed is not intended to be limiting; in
some cases a particular component might appropriately fit in more
than one category. Also, as will be appreciated, the same component
can sometimes perform different functions, or can perform more than
one function, in the context of a particular formulation, for
example depending upon the amount of the ingredient and/or the
presence of other ingredients and/or active compound(s). In some
embodiments, the pharmaceutically acceptable composition is a
blended powder.
[0083] i. Binders and Diluents
[0084] Pharmaceutical compositions for use in the present invention
may comprise one or more binders. Binders are used in the
formulation of solid oral dosage forms to hold the active
pharmaceutical ingredient and inactive ingredients together in a
cohesive mix. In some embodiments, pharmaceutical compositions of
the present invention comprise about 5% to about 50% (w/w) of one
or more binders and/or diluents. In some embodiments,
pharmaceutical compositions of the present invention comprise about
20% (w/w) of one or more binders and/or diluents. Suitable binders
and/or diluents (also referred to as "fillers") are known in the
art. Representative binders and/or diluents include, but are not
limited to, starches such as celluloses (low molecular weight HPC
(hydroxypropyl cellulose), microcrystalline cellulose (e.g.,
Avicel), low molecular weight HPMC (hydroxypropyl methylcellulose),
low molecular weight carboxymethyl cellulose, ethylcellulose),
sugars such as lactose (i.e. lactose monohydrate), sucrose,
dextrose, fructose, maltose, glucose, and polyols such as sorbitol,
mannitol, lactitol, malitol and xylitol, or a combination thereof.
In some embodiments, a provided composition comprises a binder of
microcrystalline cellulose and/or lactose monohydrate.
[0085] ii. Disintegrants
[0086] Pharmaceutical compositions for use in the present invention
may further comprise one or more disintegrants. Suitable
disintegrants are known in the art and include, but are not limited
to, agar, calcium carbonate, sodium carbonate, sodium bicarbonate,
cross-linked sodium carboxymethyl cellulose (croscarmellose
sodium), sodium carboxymethyl starch (sodium starch glycolate),
microcrystalline cellulose, or a combination thereof. In some
embodiments, provided formulations comprise from about 1%, to about
25% disintegrant, based upon total weight of the formulation.
[0087] iii. Wetting Agents
[0088] Wetting agents, also referred to as bioavailability
enhancers, are well known in the art and typically facilitate drug
release and absorption by enhancing the solubility of
poorly-soluble drugs. Representative wetting agents include, but
are not limited to, poloxamers, polyoxyethylene ethers,
polyoxyethylene fatty acid esters, polyethylene glycol fatty acid
esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene
alkyl ether, polysorbates, and combinations thereof. In certain
embodiments, the wetting agent is a poloxamer. In some such
embodiments, the poloxamer is poloxamer 407. In some embodiments,
compositions for use in the present invention comprise from about
1% to about 30% by weight of wetting agent, based upon total weight
of the blended powder.
[0089] iv. Lubricants
[0090] Pharmaceutical compositions of the present invention may
further comprise one or more lubricants. Lubricants are agents
added in small quantities to formulations to improve certain
processing characteristics. Lubricants prevent the formulation
mixture from sticking to the compression machinery and enhance
product flow by reducing interparticulate friction. Representative
lubricants include, but are not limited to, magnesium stearate,
glyceryl behenate, sodium stearyl fumarate and fatty acids (i.e.
palmitic and stearic acids). In certain embodiments, a lubricant is
magnesium stearate. In some embodiments, provided formulations
comprise from about 0.2% to about 3% lubricant, based upon total
weight of given formulation.
[0091] v. Adsorbents
[0092] Pharmaceutical compositions of the present invention may
further comprise one or more adsorbents. Representative adsorbents
include, but are not limited to, silicas (i.e. fumed silica),
microcrystalline celluloses, starches (i.e. corn starch) and
carbonates (i.e. calcium carbonate and magnesium carbonate). In
some embodiments, provided formulations comprise from about 0.2% to
about 3% adsorbent, based upon total weight of given
formulation.
[0093] vi.
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-yl-
amino)phenyl)acrylamide besylate
[0094] As described above, the present invention provides a method
of treating a disease or disorder selected from B-cell
non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutically
acceptable composition comprising Compound 1. The besylate salt of
Compound 1,
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide benzenesulfonic acid salt, has recently been
identified and is currently in clinical trials as monotherapy in
subjects with relapsed or refractory B-cell non-Hodgkin's lymphoma
(B-NHL), chronic lymphocytic leukemia (CLL) and Waldenstrom's
macroglobulinemia (WM). Thus, in some embodiments, provided methods
comprise administering to a patient in need thereof a besylate salt
of Compound 1.
[0095] In some embodiments, provided methods comprise administering
to a patient in need thereof a pharmaceutically acceptable
composition comprising from about 5% to about 60% of the besylate
salt of Compound 1, based upon total weight of the formulation. In
some embodiments, provided methods comprise administering to a
patient in need thereof a pharmaceutically acceptable composition
comprising from about 5% to about 15% or about 7% to about 15% or
about 7% to about 10% or about 9% to about 12% of the besylate salt
of Compound 1, based upon total weight of the composition. In some
embodiments, provided methods comprise administering to a patient
in need thereof a pharmaceutically acceptable composition
comprising from about 25% to about 75% or about 30% to about 60% or
about 40% to about 50% or about 40% to about 45% of the besylate
salt of Compound 1, based upon total weight of the formulation. In
certain embodiments, provided methods comprise administering to a
patient in need thereof a pharmaceutically acceptable composition
comprising from about 8%, about 9%, about 10%, about 11%, about
12%, about 13%, about 20%, about 30%, about 40%, about 41%, about
42%, about 43%, about 44%, about 45%, about 50%, about 60%, about
70%, or about 75% of the besylate salt of Compound 1, based upon
total weight of given composition or formulation.
[0096] In some such embodiments, provided methods comprise
administering to a patient in need thereof a pharmaceutical
composition comprising a unit dose of Compound 1, wherein Compound
1 is in the form of a besylate salt. In some such embodiments, the
unit dose is an amount sufficient to provide about 25 mg, about 50
mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about
175 mg, about 200 mg, about 225 mg or about 250 mg of the free base
of Compound 1. In some embodiments, the pharmaceutical composition
comprising the besylate salt of Compound 1 is a solid oral dosage
form.
[0097] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of indolent non-Hodgkin's lymphoma, wherein said method comprises
administering to a patient in need thereof the besylate salt of
Compound 1 or a pharmaceutically acceptable composition
thereof.
[0098] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of aggressive non-Hodgkin's lymphoma, wherein said method comprises
administering to a patient in need thereof the besylate salt of
Compound 1 or a pharmaceutically acceptable composition
thereof.
[0099] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of a disease or disorder selected from the group consisting of
B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a composition comprising
the besylate salt of Compound 1 and one or more pharmaceutically
acceptable excipients selected from binders, film coatings,
diluents, disintegrants, wetting agents, lubricants and
adsorbents.
[0100] In some embodiments, the present invention provides a method
of treating, stabilizing or lessening the severity or progression
of a disease or disorder selected from the group consisting of
B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia and
Waldenstrom's macroglobulinemia, the method comprising
administering to a patient in need thereof a pharmaceutical
composition comprising the besylate salt of Compound 1, wherein the
amount of besylate salt is sufficient to deliver about 125 mg,
about 250 mg, about 325 mg, about 375 mg, about 400 mg, about 500
mg, about 625 mg, about 750 mg, about 1000 mg or about 1250 mg of
the free base of Compound 1. In some such embodiments, the
pharmaceutical composition further comprises one or more
pharmaceutically acceptable excipients selected from binders, film
coating, diluents, disintegrants, wetting agents, lubricants and
adsorbents. In some such embodiments, the pharmaceutical
composition comprises one or more pharmaceutically acceptable
excipients selected from microcrystalline cellulose, lactose
monohydrate, sodium starch, poloxamer 407, fumed silica and
magnesium stearate.
V. Process for Preparing Pharmaceutical Compositions
[0101] Dry Blend Process:
[0102] Milled
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate, milled microcrystalline cellulose, milled
sodium starch glycolate, milled lactose monohydrate, milled
poloxamer 407, and sieved fumed silica are weighed and mechanically
blended. An intragranular portion of sieved magnesium stearate
(0.5% or 2.0%, per Table 1, below) is added to the blender and the
formulation blended. This blended formulation is then roller
compacted, milled, and then blended. The remainder or extragranular
portion of the magnesium stearate (0.5% or 1.0%, per Table 1,
below) is added and the final formulation is blended. Capsules are
either mechanically filled or manually filled via the flood fill
method.
[0103] All features of each of the aspects of the invention apply
to all other aspects mutatis mutandis.
[0104] In order that the invention described herein may be more
fully understood, the following examples are set forth. It should
be understood that these examples are for illustrative purposes
only and are not to be construed as limiting this invention in any
manner.
EXEMPLIFICATION
[0105] As depicted in the Examples below, in certain exemplary
embodiments, compounds are prepared according to the following
general procedures. It will be appreciated that, although the
general methods depict the synthesis of certain compounds of the
present invention, the following general methods, and other methods
known to one of ordinary skill in the art, can be applied to all
compounds and subclasses and species of each of these compounds, as
described herein.
Example 1
Dose Escalation Study
[0106] The active pharmaceutical ingredient (API),
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate, is a chemically synthesized small molecule
substituted pyrimidine developed as the benzenesulfonic acid salt
and is a white to off-white crystalline powder.
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate is an oral, potent (IC.sub.50<0.5 nM) and
selective small molecule inhibitor of Btk.
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate exhibits solubility of approximately 0.16
mg/mL in water and a maximum aqueous solubility of 0.40 mg/mL at
approximately pH 3.0. The solubility of
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate in ethanol is approximately 10 mg/mL.
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate exhibits no environmental instabilities
(i.e. heat, acid, base) that require special handling.
[0107] The API was formulated into capsules containing the
components and quantities listed in Table 1 to obtain the study
drug. All capsules listed in Table 1 either were administered or
will be administered during the dose escalation and expansion
cohort studies.
TABLE-US-00001 TABLE 1 Components of
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-
ylamino)phenyl)acrylamide besylate capsules First Generation
Capsules Second Generation Capsules Amount per Amount per Amount
per Amount per 25 mg 125 mg 25 mg 125 mg Component Capsule Capsule
Capsule Capsule Capsule shell 1, size 0 dark 1, size 0 1, size 0 1,
size 0 green capsule white capsule white capsule white capsule
N-(3-(5-fluoro-2-(4-(2- 34.97 mg 174.86 mg 34.97 mg 174.30 mg
methoxyethoxy)phenylamino) (25 mg free (125 mg free (25 mg free
(125 mg free pyrimidin-4-ylamino)phenyl) base) base) base) base)
acrylamide besylate Microcrystalline cellulose 186.03 mg 105.27 mg
186.03 mg 101.68 mg Lactose monohydrate 32.50 mg 41.50 mg 32.50 mg
41.50 mg Sodium starch glycolate 32.50 mg 41.50 mg 32.50 mg 41.50
mg Poloxamer 407 32.50 mg 41.50 mg 32.50 mg 41.50 mg Fumed silica
3.25 mg 4.15 mg 3.25 mg 4.15 mg Magnesium stearate 3.25
mg.sup..dagger. 6.23 mg{circumflex over ( )} 3.25 mg.sup..dagger.
10.38 mg.sup..dagger-dbl. .sup..dagger.0.5% (1.625 mg)
intragranular; 0.5% (1.625 mg) extragranular. {circumflex over (
)}0.5% (2.08 mg) intragranular; 1.0% (4.15 mg) extragranular.
.sup..dagger-dbl.2.0% (8.30 mg) intragranular; 0.5% (2.08 mg)
extragranular.
[0108] Study Design: Cohorts 1-5.
[0109] Subjects with relapsed or refractory B-NHL, CLL/SLL, or WM
who failed at least one prior treatment regimen and who had an ECOG
Performance Status grade of 2 or less and exhibit adequate organ
function were enrolled in a series of escalating dose cohorts
according to a modified Fibonacci sequence. Dose escalation
proceeded by a standard "3+3" methodology up to Cohort 5 (750 mg
dose), with three patients enrolled to dose level 1 and treated QD
for 28 days. Dose escalation, via enrollment in the next higher
dose, was allowed only if none (0) of the first three (3) enrolled
subjects, or no more than one (1) of the first six (6) enrolled
subjects, experienced dose limiting toxicity ("DLT") during the
first 28 days of treatment at the lower dose. Intrapatient dose
escalation was allowed.
[0110] Six (6) dose levels and two (2) contingent dose levels were
defined and outlined in Table 2.
TABLE-US-00002 TABLE 2 Study Dosing Schema for Escalating Dose
Portion of Study COHORT DOSE LEVEL FREQUENCY 1 Starting Dose 125 mg
QD .times. 28 d 2 250 mg QD .times. 28 d 2.5 (contingent)* 325 mg
QD .times. 28 d 3 400 mg QD .times. 28 d 3.5 (contingent)* 500 mg
QD .times. 28 d 4 625 mg QD .times. 28 d 5 750 mg QD .times. 28 d
*During the dose escalation study it was intended to proceed
directly from dose level 2 to 3 and from dose level 3 to 4 if dose
levels 2 and 3 proved safe and well tolerated. Contingent dose
levels 2.5 and 3.5 were defined in the event that either dose level
3 or 4 was found to exceed the maximum tolerated dose ("MTD")
(.gtoreq.2 of 6 subjects experience DLTs).
[0111] Enrollment for Cohorts 1-5 was not restricted or contingent
on the basis of specific B-NHL/CLL/WM diagnosis. Within each
cohort, subjects were treated PO (oral) QD (daily) with
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl) acrylamide besylate monotherapy during an initial 28-day
treatment cycle and were assessed for safety, tolerability, DLT,
pharmacokinetic ("PK"), and pharmacodynamic ("PD"), and disease
response. In certain instances, the physician-investigator may
elect to rest a patient during the study, during which time the
patient does not receive treatment. For example, the
physician-investigator may elect to rest a patient due to
occurrence or recurrence of adverse events. For purposes of
clarity, a patient who has been rested is still enrolled in the
study until the physician-investigator determines that the patient
should not continue treatment, at which time such patients are
discontinued from further treatment. In this context, treatment
duration refers to the time a patient is enrolled in the study,
inclusive of all rest periods, until treatment is discontinued.
[0112] Study Design: Cohorts 6A/B-7A/B.
[0113] Beginning with Cohort 6 (1000 mg), twelve (12) patients were
enrolled in each subsequent DL and dose. Four (4) dose levels were
defined and outlined in Table 3.
TABLE-US-00003 TABLE 3 Expanded Cohorts-Cohorts 6A/B and 7A/B
COHORT DOSE LEVEL FREQUENCY 6A* 1000 mg QD .times. 28 d 6B* 375 mg
BID .times. 28 d 7A.sup.+ 1250 mg QD .times. 28 d 7B.sup.+ 500 mg
BID .times. 28 d *Cohorts 6A and 6B were recruited and initiated in
parallel with subject enrollment alternating between the two
cohorts. If an expanded cohort(s) is simultaneously active, subject
enrollment will also alternate with the expanded cohort(s).
.sup.+Cohort 7A will proceed provided Cohort 6A proves safe and
well-tolerated. Cohort 7B will proceed provided Cohort 6B proves
safe and well-tolerated. If an expanded cohort(s) is simultaneously
active, enrollment will also alternate with the expanded
cohort(s).
[0114] Six (6) subjects diagnosed with CLL and six (6) patients
diagnosed with B-NHL were enrolled in each of Cohorts 6A and 6B.
Cohorts 6A and 6B were enrolled concurrently, and if meeting the
requirements for continued escalation, Cohorts 7A and 7B will be
enrolled and evaluated. Within each cohort, subjects were treated
PO (oral) either QD (daily) or BID (twice daily), as set forth in
Table 3, with
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate monotherapy during an initial 28-day
treatment cycle and were assessed for safety, tolerability, and
dose limiting toxicity ("DLT"), and for pharmacokinetic ("PK"),
pharmacodynamic ("PD"), and disease response.
[0115] For all cohorts, dose limiting toxicities (DLTs) were
specified adverse events (AEs) that observed within the first
28-day cycle and deemed to be related to treatment. Hematologic
DLTs were graded in accordance with the International Workshop
Criteria 2008 for patients with CLL and the National Cancer
Institute Common Terminology Criteria for AEs v4 for patients with
B-NHL or WM. Hematologic DLTs included Grade 4 anemia or
thrombocytopenia, Grade 4 neutropenia greater than 5 days despite
granulocyte colony-stimulating factor (G-CSF) and Grade 3 or higher
febrile neutropenia. Non-hematologic DLTs included Grade 3 or
higher non-hematologic AEs, with the exception of nausea, vomiting
and diarrhea lasting less than 24 hours following medical therapy,
tumor lysis syndrome which did not progress to grade 4 and was
resolved in less than 7 days with medical management, and
transient, rapidly reversible and asymptomatic grade 3
non-hematologic laboratory anomaly.
[0116] Subjects without disease progression and without DLT at the
end of the first 28-day cycle of treatment will be eligible to
continue receiving
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-yl-
amino)phenyl)acrylamide besylate as monotherapy for additional
28-day cycles until (i) the patient experiences unacceptable
toxicity, (ii) the underlying malignancy progresses, (iii) the
patient withdraws consent, or (iv) the treating
physician-investigator otherwise determines that the patient should
not continue treatment. Subjects with CLL experiencing nodal
response with lymphocytosis (which may be related to drug-mediated
lymphocyte redistribution) were also eligible for additional
treatment. Subjects with WM with increasing serum Immunoglobulin M
("IgM") levels at the end of the first 28-day cycle were also
evaluated for lymphadenopathy/organomegaly and marrow infiltration.
Investigators were permitted to use judgment in determining whether
to continue these subjects into the second 28-day cycle if there
was a discordant response between increased IgM and stable or
decreased lymphadenopathy/organomegaly and marrow infiltration.
[0117] Dose escalation will continue until a DLT is observed. Dose
escalation, via enrollment in the next higher dose was allowed only
if none (0) of the first three (3) enrolled subjects, or no more
than one (1) of the first six (6) enrolled subjects in the
preceding dose cohort experienced a DLT during the first 28-day
cycle of treatment and observation. One key objective for the dose
escalation portion of the study was to identify the maximum
tolerated dose (MTD) and Optimal Biological Effect dose (OBE). The
OBE was defined as: [0118] a. .gtoreq.90% target occupancy in 9 of
12 subjects in either peripheral blood or lymph node biopsy at any
dose level; and/or [0119] b. no further increase in exposure with
increasing doses; and/or [0120] c. results in a .gtoreq.25%
increase in lymphocytosis in 4/6 CLL subjects sub-cohort during
cycles 1 through 3.
Results
[0121] Summary of Study Results.
[0122] Sixty (60) patients with previously treated CLL or B-NHL
were enrolled as of Sep. 11, 2012. Thirty-six (36) patients were
enrolled in dose escalation cohorts 1-6A/B as follows:
TABLE-US-00004 TABLE 4 Number of Patients in Dose Escalation
Cohorts Number of Enrolled Cohort Dose Patients 1 125 mg QD 3 2 250
mg QD 3 3 400 mg QD 6 4 625 mg QD 6 5 750 mg QD 6 6A 1000 mg QD 7
6B 375 mg BID 5
[0123] Another twenty-four (24) patients were enrolled in the CLL
expansion cohort, discussed in greater detail below in Example 2.
Nineteen (19) patients were diagnosed with CLL in dose escalation
cohorts 1-6A/B. The thirteen CLL patients in cohorts 1-5 exhibited
the following chromosomal abnormalities (fluorescent in situ
hybridization, FISH): two (2) 17p-, one (1) 11q22-, one (1)
17p-/11q22-/13q-/+12, one (1) 17p-/11q22-/13q-, one (1) 17p-/13q-;
one (1) 11q22-/13q-, one (1) 13q-/+12, one (1)+12, three (3) with
no identifiable chromosomal abnormalities, and one (1) with unknown
chromosomal status. Three (3) of the thirteen had mutated IGHV,
eight (8) had unmutated IGHV, and in two (2) the IGHV status was
unknown.
[0124] Seventeen (17) patients were diagnosed with B-NHL (4 diffuse
large B cell lymphoma (DLBCL); 5 follicular (FL); 1 splenic
marginal zone (sMZL), 1 marginal zone lymphoma (MZL); 2 mantle cell
lymphoma (MCL), 2 Waldenstrom's Macroglobulinemia (WM), 1
mediastinal large B cell lymphoma (MLBCL) and 1 small lymphocytic
lymphoma (SLL)).
[0125] Twenty-four (24) patients were administered API in one of
five cohorts of 125, 250, 400, 625 or 750 mg po QD using a 3+3
design in continuous 28 day cycles until progressive disease (PD)
or toxicity. Twelve (12) patients were administered API in one of
two cohorts of 1000 mg po QD (7 patients) or 375 mg po BID (5
patients). Of the twelve patients in cohorts 6A and 6B, six
patients were diagnosed with CLL and six patients were diagnosed
with B-NHL. Key objectives were safety, DLT, MTD, PK and Btk
occupancy. Plasma API levels were assessed by LC-MS-MS. Btk
occupancy levels were assessed by covalent probe assay in
peripheral blood mononuclear cells. To date, twenty-three of
thirty-six patients continue on treatment, with a median time of
treatment of 77.5 days (range of 9-357 days).
[0126] Cohort 1.
[0127] Three subjects suffering from CLL were enrolled in the first
cohort (125 mg). The one male and two female cohort 1 patients had
a median age of 59 (range of 45-64), with a median of 2 prior
therapies (range of 2-10). None of the subjects showed DLT or
disease progression and treatment was continued. Two of the three
patients in cohort 1 (125 mg) were escalated to 250 mg at or near
the end of the fourth 28-day cycle. One of the two subjects at the
escalated 250 mg dose was further escalated to 625 mg at or near
the end of the tenth 28-day cycle. All three patients showed
progressive disease after 187 days (6.68 cycles), 319 days (11.4
cycles) and 332 days (11.9 cycles), respectively, and treatment was
discontinued.
[0128] Cohort 2.
[0129] The second cohort consisted of one subject diagnosed with
CLL and two subjects diagnosed with B-NHL (one splenic marginal
zone lymphoma and one DLBCL). The one male and two female cohort 2
patients had a median age of 69 (range of 67-76), with a median of
5 prior therapies (range of 2-5). Two of the three subjects treated
in the second cohort (250 mg) showed no DLT or disease progression,
and treatment was continued. The subject diagnosed with DLBCL
showed progressive disease after 28 days of treatment and treatment
was discontinued. One patient was escalated to 400 mg dose at or
near the end of the sixth 28-day cycle. One patient was escalated
to 750 mg dose at or near the end of the eleventh 28-day cycle.
Both patients are currently in the thirteenth 28-day cycle.
[0130] Cohort 3.
[0131] The third cohort consisted of four subjects diagnosed with
CLL and two subjects diagnosed with B-NHL (one marginal zone
lymphoma and one follicular lymphoma). The three male and three
female cohort 3 patients had a median age of 69 (range of 51-79),
with a median of 2.5 prior therapies (range of 1-5). Three
patients, one diagnosed with marginal zone lymphoma (MZL) and two
diagnosed with CLL, treated in the third cohort (400 mg) showed no
DLT or disease progression and treatment was continued. The patient
with marginal zone lymphoma (MZL) was escalated to 625 mg dose at
or near the end of the seventh 28-day cycle. The CLL patients
continued to show no DLT or disease progression and are currently
in the eleventh 28-day cycle of treatment. The subject diagnosed
with follicular lymphoma experienced dose limiting toxicity
thrombocytopenia (low platelet count; Grade 4) and treatment was
discontinued before the completion of the first 28-day cycle. The
remaining CLL patients showed progressive disease, one after 168
days (six cycles) and one after 231 days (eight cycles), and
treatment was discontinued.
[0132] Cohort 4.
[0133] The fourth cohort consisted of one subject diagnosed with
CLL and five subjects diagnosed with B-NHL (three follicular
lymphoma, one mantle cell lymphoma (MCL) and one DLBCL). The three
male and three female cohort 4 patients had a median age of 62.5
(range of 52-74), with a median of 1.5 prior therapies (range of
1-6). One patient (follicular lymphoma) showed no DLT or disease
progression and continued to treatment for seven, and is currently
in the eighth 28-day cycle. Four patients have exhibited
progressive disease. The mantle cell lymphoma patient exhibited
progressive disease after 105 days (3.75 cycles) and treatment was
discontinued. The DLBCL patient exhibited progressive disease after
33 days (1.18 cycles) and treatment was discontinued. The remaining
two follicular lymphoma patients exhibited progressive disease
after two cycles (56 days) and 7.6 cycles (212 days), respectively,
and treatment was discontinued. The CLL patient exhibited
neutropenia (adverse event) after completion of three cycles (85
days) and treatment was discontinued.
[0134] Cohort 5.
[0135] The fifth cohort consisted of four subjects diagnosed with
CLL, one subject diagnosed with B-NHL (DLBCL) and one subject
diagnosed with mediastinal large B cell lymphoma (MLBCL). The four
male and two female cohort 5 patients had a median age of 67 (range
of 43-81), with a median of 3 prior therapies (range 2-6). Five
patients showed no DLT or disease progression and treatment was
continued. Two CLL patients have completed three, and are currently
in the fourth 28-day cycle. The two remaining CLL patients have
completed four, and are currently in the fifth 28-day cycle. The
DLBCL patient completed five 28-day cycles before discontinuing
treatment due to an unrelated adverse event. The MLBCL patient
exhibited progressive disease after 64 days (2.3 cycles) and
treatment was discontinued.
[0136] Cohorts 6A and 6B.
[0137] The sixth cohort consisted of six subjects with CLL, two
subjects with Waldenstrom's Macroglobulinemia (WM), one subject
with FL, one subject with SLL, one subject with DLBCL and one
subject with MCL. As of Sep. 11, 2012 eleven patients showed no DLT
or disease progression and continue to receive
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate as continuous monotherapy. Enrollment in
Cohorts 6A and 6B is ongoing.
[0138] FIG. 1 depicts the treatment duration for cohorts 1, 2, 3, 4
and 5. FIG. 2 depicts the treatment duration for cohorts 6A and 6B.
The dotted bars indicate subjects still on treatment as of Sep. 11,
2012. The hashed bars indicate subjects off treatment. Each subject
was administered the respective milligram dose once daily for
cohorts 1-5 and 6A or twice daily for cohort 6B.
[0139] Btk Occupancy.
[0140] The covalent mechanism of action of
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate allowed for development of a covalent probe
to detect free, uninhibited Btk in lysates derived from tissue
culture, animal tissues, or clinical samples. PBMC lysates isolated
from whole blood samples 30 minutes before dosing, 4 hours or 24
hours post-dose were incubated with the biotinylated covalent
probe. Uninhibited Btk was captured by the covalent probe and
quantitated by ELISA. Normalization to untreated control sample
allowed for determination of the % Btk occupancy.
[0141] Btk Target Site Occupancy ELISA:
[0142] Cell lysates or spleen homogenates were incubated with 1
.mu.M
N.sup.1-(3-(3-(4-(3-acrylamidophenylamino)-5-methylpyrimidin-2-ylamino)ph-
enoxy)propyl)-N.sup.5-(15-oxo-19-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,-
4-d]imidazol-4-yl)-4,7,10-trioxa-14-azanonadecyl)glutaramide (2) in
a PBS, 0.05% Tween-20, 1% BSA solution for 1 h at room temperature.
Compound 2 has the following structure:
##STR00002##
[0143] Standards and samples were transferred to a
streptavidin-coated 96-well ELISA plate and mixed while shaking for
1 h at room temperature. The a-Btk antibody (BD 611116, 1:1000
dilution in PBS+0.05% Tween-20+0.5% BSA) was then incubated for 1 h
at room temperature. After wash, goat a-mouse-HRP (1:5000 dilution
in PBS+0.05% Tween-20+0.5% BSA) was added and incubated for 1 h at
room temperature. The ELISA was developed with addition of
tetramethyl benzidine (TMB) followed by Stop Solution and read at
OD 450 nm. The standard curve (11.7-3000 pg/.mu.L) was generated
with human full-length recombinant Btk protein and plotted using a
4 parameter curve fit in Gen5 software. Uninhibited Btk detected
from samples was normalized to .mu.g total protein as determined by
BCA protein analysis (Pierce Cat. 23225).
[0144] FIG. 4 depicts the Btk occupancy for cohorts 2, 3 and 4.
Complete target occupancy was achieved 4 hours after
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate dosing at each dose level in all cases.
Occupancy from only one of three patients in cohort 1 was evaluable
and demonstrated 76% occupancy 4 hours post-dose and 36% occupancy
on day 29 pre-dose. These results suggest that dose levels
achieving Btk occupancy identified in
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate also deliver complete occupancy with
repeated once daily dosing in patients with CLL and B-NHL. Btk
occupancy for cohorts 5, 6A and 6B are under evaluation.
[0145] Adverse Events.
[0146] FIG. 5 depicts the adverse events reported for cohorts 1, 2,
3, 4 and initial cohort 5 through May 22, 2012. Adverse events for
expanded cohort 5, as well as cohorts 6A and 6B, are under
review.
[0147] Subjects in cohort 1 reported incidences of contusion
(bruising) (2 patients), diarrhea (3 patients), nausea (1 patient),
upper respiratory infection (2 patients), fatigue (2 patients),
headache (2 patients), pneumonia (1 patient), thrombocytopenia (1
patient), dyspnea (1 patient), lymph node pain (2 patients),
dyspepsia (1 patient), abdominal distension (1 patient), jaw pain
(1 patient), muscle spasm (1 patient), weight loss (1 patient),
rash (1 patient), urticaria (1 patient) and sinusitis (1
patient).
[0148] Subjects in cohort 2 reported incidences of decreased
diarrhea (2 patients), nausea (1 patient), fatigue (1 patient),
pneumonia (1 patient), cough (1 patient), dyspnea (1 patient),
dysgeusia (1 patient), neutropenia (1 patient), abdominal
distension (1 patient) and weight loss (1 patient).
[0149] Subjects in cohort 3 reported incidences of diarrhea (4
patients), upper respiratory infection (2 patients), pneumonia (1
patient), thrombocytopenia (3 patients), neutropenia (2 patients),
cough (2 patients), headache (1 patient), fatigue (1 patient),
anemia (1 patient), jaw pain (1 patient), muscle spasm (1 patient),
influenza-like illness (1 patient), rash (1 patient), urticaria (1
patient), urinary retention (1 patient) and insomnia (1
patient).
[0150] Subjects in cohort 4 reported incidences of diarrhea 5
patients), nausea (2 patients), thrombocytopenia (1 patient),
headache (2 patients), neutropenia (1 patient), abdominal pain (2
patients), dyspepsia (2 patients), dysgeusia (2 patients), anemia
(1 patient), influenza-like illness (1 patient), dehydration (2
patients), urinary retention (1 patient), insomnia (1 patient), eye
pain (2 patients) and sinusitis (1 patient).
[0151] Subjects in cohort 5 reported incidences of diarrhea (1
patient) and abdominal pain (1 patient).
[0152] Adverse events reported were severity Grade 1 and 2 except
for decreased ANC (neutropenia), pneumonia and thrombocytopenia.
Four (4) patients reported Grade 3-4 thrombocytopenia. Two (2)
patients reported Grade 3-4 pneumonia. Three (3) patients reported
Grade 3-4 neutropenia.
[0153] Besides the DLT reported for the follicular lymphoma patient
in cohort 3, no other DLTs have occurred and MTD has not been
reached. Serious adverse events not related to the study include
disseminated Herpes zoster (1 patient in cohort 1), pneumonia (1
patient in cohort 1), atrial fibrillation (1 patient in cohort 2),
hematuria/urinary retention (1 patient in cohort 3),
pneumonia/thrombocytopenia/ANC decreased (1 patient in cohort 3)
and tonsillar hypertrophy (1 patient in cohort 4).
[0154] Most frequent treatment emergent AEs (TEAEs) (defined as an
adverse event reported for at least 2 subjects regardless of dose)
included grade 1 or 2 transient diarrhea (15/21; 71.4%), grade 1 or
2 headache (5/21; 23.8%), and thrombocytopenia (5/21; 23.8%). The
most common Grade 3/4 adverse events included neutropenia (3/21;
probably related), pneumonia (2/21; probably related) and
thrombocytopenia (4/21; probably related).
[0155] Lymph Node Size in CLL Patients.
[0156] FIG. 6 depicts the change in lymph node size in CLL patients
with available lymph node assessment, twelve (12) of whom are from
cohorts 1-5. These patients have experienced some degree of lymph
node reduction: 2/12 patients have experienced nodal response
(>50% reduction); 6/12 patients have experienced between 25 and
50% reduction over the treatment and follow-up periods indicated in
the figure. The doses indicated refer to the patient's starting
dose. The numbers at the top of each bar indicate the number of
cycles completed for each subject as of the last available lymph
node measurement.
[0157] Absolute Lymphocyte Count in CLL Patients.
[0158] FIG. 7 depicts the change in absolute lymphocyte count (ALC)
in CLL patients. As of Sep. 11, 2012, eleven (11) of fifteen (15)
CLL patients in cohorts 1-6A/B who had completed at least one
28-day cycle and for whom absolute lymphocyte counts (ALC) were
available exhibited early increases (.gtoreq.25%) in absolute
lymphocyte counts (ALC) during the first 28-day cycle, which was
consistent with the hypothesis that the API affects CLL lymphocyte
trafficking. FIG. 7 shows the increase or decrease in ALC from
baseline to C1D8 (cycle 1, day 8) as well as the percentage change
in ALC from baseline to the maximum observed at any time during
cycle 1 up to and including day 29 (cycle 2, day 1 or C2D1). All
CLL subjects with follow-up through cycle 1 at all dose levels are
shown. Subjects treated with 750 mg or higher are indicated under
the dotted line.
[0159] Lymph Node Size in NHL Patients.
[0160] Six B-NHL patients exhibited decreased lymph node size. FIG.
8 depicts the lymph node size percent change for those B-NHL
patients who have had a baseline lymph node measurement and at
least one follow-up measurement post-treatment. The doses indicated
refer to the patient's starting dose. The numbers at the top of
each bar indicate the number of cycles completed for each subject
as of the last available lymph node measurement. One patient with
FL is not displayed because the patient was withdrawn from the
study in the first cycle of treatment for DLT and was not evaluable
for response.
[0161] Observations.
[0162] Across the first five doses, once daily dosing with 125 mg,
250 mg, 400 mg, 625 mg and 750 mg
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate was found to be generally safe and
well-tolerated. As of Sep. 11, 2012, twenty-one (21) of thirty-six
(36) patients in cohorts 1-6A/B continue on treatment, with a
median time of treatment of 77.5 days (range of 9-357 days). PK
exposure (AUC.sub.last) was linear with no accumulation from Day 1
to 15. Full Btk occupancy was achieved with dose levels .gtoreq.250
mg QD and PK was predictable with no accumulation. Additional study
of 750 mg QD is ongoing. MTD has not yet been reached and cohort
expansion is planned.
Example 2
Diagnosis-Specific Expansion Cohorts
[0163] After completion of observation for DLTs in Example 1, the
accumulated safety, PK, and PD data from Example 1 were evaluated
to select a preliminary recommended Phase 2 dose for administration
to additional subjects enrolled into an independent and
non-randomized diagnosis-specific expansion cohorts in the
Diagnosis Specific Expansion Cohorts study. [0164] Cohort A:
Relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL);
[0165] Cohort B: Relapsed and/or refractory indolent and mantle
B-cell lymphomas, Waldenstrom's macroglobulinemia, and other B
lymphoproliferative disorders of uncertain malignant potential (at
least 10 of the 24 enrollment slots will be reserved for subjects
with mantle cell lymphoma); and [0166] Cohort C: Relapsed and/or
refractory CLL/SLL.
[0167] Study Results: Cohort C.
[0168] 24 subjects were enrolled into the CLL expansion cohort C
and were assessed for safety, tolerability, DLT, PK, PD and disease
response. Each subject was evaluated prior to enrollment to ensure
that minimum hematological criteria were satisfied:
TABLE-US-00005 TABLE 5 Minimum Hematological Criteria CLL Platelets
.gtoreq.30,000/mm.sup.3 Absolute Neutrophil Count
.gtoreq.1,000/mm.sup.3 (ANC) Hemoglobin (Hgb) .gtoreq.8 g/dL
[0169] Within cohort C, 24 subjects were treated 750 mg po QD with
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate as monotherapy during an initial 28-day
treatment cycle and were assessed for safety, tolerability, DLT,
PK, PD, and disease response.
[0170] All subjects enrolled in expansion cohort C were
continuously evaluated for DLTs (see DLT definitions below).
Twenty-four patients showed no DLT and twenty-three patients showed
no disease progression and continue to receive
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phen-
yl)acrylamide besylate as continuous monotherapy. One patient
exhibited progressive disease after 73 days (2.6 cycles) and
treatment was discontinued. FIG. 3 depicts the treatment duration
of the CLL expansion cohort C through Sep. 11, 2012.
[0171] FIG. 6 depicts the change in lymph node size in CLL patients
with available lymph node assessment, eleven (11) of whom are from
Expansion Cohort C. These patients have experienced some degree of
lymph node reduction: 1/11 patients has experienced nodal response
(>50% reduction); 6/11 patients have experienced between 25 and
50% reduction over the treatment and follow-up periods indicated in
the figure.
[0172] As of Sep. 11, 2012, seventeen (17) of eighteen (18)
patients enrolled in the CLL Expansion Cohort C who had completed
at least one 28-day cycle and for whom absolute lymphocyte counts
(ALC) were available exhibited early increases (.gtoreq.25%) in
absolute lymphocyte counts (ALC) during the first 28-day cycle,
which was consistent with the hypothesis that the API affects CLL
lymphocyte trafficking. The ALC for expansion cohort C are
presented in FIG. 7.
[0173] A similar protocol will be used for expansion cohorts A and
B. In particular, however, if in any specific expansion cohort
.gtoreq.9 subjects experience DLT, then all future subjects
enrolling in that specific expansion cohort and subjects then
currently still in Cycle 1 of that specific cohort will be dose
reduced by 1 dose level (per Table 2). In the event that 2 or more
subjects in any specific expansion cohort experience the same DLT
of grade .gtoreq.4, then all subjects in that cohort will be
reduced by 1 dose level, and the investigators and Sponsor will
determine whether to apply the dose reduction to all 3 expansion
cohorts. If applicable, this dose reduction will also apply to any
subjects from Example 2 who entered the Continuation Phase and were
intra-subject dose escalated to the initial preliminary recommended
Phase 2 dose.
Example 3
Continuation Phase of Treatment
[0174] In both Dose Escalation and Diagnosis-Specific Expansion
Cohort studies, subjects who complete the first 28-day cycle of
therapy will be evaluated for entry into a Continuation Phase of
the study. Subjects will be eligible for continuation if: 1) they
demonstrate no evidence of disease progression; 2) in the opinion
of the investigator, they are deemed likely to continue to benefit
from treatment; and 3) they have not experienced any toxicity
requiring discontinuation. Subjects with CLL experiencing nodal
response with lymphocytosis will also be eligible for additional
treatment. Subjects with WM with increased serum IgM levels at the
end of 6 cycles of treatment should also be evaluated for
lymphadenopathy/organomegaly and marrow infiltration. Investigators
may use judgment in determining whether to continue these subjects
into continuation cycles if there is a discordant response between
increased IgM and stable or decreased lymphadenopathy/organomegaly
and marrow infiltration. During continuation therapy, subjects will
continue to receive
N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylam-
ino)phenyl)acrylamide besylate as monotherapy in 28-day cycles
until unacceptable toxicity or the subject or investigator decide
to discontinue treatment for any reason.
* * * * *