U.S. patent application number 17/589562 was filed with the patent office on 2022-07-28 for methods for treating lymphoma.
The applicant listed for this patent is Alexion Pharmaceuticals, Inc.. Invention is credited to Matthew Birrell, Gregory Coffey, Pamela B. Conley, John T. Curnutte, Glenn Michelson, Anjali Pandey, Andrew Steele.
Application Number | 20220233533 17/589562 |
Document ID | / |
Family ID | 1000006290292 |
Filed Date | 2022-07-28 |
United States Patent
Application |
20220233533 |
Kind Code |
A1 |
Coffey; Gregory ; et
al. |
July 28, 2022 |
METHODS FOR TREATING LYMPHOMA
Abstract
Compositions and methods for treating lymphoma, in particular,
T-cell lymphoma and follicular lymphoma, in a human patient are
provided. The methods entail administering to the patient an
effective amount of cerdulatinib.
Inventors: |
Coffey; Gregory; (San
Carlos, CA) ; Birrell; Matthew; (Lafayette, CA)
; Conley; Pamela B.; (Palo Alto, CA) ; Curnutte;
John T.; (Tustin, CA) ; Pandey; Anjali;
(Fremont, CA) ; Steele; Andrew; (Haslemere,
GB) ; Michelson; Glenn; (Fairfax, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alexion Pharmaceuticals, Inc. |
Boston |
MA |
US |
|
|
Family ID: |
1000006290292 |
Appl. No.: |
17/589562 |
Filed: |
January 31, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16403227 |
May 3, 2019 |
11266645 |
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17589562 |
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62736047 |
Sep 25, 2018 |
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62678934 |
May 31, 2018 |
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62667249 |
May 4, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 39/3955 20130101;
A61K 31/635 20130101; A61K 31/52 20130101; A61P 35/02 20180101;
A61K 2039/505 20130101; A61K 31/506 20130101; A61K 9/0053 20130101;
A61K 31/519 20130101; A61K 31/5377 20130101 |
International
Class: |
A61K 31/506 20060101
A61K031/506; A61P 35/02 20060101 A61P035/02; A61K 39/395 20060101
A61K039/395; A61K 31/635 20060101 A61K031/635; A61K 31/519 20060101
A61K031/519; A61K 31/52 20060101 A61K031/52; A61K 31/5377 20060101
A61K031/5377; A61K 9/00 20060101 A61K009/00 |
Claims
1-36. (canceled)
37. A method of treating a lymphoma in a human patient in need
thereof wherein the patient has one or more mutations in FAT4,
CCND3, MYOM2, ZMYM3, NOTCH1, KMT2D, TCF3, ARID1A, AXIN1, SYK, JAK1,
JAK3, or TYK2, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal, or solvate thereof.
38. The method of claim 37, wherein the patient has one or more
mutations in BCL2 or BCL6.
39. The method of claim 37, wherein the lymphoma is relapsed or
refractory lymphoma.
40. The method of claim 37, wherein the lymphoma is indolent
lymphoma or B cell acute lymphocytic leukemia.
41. The method of claim 37, wherein the patient has one or more
mutations in SYK, JAK1, JAK3, or TYK2.
42. The method of claim 37, wherein the effective amount of
cerdulatinib is from about 15 mg to about 30 mg, and the step of
administering comprises twice daily administration of the about 15
mg to about 30 mg.
43. The method claim 37, wherein the effective amount of
cerdulatinib is about 15 mg, about 20 mg, about 25 mg, or about 30
mg, and the step of administering comprises twice daily
administration of the about 15 mg, about 20 mg, about 25 mg, or
about 30 mg.
44. The method of claim 37, further comprising administering to the
patient an effective amount of rituximab.
45. A method of treating a lymphoma in a human patient in need
thereof wherein the patient has one or more mutations in ZMYM3,
KMT2D, FAT4, SYK, JAK1, JAK3, or TYK2, comprising administering to
the patient an effective amount of cerdulatinib or a
pharmaceutically acceptable salt, co-crystal, or solvate
thereof.
46. The method of claim 45, wherein the patient has one or more
mutations in SYK, JAK1, JAK3, or TYK2.
47. The method of claim 45, wherein the effective amount of
cerdulatinib is from about 15 mg to about 30 mg, and the step of
administering comprises twice daily administration of the about 15
mg to about 30 mg.
48. The method claim 45, wherein the effective amount of
cerdulatinib is about 15 mg, about 20 mg, about 25 mg, or about 30
mg, and the step of administering comprises twice daily
administration of the about 15 mg, about 20 mg, about 25 mg, or
about 30 mg.
49. The method of claim 45, further comprising administering to the
patient an effective amount of rituximab.
50. A method of treating lymphoma in a human patient in need
thereof wherein the patient has one or more mutations in NOTCH1,
SETD2, SIGLEC10, SPEN, PCLO, TET2, MK167, FAT3, KRAS, REL,
HIST1H1E, KMT2C, KMT2D, or SF3B1, comprising administering to the
patient an effective amount of cerdulatinib or a pharmaceutically
acceptable salt, co-crystal, or solvate thereof.
51. The method of claim 50, wherein the patient has one or more
mutations in SYK, JAK1, JAK2, JAK3, TYK2, TP53, STAT, A20 or
ATM.
52. The method of claim 51, wherein the patient has one or more
mutations in SYK, JAK1, JAK3, or TYK2.
53. The method of claim 50, further comprising administering to the
patient an effective amount of rituximab.
54. The method of claim 53, wherein the administration of the
cerdulatinib and the rituximab comprises co-administration of the
cerdulatinib and the rituximab.
55. The method of claim 50, wherein the effective amount of
cerdulatinib is from about 15 mg to about 30 mg, and the step of
administering comprises twice daily administration of the about 15
mg to about 30 mg.
56. The method claim 50, wherein the effective amount of
cerdulatinib is about 15 mg, about 20 mg, about 25 mg, or about 30
mg, and the step of administering comprises twice daily
administration of the about 15 mg, about 20 mg, about 25 mg, or
about 30 mg.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/403,227, filed on May 3, 2019, which claims the benefit
under 35 U.S.C. .sctn. 119(e) of U.S. Provisional Applications
62/667,249, filed on May 4, 2018, 62/678,934, filed on May 31,
2018, and 62/736,047, filed on Sep. 25, 2018, each of which is
hereby incorporated by reference in its entirety.
FIELD
[0002] The present disclosure relates generally to treatment of
hematological cancers, in particular lymphomas.
BACKGROUND
[0003] Lymphoma is a cancer of a part of the immune system called
the lymph system. There are many types of lymphoma. One type is
Hodgkin disease. The rest are called non-Hodgkin lymphomas.
Non-Hodgkin lymphoma (NHL) is generally divided into two main
types, based on whether its origin is B cells (B-cell lymphomas) or
T cells (T-cell lymphomas).
[0004] Lymphomas as a group are the seventh-most common form of
cancers, accounting for 3-4% of all cancers. Worldwide, lymphomas
developed in about 566,000 people in 2012 and caused about 305,000
deaths. The five-year survival rate in the United States for all
Hodgkin lymphoma subtypes is 85%, while that for non-Hodgkin
lymphomas is 69%. Therefore, there remains a need for new therapies
for lymphomas, especially non-Hodgkin lymphomas.
SUMMARY
[0005] The present disclosure relates to the use of cerdulatinib in
the treatment of lymphomas.
[0006] Cerdulatinib is a small molecule, ATP-competitive,
reversible inhibitor of both SYK and JAK family members and is
described in U.S. Pat. Nos. 8,138,339 and 8,501,944. Cerdulatinib
has a chemical name of
4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)phenyl)amino)-
pyrimidine-5-carboxamide, and the structure of formula I:
##STR00001##
[0007] In some embodiments, provided herein is a method of treating
a T-cell lymphoma in a human patient in need thereof, comprising
administering to the patient an effective amount of cerdulatinib or
a pharmaceutically acceptable salt, co-crystal or solvate
thereof.
[0008] In some embodiments, the T-cell lymphoma is relapsed or
refractory T-cell lymphoma. In some embodiments, the T-cell
lymphoma has not been previously treated with an agent for treating
T-cell lymphoma (i.e., treatment naive). In some embodiments, the
T-cell lymphoma is T-cell non-Hodgkin lymphoma. In some
embodiments, the T-cell lymphoma is relapsed or refractory T-cell
non-Hodgkin lymphoma. In some embodiments, the T-cell lymphoma is
peripheral T-cell lymphoma. In some embodiments, the T-cell
lymphoma is relapsed or refractory peripheral T-cell lymphoma.
[0009] In some embodiments, provided herein is a method of treating
a lymphoma in a human patient in need thereof and expressing one or
more of Mcl-1, FoxP1, GAB1, SOCS1, or SOCS3 above a normal baseline
or having (or known to have) one or more mutations in FAT4, CCND3,
MYOM2, ZMYM3, NOTCH1, KMT2D, TCF3, ARID1A, AXIN1, NOTCH1, SETD2,
SIGLEC10, SPEN, PCLO, TET2 (e.g., TET2.sup.M66L), MK167, FAT3,
KRAS, REL (e.g., REL.sup.I354T), HIST1H1E (e.g.,
HIST1H1E.sup.A47V), KMT2C, KMT2D, and/or SF3B1, comprising
administering to the patient an effective amount of cerdulatinib or
a pharmaceutically acceptable salt, co-crystal or solvate
thereof.
[0010] In some embodiments, provided herein is a method of treating
a lymphoma in a human patient in need thereof and having (or known
to have) one or more mutations in ZMYM3, KMT2D, and FAT4,
comprising administering to the patient an effective amount of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof.
[0011] In some embodiments, the patient further has one or more
mutations in BCL2, and/or BCL6.
[0012] In some embodiments, the lymphoma is follicular lymphoma
(FL), transformed follicular lymphoma (tFL), diffuse large B-cell
lymphoma (DLBCL), T-cell lymphoma, or mantle cell lymphoma
(MCL).
[0013] In some embodiments, the lymphoma is indolent lymphoma or B
cell acute lymphocytic leukemia. In some embodiments, the lymphoma
is indolent lymphoma. In some embodiments, the indolent lymphoma is
follicular lymphoma. In some embodiments, the indolent lymphoma is
Waldenstrom's macroglobulinemia. In some embodiments, the indolent
lymphoma is marginal zone lymphoma. In some embodiments, the
lymphoma is B cell acute lymphocytic leukemia. In some embodiments,
the lymphoma is relapsed or refractory follicular lymphoma. In some
embodiments, the lymphoma is transformed follicular lymphoma. In
some embodiments, the lymphoma is relapsed or refractory
transformed follicular lymphoma.
[0014] In some embodiments, provided herein is a method of treating
progressive chronic lymphocytic leukemia (U-CLL) or indolent
chronic lymphocytic leukemia (M-CLL) in a human patient in need
thereof, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof.
[0015] In some embodiments, provided herein is a method of treating
chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
(SLL) in a human patient in need thereof and having (or known to
have) one or more mutations in NOTCH1, SETD2, SIGLEC10, SPEN, PCLO,
TET2 (e.g., TET2.sup.M66L), MK167, FAT3, KRAS, REL (e.g.,
REL.sup.I354T), HIST1H1E (e.g., HIST1H1E.sup.A47V), KMT2C, KMT2D,
and/or SF3B1, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof.
[0016] In some embodiments, provided herein is a method of treating
chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
(SLL) in a human patient in need thereof and having (or known to
have) one or more mutations in SETD2, SIGLEC10, SPEN, PCLO, TET2
(e.g., TET2.sup.M66L), MK167, FAT3, KRAS, REL (e.g.,
REL.sup.I354T), HIST1H1E (e.g., HIST1H1E.sup.A47V), KMT2C, KMT2D,
and/or SF3B1, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof.
[0017] In some embodiments, provided herein is a method of treating
chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
(SLL) in a human patient in need thereof and having (or known to
have) one or more mutations in TET2 (e.g., TET2.sup.M66L), MK167,
FAT3, KRAS, HIST1H1E (e.g., HIST1H1E.sup.A47V), KMT2C, KMT2D,
and/or SF3B1, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof.
[0018] In some embodiments, the patient further has one or more
mutations in SYK, JAK1, JAK2, JAK3, TYK2, TP53, STAT (e.g.,
STAT6.sup.S86A), A20 (e.g., A20.sup.Q150R) and/or ATM.
[0019] In some embodiments, the patient does not have a mutation in
EP300, TP53 and/or BTK. In some embodiments, the patient does not
have EP300.sup.S697R, EP300.sup.C1247F, TP53.sup.N285K,
TP53.sup.R273C and/or BTK.sup.C481S.
[0020] In some embodiments, provided herein is a method of treating
a follicular lymphoma or indolent non-Hodgkin's Lymphoma (iNHL) in
a human patient in need thereof, comprising administering to the
patient an effective amount of cerdulatinib or a pharmaceutically
acceptable salt, co-crystal or solvate thereof to achieve and
maintain a steady state minimum plasma cerdulatinib concentration
of between about 0.05 .mu.M to about 3 .mu.M in the patient.
[0021] In some embodiments, provided herein is a method of treating
a chronic lymphocytic leukemia or small lymphocytic lymphoma in a
human patient in need thereof, comprising administering to the
patient an effective amount of cerdulatinib or a pharmaceutically
acceptable salt, co-crystal or solvate thereof to achieve and
maintain a steady state minimum plasma cerdulatinib concentration
of between about 0.05 .mu.M to about 3 .mu.M in the patient.
[0022] In some embodiments, provided herein is a method of treating
a marginal zone lymphoma, Waldenstrom's macroglobulinemia, chronic
lymphocytic leukemia or small lymphocytic lymphoma in a human
patient in need thereof, comprising administering to the patient an
effective amount of cerdulatinib or a pharmaceutically acceptable
salt, co-crystal or solvate thereof to achieve and maintain a
steady state minimum plasma cerdulatinib concentration of between
about 0.05 .mu.M to about 3 .mu.M in the patient.
[0023] In some embodiments, provided herein is a method of treating
a lymphoma in a human patient in need thereof comprising
administering to the patient an effective amount of cerdulatinib or
a pharmaceutically acceptable salt, co-crystal or solvate thereof
and an effective amount of a Mcl-1 inhibitor or a pharmaceutically
acceptable salt, co-crystal or solvate thereof.
[0024] In some embodiments, provided herein is a use of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof in a treatment method described herein.
[0025] In some embodiments, provided herein is a use of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof in the manufacture of a medicament for use in a
treatment method described herein.
[0026] In some embodiments, provided herein is a method of treating
a lymphoma in a human patient in need thereof, comprising
administering to the patient an effective amount of cerdulatinib or
a pharmaceutically acceptable salt, co-crystal or solvate thereof
and an effective amount of rituximab.
[0027] In some embodiments, provided herein is a use of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof and rituximab in a treatment method described
herein.
[0028] In some embodiments, provided herein is a composition
comprising an effective amount of cerdulatinib or a
pharmaceutically acceptable salt, co-crystal or solvate thereof and
an effective amount of rituximab.
[0029] In some embodiments, provided herein is a use of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof and rituximab in the manufacture of a medicament
for use in a treatment method described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1 shows tumor response to cerdulatinib and association
with exposure in CLL/SLL and FL patients.
[0031] FIG. 2 shows tumor response as it relates to SYK/JAK
inhibition.
[0032] FIG. 3 shows inhibition of serum markers of inflammation
significantly correlate with tumor response in CLL/SLL
patients.
[0033] FIG. 4 shows inhibition of serum markers of inflammation
significantly correlate with tumor response in FL patients.
[0034] FIG. 5A shows significant inhibition of serum markers of
inflammation in CLL/SLL patients following treatment with
cerdulatinib. FIG. 5B shows significant inhibition of serum markers
of inflammation in FL patients following treatment with
cerdulatinib.
[0035] FIG. 6A and FIG. 6B show cerdulatinib treatment-related
increases in blood absolute lymphocyte counts (ALC) occurred in
CLL/SLL (FIG. 6A) and FL patients (FIG. 6B), respectively.
[0036] FIG. 7A and FIG. 7B show cerdulatinib treatment-related
changes in tumor cell surface activation and homing markers in a
CLL patient having 52% nodal reduction (FIG. 7A) and a CLL patient
having 59% nodal reduction (FIG. 7B), respectively.
[0037] FIG. 8 shows the duration of time on cerdulatinib for each
of the dosed patients in Example 1.
[0038] FIG. 9A and FIG. 9B show immunoblots demonstrating protein
expression among progressive (U-CLL) (FIG. 9A) and indolent CLL
(M-CLL) (FIG. 9B) cell lines, respectively, following treatment
with and without IL-4 in the presence or absence of
cerdulatinib.
[0039] FIG. 10A, FIG. 10B, FIG. 10C, FIG. 10D, FIG. 10E, FIG. 10F,
and FIG. 10G are summary of the immunoblot densitometry indicating
changes in expression of FOXP1 (FIG. 10A), GAB1 (FIG. 10B), SOCS1
(FIG. 10C), PTPN22 (FIG. 10D), SOCS3 (FIG. 10E), CD79b (FIG. 10F),
and pSTAT6 (FIG. 10G), respectively, in CLL cells following
treatment with and without IL-4 in the presence or absence of 1
.mu.M cerdulatinib as compared with control. In each of FIG. 10A,
FIG. 10B, FIG. 10C, FIG. 10D, FIG. 10E, FIG. 10F, and FIG. 10G, the
bars from left to right represent control, IL-4 treatment alone,
cerdulatinib treatment alone and IL-4+cerdulatinib,
respectively.
[0040] FIG. 11A, FIG. 11B, FIG. 11C, FIG. 11D, FIG. 11E, FIG. 11F,
and FIG. 11G are summary of the immunoblot densitometry indicating
changes in expression of FOXP1 (FIG. 11A), GAB1 (FIG. 11B), SOCS1
(FIG. 11C), PTPN22 (FIG. 11D), SOCS3 (FIG. 11E), CD79b (FIG. 11F),
and pSTAT6 (FIG. 11G), respectively, in progressive CLL cells
following treatment with and without IL-4 in the presence or
absence of 1 .mu.M cerdulatinib as compared with control. In each
of FIG. 11A, FIG. 11B, FIG. 11C, FIG. 11D, FIG. 11E, FIG. 11F, and
FIG. 11G, the bars from left to right represent control, IL-4
treatment alone, cerdulatinib treatment alone and
IL-4+cerdulatinib, respectively.
[0041] FIG. 12A, FIG. 12B, FIG. 12C, FIG. 12D, FIG. 12E, FIG. 12F,
and FIG. 12G are summary of the immunoblot densitometry indicating
changes in expression of FOXP1 (FIG. 12A), GAB1 (FIG. 12B), SOCS1
(FIG. 12C), PTPN22 (FIG. 12D), SOCS3 (FIG. 12E), CD79b (FIG. 12F),
and pSTAT6 (FIG. 12G), respectively, in indolent CLL cells
following treatment with and without IL-4 in the presence or
absence of 1 .mu.M cerdulatinib as compared with control. In each
of FIG. 12A, FIG. 12B, FIG. 12C, FIG. 12D, FIG. 12E, FIG. 12F, and
FIG. 12G, the bars from left to right represent control, IL-4
treatment alone, cerdulatinib treatment alone and
IL-4+cerdulatinib, respectively.
DETAILED DESCRIPTION
[0042] It is to be understood that this disclosure is not limited
to particular embodiments described, as such may, of course, vary.
It is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments only, and is not
intended to be limiting, since the scope of the present disclosure
will be limited only by the appended claims.
1. Definitions
[0043] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this disclosure belongs. As used
herein the following terms have the following meanings.
[0044] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "an agent" includes a plurality of
agents.
[0045] As used herein, the term "comprising" or "comprises" is
intended to mean that the compositions and methods include the
recited elements, but not excluding others. "Consisting essentially
of" when used to define compositions and methods, shall mean
excluding other elements of any essential significance to the
combination for the stated purpose. Thus, a composition consisting
essentially of the elements as defined herein would not exclude
other materials or steps that do not materially affect the basic
and novel characteristic(s) claimed. "Consisting of" shall mean
excluding more than trace elements of other ingredients and
substantial method steps. Embodiments defined by each of these
transition terms are within the scope of this disclosure.
[0046] The term "about" when used before a numerical designation,
e.g., amount, and concentration, including range, indicates
approximations which may vary by (+) or (-) 10%, 5% or 1%.
[0047] As used herein, the term "treating" refers to preventing,
curing, reversing, attenuating, alleviating, minimizing,
suppressing or halting tumor growth, spreading, metastasis, or
development.
[0048] As used herein, the term "patient" refers to a subject
having a cancer or tumor, which can be benign or malignant. In
certain embodiments, the patent is a human or an animal.
[0049] As used herein, the term "pharmaceutically acceptable"
indicates that the indicated material does not have properties that
would cause a reasonably prudent medical practitioner to avoid
administration of the material to a patient, taking into
consideration the disease or conditions to be treated and the
respective route of administration. For example, it is commonly
required that such a material be essentially sterile.
[0050] As used herein, the term "pharmaceutically acceptable
carrier" refers to pharmaceutically acceptable materials,
compositions or vehicles, such as a liquid or solid filler,
diluent, excipient, solvent or encapsulating material, involved in
carrying or transporting any supplement or composition, or
component thereof, from one organ, or portion of the body, to
another organ, or portion of the body, or to deliver an agent to
the cancerous tissue or a tissue adjacent to the cancerous
tissue.
[0051] As used herein, the term "pharmaceutically acceptable salt"
refers to any acid or base addition salt whose counter-ions are
non-toxic to the patient in pharmaceutical doses of the salts. A
host of pharmaceutically acceptable salts are well known in the
pharmaceutical field. If pharmaceutically acceptable salts of the
compounds of this disclosure are utilized in these compositions,
those salts are preferably derived from inorganic or organic acids
and bases. Included among such acid salts are the following:
acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate,
bisulfate, butyrate, citrate, camphorate, camphor sulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, fumarate, lucoheptanoate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate,
pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate,
pivalate, propionate, succinate, tartrate, thiocyanate, tosylate,
undecanoate, hydrohalides (e.g., hydrochlorides and hydrobromides),
sulphates, phosphates, nitrates, sulphamates, malonates,
salicylates, methylene-bis-b-hydroxynaphthoates, gentisates,
isethionates, di-p-toluoyltartrates, ethanesulphonates,
cyclohexylsulphamates, quinates, and the like. Pharmaceutically
acceptable base addition salts include, without limitation, those
derived from alkali or alkaline earth metal bases or conventional
organic bases, such as triethylamine, pyridine, piperidine,
morpholine, N-methylmorpholine, ammonium salts, alkali metal salts,
such as sodium and potassium salts, alkaline earth metal salts,
such as calcium and magnesium salts, salts with organic bases, such
as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with
amino acids such as arginine, lysine, and so forth.
[0052] As used herein, the term "formulated" or "formulation"
refers to the process in which different chemical substances,
including one or more pharmaceutically active ingredients, are
combined to produce a dosage form. In certain embodiments, two or
more pharmaceutically active ingredients can be co-formulated into
a single dosage form or combined dosage unit, or formulated
separately and subsequently combined into a combined dosage unit. A
sustained release formulation is a formulation which is designed to
slowly release a therapeutic agent in the body over an extended
period of time, whereas an immediate release formulation is a
formulation which is designed to quickly release a therapeutic
agent in the body over a shortened period of time.
[0053] As used herein, the term "delivery" refers to approaches,
formulations, technologies, and systems for transporting a
pharmaceutical composition in the body as needed to safely achieve
its desired therapeutic effect. In some embodiments, an effective
amount of the composition is formulated for delivery into the blood
stream of a patient.
[0054] Abbreviations:
[0055] ABVD doxorubicin, bleomycin, vinblastine, and
dacarbazine
[0056] AUC area under curve
[0057] BEAM carmustine, etopside, cytarabine, and melphalan
[0058] BID: once daily
[0059] CHOP cyclophosphamide, doxorubicin, vincristine, and
prednisone
[0060] C.sub.max maximum (or peak) concentration
[0061] C.sub.min minimum (or trough) concentration
[0062] CR: complete response
[0063] EPOCH etoposide, prednisone, vincristine, cyclophosphamide
and doxorubicin
[0064] IC.sub.50 half maximal inhibitory concentration
[0065] mg milligram
[0066] mL milliliter
[0067] ORR: overall response rate
[0068] PD progressive disease
[0069] pg picogram
[0070] PR: partial response
[0071] QD: twice daily
[0072] SD stable disease
[0073] SSC.sub.min steady state C.sub.min
[0074] .mu.L microliter
[0075] .mu.M micromolar
2. Methods of Treatment
[0076] Provided herein are methods of treating lymphomas with
cerdulatinib.
[0077] Cerdulatinib is a small molecule, ATP-competitive,
reversible inhibitor of both SYK and JAK family members.
Cerdulatinib has a chemical name of
4-(cyclopropylamino)-2-((4-(4-(ethylsulfonyl)piperazin-1-yl)pheny-
l)amino)pyrimidine-5-carboxamide or
4-(cyclopropylamino)-2-({4-[4-(ethanesulfonyl)piperazin-1-yl]phenyl}amino-
)pyrimidine-5-carboxamide, and the chemical structure of formula
I:
##STR00002##
[0078] Treatment of T-Cell Lymphoma
[0079] In some embodiments, provided herein is a method of treating
a T-cell lymphoma (TCL) in a human patient in need thereof,
comprising administering to the patient an effective amount of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof.
[0080] There are many different forms of T-cell lymphomas, some of
which are aggressive (fast-growing) and some of which are indolent
(slow-growing). T-cell lymphomas include immature T-cell lymphoma,
such as T-cell lymphoblastic lymphoma (T-LBL), and mature T-cell
lymphomas, such as peripheral T-cell lymphoma (PTCL).
[0081] Peripheral T-cell lymphomas (PTCLs), developed in mature
white blood cells called T-cells, are aggressive types of
non-Hodgkin lymphoma (NHL) with a median survival of less than 5
years, and typically have a poorer prognosis compared to their B
cell counterparts. O'Connor, O. A., et al., Changing the Paradigms
of Treatment in Peripheral T-cell Lymphoma: From Biology to
Clinical Practice. Clin Cancer Res, 2014. 20(20):5240-5254;
Swerdlow, S. H., et al., The 2016 revision of the World Health
Organization classification of lymphoid neoplasms. Blood, 2016.
127(20):2375-2390; Gaulard, P., and de Leval, L., Pathology of
Peripheral T-Cell Lymphomas: Where Do We Stand? Seminars in
Hematology, 2014. 51(1):5-16. In general, patients with PTCL have
an inferior survival when compared to patients with B-cell NHL.
Swerdlow, S. H., et al., The 2016 revision of the World Health
Organization classification of lymphoid neoplasms. Blood, 2016.
127(20):2375-2390; Vose, J. M., et. al, International Peripheral
T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings
and Clinical Outcomes. Journal of Clinical Oncology, 2008.
26(25):4124-4130; Gisselbrecht, C., et. al, Prognostic Significance
of T-Cell Phenotype in Aggressive Non-Hodgkin's Lymphomas. Blood,
1998. 92(1):76-82.
[0082] Front-line therapy for PTCL is typically CHOP
(cyclophosphamide, doxorubicin, vincristine, prednisone) or CHO(E)P
in which etoposide is included, or other intense chemotherapy,
albeit with outcomes inferior to those described in B-cell
malignancies. The majority of patients relapse following standard
therapy, and overall survival (OS) remains low. For PTCL patients
(other than ALCL) who relapse after, or are refractory to,
frontline therapies, median OS is 6 months. Mak, V., et. al.,
Survival of patients with peripheral T-cell lymphoma after first
relapse or progression: spectrum of disease and rare long-term
survivors. J Clin Oncol, 2013. 31(16):1970-1976.
[0083] A limited number of options exist for patients who fail
frontline chemotherapy. In the United States, belinostat (HDAC
inhibitor), pralatrexate (anti-folate), and romidepsin are approved
for patients with relapsed or refractory PTCL, which have poor
overall response rates (ORRs) of approximately 25%, with a complete
response (CR) rate of 8 to 15% and a median duration of response
(DOR) up to 12 months, see Table 1.
TABLE-US-00001 TABLE 1 Clinical Data for the Agents Approved for
Relapsed/Refractory PTCL Pralatrexate.sup.a Romidepsin.sup.b
Belinostat Brentuximab.sup.c Mechanism of Anti-folate HDAC
inhibitor HDAC inhibitor CD30-directed Action antibody-drug
conjugate Approval Year 2009 2011 2014 2011 Dosing and 30
mg/m.sup.2 IV 14 mg/m.sup.2 IV 1,000 mg/m.sup.2, IV infusion over
Administration infusion over 3 to infusion over a 30 minute IV 30
minutes every 5 minutes once 4-hour period on infusion on Days 3
weeks. 1.8 weekly for 6 Days 1, 8, and 15 1-5, q3w (21-day mg/kg up
to a weeks in 7-wk of a 28-day cycles). maximum of cycles. cycle.
180 mg. Clinical Trial 115 131 129 58 Patient Number Efficacy ORR:
27% ORR: 26% ORR: 26% ORR: 86% Results (6% CR) (13% CR) (11% CR)
(57% CR) DOR: 9.4 months DOR: 11-15 DOR: 8.4 months DOR: 12.6
months months Safety Thrombocytopenia: Thrombocytopenia: Anemia:
11% Neutropenia: 21% (Grade 3/4 33% 21% Thrombocytopenia:
Peripheral sensory AEs) Mucositis: 21% Fatigue: 13% 7% neuropathy:
10% Neutropenia: Nausea: 4% Fatigue: 5% Thrombocytopenia: 20% 10%
Anemia: 17% Fatigue: 7% .sup.aFOLOTYN .RTM. (pralatrexate
injection) package insert; Westminster, CO; Allos Therapeutics,
Inc. 2016; .sup.bISTODAX .RTM. and (romidepsin) package insert;
Summit, NJ; Celegene Corporation, 2016; .sup.capproved only for
anaplastic large cell lymphoma.
[0084] In comparison, cerdulatinib treatment (e.g., 30 mg BID) in a
clinical trial achieved a 47% ORR and CR were observed in 5/15
evaluable patients (33%), representing diverse subtypes of PTCL.
Importantly, partial response (PR) and CR occurred in patients
refractory to multiple lines of therapy, including pralatrexate,
romidepsin, belinostat, and an investigational PI3K inhibitor.
[0085] The safety profile of cerdulatinib is both predictable and
manageable. The safety data for PTCL (n=16) includes 4 study
drug-related Serious Adverse Events (SAEs) which were Grade 3 to 4
in 8 patients with no deaths or discontinuations in the PTCL
patients due to Treatment Emergent Adverse Events (TEAEs). Table 2
shows a comparison the safety data of cerdulatinib and FDA approved
drugs in PTCL patents.
TABLE-US-00002 TABLE 2 Toxicities .gtoreq. Grade 3 in Approved
Agents for r/r PTCL vs. Cerdulatinib Romidepsin Belinostat
Pralatrexate Brentuximab Cerdulatinib N = 121 N = 139 N = 115 N =
58 N = 16 Mucositis -- -- 23% -- -- Infection 19% 8.5% -- 18.8%
Sepsis 5% -- 5% -- -- Asthenia/Fatigue 8-19% 5% 8% 4% 6.3% Pyrexia
6-17% 2% 2% 2% -- Thrombocytopenia 24-36% 7% 33% 10% -- Neutropenia
20-47% -- 20% 21% 6.3% Anemia 11-28% 11% 17% 2% -- Leukopenia 6-45%
-- 7% -- -- Diarrhea/Colitis -- -- -- 3% 6.3%
[0086] Peripheral T-cell lymphomas include various subtypes, such
as peripheral T-cell lymphoma not otherwise specified (PTCL-NOS),
angioimmunoblastic T-cell lymphoma (AITL), follicular T-cell
lymphoma (FTCL), anaplastic large cell lymphoma (ALCL),
enteropathy-associated T-cell lymphoma (EATL), adult T-cell
leukemia/lymphoma (ATLL), nasal NK/T-cell lymphoma, hepatosplenic
T-cell lymphoma, cutaneous (skin) T-cell lymphoma (CTCL), and are
grouped into three categories: nodal, extranodal and leukemic.
[0087] Peripheral T-cell lymphoma not otherwise specified
(PTCL-NOS) refers to a group of aggressive diseases that do not fit
into any of the other subtypes of PTCL. PTCL-NOS is the most common
PTCL subtype, making up about one-quarter of all PTCLs. Most
patients with PTCL-NOS are diagnosed with their disease confined to
the lymph nodes. Sites outside the lymph nodes, such as the liver,
bone marrow, gastrointestinal tract, and skin, may also be
involved.
[0088] Anaplastic large cell lymphoma (ALCL) is an aggressive
T-cell lymphoma that accounts for approximately 12% to 15% of all
T-cell lymphomas in adults and between 10% and 30% of all lymphomas
in children. It can be divided into three types: two systemic
(presents in lymph nodes or organs) subtypes and one non-systemic
type. The systemic subtypes are anaplastic lymphoma kinase (ALK)
positive anaplastic large cell lymphoma (an abnormal form of the
ALK protein is present on the surface of the lymphoma cells) or ALK
negative anaplastic large cell lymphoma (an abnormal form of the
ALK protein is absent on the surface of the lymphoma cells). The
non-systemic type appears only on the skin and is called primary
cutaneous anaplastic large cell lymphoma. The systemic types are
usually fast-growing, while the non-systemic type is usually more
slow-growing.
[0089] Angioimmunoblastic lymphoma (AITL) is an aggressive T-cell
lymphoma accounting for 15% to 18% of all T-cell lymphomas in the
United States. Symptoms of AITL include high fever, skin rash,
night sweats, and autoimmune disorders such as autoimmune hemolytic
anemia (AIHA) and immune thrombocytopenia (ITP). As a result of
these autoimmune disorders, the body's immune system does not
recognize, and consequently destroys, its own cells and tissues,
such as red blood cells (in the case of AIHA) or platelets (in the
case of ITP). Stage I AITL is localized and has not spread beyond
the tumor. Stage II affects only a nearby lymph node. In stage III,
affected lymph nodes are found both above and below the diaphragm.
In stage IV, one or more organs beyond the lymph nodes are
affected, such as the bone, bone marrow, skin, or liver.
[0090] Cutaneous T-cell lymphoma (CTCL) is a group of typically
slow-growing cancers that appear on, and are most often confined
to, the skin. The most common type of cutaneous T-cell lymphoma is
mycosis fungoides, which appears as skin patches or plaques. Other
types include Sezary syndrome, primary cutaneous anaplastic large
cell lymphoma and lymphomatoid papulosis.
[0091] Adult T-cell leukemia/lymphoma (ATLL) is a rare form of
T-cell lymphoma linked to infection by the human T-cell
lymphotropic virus type 1 (HTLV-1) virus. About two percent who
carry the virus will develop lymphoma. There are 4 subtypes of
ATLL: 2 aggressive subtypes, lymphoma-type ATLL and acute ATLL,
chronic ATLL, which usually grows more slowly, and smouldering
ATLL, which the slowest-growing type.
[0092] Enteropathy-type T-cell lymphoma (EATL) is an extremely rare
subtype of T-cell lymphoma that appears in the intestines and is
strongly associated with celiac disease. There are 2 types of EATL:
type 1, classical EATL, and type 2, monomorphic EATL, which is also
called monomorphic epitheliotropic intestinal T-cell lymphoma.
[0093] Hepatosplenic T-cell lymphoma (HSTL) is a rare extranodal
and systemic neoplasm derived from cytotoxic T-cells. HSLT has two
types: gamma-delta (.gamma..delta.) T-cell receptor type and
alpha-beta (.alpha..beta.) type. There is another .gamma..delta.
T-cell lymphoma, primary cutaneous .gamma..delta. T-cell lymphoma
(PCGD-TCL). These lymphomas share an aggressive course and a dismal
prognosis with most of the other TCLs.
[0094] T-cell lymphoblastic lymphoma (T-LBL) is fast-growing and
most often diagnosed in children.
[0095] Nasal NK/T-cell Lymphomas are fast-growing lymphomas that
typically originate in the lining of the nose or upper airway.
[0096] In some embodiments, the T-cell lymphoma is an aggressive
T-cell lymphoma.
[0097] In some embodiments, the T-cell lymphoma is an indolent
T-cell lymphoma.
[0098] In some embodiments, the T-cell lymphoma is an immature
T-cell lymphoma.
[0099] In some embodiments, the T-cell lymphoma is a mature T-cell
lymphoma.
[0100] In some embodiments, the T-cell lymphoma is nodal T-cell
lymphoma.
[0101] In some embodiments, the T-cell lymphoma is extranodal
T-cell lymphoma.
[0102] In some embodiments, the T-cell lymphoma is leukemic T-cell
lymphoma.
[0103] In some embodiments, the T-cell lymphoma is selected from
peripheral T-cell lymphomas, peripheral T-cell lymphomas not
otherwise specified, angioimmunoblastic T-cell lymphoma, follicular
T-cell lymphoma, anaplastic large cell lymphoma,
enteropathy-associated T-cell lymphoma, adult T-cell
leukaemia/lymphoma, T-cell leukemia, nasal NK/T-cell lymphoma,
hepatosplenic T-cell lymphoma, and cutaneous (skin) T-cell
lymphoma.
[0104] In some embodiments, the T-cell lymphoma is peripheral
T-cell lymphoma.
[0105] In some embodiments, the T-cell lymphoma is peripheral
T-cell lymphoma not otherwise specified.
[0106] In some embodiments, the T-cell lymphoma is
angioimmunoblastic T-cell lymphoma.
[0107] In some embodiments, the T-cell lymphoma is follicular
T-cell lymphoma.
[0108] In some embodiments, the T-cell lymphoma is anaplastic large
cell lymphoma.
[0109] In some embodiments, the T-cell lymphoma is
enteropathy-associated T-cell lymphoma.
[0110] In some embodiments, the T-cell lymphoma is adult T-cell
leukemia/lymphoma.
[0111] In some embodiments, the T-cell lymphoma is cutaneous (skin)
T-cell lymphoma.
[0112] In some embodiments, the T-cell lymphoma is nasal NK/T-cell
Lymphoma.
[0113] In some embodiments, the T-cell lymphoma is relapsed or
refractory T-cell lymphoma or any subtype as described herein. In
some embodiments, the T-cell lymphoma is relapsed after or
refractory to treatment with a BTK inhibitor, a Bcl-2 inhibitor
(e.g., venetoclax), and/or a phosphatidylinositol 3 kinase
inhibitor (e.g., tenalisib). In some embodiments, the T-cell
lymphoma is relapsed after or refractory to treatment with one or
more of alkylating agent, anthracyclines, anti-CD20 antibody,
B-cell receptor (BCR) pathway inhibitor, bendamustine, belinostat,
bleomycin, bosutinib, brentuximab, carmustine, cytarabine,
cyclophosphamide, dacarbazine, doxorubicin, etoposide, gemcitabine,
oxiplatin, high-dose steroids, lenalidomide, melphalan, ixazomib,
fludarabine, fenretinide, pralatrexate, prednisone, R-CHEP,
rituximab, romidepsin, vinblastine, vincristine, and RP-6530. In
some embodiments, the T-cell lymphoma is relapsed after or
refractory to treatment with one or more of CHOP,
brentuximab+rituximab, rituximab+CHOP, gemcitabine+oxiplatin,
gemcitabine, high-dose steroids, BEAM, BEAM/R-CHEP, EPOCH, ABVD,
lenalidomide, ixazomib, bosutinib, fenretinide, pralatrexate,
romidepsin, belinostat, and a PI3K inhibitor, such as tenalisib. In
some embodiments, the T-cell lymphoma is relapsed after or
refractory to treatment with one or more of belinostat, brentuximab
vedotin, pralatrexate, romidepsin, and a PI3K inhibitor.
[0114] In some embodiments, cerdulatinib is administered as a
second line treatment, third line treatment, fourth line treatment,
fifth line treatment, sixth line treatment, seventh line treatment,
eighth line treatment, ninth line treatment, tenth line treatment
or eleventh line treatment.
[0115] In some embodiments, the T-cell lymphoma has not been
previously treated with an agent for treating T-cell lymphoma
(i.e., treatment naive).
[0116] In some embodiments, the T-cell lymphoma is T-cell
non-Hodgkin lymphoma. In some embodiments, the T-cell lymphoma is
relapsed or refractory T-cell non-Hodgkin lymphoma. In some
embodiments, the T-cell lymphoma is peripheral T-cell lymphoma. In
some embodiments, the T-cell lymphoma is relapsed or refractory
peripheral T-cell lymphoma. In some embodiments, the T-cell
lymphoma is a relapsed or refractory subtype of T-cell lymphoma as
described herein.
[0117] In some embodiments, the patient has a T-cell lymphoma with
follicular involvement.
[0118] In some embodiments, the T-cell lymphoma is a subtype of
T-cell lymphoma as described herein with follicular involvement. In
some embodiments, the patient has AITL with follicular involvement.
In some embodiments, the patient has PTCL-NOS with follicular
involvement. In some embodiments, the T-cell lymphoma is relapsed
or refractory T-cell lymphoma as described herein with follicular
involvement.
[0119] In some embodiments, the T-cell lymphoma has at least about
30%, at least about 40%, at least about 50%, at least about 60%, at
least about 70%, at least about 80%, or at least about 90%
reduction from baseline disease after treatment.
[0120] In some embodiments, the patient has at least a stable
disease after cerdulatinib treatment. A "stable disease" can refer
to a response to the cerdulatinib treatment (alone or in
combination with another agent, such as rituximab) where the
lymphoma is neither decreasing nor increasing (e.g., substantially)
in extent or severity. In some embodiments, the patient has at
least a partial response after cerdulatinib treatment. In some
embodiments, the patient has a complete response after cerdulatinib
treatment. In some embodiments, the patient has a duration of
response to cerdulatinib of at least about 2 months, at least about
3 months, at least about 4 months, at least about 5 months, at
least about 6 months, at least about 9 months or at least about 12
months. In some embodiments, the patient has at least a partial
response with a duration of response to cerdulatinib of at least
about 2 months, at least about 3 months, at least about 4 months,
at least about 5 months, at least about 6 months, at least about 9
months or at least about 12 months. In some embodiments, the
patient has a complete response with a duration of response to
cerdulatinib of at least about 2 months, at least about 3 months,
at least about 4 months, at least about 5 months, at least about 6
months, at least about 9 months or at least about 12 months. In
some embodiments, at least about 30%, at least about 40%, or at
least about 50% of the patients being treated with cerdulatinib
have at least a stable disease. In some embodiments, at least 30%
or at least 40% of the patients being treated with cerdulatinib
have at least a partial response.
[0121] In some embodiments, the T-cell lymphoma is monomorphic
epitheliotropic intestinal T-cell lymphoma. In some embodiments,
the monomorphic epitheliotropic intestinal T-cell lymphoma has at
least about 30%, at least about 40%, at least about 50%, or at
least about 60%, or about 90% reduction in baseline disease after
treatment.
[0122] In some embodiments, the effective amount of cerdulatinib is
a daily dosage of from about 30 mg to about 90 mg. In some
embodiments, the effective amount of cerdulatinib is a daily dosage
of from about 40 mg, about 50 mg, about 60 mg, or about 70 mg,
administered once or twice daily. In some embodiments, the
effective amount of cerdulatinib is about 35 mg twice daily. In
some embodiments, the effective amount of cerdulatinib is about 30
mg twice daily. In some embodiments, the effective amount of
cerdulatinib is about 25 mg twice daily. In some embodiments, the
effective amount of cerdulatinib is about 20 mg twice daily. In
some embodiments, the effective amount of cerdulatinib is about 30
mg twice daily, and is reduced about 25 mg twice daily. In some
embodiments, the effective amount of cerdulatinib is further
reduced to about 20 mg twice daily. In some embodiments, the
effective amount of cerdulatinib is further reduced to about 15 mg
twice daily.
[0123] In some embodiments, provided is a method of treating a
T-cell lymphoma (e.g., PTCL, PTCL-NOS, ALCL, AITL, CTCL, ATLL,
EATL, HSTL, T-LBL, or nasal NK/T-cell lymphoma) in a human patient
in need thereof, comprising administering to the patient an
effective amount of cerdulatinib or a pharmaceutically acceptable
salt, co-crystal or solvate thereof, wherein the effective amount
is about 40 mg to about 80 mg of cerdulatinib per day or a
corresponding amount of a pharmaceutically acceptable salt of
cerdulatinib.
[0124] In some embodiments, provided is a method of treating a
T-cell lymphoma (e.g., PTCL, PTCL-NOS, ALCL, AITL, CTCL, ATLL,
EATL, HSTL, T-LBL, or nasal NK/T-cell lymphoma) in a human patient
in need thereof, comprising administering to the patient an
effective amount of cerdulatinib or a pharmaceutically acceptable
salt, co-crystal or solvate thereof, wherein the effective amount
is about 20 mg to about 40 mg of cerdulatinib per dose twice daily
or a corresponding amount of a pharmaceutically acceptable salt of
cerdulatinib. In some embodiments, the effective amount is about 30
mg of cerdulatinib per dose twice daily or a corresponding amount
of a pharmaceutically acceptable salt of cerdulatinib. In some
embodiments, the effective amount is about 35 mg of cerdulatinib
per dose twice daily or a corresponding amount of a
pharmaceutically acceptable salt of cerdulatinib.
[0125] In some embodiments, provided is a method of treating a
T-cell lymphoma (e.g., PTCL, PTCL-NOS, ALCL, AITL, CTCL, ATLL,
EATL, HSTL, T-LBL, or nasal NK/T-cell lymphoma) in a human patient
in need thereof, wherein the patient is relapsed after or
refractory to treatment with a BTK inhibitor, a Bcl-2 inhibitor,
and/or a phosphatidylinositol 3 kinase inhibitor, and the method
comprises administering to the patient an effective amount of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof, wherein the effective amount is about 20 mg to
about 40 mg of cerdulatinib per dose twice daily or a corresponding
amount of a pharmaceutically acceptable salt of cerdulatinib. In
some embodiments, the effective amount is about 30 mg of
cerdulatinib per dose twice daily or a corresponding amount of a
pharmaceutically acceptable salt of cerdulatinib. In some
embodiments, the effective amount is about 35 mg of cerdulatinib
per dose twice daily or a corresponding amount of a
pharmaceutically acceptable salt of cerdulatinib. In some
embodiments, the patient is relapsed after or refractory to
treatment with one or more of alkylating agent, anthracyclines,
anti-CD20 antibody, B-cell receptor (BCR) pathway inhibitor,
bendamustine, belinostat, bleomycin, bosutinib, brentuximab,
carmustine, cytarabine, cyclophosphamide, dacarbazine, doxorubicin,
etoposide, gemcitabine, oxiplatin, high-dose steroids,
lenalidomide, melphalan, ixazomib, fludarabine, fenretinide,
pralatrexate, prednisone, R-CHEP, rituximab, romidepsin,
vinblastine, vincristine, and RP-6530. In some embodiments, the
patient is relapsed after or refractory to treatment with one or
more of CHOP, brentuximab+rituximab, rituximab+CHOP,
gemcitabine+oxiplatin, gemcitabine, high-dose steroids, BEAM,
BEAM/R-CHEP, EPOCH, ABVD, lenalidomide, ixazomib, bosutinib,
fenretinide, pralatrexate, romidepsin, belinostat, and a PI3K
inhibitor, such as tenalisib. In some embodiments, the patient is
relapsed after or refractory to treatment with one or more of
belinostat, brentuximab vedotin, pralatrexate, romidepsin, and a
PI3K inhibitor.
[0126] In some embodiments, cerdulatinib is administered with or
without food. In some embodiments, cerdulatinib is administered
with a proton pump inhibitor, such as esomeprazole, omeprazole,
lansoprazole, rabeprazole, dexlansoprazole, or a pharmaceutically
acceptable salt thereof.
[0127] Treatment of Lymphoma
[0128] In some embodiments, provided herein is a method of treating
a lymphoma in a human patient in need thereof and wherein the
lymphoma expresses one or more of Mcl-1, FOXP1, GAB1, SOCS1, and
SOCS3, comprising administering to the patient an effective amount
of cerdulatinib or a pharmaceutically acceptable salt, co-crystal
or solvate thereof. In some embodiments, lymphoma expresses one or
more of Mcl-1, FOXP1, GAB1, SOCS1, and SOCS3 above base line. In
some embodiments, base line is the expression level in a human that
does not have a lymphoma. In some embodiments, the lymphoma is a
B-cell lymphoma. In some embodiments, the lymphoma is a T-cell
lymphoma. In some embodiments, the lymphoma is a Hodgkin's
lymphoma. In some embodiments, the lymphoma is a non-Hodgkin's
lymphoma. In some embodiments, the lymphoma is chronic lymphocytic
leukemia (CLL), small lymphocytic lymphoma (SLL), follicular
lymphoma (FL), transformed follicular lymphoma (tFL), diffuse large
B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), B-cell
non-Hodgkin's lymphoma (NHL), peripheral T-cell lymphoma (PTCL),
cutaneous T-cell lymphoma (CTCL), marginal zone lymphoma,
mucosa-associated lymphoid tissue (MALT), or Waldenstrom
macroglobluinemia (WM).
[0129] In some embodiments, provided herein is a method of treating
a lymphoma in a human patient in need thereof and having (or known
to have) one or more of mutations in FAT4, CCND3, MYOM2, ZMYM3,
NOTCH1, KMT2D, TCF3, ARID1A, AXIN1, SYK, JAK1, JAK3, and/or TYK2,
comprising administering to the patient an effective amount of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof. In some embodiments, the lymphoma is a B-cell
lymphoma. In some embodiments, the lymphoma is a T-cell lymphoma.
In some embodiments, the lymphoma is a Hodgkins lymphoma. In some
embodiments, the lymphoma is a non-Hodgkins lymphoma. In some
embodiments, the lymphoma is chronic lymphocytic leukemia (CLL),
small lymphocytic lymphoma (SLL), follicular lymphoma (FL),
transformed follicular lymphoma (tFL), diffuse large B-cell
lymphoma (DLBCL), mantle cell lymphoma (MCL), B-cell non-Hodgkin's
lymphoma (NHL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell
lymphoma (CTCL), marginal zone lymphoma, mucosa-associated lymphoid
tissue (MALT), or Waldenstrom macroglobluinemia (WM). In some
embodiments, the lymphoma is a PTCL, FL, CLL or SLL. In some
embodiments, the patient has one or more mutations in FAT4, CCND3,
MYOM2, ZMYM3, KMT2D, TCF3, ARID1A, and/or AXIN1. In some
embodiments, the patient has one or more mutations in ZMYM3, KMT2D,
and FAT4.
[0130] In some embodiments, provided herein is a method of treating
a follicular lymphoma or in a human patient in need thereof and
having (or known to have) one or more of mutations in FAT4, CCND3,
MYOM2, ZMYM3, NOTCH1, KMT2D, TCF3, ARID1A, AXIN1, SYK, JAK1, JAK3,
and/or TYK2, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof.
[0131] In some embodiments, provided herein is a method of treating
a follicular lymphoma in a human patient in need thereof and having
(or known to have) one or more of mutations in FAT4, CCND3, MYOM2,
ZMYM3, KMT2D, TCF3, ARID1A, AXIN1, SYK, JAK1, JAK3, and/or TYK2,
comprising administering to the patient an effective amount of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof.
[0132] In some embodiments, provided herein is a method of treating
a follicular lymphoma in a human patient in need thereof and having
(or known to have) one or more of mutations in ZMYM3, KMT2D, FAT4,
SYK, JAK1, JAK3, and/or TYK2, comprising administering to the
patient an effective amount of cerdulatinib or a pharmaceutically
acceptable salt, co-crystal or solvate thereof.
[0133] In some embodiments, the patient further has one or more
mutations in BCL2, and/or BCL6.
[0134] In some embodiments, the follicular lymphoma is relapsed or
refractory follicular lymphoma. In some embodiments, the follicular
lymphoma is transformed follicular lymphoma. In some embodiments,
the follicular lymphoma is relapsed or refractory transformed
follicular lymphoma.
[0135] In some embodiments, provided herein is a method of treating
a lymphoma in a human patient in need thereof and having (or known
to have) one or more of mutations in NOTCH1, SETD2, SIGLEC10, SPEN,
PCLO, TET2 (e.g., TET2.sup.M66L), MK167, FAT3, KRAS, REL (e.g.,
REL.sup.I354T), HIST1H1E (e.g., HIST1H1E.sup.A47V), KMT2C, KMT2D,
and/or SF3B1, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof. In some embodiments, the lymphoma is
a B-cell lymphoma. In some embodiments, the lymphoma is a T-cell
lymphoma. In some embodiments, the lymphoma is a Hodgkins lymphoma.
In some embodiments, the lymphoma is a non-Hodgkins lymphoma. In
some embodiments, the lymphoma is chronic lymphocytic leukemia
(CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL),
transformed follicular lymphoma (tFL), diffuse large B-cell
lymphoma (DLBCL), mantle cell lymphoma (MCL), B-cell non-Hodgkin's
lymphoma (NHL), peripheral T-cell lymphoma (PTCL), cutaneous T-cell
lymphoma (CTCL), marginal zone lymphoma, mucosa-associated lymphoid
tissue (MALT), or Waldenstrom macroglobluinemia (WM). In some
embodiments, the lymphoma is a PTCL, FL, CLL or SLL. In some
embodiments, the patient has one or more mutations in TET2 (e.g.,
TET2.sup.M66L), MK167, FAT3, HIST1H1E (e.g., HIST1H1E.sup.A47V),
KMT2C, KMT2D, and/or SF3B1. In some embodiments, the patient has
one or more mutations in SYK, JAK1, JAK2, JAK3, TYK2, TP53, STAT
(e.g., STAT6.sup.S86A), A20 (e.g., A20.sup.Q150R) and/or ATM.
[0136] In some embodiments, provided herein is a method of treating
chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
(SLL) in a human patient in need thereof and having (or known to
have) one or more of mutations in NOTCH1, SETD2, SIGLEC10, SPEN,
PCLO, TET2 (e.g., TET2.sup.M66L), MK167, FAT3, KRAS, REL (e.g.,
REL.sup.1354T), HIST1H1E (e.g., HIST1H1E.sup.A47V), KMT2C, KMT2D,
and/or SF3B1, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof.
[0137] In some embodiments, provided herein is a method of treating
chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
(SLL) in a human patient in need thereof and having (or known to
have) one or more of mutations in SETD2, SIGLEC10, SPEN, PCLO, TET2
(e.g., TET2.sup.M66L), MK167, FAT3, KRAS, REL (e.g.,
REL.sup.1354T), HIST1H1E (e.g., HIST1H1E.sup.A47V), KMT2C, KMT2D,
and/or SF3B1, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof.
[0138] In some embodiments, provided herein is a method of treating
chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma
(SLL) in a human patient in need thereof and having (or known to
have) one or more of mutations in TET2 (e.g., TET2.sup.M66L),
MK167, FAT3, HIST1H1E (e.g., HIST1H1E.sup.A47V), KMT2C, KMT2D,
and/or SF3B1, comprising administering to the patient an effective
amount of cerdulatinib or a pharmaceutically acceptable salt,
co-crystal or solvate thereof.
[0139] In some embodiments, the patient further has one or more
mutations in SYK, JAK1, JAK2, JAK3, TYK2, TP53, STAT (e.g.,
STAT6.sup.S86A), A20 (e.g., A20.sup.Q150R) and/or ATM.
[0140] In some embodiments, the patient does not have a mutation in
EP300, TP53 and/or BTK. In some embodiments, the patient does not
have EP300S697R, Ep300C1247F, Tp53N285K, TP53.sup.R273C and/or
BTK.sup.C481S.
[0141] In some embodiments, the CLL or SLL is relapsed or
refractory CLL or SLL.
[0142] In some embodiments, provided herein is a method of treating
a lymphoma (as described herein) in a human patient in need thereof
comprising administering to the patient an effective amount of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof and an effective amount of a Mcl-1 inhibitor or a
pharmaceutically acceptable salt, co-crystal or solvate
thereof.
[0143] In some embodiments, the Mcl-1 inhibitor is 563845, MIK665,
483-LM, AZD5991, AMG 176, or a compound described in
Structure-Guided Design of a Series of MCL-1 Inhibitors with High
Affinity and Selectivity, Bruncko, et al., J. Med. Chem., 2015, 58
(5):2180-2194, Small Molecule Mcl-1 Inhibitors for the Treatment of
Cancer, Belmar, et al., Pharmacol. Ther., 2015, 145:76-84, or
Small-Molecule Inhibitors of the Mcl-1 Oncoprotein, Chen, et al.,
Austin J. Anal. Pharm. Chem., 2014, 1(3), which are hereby
incorporated by reference in their entirety.
[0144] In some embodiments, the effective amount of the Mcl-1
inhibitor is between about 0.01 and 200 mg/kg. In some embodiments,
about 0.01 and 150 mg/kg may be administered. In other embodiments,
a dosage of between 0.05 and 100 mg/kg may be administered. The
daily dosage is described as a total amount of a Mcl-1 inhibitor
administered per day. Daily dosage of a Mcl-1 inhibitor may be
between about 0.1 mg and 2,000 mg/day, between about 1 to 2,000
mg/day, between about 1 to 1,000 mg/day, between about 1 to 500
mg/day, between about 10 to 150 mg/day, between about 1 to 100
mg/day, between about between about 1 to 50 mg/day, between about 5
to 100 mg/day, between about 10 to 125 mg/day, between about 10 to
100 mg/day, or between about 5 to 200 mg/day. The daily dosage of a
Mcl-1 inhibitor may be administered all in one time (once a day) or
in several times, such as two times, three times, four times, five
times or more throughout the day.
[0145] In some embodiments, provided herein is a method of treating
a lymphoma (as described herein) in a human patient in need thereof
comprising administering to the patient an effective amount of
cerdulatinib or a pharmaceutically acceptable salt, co-crystal or
solvate thereof and an effective amount of rituximab (e.g.,
RITUXAN.RTM., MABTHERA.RTM., ZYTUX.RTM.).
[0146] In some embodiments, the lymphoma is relapsed or refractory
lymphoma. In some embodiments, the lymphoma is B-cell lymphoma. In
some embodiments, the B-cell lymphoma is Hodgkin's lymphoma. In
some embodiments, the B-cell lymphoma is non-Hodgkin lymphomas. In
some embodiments, the lymphoma is follicular lymphoma. In some
embodiments, the lymphoma is B-cell chronic lymphocytic leukemia
(B-CLL) (also known as chronic lymphoid leukemia (CLL)). In some
embodiments, the B-cell lymphoma is small lymphocytic lymphoma
(SLL). In some embodiments, the lymphoma is diffuse large B-cell
lymphoma (DLBCL or DLBL). In some embodiments, the lymphoma is
selected from the group consisting of non-Hodgkin's lymphoma (NHL),
Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma
(SLL), Follicular Lymphoma (FL), transformed Follicular Lymphoma
(tFL), Diffuse Large B-cell Lymphoma (DLBCL), and Mantle Cell
Lymphoma (MCL).
[0147] In some embodiments, the lymphoma is follicular lymphoma. In
some embodiments, the lymphoma is PTCL. In some embodiments,
rituximab is co-administered to manage viral infection in the human
patient having PTCL.
[0148] In some embodiments, the effective amount of rituximab is
between about 0.01 and 200 mg/kg. In some embodiments, about 0.01
and 150 mg/kg of rituximab may be administered. In other
embodiments, a dosage of between 0.05 and 100 mg/kg of rituximab
may be administered. The dosage is described as a total amount of
rituximab administered per time period. The dosage of rituximab may
be between about 0.1 mg and 2,000 mg/time period, between about 1
to 2,000 mg/time period, between about 1 to 1,000 mg/time period,
between about 1 to 500 mg/time period, between about 10 to 150
mg/time period, between about 1 to 100 mg/time period, between
about between about 1 to 50 mg/time period, between about 5 to 100
mg/time period, between about 10 to 125 mg/time period, between
about 10 to 100 mg/time period, or between about 5 to 200 mg/time
period. The dosage of rituximab may be administered all in one time
(once per time period) or in several times, such as two times,
three times, four times, five times or more throughout the time
period. In some embodiments, the time period is, or is about, every
day, every two days, every three days, every four days, every five
days, every six days, every week, every two weeks, every three
weeks, every four weeks, every one month, every two months, every
three months, every four months, every five months, every six
months, every seven months, every eight months, every nine months,
every ten months, every eleven months, every year, or a number or a
range between any two of these values.
[0149] Dosages
[0150] A variety of regimens for administering cerdulatinib may be
used. For example, the cerdulatinib may be administered as a single
daily dose or as a multiple-dose daily regimen. In some
embodiments, the cerdulatinib is administered once, twice, three
times or four times a day. In some embodiments, cerdulatinib is
administered once daily or twice daily. In some embodiments,
cerdulatinib is administered orally.
[0151] The specific amount of cerdulatinib described herein refers
to the amount of cerdulatinib free base, i.e., the compound of
formula I. However, it is understood that a pharmaceutically
acceptable salt, co-crystal or solvate of cerdulatinib or a mixture
thereof may be administered in an amount that provides the stated
amount of cerdulatinib. Examples of pharmaceutically acceptable
salts of cerdulatinib include those derived from inorganic or
organic acids, such as cerdulatinib acetate, adipate, alginate,
aspartate, benzoate, benzene sulfonate, bisulfate, butyrate,
citrate, camphorate, camphor sulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, edisylate, fumarate,
lucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, hydrochloride, bis-hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,
methanesulfonate, bis-methanesulfonate, 2-naphthalenesulfonate,
naphthalene disulfate, nicotinate, oxalate, pamoate, pectinate,
persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate, undecanoate,
hydrohalides (e.g., hydrochlorides and hydrobromides), sulfates,
phosphates, nitrates, sulphamates, malonates, salicylates,
methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,
di-ptoluoyltartrates, ethanesulphonates, cyclohexylsulphamates,
quinates, and the like.
[0152] Cerdulatinib or a salt thereof can be administered in
unsolvated forms as well as solvated forms, including hydrated
forms, or form co-crystals with another compound. "Hydrate" refers
to a complex formed by combination of water molecules with
molecules or ions of the solute. "Solvate" refers to a complex
formed by combination of solvent molecules with molecules or ions
of the solute. The solvent can be an organic compound, an inorganic
compound, or a mixture of both. Solvate is meant to include
hydrate, hemi-hydrate, channel hydrate etc. Some examples of
solvents include, but are not limited to, methanol,
N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and
water.
[0153] In some embodiments, cerdulatinib is administered as a
hydrochloride salt (cerdulatinib HCl). In some embodiments, the
cerdulatinib HCl is in a crystalline form. In some embodiments, the
cerdulatinib HCl is in a crystalline form characterized by an X-ray
powder diffractogram comprising peaks at 8.7, 15.9, and
20.0.degree. 20, each .+-.0.2.degree. 20, as determined on a
diffractometer using Cu-K.alpha. radiation (cerdulatinib HCl Form
I). In some embodiments, cerdulatinib HCl Form I is further
characterized by one or more peaks at 11.5, 22.5, and 25.5.degree.
20, each .+-.0.2.degree. 20. In some embodiments, cerdulatinib HCl
Form I is further characterized by a differential scanning
calorimetry curve comprising an endotherm with onset at about
288.degree. C.
[0154] It has been found that the steady state plasma minimum
concentration (SSC.sub.min) of cerdulatinib is important for
achieving better efficacy. A given dosage, such as the dosages
described herein, was found to produce different SSC.sub.min in
different patients, and SSC.sub.min needed for achieving better
efficacy in different diseases was also found to be different.
Accordingly, personalized dosages that achieve sufficient but not
excessive SSC.sub.min in individual patients tailored for
particular diseases will maximize response with minimum side
effects.
[0155] In some embodiments, the therapeutically effective amount is
at least about 5 mg of cerdulatinib per day. In some embodiments,
the therapeutically effective amount is at least about 10 mg, 15
mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg,
65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg of
cerdulatinib per day. In some embodiments, the therapeutically
effective amount is at least about 10, 20, 30, 40, or 50 mg of
cerdulatinib per dosage. In some embodiments, the therapeutically
effective amount is at least about 15 mg, 20 mg, 25 mg, 30 mg, or
35 mg of cerdulatinib per dosage and is administered twice
daily.
[0156] In some embodiments, the therapeutically effective amount is
no more than about 100 mg, 95 mg, 90 mg, 85 mg, 80 mg, or 75 mg of
cerdulatinib per day. In some embodiments, the therapeutically
effective amount is no more than about 90 mg, 80 mg, 70 mg, 60 mg,
55 mg or 50 mg of cerdulatinib per dosage. In some embodiments, the
therapeutically effective amount is no more than 45 mg, 40 mg, 35
mg, or 30 mg of cerdulatinib per dosage and is administered twice
daily.
[0157] In some embodiments, the therapeutically effective amount is
from about 10 mg to 200 mg, from about 10 mg to 150 mg, from about
25 mg to 150 mg, from about 25 to 120 mg, from 30 mg to 110 mg,
from about 50 to 120 mg, from about 30 to 80 mg, from 50 mg to 80
mg, from about 40 to 50 mg or from about 80 to 100 mg of
cerdulatinib per day.
[0158] In some embodiments, the daily dose of cerdulatinib is about
30 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85
mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150
mg.
[0159] In some embodiments, from about 30 mg to about 80 mg of
cerdulatinib is administered once a day. In some embodiments, the
effective amount is about 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg,
or 70 mg of cerdulatinib administered once daily.
[0160] In some embodiments, the effective amount is about 15 mg to
about 65 mg, about 25 mg to about 50 mg, about 25 mg to about 40
mg, about 30 mg to about 40 mg or about 40 mg to about 50 mg of
cerdulatinib per dosage administered twice daily. In some
embodiments, about 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg
or 60 mg of cerdulatinib is administered twice daily. In some
embodiments, about 45 mg of cerdulatinib is administered twice
daily. In some embodiments, about 35 mg of cerdulatinib is
administered twice daily.
[0161] In some embodiments, the effective amount of cerdulatinib is
from about 10 mg to about 45 mg daily. In some embodiments, the
effective amount of cerdulatinib is from about 15 mg to about 30 mg
twice daily. In some embodiments, the effective amount of
cerdulatinib is about 15 mg, 20 mg, 25 mg, or 30 mg twice
daily.
[0162] In some embodiments, cerdulatinib is administered, is
administered about, is administered at least, or is administered at
most, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times, 20
times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times,
90 times, 100 times, or a number or a range between any two of
these values.
[0163] In some embodiments, provided herein is a method of treating
a follicular lymphoma or non-Hodgkin's Lymphoma (iNHL) in a human
patient in need thereof, comprising administering to the patient an
effective amount of cerdulatinib or a pharmaceutically acceptable
salt, co-crystal or solvate thereof to achieve and maintain a
steady state minimum plasma cerdulatinib concentration of between
about 0.05 .mu.M to about 3 .mu.M in the patient. In some
embodiments, the method achieves at least a partial response in the
treated patient.
[0164] In some embodiments, the follicular lymphoma is relapsed or
refractory follicular lymphoma. In some embodiments, the follicular
lymphoma is transformed follicular lymphoma. In some embodiments,
the follicular lymphoma is relapsed or refractory transformed
follicular lymphoma. In some embodiments, cerdulatinib or a
pharmaceutically acceptable salt, co-crystal or solvate thereof is
administered to a FL patient for at least 30 weeks, or at least 40
weeks, or at least 50 weeks.
[0165] In some embodiments, provided herein is a method of treating
a marginal zone lymphoma, Waldenstrom's macroglobulinemia, chronic
lymphocytic leukemia or small lymphocytic lymphoma in a human
patient in need thereof, comprising administering to the patient an
effective amount of cerdulatinib or a pharmaceutically acceptable
salt, co-crystal or solvate thereof to achieve and maintain a
steady state minimum plasma cerdulatinib concentration of between
about 0.05 .mu.M to about 3 .mu.M in the patient. In some
embodiments, the method achieves at least a partial response in the
treated patient. In some embodiments, the marginal zone lymphoma is
relapsed or refractory marginal zone lymphoma. In some embodiments,
the Waldenstrom's macroglobulinemia is relapsed or refractory
Waldenstrom's macroglobulinemia. In some embodiments, the chronic
lymphocytic leukemia or small lymphocytic lymphoma is relapsed or
refractory chronic lymphocytic leukemia or small lymphocytic
lymphoma.
[0166] In some embodiments, the steady state minimum plasma
cerdulatinib concentration achieved and maintained in the human
patient is from about 0.7 .mu.M to about 3 .mu.M. In some
embodiments, the steady state minimum plasma cerdulatinib
concentration achieved and maintained in the human patient is from
about 0.05 .mu.M to about 0.5 .mu.M. In some embodiments, the
steady state minimum plasma cerdulatinib concentration achieved in
the human patient is, is about, is at most, or is at least, 0.001
.mu.M, 0.002 .mu.M, 0.003 .mu.M, 0.004 .mu.M, 0.005 .mu.M, 0.006
.mu.M, 0.007 .mu.M, 0.008 .mu.M, 0.009 .mu.M, 0.01 .mu.M, 0.02
.mu.M, 0.03 .mu.M, 0.04 .mu.M, 0.05 .mu.M, 0.06 .mu.M, 0.07 .mu.M,
0.08 .mu.M, 0.09 .mu.M, 0.1 .mu.M, 0.1 .mu.M, 0.2 .mu.M, 0.3 .mu.M,
0.4 .mu.M, 0.5 .mu.M, 0.6 .mu.M, 0.7 .mu.M, 0.8 .mu.M, 0.9 .mu.M,
1.0 .mu.M, 1.1 .mu.M, 1.2 .mu.M, 1.3 .mu.M, 1.4 .mu.M, 1.5 .mu.M,
1.6 .mu.M, 1.7 .mu.M, 1.8 .mu.M, 1.9 .mu.M, 2.0 .mu.M, 2.1 .mu.M,
2.2 .mu.M, 2.3 .mu.M, 2.4 .mu.M, 2.5 .mu.M, 2.6 .mu.M, 2.7 .mu.M,
2.8 .mu.M, 2.9 .mu.M, 3.0 .mu.M, 3.1 .mu.M, 3.2 .mu.M, 3.3 .mu.M,
3.4 .mu.M, 3.5 .mu.M, 3.6 .mu.M, 3.7 .mu.M, 3.8 .mu.M, 3.9 .mu.M,
4.0 .mu.M, 4.1 .mu.M, 4.2 .mu.M, 4.3 .mu.M, 4.4 .mu.M, 4.5 .mu.M,
4.6 .mu.M, 4.7 .mu.M, 4.8 .mu.M, 4.9 .mu.M, 5.0 .mu.M, or a number
or a range between any two of these values.
[0167] In some embodiments, the method achieves at least a 30%
nodal reduction in the treated patient. In some embodiments, the
method achieves at least a 40% nodal reduction in the treated
patient. In some embodiments, the method achieves at least a 50%
nodal reduction in the treated patient.
[0168] Steady state minimum plasma cerdulatinib concentrations may
be determined by methods described herein or known in the art. In
some embodiments, the patient's steady state minimum plasma
cerdulatinib concentration is determined after the patient is
administered cerdulatinib for one day, two days, three days, or one
week. In some embodiments, the dosage administered to the patient
is adjusted so that the steady state minimum plasma cerdulatinib
concentration is within the desired ranges.
[0169] Patients
[0170] In some embodiments of the methods described herein, the
patient has resistance to a drug, which is not cerdulatinib.
Non-limiting examples of these drugs are an anti-CD20 antibody, a
BCL-2 inhibitor, a BTK inhibitor, a P13K.delta. inhibitor,
rituximab, a platinum-based drug, an antimetabolite, ibrutinib,
idelalisib, fludararbine (fludarabine phosphate, FLUDARA.RTM.),
anthracyclines, a BCR pathway inhibitor, ABT-199 (venetoclax),
tofacitinib, or another chemotherapeutic agent used for treating a
hematologic cancer. Other non-limiting examples of chemotherapeutic
agents include alkylating agents, cytoskeletal disruptors,
epothiolones, histone deacetylase inhibitors, inhibitors of
topoisomerase I, inhibitors of topoisomerase II, nucleotide analogs
and precursor analogs, antibiotics, platinum-based agents,
retinoids, vinca alkaloids, or a combination thereof.
[0171] In some embodiments of the methods described herein, the
patient has resistance to an anti-CD20 antibody, a BCL-2 inhibitor,
a BTK inhibitor, a P13K.delta. inhibitor, a platinum-based drug, an
antimetabolite, ananthracycline, a BCR pathway inhibitor, or
another chemotherapeutic agent used for treating a hematologic
cancer. In some embodiments, the patient has resistance to a drug
selected from the group consisting of ibrutinib, idelalisib,
tofacitinib, fludararbine (fludarabine phosphate, FLUDARA.RTM.), or
ABT-199 (venetoclax). In some embodiments, the patient has
resistance to ibrutinib.
[0172] In some embodiments, the patient was previously administered
a drug for treating a hematological cancer. Non-limiting examples
of the drug include an alkylating agent, an anti-CD20 antibody, a
BCL-2 inhibitor, a BTK inhibitor, a P13K.delta. inhibitor,
rituximab, a platinum-based drug, an antimetabolite, ibrutinib,
idelalisib, tofacitinib, fludararbine (fludarabine phosphate,
FLUDARA.RTM.), anthracyclines, a BCR pathway inhibitor, ABT-199
(venetoclax), and other agents used for treating a hematologic
cancer.
[0173] Other non-limiting examples of chemotherapeutic agents
include cytoskeletal disruptors, epothiolones, histone deacetylase
inhibitors, inhibitors of topoisomerase I, inhibitors of
topoisomerase II, nucleotide analogs and precursor analogs,
antibiotics, platinum-based agents, retinoids, vinca alkaloids, or
a combination thereof.
[0174] In some embodiments, the patient was administered a drug
selected from the group consisting of an alkylating agent, an
anti-CD20 antibody, a BCL-2 inhibitor, a BTK inhibitor, a
P13K.delta. inhibitor, a platinum-based drug, an antimetabolite, an
anthracycline, a BCR pathway inhibitor, and other agents used for
treating a hematologic cancer. In some embodiments, the drug is
rituximab, ibrutinib, idelalisib, tofacitinib, fludararbine
(fludarabine phosphate, FLUDARA.RTM.), or ABT-199 (venetoclax). In
some embodiments, the drug is R-CHOP (rituximab; cyclophosphamide;
doxorubicin hydrochloride; (vincristine); prednisone). In some
embodiments, the drug is R-CVP (rituximab; cyclophosphamide;
vincristine; prednisone). In some embodiments, the drug is
bevacizumab. In some embodiments, the drug is a combination of
fludarabine and rituximab, a combination of bendamustine and
rituximab, or a combination of bevacizumab and rituximab.
[0175] In certain embodiments, the patient is 60 years or older and
relapsed after a first line cancer therapy. In certain embodiments,
the patient is 18 years or older and is relapsed or refractory
after a second line cancer therapy. In certain embodiments, the
patient is 60 years or older and is primary refractory to a first
line cancer therapy. In certain embodiments, the patient is 70
years or older and is previously untreated. In certain embodiments,
the patient is 70 years or older and is ineligible and/or unlikely
to benefit from cancer therapy.
3. Combination Treatments
[0176] In one embodiment, the treatment methods can further include
administration of an effective amount of another agent, such as a
chemotherapeutic agent useful for treating the cancer. In some
embodiments, cerdulatinib is co-administered (simultaneously or
sequentially) with an effective amount of the another agent or a
pharmaceutically acceptable salt, co-crystal or solvate thereof. In
some embodiments, the another agent is a chemotherapeutic agent. In
some embodiments, the agent that is co-administered with
cerdulatinib is a Mcl-1 inhibitor. In some embodiments, the agent
that is co-administered with cerdulatinib is rituximab. In some
embodiments, the agent is co-administered with cerdulatinib
simultaneously or sequentially.
[0177] The compounds of the present disclosure can be used in
combination with one or more other enzyme/protein/receptor
inhibitors for the treatment of diseases, such as cancer. Examples
of cancers include solid tumors and liquid tumors, such as blood
cancers. For example, the compounds of the present disclosure can
be combined with one or more inhibitors of the following kinases
for the treatment of cancer: Akt1, Akt2, Akt3, TGF.beta.R, PKA,
PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR,
EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF.alpha.R,
PDGF.beta.R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1,
FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3,
VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src,
Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf.
[0178] In some embodiments, the compounds of the present disclosure
can be combined with one or more of the following inhibitors for
the treatment of cancer. Non-limiting examples of inhibitors that
can be combined with the compounds of the present disclosure for
treatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3
or FGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120,
TK1258, lucitanib, dovitinib, TAS-120, JNJ-42756493, Debio1347,
INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or
JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO
inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g.,
GSK2979552, INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta
inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gamma inhibitor
such as a PI3K-gamma selective inhibitor, a CSF1R inhibitor (e.g.,
PLX3397 and LY3022855), a TAM receptor tyrosine kinases (Tyro-3,
Axl, and Mer), an angiogenesis inhibitor, an interleukin receptor
inhibitor, bromo and extra terminal family members inhibitors (for
example, bromodomain inhibitors or BET inhibitors such as OTX015,
CPI-0610, INCB54329 and INCB57643) and an adenosine receptor
antagonist or combinations thereof. Inhibitors of HDAC such as
panobinostat and vorinostat. Inhibitors of c-Met such as
onartumzumab, tivantnib, and INC-280. Inhibitors of BTK such as
ibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,
temsirolimus, and everolimus. Inhibitors of Raf, such as
vemurafenib and dabrafenib. Inhibitors of MEK such as trametinib,
selumetinib and GDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin),
cyclin dependent kinases (e.g., palbociclib), PARP (e.g., olaparib)
and Pim kinases (LGH447, INCB053914 and SGI-1776) can also be
combined with compounds of the present disclosure.
[0179] Compounds of the present disclosure can be used in
combination with one or more immune checkpoint inhibitors.
Exemplary immune checkpoint inhibitors include inhibitors against
immune checkpoint molecules such as CD20, CD27, CD28, CD39, CD40,
CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K
gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR,
B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and
PD-L2. In some embodiments, the immune checkpoint molecule is a
stimulatory checkpoint molecule selected from CD27, CD28, CD40,
ICOS, OX40, GITR and CD137. In some embodiments, the immune
checkpoint molecule is an inhibitory checkpoint molecule selected
from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3,
and VISTA. In some embodiments, the compounds provided herein can
be used in combination with one or more agents selected from KIR
inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors,
2B4 inhibitors and TGFR beta inhibitors.
[0180] In some embodiments, the inhibitor of an immune checkpoint
molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4
antibody.
[0181] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal
antibody. In some embodiments, the anti-PD-1 monoclonal antibody is
nivolumab, pembrolizumab (also known as MK-3475), pidilizumab,
SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1
monoclonal antibody is nivolumab or pembrolizumab. In some
embodiments, the anti-PD1 antibody is pembrolizumab. In some
embodiments, the anti PD-1 antibody is SHR-1210.
[0182] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal
antibody. In some embodiments, the anti-PD-L1 monoclonal antibody
is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or
MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal
antibody is MPDL3280A or MEDI4736.
[0183] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
In some embodiments, the anti-CTLA-4 antibody is ipilimumab.
[0184] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CSF1R, e.g., an anti-CSF1R antibody. In
some embodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.
[0185] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of LAGS, e.g., an anti-LAGS antibody. In
some embodiments, the anti-LAGS antibody is BMS-986016, LAG525,
IMP321 or GSK2831781.
[0186] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In
some embodiments, the anti-GITR antibody is TRX518, MK-4166,
MK1248, BMS-986156, MEDI1873 or GWN323.
[0187] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or
OX40L fusion protein. In some embodiments, the anti-OX40 antibody
is MEDI0562, MEDI6469, MOXR0916, PF-04518600 or GSK3174998. In some
embodiments, the OX40L fusion protein is MEDI6383.
[0188] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of TIM3, e.g., an anti-TIM3 antibody. In
some embodiments, the anti-TIM3 antibody is MBG-453.
[0189] In some embodiments, the inhibitor of an immune checkpoint
molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody. In
some embodiments, the anti-CD20 antibody is obinutuzumab or
rituximab In some embodiments, the compounds of the invention can
be used in combination with one or more metabolic enzyme
inhibitors. In some embodiments, the metabolic enzyme inhibitor is
an inhibitor of IDO1, TDO, or arginase. Examples of IDO1 inhibitors
include epacadostat and NGL919. An example of an arginase inhibitor
is CB-1158.
[0190] The compounds of the present disclosure can be used in
combination with bispecific antibodies. In some embodiments, one of
the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4,
GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGF.beta. receptor.
[0191] Compounds of the present disclosure can be used in
combination with one or more agents for the treatment of diseases
such as cancer. In some embodiments, the agent is an alkylating
agent, a proteasome inhibitor, a corticosteroid, or an
immunomodulatory agent. Examples of an alkylating agent include
bendamustine, nitrogen mustards, ethylenimine derivatives, alkyl
sulfonates, nitrosoureas and triazenes, uracil mustard,
chlormethine, cyclophosphamide (Cytoxan.TM.), ifosfamide,
melphalan, chlorambucil, pipobroman, triethylene-melamine,
triethylenethiophosphoramine, busulfan, carmustine, lomustine,
streptozocin, dacarbazine, and temozolomide. In some embodiments,
the proteasome inhibitor is carfilzomib. In some embodiments, the
corticosteroid is dexamethasone (DEX). In some embodiments, the
immunomodulatory agent is lenalidomide (LEN) or pomalidomide
(POM).
[0192] The compounds of the present disclosure can further be used
in combination with other methods of treating cancers, for example
by chemotherapy, irradiation therapy, tumor-targeted therapy,
adjuvant therapy, immunotherapy or surgery. Examples of
immunotherapy include cytokine treatment (e.g., interferons,
GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine,
monoclonal antibody, adoptive T cell transfer, oncolytic
virotherapy and immunomodulating small molecules, including
thalidomide or JAK1/2 inhibitor and the like. The compounds can be
administered in combination with one or more anti-cancer drugs,
such as a chemotherapeutics. Example chemotherapeutics include any
of: abarelix, abiraterone, afatinib, aflibercept, aldesleukin,
alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole,
arsenic trioxide, asparaginase, axitinib, azacitidine, bevacizumab,
bexarotene, baricitinib, bicalutamide, bleomycin, bortezombi,
bortezomib, brivanib, buparlisib, busulfan intravenous, busulfan
oral, calusterone, capecitabine, carboplatin, carmustine,
cediranib, cetuximab, chlorambucil, cisplatin, cladribine,
clofarabine, crizotinib, cyclophosphamide, cytarabine, dacarbazine,
dacomitinib, dactinomycin, dalteparin sodium, dasatinib,
dactinomycin, daunorubicin, decitabine, degarelix, denileukin,
denileukin diftitox, deoxycoformycin, dexrazoxane, docetaxel,
doxorubicin, droloxafine, dromostanolone propionate, eculizumab,
enzalutamide, epidophyllotoxin, epirubicin, erlotinib,
estramustine, etoposide phosphate, etoposide, exemestane, fentanyl
citrate, filgrastim, floxuridine, fludarabine, fluorouracil,
flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab
ozogamicin, goserelin acetate, histrelin acetate, ibritumomab
tiuxetan, idarubicin, idelalisib, ifosfamide, imatinib mesylate,
interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide,
letrozole, leucovorin, leuprolide acetate, levamisole, lomustine,
meclorethamine, megestrol acetate, melphalan, mercaptopurine,
methotrexate, methoxsalen, mithramycin, mitomycin C, mitotane,
mitoxantrone, nandrolone phenpropionate, navelbene, necitumumab,
nelarabine, neratinib, nilotinib, nilutamide, nofetumomab,
oserelin, oxaliplatin, paclitaxel, pamidronate, panitumumab,
pazopanib, pegaspargase, pegfilgrastim, pemetrexed disodium,
pentostatin, pilaralisib, pipobroman, plicamycin, ponatinib,
prednisone, procarbazine, quinacrine, rasburicase, regorafenib,
reloxafine, rituximab, ruxolitinib, sorafenib, streptozocin,
sunitinib, sunitinib maleate, tamoxifen, tegafur, temozolomide,
teniposide, testolactone, thalidomide, thioguanine, thiotepa,
topotecan, toremifene, tositumomab, trastuzumab, tretinoin,
triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine,
vincristine, vinorelbine, vorinostat and zoledronate.
[0193] Other anti-cancer agent(s) include antibody therapeutics
such as trastuzumab (Herceptin), antibodies to costimulatory
molecules such as CTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB,
antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10,
TGF-.beta., etc.). Examples of antibodies to PD-1 and/or PD-L1 that
can be combined with compounds of the present disclosure for the
treatment of cancer or infections such as viral, bacteria, fungus
and parasite infections include, but are not limited to, nivolumab,
pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.
[0194] Other anti-cancer agents include inhibitors of kinases
associated cell proliferative disorder. These kinases include but
not limited to Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9,
ephrin receptor kinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes,
Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC,
Rsk and SGK.
[0195] Other anti-cancer agents also include those that block
immune cell migration such as antagonists to chemokine receptors,
including CCR2 and CCR4.
[0196] The compounds of the present disclosure can further be used
in combination with one or more anti-inflammatory agents, steroids,
immunosuppressants or therapeutic antibodies.
[0197] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be combined with another
immunogenic agent, such as cancerous cells, purified tumor antigens
(including recombinant proteins, peptides, and carbohydrate
molecules), cells, and cells transfected with genes encoding immune
stimulating cytokines. Non-limiting examples of tumor vaccines that
can be used include peptides of melanoma antigens, such as peptides
of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor
cells transfected to express the cytokine GM-CSF.
[0198] The compounds of Formula (I) or any of the formulas as
described herein, a compound as recited in any of the claims and
described herein, or salts thereof can be used in combination with
a vaccination protocol for the treatment of cancer. In some
embodiments, the tumor cells are transduced to express GM-CSF. In
some embodiments, tumor vaccines include the proteins from viruses
implicated in human cancers such as Human Papilloma Viruses (HPV),
Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus
(KHSV). In some embodiments, the compounds of the present
disclosure can be used in combination with tumor specific antigen
such as heat shock proteins isolated from tumor tissue itself. In
some embodiments, the compounds of Formula (I) or any of the
formulas as described herein, a compound as recited in any of the
claims and described herein, or salts thereof can be combined with
dendritic cells immunization to activate potent anti-tumor
responses.
[0199] The compounds of the present disclosure can be used in
combination with bispecific macrocyclic peptides that target Fe
alpha or Fe gamma receptor-expressing effectors cells to tumor
cells. The compounds of the present disclosure can also be combined
with macrocyclic peptides that activate host immune
responsiveness.
[0200] The compounds of the present disclosure can be used in
combination with bone marrow transplant for the treatment of a
variety of tumors of hematopoietic origin.
[0201] Suitable antiviral agents contemplated for use in
combination with the compounds of the present disclosure can
comprise nucleoside and nucleotide reverse transcriptase inhibitors
(NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs),
protease inhibitors and other antiviral drugs.
[0202] Example suitable NRTIs include zidovudine (AZT); didanosine
(ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC);
abacavir (1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir
(BMS-180194); BCH-10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also
called beta-L-D4D and named
beta-L-2',3'-dicleoxy-5-fluoro-cytidene); DAPD,
((-)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).
Typical suitable NNRTIs include nevirapine (BI-RG-587);
delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721;
AG-1549; MKC-442
(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimid-
-inedione); and (+)-calanolide A (NSC-675451) and B. Typical
suitable protease inhibitors include saquinavir (Ro 31-8959);
ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343);
amprenavir (141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623;
ABT-378; and AG-1 549. Other antiviral agents include hydroxyurea,
ribavirin, IL-2, IL-12, pentafuside and Yissum Project No.
11607.
[0203] When more than one pharmaceutical agent is administered to a
patient, they can be administered simultaneously, separately,
sequentially, or in combination (e.g., for more than two agents).
In some embodiments, the another agent can be selected from one of
the classes detailed below. [0204] Polyfunctional alkylating
agents, exemplified by cyclophosphamide (cytoxan), mechlorethamine,
melphalan (alkeran), chlorambucil (leukeran), thiopeta (thioplex),
busulfan (myleran); [0205] Alkylating drugs, exemplified by
procarbazine (matulane), dacarbazine (dtic), altretamine (hexalen),
clorambucil, cisplatin (platinol), carboplatin, ifosafamide,
oxaliplatin; [0206] Antimetabolites, exemplified by methotrexate
(MTX), 6-thiopurines (mercaptopurine [6-mp], thioguanine [6-TG]),
mercaptopurine (purinethol), thioguanine, fludarabine phosphate,
cladribine: (leustatin), pentostatin, flurouracil (5-Fu),
cytarabine (ara-C), azacitidine; [0207] Plant alkaloids, terpenoids
and topoisomerase inhibitors, exemplified by vinblastine (velban),
vincristine (oncovin), vindesine, vinorelbine, podophyllotoxins
(etoposide (VP-16) and teniposide (VM-26)), camptothecins
(topotecan and irinotecan), taxanes such as paclitaxel (taxol) and
docetaxel (taxotere); [0208] Antibiotics, exemplified by
doxorubicin (adriamycin, rubex, doxil), daunorubicin, idarubicin,
dactinomycin (cosmegen), plicamycin (mithramycin), mitomycin:
(mutamycin), bleomycin (blenoxane); [0209] Hormonal agents,
exemplified by estrogen and androgen inhibitors (tamoxifen and
flutamide), gonadotropin-releasing hormone agonists (leuprolide and
goserelin (Zoladex)), aromatase inhibitors (aminoglutethimide and
anastrozole (arimidex)); [0210] Miscellaneous Anticancer Drugs,
exemplified by amsacrine, asparaginase (El-spar), hydroxyurea,
mitoxantrone (novantrone), mitotane (lysodren), retinoic acid
derivatives, bone marrow growth factors (sargramostim and
filgrastim), amifostine; [0211] Agents disrupting folate
metabolism, e.g., pemetrexed; [0212] DNA hypomethylating agents,
e.g., azacitidine, decitabine; [0213] Poly(adenosine diphosphate
[ADP]-ribose) polymerase (PARP) pathway inhibitors, such as
iniparib, olaparib, veliparib; [0214] PI3K/Akt/mTOR pathway
inhibitors, e.g., everolimus; [0215] Histone deacetylase (HDAC)
inhibitors, e.g., vorinostat, entinostat (SNDX-275), mocetinostat
(MGCD0103), panobinostat (LBH589), romidepsin, valproic acid;
[0216] Cyclin-dependent kinase (CDK) inhibitors, e.g.,
flavopiridol, olomoucine, roscovitine, kenpaullone, AG-024322
(Pfizer), fascaplysin, ryuvidine, purvalanol A, NU2058, BML-259, SU
9516, PD-0332991, P276-00; [0217] Heat shock protein (HSP90)
inhibitors, e.g., geldanamycin, tanespimycin, alvespimycin,
radicicol, deguelin, BIIB021; [0218] Murine double minute 2 (MDM2)
inhibitors, e.g., cis-imidazoline, benzodiazepinedione,
spiro-oxindoles, isoquinolinone, thiophene, 5-deazaflavin,
tryptamine; [0219] Anaplastic lymphoma kinase (ALK) inhibitors,
e.g., aminopyridine, diaminopyrimidine, pyridoisoquinoline,
pyrrolopyrazole, indolocarbazole, pyrrolopyrimidine,
dianilinopyrimidine; [0220] Poly [ADPribose] polymerase (PARP)
inhibitors, illustrated by benzamide, phthalazinone, tricyclic
indole, benzimidazole, indazole, pyrrolocarbazole, phthalazinone,
or isoindolinone; [0221] A platinum-based drug, an antimetabolite,
a BCL-2 inhibitor, a BTK inhibitor, a P13K.delta. inhibitor, an
anti-CD20 antibody, such as rituximab, obinutuzumab, ibritumomab
tiuxetan, tositumomab, or veltuzumab, or a combination thereof; or
[0222] ABT-199 (Venetoclax), rituximab (RITUXAN.RTM.,
MABTHERA.RTM., ZYTUX.RTM.), ibrutinib (IMBRUVICA.RTM.), idelalisib
(ZYDELIG.RTM.), tofacitinib, or a combination thereof.
[0223] In some embodiments, the other chemotherapeutic agent is a
p90RSK inhibitor, such as those described in Cohen et al., "A
clickable inhibitor reveals context-dependent autoactivation of p90
RSK," Nat Chem Biol. 2007 March; 3(3): 156-160, and U.S. Pat. No.
7,605,241. In one aspect, the p90RSK inhibitor is one or more of
dexamethasone, melphalan, doxorubicin, bortezomib, lenalidomide,
prednisone, carmustine, etoposide, cisplatin, vincristine,
cyclophosphamide, BI-D1870, and thalidomide.
[0224] In some embodiments, cerdulatinib, or a pharmaceutically
acceptable salt, co-crystal or solvate thereof, can be administered
with a proton pump inhibitor, such as esomaprazole, omeprazole,
lansoprazole, rabeprazole, dexlansoprazole, or a pharmaceutically
acceptable salt thereof.
[0225] The specific amount of the agent co-administered with
cerdulatinib described herein refers to the amount of the
co-administered agent as a free base. However, it is understood
that a pharmaceutically acceptable salt, co-crystal or solvate of
the agent co-administered with cerdulatinib or a mixture thereof
may be administered in an amount that provides the stated amount of
the co-administered agent. Examples of pharmaceutically acceptable
salts of the agent co-administered with cerdulatinib include those
derived from inorganic or organic acids, such as acetate, adipate,
alginate, aspartate, benzoate, benzene sulfonate, bisulfate,
butyrate, citrate, camphorate, camphor sulfonate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, edisylate, fumarate, lucoheptanoate,
glycerophosphate, hemisulfate, heptanoate, hexanoate,
hydrochloride, bis-hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,
bis-methanesulfonate, 2-naphthalenesulfonate, naphthalene
disulfate, nicotinate, oxalate, pamoate, pectinate, persulfate,
3-phenyl-propionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, tosylate, undecanoate, hydrohalides (e.g.,
hydrochlorides and hydrobromides), sulfates, phosphates, nitrates,
sulphamates, malonates, salicylates,
methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,
di-ptoluoyltartrates, ethanesulphonates, cyclohexylsulphamates,
quinates, and the like.
[0226] The co-administered agent or a salt thereof can be
administered in unsolvated forms as well as solvated forms,
including hydrated forms, or form co-crystals with another
compound. "Hydrate" refers to a complex formed by combination of
water molecules with molecules or ions of the solute. "Solvate"
refers to a complex formed by combination of solvent molecules with
molecules or ions of the solute. The solvent can be an organic
compound, an inorganic compound, or a mixture of both. Solvate is
meant to include hydrate, hemi-hydrate, channel hydrate etc. Some
examples of solvents include, but are not limited to, methanol,
N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and
water.
[0227] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib (e.g., rituximab) is at least
about 5 mg per day. In some embodiments, the effective amount of
the agent co-administered with cerdulatinib is at least about 10
mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg,
60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg or 100 mg
per day. In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is at least about 10, 20, 30, 40,
or 50 mg per dosage. In some embodiments, the effective amount of
the agent co-administered with cerdulatinib is at least about 15
mg, 20 mg, 25 mg, 30 mg, or 35 mg per dosage and is administered
twice daily.
[0228] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is no more than about 100 mg, 95
mg, 90 mg, 85 mg, 80 mg, or 75 mg of per day. In some embodiments,
the effective amount of the agent co-administered with cerdulatinib
is no more than about 90 mg, 80 mg, 70 mg, 60 mg, 55 mg or 50 mg
per dosage. In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is no more than 45 mg, 40 mg, 35
mg, or 30 mg per dosage and is administered twice daily.
[0229] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is from about 10 mg to 200 mg,
from about 10 mg to 150 mg, from about 25 mg to 150 mg, from about
25 to 120 mg, from 30 mg to 110 mg, from about 50 to 120 mg, from
about 30 to 80 mg, from 50 mg to 80 mg, from about 40 to 50 mg or
from about 80 to 100 mg per day.
[0230] In some embodiments, the daily dose of the agent
co-administered with cerdulatinib is about 30 mg, 45 mg, 50 mg, 55
mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg,
110 mg, 120 mg, 130 mg, 140 mg, or 150 mg.
[0231] In some embodiments, from about 30 mg to about 80 mg of the
agent is co-administered with cerdulatinib once a day. In some
embodiments, the effective amount is about 40 mg, 45 mg, 50 mg, 55
mg, 60 mg, 65 mg, or 70 mg of the agent co-administered with
cerdulatinib once daily.
[0232] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is about 15 mg to about 65 mg,
about 25 mg to about 50 mg, about 25 mg to about 40 mg, about 30 mg
to about 40 mg or about 40 mg to about 50 mg per dosage
administered twice daily. In some embodiments, about 25 mg, 30 mg,
35 mg, 40 mg, 45 mg, 50 mg, 55 mg or 60 mg of the agent is
co-administered with cerdulatinib twice daily. In some embodiments,
about 45 mg of the agent is co-administered with cerdulatinib twice
daily. In some embodiments, about 35 mg of the agent
co-administered with twice daily.
[0233] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is a daily dosage of from about
30 mg to about 90 mg. In some embodiments, the effective amount of
the agent co-administered with cerdulatinib is a daily dosage of
from about 40 mg, about 50 mg, about 60 mg, or about 70 mg,
administered once or twice daily. In some embodiments, the
effective amount of the agent co-administered with cerdulatinib is
about 35 mg twice daily. In some embodiments, the effective amount
of the agent co-administered with cerdulatinib is about 30 mg twice
daily. In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is about 25 mg twice daily. In
some embodiments, the effective amount of the agent co-administered
with cerdulatinib is about 20 mg twice daily. In some embodiments,
the effective amount of the agent co-administered with cerdulatinib
is about 30 mg twice daily, and is reduced about 25 mg twice daily.
In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is further reduced to about 20 mg
twice daily. In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is further reduced to about 15 mg
twice daily.
[0234] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib is between about 0.01 and 200
mg/kg. In some embodiments, about 0.01 and 150 mg/kg of agent may
be co-administered with cerdulatinib. In other embodiments, a
dosage of between 0.05 and 100 mg/kg of rituximab may be
co-administered with cerdulatinib. The dosage is described as a
total amount of rituximab administered per time period. The dosage
of the agent co-administered with cerdulatinib may be between about
0.1 mg and 2,000 mg/time period, between about 1 to 2,000 mg/time
period, between about 1 to 1,000 mg/time period, between about 1 to
500 mg/time period, between about 10 to 150 mg/time period, between
about 1 to 100 mg/time period, between about between about 1 to 50
mg/time period, between about 5 to 100 mg/time period, between
about 10 to 125 mg/time period, between about 10 to 100 mg/time
period, or between about 5 to 200 mg/time period. The dosage of
rituximab may be administered all in one time (once per time
period) or in several times, such as two times, three times, four
times, five times or more throughout the time period. In some
embodiments, the time period is, or is about, every week, every two
weeks, every three weeks, every four weeks, every one month, every
two months, every three months, every four months, every five
months, every six months, every seven months, every eight months,
every nine months, every ten months, every eleven months, every
year, or a number or a range between any two of these values.
[0235] In some embodiments, rituximab is co-administered per its
package insert. In some embodiments, rituximab is administered by
infusion, such as by intravenous injection. In some embodiments,
the effective amount of rituximab is 375 mg/m.sup.2, for example,
to treat a patient with Non-Hodgkin's Lymphoma (NHL). In some
embodiments, the NHL is relapsed or refractory, low grade or
follicular, CD20-positive B-cell NHL. In some embodiments, the NHL
is previously untreated follicular, CD20-positive, B-cell NHL, for
example, in combination with first line chemotherapy. In some
embodiments, the patient has achieved a complete or partial
response to rituximab, for example, in combination with
chemotherapy, and rituximab, for example, in combination with
cerdulatinib, can be used for maintenance therapy. In some
embodiments, the NHL is non-progressing (including stable disease),
low-grade, CD20-positive, B-cell NHL, for example, after first-line
cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
In some embodiments, the NHL is previously untreated diffuse large
B-cell, CD20-positive NHL, for example, in combination with
(cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP)
or other anthracycline-based chemotherapy regimens. In some
embodiments, the effective amount of rituximab is 375 mg/m.sup.2
the first cycle and 500 mg/m.sup.2 in cycles 2-6 in combination
with fludarabine and cyclophosphamide (FC), administered every 28
days, for example, to treat a patient with Chronic Lymphocytic
Leukemia (CLL). In some embodiments, the effective amount of
rituximab is 250 mg/m.sup.2, for example, in combination with
ibritumomab tiuxetan. In some embodiments, the effective amount of
rituximab, for example in combination with methotrexate, is
two-1000 mg intravenous infusions separated by 2 weeks (one course)
every 24 weeks or based on clinical evaluation, but not sooner than
every 16 weeks. In some embodiments, the effective amount of
rituximab is 375 mg/m.sup.2 (for example in combination with
glucocorticoids) once weekly for 4 weeks, and, for example, to
treat a patient who has achieved disease control, two 500 mg
intravenous infusions separated by two weeks, followed by a 500 mg
intravenous infusion every 6 months thereafter based on clinical
evaluation. In some embodiments, the effective amount of rituximab
is two-1000 mg intravenous infusions separated by 2 weeks in
combination with a tapering course of glucocorticoids, then a 500
mg intravenous infusion at Month 12 and every 6 months thereafter
or based on clinical evaluation, and upon relapse is a 1000 mg
intravenous infusion, with subsequent infusions no sooner than 16
weeks after the previous infusion.
[0236] In some embodiments, rituximab is administered in the dosage
forms and strengths of 100 mg/10 mL (10 mg/mL) and 500 mg/50 mL (10
mg/mL) solution, for example, in single-dose vials.
[0237] In some embodiments, rituximab is administered at a dose of
375 mg/m.sup.2 as an intravenous infusion. In some embodiments,
rituximab is administered once weekly for 4 or 8 doses, for
example, to treat a patient with Relapsed or Refractory, Low-Grade
or Follicular, CD20-Positive, B-Cell NHL. In some embodiments,
rituximab is administered once weekly for 4 doses, for example, to
treat a patient with Relapsed or Refractory, Low-Grade or
Follicular, CD20-Positive, B-Cell NHL. In some embodiments,
rituximab is administered on Day 1 of each cycle of chemotherapy,
for up to 8 doses, for example, to treat a patient with Previously
Untreated, Follicular, CD20-Positive, B-Cell NHL. In some
embodiments, if complete or partial response is achieved, rituximab
maintenance is initiated eight weeks following completion of
rituximab administering, for example, in combination with
chemotherapy. In some embodiments, rituximab maintenance includes
administering rituximab with cerdulatinib every 8 weeks for 12
doses. In some embodiments, rituximab is administered once weekly
for 4 doses at 6-month intervals to a maximum of 16 doses, for
example, to treat a patient with Non-progressing, Low-Grade,
CD20-Positive, B-Cell NHL (e.g., after first-line CVP
chemotherapy). In some embodiments, rituximab is administered on
Day 1 of each cycle of chemotherapy for up to 8 infusions, for
example, to treat a patient with Diffuse Large B-Cell NHL.
[0238] In some embodiments, rituximab is administered at a dose of
375 mg/m.sup.2 the day prior to the initiation of FC chemotherapy,
then 500 mg/m.sup.2 on Day 1 of cycles 2-6 (every 28 days), for
example, to treat a patient with Chronic Lymphocytic Leukemia
(CLL).
[0239] In some embodiments, rituximab is administered at a dose of
250 mg/m.sup.2, for example, to treat a patient with NHL. In some
embodiments, rituximab is administered 4 hours prior to the
administration of Indium-111-(In-111-) Zevalin and within 4 hours
prior to the administration of Yttrium-90-(Y-90-) Zevalin. IN some
embodiments, rituximab and In-111-Zevalin are administered 7-9 days
prior to RITUXAN and Y-90-Zevalin are administered.
[0240] In some embodiments, the effective amount of rituximab is an
amount determined by a medical practitioner for treatment of the
disease or indication.
[0241] In some embodiments, the effective amount of rituximab
(e.g., for the dose of the first cycle and for the doses of the
subsequent cycles) is, or is about, 100 mg/m.sup.2, 110 mg/m.sup.2,
120 mg/m.sup.2, 130 mg/m.sup.2, 140 mg/m.sup.2, 150 mg/m.sup.2, 160
mg/m.sup.2, 170 mg/m.sup.2, 180 mg/m.sup.2, 190 mg/m.sup.2, 200
mg/m.sup.2, 210 mg/m.sup.2, 220 mg/m.sup.2, 230 mg/m.sup.2, 240
mg/m.sup.2, 250 mg/m.sup.2, 260 mg/m.sup.2, 270 mg/m.sup.2, 280
mg/m.sup.2, 290 mg/m.sup.2, 300 mg/m.sup.2, 310 mg/m.sup.2, 320
mg/m.sup.2, 330 mg/m.sup.2, 340 mg/m.sup.2, 350 mg/m.sup.2, 360
mg/m.sup.2, 370 mg/m.sup.2, 375 mg/m.sup.2, 380 mg/m.sup.2, 390
mg/m.sup.2, 400 mg/m.sup.2, 410 mg/m.sup.2, 420 mg/m.sup.2, 430
mg/m.sup.2, 440 mg/m.sup.2, 450 mg/m.sup.2, 460 mg/m.sup.2, 470
mg/m.sup.2, 480 mg/m.sup.2, 490 mg/m.sup.2, 500 mg/m.sup.2, 510
mg/m.sup.2, 520 mg/m.sup.2, 530 mg/m.sup.2, 540 mg/m.sup.2, 550
mg/m.sup.2, 560 mg/m.sup.2, 570 mg/m.sup.2, 580 mg/m.sup.2, 590
mg/m.sup.2, 600 mg/m.sup.2, 610 mg/m.sup.2, 620 mg/m.sup.2, 630
mg/m.sup.2, 640 mg/m.sup.2, 650 mg/m.sup.2, 660 mg/m.sup.2, 670
mg/m.sup.2, 680 mg/m.sup.2, 690 mg/m.sup.2, 700 mg/m.sup.2, 710
mg/m.sup.2, 720 mg/m.sup.2, 730 mg/m.sup.2, 740 mg/m.sup.2, 750
mg/m.sup.2, 760 mg/m.sup.2, 770 mg/m.sup.2, 780 mg/m.sup.2, 790
mg/m.sup.2, 800 mg/m.sup.2, 810 mg/m.sup.2, 820 mg/m.sup.2, 830
mg/m.sup.2, 840 mg/m.sup.2, 850 mg/m.sup.2, 860 mg/m.sup.2, 870
mg/m.sup.2, 880 mg/m.sup.2, 890 mg/m.sup.2, 900 mg/m.sup.2, 910
mg/m.sup.2, 920 mg/m.sup.2, 930 mg/m.sup.2, 940 mg/m.sup.2, 950
mg/m.sup.2, 960 mg/m.sup.2, 970 mg/m.sup.2, 980 mg/m.sup.2, 990
mg/m.sup.2, 1000 mg/m.sup.2, or a number or a range between any two
of these values, per dose or time period for a number of times or
cycles.
[0242] In some embodiments, the effective amount of rituximab per
dose is from about 50 mg to about 1000 mg every three to five weeks
up to five to seven times. In some embodiments, the effective
amount of rituximab is from about 100 mg to about 500 mg every
three to five weeks up to six times. In some embodiments, the
effective amount of rituximab is from about 100 mg to about 500 mg
every 28 days up to six times. In some embodiments, the effective
amount of rituximab (e.g., for the dose of the first cycle and for
the doses of the subsequent cycles) is, or is about, 50 mg, 100 mg,
150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550
mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg
1000 mg, or a number or a range between any two of these values,
per dose or time period for a number of times or cycles.
[0243] In some embodiments, the effective amount of rituximab is
once weekly for about 4 or 8 doses. In some embodiments, the
effective amount of rituximab is once weekly for about 4 doses. In
some embodiments, the time period between two consecutive doses is,
or is about, every day, every two days, every three days, every
four days, every five days, every six days, every week, every two
weeks, every three weeks, every four weeks, every one month, every
two months, every three months, every four months, every five
months, every six months, every seven months, every eight months,
every nine months, every ten months, every eleven months, every
twelve months, or a number or a range between any two of these
values. In some embodiments, the number of times or cycles is, is
about, or is at most, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, or a number or a range between any two of
these values.
[0244] In some embodiments, the dose for the first cycle and the
doses of the subsequent cycles are identical. In some embodiments,
the dose for the first cycle and the doses of the subsequent cycles
are different.
[0245] In some embodiments, the effective amount of rituximab
includes two initial doses separated by about two weeks and
subsequent doses every six months thereafter. In some embodiments,
the effective amount of rituximab includes two initial doses
separated by about two weeks and subsequent doses at month 12 and
every six months thereafter. In some embodiments, the effective
amount of rituximab includes a number of initial doses, such as 1
dose, 2 doses, 3 doses, 4 dose, 5 doses, 6 doses, 7 doses, 8 doses,
9 doses, or 10 doses. In some embodiments, the two consecutive
initial doses are separated by, or by about, 1 day, 2 days, 3 days,
4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks,
6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, or a number or a
range between any two of these values. In some embodiments,
subsequent doses are administered starting, or starting about, 6
months, 7 months, 8 months, 9 months, 10 months, 11 months, 12
months, 13 months, 14 months, 15 months, 16 months, 17 months, 18
months, or a number or a range between any two of these values. In
some embodiments, the subsequent doses are administered, or
administered about, every 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12
weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks,
or a number or a range between any two of these values. In some
embodiments, the number of subsequent doses is, or is about, 1
dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8
doses, 9 doses, 10 doses, 11 doses, 12 doses, 13 doses, 14 doses,
15 doses, 16 doses, 17 doses, 19 doses, 19 doses, 20 doses, or a
number or a range between of these two values.
[0246] In some embodiments, rituximab (e.g., in combination with
cerdulatinib) is used for maintenance after complete or partial
response begins about eight weeks following completion of a
rituximab product. In some embodiments, rituximab used for
maintenance is administered every 8 weeks for 12 doses. In some
embodiments, rituximab is used for maintenance after complete or
partial response following, or following about, 1 week, 2 weeks, 3
weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10
weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks,
17 weeks, 18 weeks, 19 weeks, 20 weeks, or a number or a range
between of these two values, completion of a rituximab product. In
some embodiments, rituximab used for maintenance is administered,
or administered about, every 1 week, 2 weeks, 3 weeks, 4 weeks, 5
weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12
weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks,
19 weeks, 20 weeks, or a number or a range between of these two
values. In some embodiments, rituximab used for maintenance is
administered, or administered about, 1 dose, 2 doses, 3 doses, 4
doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses, 11
doses, 12 doses, 13 doses, 14 doses, 15 doses, 16 doses, 17 doses,
19 doses, 19 doses, 20 doses, or a number or a range between of
these two values.
[0247] In some embodiments, the effective amount of rituximab is
co-administered with cerdulatinib at from about 100 mg/10 mL to
about 500 mg/50 mL. In some embodiments, the effective amount of
rituximab is co-administered with cerdulatinib at from about 100
mg/10 mL to about 200 mg/20 mL. In some embodiments, the effective
amount of rituximab is co-administered with cerdulatinib at from
about 200 mg/20 mL to about 300 mg/30 mL. In some embodiments, the
effective amount of rituximab is co-administered with cerdulatinib
at from about 300 mg/30 mL to about 400 mg/40 mL. In some
embodiments, the effective amount of rituximab is co-administered
with cerdulatinib at from about 400 mg/40 mL to about 500 mg/50
mL.
[0248] In some embodiments, the effective amount of rituximab is
co-administered with cerdulatinib in a concentration of about 5
mg/mL. In some embodiments, the effective amount of rituximab is
co-administered with cerdulatinib in a concentration of about 10
mg/mL. In some embodiments, the effective amount of rituximab is
co-administered with cerdulatinib in a concentration of about 15
mg/mL. In some embodiments, the effective amount of rituximab is
co-administered with cerdulatinib in a concentration of from about
5 mg/mL to about 15 mg/mL. In some embodiments, the effective
amount of rituximab is co-administered with cerdulatinib in a
concentration of from about 5 mg/mL to about 10 mg/mL. In some
embodiments, the effective amount of rituximab is co-administered
with cerdulatinib in a concentration of from about 10 mg/mL to
about 15 mg/mL. In some embodiments, the effective amount of
rituximab is co-administered in a concentration of from about 15
mg/mL to about 20 mg/mL. In some embodiments, the effective amount
of rituximab (or another agent) is co-administered with
cerdulatinib in a concentration of about 1 mg/mL, 2 mg/mL, 3 mg/mL,
4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL. 11
mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL,
18 mg/mL, 19 mg/mL, 20 mg/mL. 21 mg/mL, 22 mg/mL, 23 mg/mL, 24
mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL,
or a number or a range between any two of these values.
[0249] In some embodiments is provided a composition comprising
cerdulatinib and the agent co-administered with cerdulatinib (e.g.,
rituximab). In some embodiments, the molar ratio of cerdulatinib to
the co-administered agent is about 300:1 to about 3:1. In some
embodiments, the composition comprises cerdulatinib and the agent
co-administered with cerdulatinib in a molar ratio of about 9:1 to
about 1:9. In some embodiments, the composition comprises
cerdulatinib and the agent co-administered with cerdulatinib in a
molar ratio of about 2:1 to about 1:2. In some embodiments, the
composition comprises cerdulatinib and the agent co-administered
with cerdulatinib in a molar ratio of about 2:1 to about 1:5. In
some embodiments, the composition comprises cerdulatinib and the
agent co-administered with cerdulatinib in a molar ratio of about
1:1. In some embodiments, the composition comprises cerdulatinib
and the agent co-administered with cerdulatinib in a molar ratio of
about 1:1, about 1:2, about 1:9, about 2:1, or about 9:1. In some
embodiments, the composition comprises cerdulatinib and the agent
co-administered with cerdulatinib in a molar ratio of, of about, of
at least, or of at most, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1,
9:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, 100:1,
or a number or a range between any two of these values. In some
embodiments, the composition comprises cerdulatinib and the agent
co-administered with cerdulatinib in a molar ratio of, of about, of
at least, or of at most, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8,
1:9, 1:10, 1:20, 1:30, 1:40, 1:50, 1:60, 1:70, 1:80, 1:90, 1:100,
or a number or a range between any two of these values.
[0250] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib (e.g., rituximab), whether for
the dose of the first cycle and for the doses of the subsequent
cycles, is, or is about, 100 mg/m.sup.2, 110 mg/m.sup.2, 120
mg/m.sup.2, 130 mg/m.sup.2, 140 mg/m.sup.2, 150 mg/m.sup.2, 160
mg/m.sup.2, 170 mg/m.sup.2, 180 mg/m.sup.2, 190 mg/m.sup.2, 200
mg/m.sup.2, 210 mg/m.sup.2, 220 mg/m.sup.2, 230 mg/m.sup.2, 240
mg/m.sup.2, 250 mg/m.sup.2, 260 mg/m.sup.2, 270 mg/m.sup.2, 280
mg/m.sup.2, 290 mg/m.sup.2, 300 mg/m.sup.2, 310 mg/m.sup.2, 320
mg/m.sup.2, 330 mg/m.sup.2, 340 mg/m.sup.2, 350 mg/m.sup.2, 360
mg/m.sup.2, 370 mg/m.sup.2, 375 mg/m.sup.2, 380 mg/m.sup.2, 390
mg/m.sup.2, 400 mg/m.sup.2, 410 mg/m.sup.2, 420 mg/m.sup.2, 430
mg/m.sup.2, 440 mg/m.sup.2, 450 mg/m.sup.2, 460 mg/m.sup.2, 470
mg/m.sup.2, 480 mg/m.sup.2, 490 mg/m.sup.2, 500 mg/m.sup.2, 510
mg/m.sup.2, 520 mg/m.sup.2, 530 mg/m.sup.2, 540 mg/m.sup.2, 550
mg/m.sup.2, 560 mg/m.sup.2, 570 mg/m.sup.2, 580 mg/m.sup.2, 590
mg/m.sup.2, 600 mg/m.sup.2, 610 mg/m.sup.2, 620 mg/m.sup.2, 630
mg/m.sup.2, 640 mg/m.sup.2, 650 mg/m.sup.2, 660 mg/m.sup.2, 670
mg/m.sup.2, 680 mg/m.sup.2, 690 mg/m.sup.2, 700 mg/m.sup.2, 710
mg/m.sup.2, 720 mg/m.sup.2, 730 mg/m.sup.2, 740 mg/m.sup.2, 750
mg/m.sup.2, 760 mg/m.sup.2, 770 mg/m.sup.2, 780 mg/m.sup.2, 790
mg/m.sup.2, 800 mg/m.sup.2, 810 mg/m.sup.2, 820 mg/m.sup.2, 830
mg/m.sup.2, 840 mg/m.sup.2, 850 mg/m.sup.2, 860 mg/m.sup.2, 870
mg/m.sup.2, 880 mg/m.sup.2, 890 mg/m.sup.2, 900 mg/m.sup.2, 910
mg/m.sup.2, 920 mg/m.sup.2, 930 mg/m.sup.2, 940 mg/m.sup.2, 950
mg/m.sup.2, 960 mg/m.sup.2, 970 mg/m.sup.2, 980 mg/m.sup.2, 990
mg/m.sup.2, 1000 mg/m.sup.2, or a number or a range between any two
of these values, per dose or time period for a number of times or
cycles.
[0251] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib (e.g., rituximab), whether for
the dose of the first cycle and for the doses of the subsequent
cycles, is, or is about, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300
mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg,
750 mg, 800 mg, 850 mg, 900 mg, 950 mg 1000 mg, or a number or a
range between any two of these values, per dose or time period for
a number of times or cycles.
[0252] In some embodiments, the time period between two consecutive
doses is, or is about, every day, every two days, every three days,
every four days, every five days, every six days, every week, every
two weeks, every three weeks, every four weeks, every one month,
every two months, every three months, every four months, every five
months, every six months, every seven months, every eight months,
every nine months, every ten months, every eleven months, every
twelve months, or a number or a range between any two of these
values. In some embodiments, the number of times or cycles is, is
about, or is at most, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, or a number or a range between any two of
these values.
[0253] In some embodiments, the effective amount of the agent
co-administered with cerdulatinib (e.g., rituximab) is
co-administered with cerdulatinib in a concentration of about 1
mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8
mg/mL, 9 mg/mL, 10 mg/mL. 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL,
15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL. 21
mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL,
28 mg/mL, 29 mg/mL, 30 mg/mL, or a number or a range between any
two of these values.
[0254] In some embodiments, the agent co-administered with
cerdulatinib (e.g., rituximab) is administered at least, or is
administered at most, 5 times, 6 times, 7 times, 8 times, 9 times,
10 times, 20 times, 30 times, 40 times, 50 times, 60 times, 70
times, 80 times, 90 times, 100 times, or a number or a range
between any two of these values.
4. Administration and Compositions
[0255] Cerdulatinib may be administered in pharmaceutical
compositions comprising an effective amount of cerdulatinib and at
least one pharmaceutically acceptable carrier or excipient.
[0256] Examples of carriers include calcium carbonate, calcium
phosphate, various sugars such as lactose, glucose, or sucrose, or
types of starch, cellulose derivatives, gelatin, vegetable oils,
polyethylene glycols and physiologically compatible solvents.
Examples of physiologically compatible solvents include sterile
solutions of water for injection (WFI), saline solution, and
dextrose.
[0257] Suitable dosage forms, in part, depend upon the use or the
route of administration, for example, oral, transdermal,
transmucosal, inhalant, or by injection (parenteral). Such dosage
forms should allow cerdulatinib to reach target cells. Other
factors are well known in the art, and include considerations such
as toxicity and dosage forms that retard the compound or
composition from exerting its effects.
[0258] Cerdulatinib can be administered by different routes
including intravenous, intraperitoneal, subcutaneous,
intramuscular, oral, transmucosal, rectal, transdermal, or
inhalant. In some embodiments, cerdulatinib can be administered by
oral administration. For oral administration, for example,
cerdulatinib can be formulated into conventional oral dosage forms
such as capsules, tablets, and liquid preparations such as syrups,
elixirs, and concentrated drops.
[0259] For inhalants, cerdulatinib may be formulated as dry powder
or a suitable solution, suspension, or aerosol. Powders and
solutions may be formulated with suitable additives known in the
art. For example, powders may include a suitable powder base such
as lactose or starch, and solutions may comprise propylene glycol,
sterile water, ethanol, sodium chloride and other additives, such
as acid, alkali and buffer salts. Such solutions or suspensions may
be administered by inhaling via spray, pump, atomizer, or
nebulizer, and the like. Cerdulatinib may also be used in
combination with other inhaled therapies, for example
corticosteroids such as fluticasone propionate, beclomethasone
dipropionate, triamcinolone acetonide, budesonide, and mometasone
furoate; beta agonists such as albuterol, salmeterol, and
formoterol; anticholinergic agents such as ipratropium bromide or
tiotropium; vasodilators such as treprostinal and iloprost; enzymes
such as DNAase; therapeutic proteins; immunoglobulin antibodies; an
oligonucleotide, such as single or double stranded DNA or RNA,
siRNA; antibiotics such as tobramycin; muscarinic receptor
antagonists; leukotriene antagonists; cytokine antagonists;
protease inhibitors; cromolyn sodium; nedocril sodium; and sodium
cromoglycate.
[0260] Pharmaceutical preparations for oral use can be obtained,
for example, by combining cerdulatinib with solid excipients,
optionally grinding a resulting mixture, and processing the mixture
of granules, after adding suitable auxiliaries, if desired, to
obtain tablets or dragee cores. Suitable excipients are, in
particular, fillers such as sugars, including lactose, sucrose,
mannitol, or sorbitol; cellulose preparations, for example, maize
starch, wheat starch, rice starch, potato starch, gelatin, gum
tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
carboxymethylcellulose (CMC), and/or polyvinylpyrrolidone (PVP:
povidone). If desired, disintegrating agents may be added, such as
the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a
salt thereof such as sodium alginate.
[0261] Pharmaceutical preparations that can be used orally include
push-fit capsules made of gelatin ("gelcaps"), as well as soft,
sealed capsules made of gelatin, and a plasticizer, such as
glycerol or sorbitol. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such
as starches, and/or lubricants such as talc or magnesium stearate
and, optionally, stabilizers. In soft capsules, cerdulatinib may be
dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols (PEGs). In
addition, stabilizers may be added.
[0262] Alternatively, injection (parenteral administration) may be
used, e.g., intramuscular, intravenous, intraperitoneal, and/or
subcutaneous. For injection, cerdulatinib is formulated in sterile
liquid solutions, such as in physiologically compatible buffers or
solutions, such as saline solution, Hank's solution, or Ringer's
solution. In addition, cerdulatinib may be formulated in solid form
and redissolved or suspended immediately prior to use. Lyophilized
forms can also be produced.
[0263] Administration can also be by transmucosal, topical,
transdermal, or inhalant means. For transmucosal, topical or
transdermal administration, penetrants appropriate to the barrier
to be permeated are used in the formulation. Such penetrants are
generally known in the art, and include, for example, for
transmucosal administration, bile salts and fusidic acid
derivatives. In addition, detergents may be used to facilitate
permeation. Transmucosal administration, for example, may be
through nasal sprays or suppositories (rectal or vaginal).
[0264] The topical compositions can be formulated as oils, creams,
lotions, ointments, and the like by choice of appropriate carriers
known in the art. Suitable carriers include vegetable or mineral
oils, white petrolatum (white soft paraffin), branched chain fats
or oils, animal fats and high molecular weight alcohol (greater
than C.sub.12). In another embodiment, the carriers are those in
which the active ingredient is soluble. Emulsifiers, stabilizers,
humectants and antioxidants may also be included as well as agents
imparting color or fragrance, if desired. Creams for topical
application are formulated from a mixture of mineral oil,
self-emulsifying beeswax and water in which mixture the active
ingredient, dissolved in a small amount solvent (e.g. an oil), is
admixed. Additionally, administration by transdermal means may
comprise a transdermal patch or dressing such as a bandage
impregnated with an active ingredient and optionally one or more
carriers or diluents known in the art.
[0265] In some embodiments, cerdulatinib, or a pharmaceutically
acceptable salt, co-crystal or solvate thereof, is administered
orally without limitation with regard to food intake, for example,
cerdulatinib can be administered with or without food.
EXAMPLES
Example 1
[0266] In a phase 1, dose-escalation study in adults with
relapsed/refractory B cell malignancies, cerdulatinib was
administered orally to sequential dose-escalation cohorts using
once daily (QD) and twice daily (BID) schedules. Repeat CT scans
were obtained from 6 patients with chronic lymphocytic leukemia
(CLL) or small lymphocytic lymphoma (SLL), 13 patients with
follicular lymphoma (FL), 12 patients with diffuse large B cell
lymphoma (DLBCL), and 6 patients with mantle cell lymphoma (MCL).
Correlation of tumor response with PD markers was determined in
patients with CLL/SLL and FL, for whom meaningful clinical
responses were observed.
[0267] Cerdulatinib was administered to sequential dose cohorts at
increasing dose levels until the maximum tolerated dose (MTD) was
identified. The starting dose level was 15 mg PO QD for 28 days
(cycle 1), except on Days 2 and 3 of Cycle 1, when single-dose
pharmacokinetic (PK) assessments were performed. If cerdulatinib
was well tolerated, patients continued to receive treatment at the
discretion of the investigator until discontinuation criteria were
met.
[0268] Reagents for Pharmacodynamic Assays
[0269] For induction of cell signaling events, the following
reagents were procured. Goat anti-human IgD (IgG fraction; Bethyl
Laboratories Inc., Montgomery, Tex.), donkey anti-human IgM F(ab)'2
(Jackson ImmunoResearch, West Grove, Pa.), and recombinant human
IL-2, IL-4, IL-6, and GM-CSF (R&D Systems, Minneapolis, Minn.).
Lyse/Fix buffer and BD FACS/Lyse buffer (BD Biosciences, San Jose,
Calif.) were used to prepare whole blood for intracellular and
surface antibody staining, respectively. Cell lineages were
identified by flow cytometry by using the antibodies: mouse
anti-human CD3 APC-Cy7 and Alexafluor PE-CF594 conjugates, CD5
Alexafluor 700, CD14 APC, CD16 APC-Cy7, CD19 FITC and PerCP
conjugates, CD20 PE-Cy7, and CD56 FITC (BD Biosciences).
Intracellular phosphorylation events were detected using rabbit
anti-human pSYK Y525/526 PE and pERK Y204 APC (Cell Signaling
Technologies, Danvers, Mass.), and mouse anti-human pAKT S473
PE-CF594, pSTAT3 Y705 PE, pSTAT5 Y695 PE, and pSTAT6 Y641 PE
conjugates (BD Biosciences). The CLL surface phenotype was
monitored using cell lineage markers combined with mouse anti-human
CD69 PE, CD86 PE-CF594, CD5 Alexafluor 700, and CXCR4 PerCP (BD
Biosciences).
[0270] Bioanalysis, Pharmacokinetics and Pharmacodynamics
[0271] Blood samples were collected on K2EDTA for the determination
of total cerdulatinib plasma concentrations on day 1 prior to
dosing and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post-dose; on Day
8 at pre-dose and 2 hours post-dose; on Day 15 pre-dose; and on Day
28 (end of the first treatment cycle) at pre-dose and at 0.5, 1, 2,
3, 4, 6, 8, and 12 hours post-dose. A liquid chromatography-tandem
mass spectrometry (LC-MS/MS) method was developed and validated by
Alturas Analytics, Inc. (Moscow, Id.) for the determination of
cerdulatinib concentration in human plasma. Plasma PK analytical
methods are described in Coffey, G., et al., The novel kinase
inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models
of autoimmunity and B-cell cancer. J Pharmacol Exp Ther, 2014. 351
(3): p. 538-48. Chromatographic separations were performed over a
Phenomenex Synergi Polar-RP column (50.times.2.0 mm, 4 .mu.m)
(Phenomenex, Torrance, Calif., USA). MS/MS analysis was performed
using a Sciex API-4000 triple quadrupole mass spectrometer with a
TurboSpray ion source (Applied Biosystems, Foster City, Calif.,
USA). The peak area of the m/z 394.fwdarw.360 cerdulatinib product
ion was measured against the peak area of the m/z 397.fwdarw.363
internal standard product ion. Intra-assay precision (% CV) and
accuracy (% bias) were within 0.8% to 4.5% and -10.1% to 7.8%,
respectively, and inter-assay precision (% CV) and accuracy (%
bias) were 2.0% to 3.8% and -7.3% to 6.0%, respectively.
[0272] For PD assessments, serial blood samples were drawn into
lithium-heparin vacutainer tubes on Day 1 prior to dosing and again
at 0.5, 1, 2, and 4 hours post-dose; on Day 8 at pre-dose and 2
hours post-dose; and Day 28 prior to dosing. Multiple assays were
performed using the Day 1 and Day 8 PD samples. SYK-mediated BCR
signaling in whole blood was measured prior to and post-dosing by
stimulating 100 .mu.L whole blood with 2 .mu.L of anti-human IgD
(IgG fraction) and 10 .mu.g anti-human IgM for 10 minutes at
37.degree. C., measuring the induction of pSYK Y525/526, pAKT 5473,
and pERK Y204. Similarly, whole blood was stimulated with 10 ng/mL
of IL-2 (JAK1/3-dependent), IL-4 (JAK1/3-dependent), IL-6
(JAK1/TYK2-dependent) or GM-CSF (JAK2-dependent) for 20 minutes,
measuring the induction of pSTAT5 Y694 in T-cells and NK cells, the
induction of pSTAT6 Y641 in B cells, T-cells, NK cells, and
monocytes, the induction of pSTAT3 Y705 in monocytes, B cells, and
T-cells, and the induction of pSTAT5 Y694 in monocytes,
respectively. The technical details for these assays were described
in Coffey, G., et al., J Pharmacol Exp Ther, 2014. 351(3): p.
538-48. With blood samples from the CLL patients only, tumor cell
surface expression of CD5, CD69, CD86, and CXCR4 pre-dose on days 1
and 28 were monitored. The recommended volume of antibodies were
applied directly to 100 .mu.L whole blood and incubated for 1 hour
at room temperature. Afterwards, 4 mL of BD Lyse/Fix reagent was
added to the blood to lyse red blood cells and fix the remaining
leukocytes, followed by washing and FACS analysis. For each assay,
data were collected using an LSR II instrument (BD Bioscience, San
Jose, Calif.) and analyzed using Flowjo software (Flowjo LLC,
Ashland, Oreg.). Data were normalized to the induction of each
parameter prior to dosing on day 1 to generate percent inhibition
post-dosing.
[0273] Whole blood for isolation of serum was collected prior to
dosing on days 1, 8, and 28 to measure changes in protein markers
of inflammation and immune function. Serum samples were snap-frozen
on dry ice immediately following its separation and stored at
-80.degree. C. Samples were analyzed using a multiplexed
luminex-based technology (Myriad RBM, Austin, Tex.), utilizing the
companies ImmunoMap (40 analytes) and InflammationMap (45 analytes)
platforms. Serum from healthy donors was used as control.
[0274] Peripheral blood B cells were isolated at baseline from CLL
patients using the RosetteSep B cell isolation kit, following the
manufacturer's protocol (Stem Cell Technologies, Vancouver,
Canada). Cells were washed twice in phosphate buffered saline and
snap-frozen as a pellet on dry ice. Cell pellets, along with
formalin-fixed, paraffin-embedded archival tumor sections, were
delivered to the Department of Genomic and Molecular Pathology at
the University of Chicago Medical Center, where DNA was isolated
using standard methods and subjected to next generating sequencing
(NGS) using Hi-Seq 2500, see Kadri, S., et al., Clinical Validation
of a Next-Generation Sequencing Genomic Oncology Panel via
Cross-Platform Benchmarking against Established Amplicon Sequencing
Assays. J Mol Diagn, 2017. 19(1): p. 43-56.
[0275] Statistical Analysis
[0276] The data were analyzed using the statistical language R and
the accessory packages ggplot2 (Wickham, H., Elegant Graphics for
Data Analysis. 2016: Springer-Verlag.) and drc (Ritz, C., et al.,
Dose-Response Analysis Using R. PLoS One, 2015. 10(12): p.
e0146021). For cell signaling assays, percent inhibition was
determined by normalizing the receptor-induced phosphorylation
events mean fluorescent intensity (MFI) to that of pre-dose
receptor-induced MFI. The resulting relative activities were
analyzed by nonlinear regression to a 3-parameter log-logistic
function with an upper and lower limit set at 100 and 0%. For the
analysis of immune and inflammation markers in serum, the varying
concentration units were converted to a common scale in pg/mL.
Values below and in excess of the detection limit were replaced by
half the detection limit and the upper limit, respectively. For
missing values, the median value for each marker from the treatment
group was imputed. Statistically significant differences between
the healthy and patient serum marker at all cycles (Cycle 1 Day 1,
Cycle 1 Day 8, and Cycle 2 Day 1) were detected by paired t test.
Dimension reduction of expression of the biomarker table in healthy
and patient serum was performed using linear discriminant analysis,
as is implemented in R. For the biomarkers and tumor response,
reduction in biomarker after treatment was normalized to that
before treatment and correlated to the maximal tumor response
(growth or reduction), representing the ratio of minimal tumor area
following treatment and tumor area before treatment. The
significance of the relation between maximum tumor response and
change in a specific biomarker was evaluated using
Spearman-Rank-correlation and p value.
[0277] It was noted that steady state C.sub.max and AUC did not
clearly affect tumor response, but preliminary analysis suggested
that steady state C.sub.min (SSC.sub.min) did. The dose-escalation
study revealed that SSC.sub.min of up to 1 .mu.M was well
tolerated. The CLL/SLL patients for the most part were in lower
dose cohorts, achieving SSC.sub.min of 0.004-0.325 .mu.M (FIG. 1).
At this exposure, 3 of 5 patients achieved >50% nodal
reductions. The one CLL patient who achieved higher exposure came
on study following an aggressive relapse on ibrutinib, and did not
respond to cerdulatinib. The FL patients appeared to have a
different response to cerdulatinib, and tumor responses were more
apparent at SSC.sub.min exposures in the range of 0.729-1.219 .mu.M
(FIG. 1). At this higher exposure range, 3 of 6 patients achieved a
partial response (including one which was a transformed FL patient,
grade 3B), whereas lower SSC.sub.min resulted in 2 stable diseases
and 1 progressive disease.
[0278] Relationship Between Tumor Response and SYK/JAK
Inhibition
[0279] The potency and selectivity for target inhibition following
oral dosing in patients using a variety of whole blood assays was
measured. High level inhibition of BCR-induced SYK
auto-phosphorylation (pSYK Y525/526) and downstream signaling to
ERK (pERK Y204) and AKT (pAKT S473) was observed at tolerated
exposures. Similarly, IL-2, IL-4, and IL-6 signaling (JAK1, JAK3,
and TYK2 dependent) were potently inhibited in a
concentration-dependent manner. To demonstrate specificity within
the JAK family, we additionally performed GM-CSF stimulations on
patient samples, which induce a JAK2-dependent STATS
phosphorylation. Consistent with pre-clinical data, cerdulatinib
demonstrated potent inhibition of SYK and JAK family members,
sparing JAK2. No inhibition of PMA-mediated B cell pERK Y204 was
observed, again demonstrating specificity of action.
[0280] The PK/PD relationships for all assays performed were
evaluated to estimate IC.sub.50's. Measures of BCR-signaling were
inhibited with IC.sub.50's in the 0.33-0.73 .mu.M range. Depending
on the cell lineage, measures of JAK/STAT signaling were inhibited
with IC.sub.50's in the 0.19-1.11 .mu.M range. The relationship
between maximum % change in tumor volume and % inhibition of SYK
and JAK signaling pathways in the whole blood assays is presented
in FIG. 2. Inhibition of BCR-induced SYK auto-phosphorylation (pSYK
Y525/526) significantly correlated with tumor response with an R of
-0.79 (p=0.02). Four of the 5 patients in which pSYK Y525/526 was
inhibited by >50% achieved a partial response. Inhibition of B
cell and monocyte (data combined) IL-4 also significantly
correlated with tumor response (R of -0.61; p=0.004), although
several patients with high level IL-4 inhibition had marginal
reductions in tumor size. This was also observed with inhibition of
T-cell IL-2 signaling, which significantly correlated with tumor
response (R of -0.53; p=0.05), despite the fact that several
patients in which >50% inhibition of the pathway was achieved
had marginal tumor responses. There was no relationship between
inhibition of IL-6 signaling and tumor response.
[0281] Serum markers that were elevated at baseline but unaffected
by cerdulatinib in both patient groups were HCC4, IL18, and MIG.
Additionally, for CLL/SLL patients only, thrombospondin, BDNF,
DKK1, MPO (myeloperoxidase), CD40, RANTES, MMP9, and ENA78 were
significantly reduced at baseline when compared with healthy
controls. Of these, MPO and CD40 serum levels were normalized with
cerdulatinib treatment. For FL patients only, CD40 and BDNF were
reduced at baseline relative to healthy, the latter being
normalized with cerdulatinib treatment.
[0282] Limited inhibition of serum inflammation markers was
observed in the aggressive lymphomas (DLBCL/MCL).
[0283] Next, tumor response was related to % inhibition of serum
markers of inflammation on Cycle 2 Day 1 (C2D1). Significant
correlations between tumor response in CLL/SLL patients and
reductions in serum CRP and IP10 were observed (FIG. 3). In FL
patients, significant correlations existed between tumor response
and inhibition of MIP3.beta., MDC, IP10, .beta.2M, and APRIL (FIG.
4). Baseline serum concentrations of these proteins did not predict
tumor response to treatment. These data demonstrate that
cerdulatinib can modulate systemic inflammation, which for several
proteins was associated with tumor response.
[0284] Relationship Between Markers of Inflammation and Tumor
Response
[0285] Cancer patients often present with underlying inflammation
that can be detected by serum protein profiling. To evaluate this,
and determine the effect of cerdulatinib on systemic inflammation,
serial serum samples collected from patients were analyzed for
serum proteins associated with inflammation and general immune
function. Serum concentrations of 90 proteins were determined, of
which 31 were consistently below limits of detection. FIG. 5A and
FIG. 5B represent an analysis of the remaining 59 proteins for
which measurements were possible. At baseline, the inflammatory
profile of CLL/SLL and FL patients was quite divergent, and could
be distinguished from each other and healthy controls by cluster
analysis, lending confidence to the validity of the data.
[0286] In both CLL/SLL and FL patients, the common serum markers
that were significantly elevated at baseline (Cycle 1 Day 1; C1D1)
were vWF, MIP3.beta.. CRP, HCC4, .beta.2M, VCAM1, IL18, TNFR2,
IP10, and MIG (FIG. 5A and FIG. 5B). By Cycle 1 Day 8 (C1D8) and
Cycle 2 Day 1 (C2D1), several of these markers lost significance
relative to healthy, indicating a normalization of inflammation
with cerdulatinib treatment. For the most part, reductions in serum
markers of inflammation occurred within the first 8 days of therapy
with cerdulatinib, by Cycle 1 Day 8 (C1D8). Cerdulatinib
significantly reduced MIP3.beta., CRP, and VCAM1 in both CLL/SLL
and FL patients.
[0287] Clinical Responses
[0288] Treatment-related increases in blood absolute lymphocyte
counts (ALC) occurred in both CLL/SLL and FL patients (FIG. 6A and
FIG. 6B). Of the 6 CLL/SLL patients treated with cerdulatinib, 5
remained on drug long enough to monitor ALC, which were elevated
0.3-10 fold relative to pre-treatment. For two of these patients,
treatment-related changes in tumor cell surface activation and
homing markers were additionally evaluated (FIG. 7A and FIG. 7B).
As shown in the ALC plots over time (FIG. 6A and FIG. 6B), by the
beginning of the second cycle of treatment (Cycle 2 Day 1; C2D1)
there was considerable mobilization of tumor cells into the
peripheral blood. FACS analysis of these cells prior to treatment
(Cycle 1 Day 1; C1D1) and again at Cycle 2 Day 1 (C2D1) revealed
decreased expression of the surface activation markers CD69 and
CD86, as well as reduced CD5 expression (a negative regulator of
BCR signaling) and enhanced CXCR4 expression (responsible for cell
homing to lymphoid tissues). These data suggest that cerdulatinib
mobilizes tumor cells into the periphery and prevents their return
to secondary lymphoid organs.
[0289] Genetic abnormalities were monitored by next generation DNA
sequencing using OncoPlus, a panel of 1,212 cancer-related genes
(Kadri, S., et al., Clinical Validation of a Next-Generation
Sequencing Genomic Oncology Panel via Cross-Platform Benchmarking
against Established Amplicon Sequencing Assays. J Mol Diagn, 2017.
19(1): p. 43-56). Fresh tumor samples were obtained from the
peripheral blood of 6 CLL patients prior to dosing with
cerdulatinib, as well as archival tumor biopsies obtained from 4 FL
patients and 1 MCL patient. A list of the mutations observed is
detailed in Table 3.
TABLE-US-00003 TABLE 3 % Change in Patient Disease Tumor (CT)
Relevant Mutations 1 Ibrutinib 100 EP300, P53, BTK.sup.C481,
NOTCH1, SPEN, PIK3R1, relapsed CLL PCDHGA2, MYOM2, KMT2D 2
Ibrutinib 100 EP300, TP53, BTK.sup.C481, XPO1, WHSC1, MED12
relapsed CLL 3 MCL 42 ID3, SETD2, WHSC1, KMT2C, ATM, KMT2D, SOCS1,
MED12 4 FL 1 NOTCH2, FAT3, FAT4, EGR2, CREBBP, KLHL14, ASXL1 5 FL
-6 FAT4, CCND3, MYOM2, KMT2D, BCL2, ZMYM3 6 FL -12 BCL6, FAT4,
NOTCH1, KMT2D, BCL2, TCF3 7 CLL -14 NOTCH1, TP53, SETD2, SIGLEC10 8
FL -20 ARID1A, STAT6.sup.S86A, AXIN1, CD79B, ZMYM3 9 CLL -27 SPEN,
PCLO 10 CLL -52 TET2, A20, MK167, FAT3, ATM, KRAS 11 CLL -59
NOTCH1, REL, HIST1H1E, KMT2C 12 CLL -64 KMT2D, MK167, TP53,
SF3B1
[0290] Clinical activity was observed in CLL patients bearing
mutations to NOTCH1, ATM, TP53, and KRAS. One of the responding
patients bore a 17p deletion encompassing the TP53 locus.
Importantly, two patients with ibrutinib-relapsed CLL who
progressed within the first cycle of therapy with cerdulatinib
uniquely shared 3 mutations in common: TP53, EP300, and
BTK.sup.C481S. Genetic correlates in FL were more limited, with
data on 4 patients, 3 of whom had stable disease as best response
to therapy and one progressed. Although the exposures are well
below that obtained by the phase 2 dose (30 mg BID, SSC.sub.min
.about.0.8 .mu.M), the two best responding patients with whom there
was genetic information bore mutations to ZMYM3, KMT2D, FAT4, BCL2,
BCL6, and STAT6. Lastly, strong clinical activity was observed in a
transformed FL patient who presented with increased MYC, BCL2, and
BCL6 expression by immunohistochemistry ("triple-hit"
lymphoma).
[0291] Patients with FL had the greatest median duration of
exposure, 33.9 weeks relative to CLL/SLL and aNHL with 11.2 and 7.9
weeks, respectively. The duration of time on cerdulatinib for each
of the dosed patients is shown in FIG. 8.
[0292] Phosphorylation events more distal to the BCR, namely pERK
Y204 and pAKT 5473, appeared to be more potently inhibited relative
to the SYK Y525/526 auto-phosphorylation site, possibly reflecting
a threshold for SYK inhibition at which the signaling pathway is
shut off. It was estimated that the IC.sub.50 of cerdulatinib
against BCR signaling to be in the range of 0.17 to 0.74 .mu.M
following oral dosing, reflecting the lower and upper limit
confidence intervals for ERK and AKT. The two assays performed that
monitored JAK/STAT pathway activation in B cells were IL-4 and IL-6
induced pSTAT6 Y641 and pSTAT3 Y705, respectively. Inhibition of
IL-4 signaling was quite variable among patients, with an average
IC.sub.50 of 1.08 .mu.M (CI; 0.36-1.79 .mu.M). IL-6 signaling was
inhibited with more consistent potency across patients with an
average IC.sub.50 of 0.22 .mu.M (CI; 0.14-0.61). Importantly,
inhibition of BCR-mediated SYK Y525/526 and IL-4-mediated pSTAT6
Y641 both significantly correlated with tumor response. These
correlations lend support to the proposed mechanism of cerdulatinib
anti-tumor activity.
[0293] During the dose escalation study, a complete inhibition of
most SYK and JAK signaling assays was achievable at tolerated
exposures. The selected phase 2 dose of 30 mg twice daily targets a
SSC.sub.min of approximately 0.8 .mu.M, which is expected to
maintain >50% inhibition of SYK and JAK in most whole blood
assays throughout the day. The exposure peak-to-trough as measured
in peripheral blood is roughly 2:1 in patients, indicating that the
phase 2 dose will achieve near-complete inhibition of SYK/JAK
signaling networks throughout the day. Exposure and extent of
target inhibition in the actual tumor microenvironment is unknown,
however, and may therefore be higher or lower than what we estimate
from the whole blood assays.
[0294] The patients enrolled in this trial presented with varying
degrees of inflammation. The nature of the inflammatory response
was divergent enough among the disease subgroups and healthy normal
subjects such that clustering analysis could distinguish them. If
it is assumed that a failed immune response to the tumor has
resulted in an inflammatory environment that now supports tumor
growth and survival, then suppressing these inflammatory signals
could negatively impact the tumor. Cerdulatinib rapidly (within
first week of therapy) and significantly reduced the serum
concentrations of several protein markers of inflammation.
Moreover, reductions of several of these serum proteins with time
on therapy significantly correlated with tumor response. In FL,
these were APRIL, .beta.2M, IP10, MDC, and MIP3.beta.. These data
suggest that one mechanism by which cerdulatinib may exert
anti-tumor activity is by disruption of key signals responsible for
the organization of the tumor microenvironment.
[0295] DNA was prepared from formalin-fixed archival tumor sections
from 4 patients with FL and one with MCL, in addition to
pre-treatment isolation of circulating CLL tumors from whole blood
and subjected to next generation sequencing. This limited data set
offered hints into a pharmacogenomics relationship. The two CLL
patients who did not respond to cerdulatinib had relapsed on
ibrutinib prior to study entry and presented with an aggressive
disease. Both of these patients carried missense mutations to EP300
(Ser697Arg in one and Cys1247Phe in the other), TP53 (Glu285Lys in
one and Arg273Cys in the other), and BTK (Cys481Ser in both).
Interestingly, one patient with FL who relapsed following 5 prior
therapies including progressive disease on bendamustin/rituximab,
progressive disease on ibrutinib, and a less than 4 month response
to R-CHOP as their last three therapies, contained a novel mutation
to STAT6 (Ser86Ala), which is contained within the STAT
dimerization domain. This patient achieved SSC.sub.min to
SSC.sub.max cerdulatinib serum concentrations of 0.32-0.38 .mu.M,
which is considerably lower than our phase II exposure, and yet
demonstrated a 20% reduction in tumor bulk with >6 month
durability of response. Additional mutations associated with the
three CLL patients with greatest nodal reductions were REL
(Ile354Thr), a component of NFkB2, TET2 (Met66Leu), a dioxygenase
that regulates DNA methylation status, A20 (G1n150Arg), an
inhibitor of NFkB, and HIST1H1E (Ala47Val).
[0296] In summary, data from the phase 1 dose-escalation study
identified a phase 2 dose that was well tolerated, achieved drug
levels which resulted in high level inhibition of SYK and JAK
signaling pathways and demonstrated evidence of anti-tumor
activity. The phase 2 study is ongoing to establish safety and
efficacy of cerdulatinib in CLL/SLL and FL patients.
Example 2
[0297] This study intended to confirm the safety and efficacy of
cerdulatinib dosed 30 mg orally BID in patients with
relapsed/refractory (r/r) B- and T-cell lymphoma. Dose reductions
were permitted to a minimum of 15 mg BID. Response was assessed by
Lugano Classification criteria.
[0298] Ninety nine patients enrolled (FL: 36, CLL/SLL: 28, PTCL:
18, marginal zone lymphoma: 8, aggressive: 5, Waldenstrom's
macroglobulinemia: 4) (Table 4). Median age is 68 (42-93) and
median # of prior therapies is 3 (1-13) (Table 5). 30 patients had
prior BTK, PI3K or BCL-2 inhibitor therapy. The most common AEs of
any grade are diarrhea (42%), fatigue (36%), and nausea (32%).
Grade 3+ AEs occurring in .gtoreq.5% patients are neutropenia
(18%), lipase increase (15%), pneumonia (12%), diarrhea (10%), and
fatigue (7%). 5 patients have had Grade 5 infections considered
related to study drug (3 of 5 in the CLL cohort). The target PK
range has been achieved with an average SSC.sub.min of .about.0.8
.mu.M.
[0299] 61% ORR in CLL/SLL, 49% in FL, and 47% in PTCL (5 CRs, 2 PRs
in 15 patients) were seen (Table 6). The first PTCL patient
achieved a CR and is on drug at 11 months. Responses typically
occurred after 2 cycles of treatment. Durable PRs have occurred in
patients who relapsed on BTK inhibitor (CLL, 5+ months, WM, 7+
months, FL, 12 months), venetoclax (SLL, 18+ months), and tenalisib
(PTCL, 3+ months) therapy. Updated PK/PD, safety and efficacy will
be presented.
[0300] Eighteen of the patients are relapsed/refractory PTCL
patients, which included PTCL-NOS (7), AITL (6), ALCL (2), HSTCL
(1), Gamma-delta TCL (1), and EITL (1); median age 70 [48-84];
prior transplant 28%; and 44% refractory to last therapy. Eleven
patients were evaluated for clinical response, 3 discontinued prior
to evaluation (2 due to progression; 1 withdrew consent), and 4
patients have yet to be evaluated. Seven patients have responded
(ORR 47%). Of these, 5 achieved a CR after 2 cycles, 2 achieved a
PR, and 2 SD. The majority of responses were observed in PTCL-NOS
and AITL.
[0301] Although the durability of the cerdulatinib response in PTCL
is still pending, the first two patients achieving a response (both
CRs) are still on drug with response durations of 10 and 6 months,
respectively (which corresponds to 12 and 8 months on treatment,
respectively). A patient with CR was referred to allogeneic
transplant and censored after cycle 2. An additional patient
achieved complete remission of target lesions, but discontinued
therapy due to a new lesion.
[0302] Importantly, CRs and PRs occurred in patients who failed
multiple lines of therapy, including CHOP, brentuximab+rituximab,
rituximab+CHOP, gemcitabine+oxiplatin, gemcitabine, high-dose
steroids, lenalidomide, EPOCH, BEAM, BEAM/R-CHEP, ABVD, ixazomib,
bosutinib, fenretinide, pralatrexate, romidepsin, belinostat, and
an investigational PI3K inhibitor, RP-6530. One AITL patient who
achieved CR with cerdulatinib had 10 different prior treatments and
experienced PD under romidepsin, bosutinib, brentuximab, and
gemcitabine+oxiplatin treatments.
[0303] The most common AEs of any grade were diarrhea (33%),
fatigue (22%), lipase increase (17%), and nausea (17%). Grade 3+
AEs occurring in .gtoreq.2 patients are neutropenia (4), diarrhea
(3), lipase increase (2), and pneumonia (2). The target PK range
was achieved with an average SSC.sub.min of .about.0.8 .mu.M.
TABLE-US-00004 TABLE 4 Other Initial dose CLL/SLL FL iNHL* PTCL
aNHL** Total 35 mg BID 6 2 4 0 5 17 30 mg BID 22 34 8 18 0 72 Total
28 36 12 18 5 99 *indolent lymphoma **aggressive lymphoma
TABLE-US-00005 TABLE 5 CLL/ Other SLL FL iNHL PTCL aNHL All n = 28
n = 36 n = 12 n = 18 n = 5 N = 99 Male sex, n (%) 16 (57) 19 (68) 8
(67) 8 (73) 4 (80) 55 (65) Median age, 70 [52- 64 [42- 65 [45- 70
[48- 78 [61- 68 [42- years [range] 93] 81] 88] 84] 93] 93] Median #
of prior 3 3 3 3 3 3 regimens [range] [1-13] [1-8] [1-5] [1-9]
[1-4] [1-13] Prior Therapies, n (%) Anti-CD20 antibody 27 (96) 35
(97) 12 (100) 3 (17) 5 (100) 82 (83) Bendamustine 10 (36) 19 (53) 5
(42) 2 (11) 1 (20) 37 (37) Any alkylating agent 21 (75) 31 (86) 10
(83) 16 (89) 5 (100) 83 (84) Fludarabine 9 (32) 0 0 0 0 9 (9)
Anthracyclines 5 (18) 17 (47) 3 (25) 14 (78) 3 (60) 42 (42) Any BCR
pathway 13 (46) 10 (28) 3 (25) 2 (11) 1 (20) 29 (29) inhibitor
Refractory disease, n (%) 11 (39) 11 (39) 6 (50) 8 (44) 0 36
(36)
TABLE-US-00006 TABLE 6 Other CLL/ Indolent DLBCL, tFL, Response SLL
FL Lymphoma and MCL PTCL N: 28 31 12 5 15 ORR 61% 49% 42% 20% 47%
CR (%) 1 (4) 3 (10) 0 0 5 (33) PR (%) 16 (57) 12 (39) 5 (42) 1 (20)
2 (13) SD (%) 2 (7) 8 (26) 2 (17) 1 (20) 2 (13) PD (%) 1 (4) 3 (10)
4 (33) 3 (60) 5 (33) NE/Safety 8 5 1 0 1
TABLE-US-00007 TABLE 7 Prior Therapies for PTCL Patients With a CR
Disease Prior therapies PTCL-NOS CHOP, Bendamustine-Rituximab,
Bendamustine, Romidepsin AITL CHOEP .fwdarw. BEAM/ASCR PTCL-NOS
EPOCH, Pralatrexate AITL BEAM AITL ABVD, Romidepsin, Romidepsin,
Belinostat, RP-6530, Fenretinide AITL ABVD, CHOP, Romidepsin,
Ixazomib, Bosutinib, Brentuximab, Gemcitabine-Oxaliplatin,
HD-Steroids, Lenalidomide, RP-6530 AITL R-CHOP, Gemcitabine
[0304] Both complete responses in PTCL-NOS have follicular
involvement.
[0305] Cerdulatinib dose of 30 mg BID demonstrates good
tolerability and efficacy in heavily pre-treated r/r B and T-cell
NHL, including PTCL.
Example 3
[0306] CellTiter Glo, Edu and caspase 3 assays were used to examine
the effects of cerdulatinib alone and in combination with
venetoclax. Percent inhibition was determined relative to vehicle
control. Edu incorporation and caspase 3 cleavage were performed
using FACS-based assays and CellTiter Glo in a 96-well black
plate.
[0307] Follicular lymphoma (FL) cell lines SU-DHL6, DOHH2, or
WSU-FSCCL were treated with cerdulatinib in the presence or absence
of venetoclax at the indicated concentrations for 24-72 hours and
analyzed by Edu, CellTiter-Glo, Annexin V/PI, and
CellTiter-Glo).
[0308] Whole cell lysates were subjected to immunoblotting on 12%
gels and probed with the indicated antibodies using established
protocols. Phosphoflow cytometry was performed on an LSRII
following cell fixing in 4% PFA and permeabilzation with 50%
methanol. Phospho-antibody staining was performed for 1 hour at
room temperature.
[0309] Cerdulatinib was functional in FL cells lines and could
inhibit basal expression of phospho (p)AKT and pERK as well as
anti-IgM and anti-IgG mediated signaling.
[0310] Cerdulatinib synergized with venetoclax to induce apoptosis
in CLL cells in part by down-regulation of MCL-1. This is important
given upregulation of MCL-1 is a key resistance mechanism to
venetoclax.
[0311] Irrespective of the assay used, the combination of
cerdulatinib and venetoclax invariably led to more potent growth
arrest and apoptosis in these FL lines.
[0312] Cerdulatinib had minimal impact on Bcl-2 expression in FL
lines, but resulted in down modulation of Mcl-1, which was most
pronounced in WSU-FSCCL cells, with minimal effect in the other
lines. Bim increased at the RNA level in both WSU and DHL6 cells,
whereas Mcl-1 RNA levels remained unchanged with cerdulatinib alone
and in combination with venetoclax.
[0313] Xenograft studies in Nude mice were performed to evaluate
cerdulatinib and venetoclax in combination. Nude mice were
inoculated with 106 SU-DHL6 cells subcutaneously. Once tumors
reached 200 mm.sup.3, the mice were randomized into 4 groups:
vehicle, cerdulatinib alone, venetoclax alone, or a combination of
cerdulatinib and venetoclax. Cerdulatinib in combination with
venetoclax resulted in a superior reduction in tumor growth
compared to the other treatments. In those tumors treated with
cerdulatinib an increase in Bim expression was observed with no
change in MCL-1, consistent with our in vitro data.
Example 4
[0314] Primary CLL cases were treated with and without IL-4/CD40 in
the presence or absence of ibrutinib, idelalisib, entospletinib,
PRT062607 or cerdulatinib (all 1 .mu.M). Combination studies were
performed with 10 or 100 nM venetoclax or 300 and 1000 nM S63846.
Cell viability was assessed by annexin V/PI using flow cytometry
and changes in protein expression by immunoblotting.
[0315] CLL cells were treated with IL-4/CD40L or the vehicle
control and immunoblotting performed for Bcl-2 family protein
expression. Basal Mcl-1, Bcl-XL and Bim protein was expressed at
relatively low levels compared to Bcl-2. However treatment with
IL-4/CD40L induced a substantial and significant increase in Mcl-1
and Bcl-XL compared to the vehicle control, whilst Bcl-2 and Bim
expression remained relatively stable. CLL cells pretreated with
ibrutinib, idelalisib, entospletinib, PRT062607 or cerdulatinib
significantly reduced IL-4/CD40L induced Mcl-1 and Bcl-XL
expression, however in all cases cerdulatinib produced a more
robust inhibition of these proteins compared to the other kinase
inhibitors. Interestingly treatment with all BCR kinase inhibitors
resulted in an increase in Bim expression at both the RNA and
protein levels. However at equivalent drug concentrations Bim was
induced to greater levels following cerdulatinib treatment compared
to idelalisib and ibrutinib. Bim co-localization with Bcl-2 and
Mcl-1 proteins was investigated using immunoprecipitation. Bim
co-localized largely with Bcl-2 and a lesser extent with Mcl-1 in
all the CLL cases in vitro. Venetoclax and S63845 synergized with
all BCR kinase inhibitors including cerdulatinib to induce greater
levels of CLL cell death by displacing Bim.
Example 5
[0316] In an open-label, randomized, 3-period crossover study,
healthy subjects received 30 mg cerdulatinib orally. The 3-period
treatments were fasted, high-fat diet, and proton pump inhibitor
(PPI) esomaprazole, with 14-day washout between treatments. Blood
samples were collected up to 72 hours after cerdulatinib treatment.
PK endpoints were area under the curve (AUC), maximum concentration
(C.sub.max), Time to C.sub.max (T.sub.max), and half-live
(T.sub.1/2).
[0317] There were 22, 24, and 21 subjects in fasted, fed, and PPI
groups, respectively. Compared to fasted group, food and PPI had no
significant effect on AUC and C.sub.max of cerdulatinib, and
T.sup.1/2 was similar (Table 8). There was a small delay in median
T.sub.max after cerdulatinib was taken with food.
[0318] Although there was a small increase in cerdulatinib exposure
with food or PPI, there was no clinically relevant impact on PK of
cerdulatinib. These preliminary results suggest that cerdulatinib
could be administered regardless of food or PPI.
TABLE-US-00008 TABLE 8 Preliminary Cerdulatinib PK Parameters
T.sub.max T.sub.1/2 C.sub.max AUC.sub.0-inf Median Mean Mean Mean
Treatment (h) (h) (ng/mL) (hr * ng/mL) Fasted Geometric 4.0 14.5
168 3460 Mean % CV (3.0-6.0) 15.2 36.5 38.2 Fed Geometric 6.00 13.6
187 4060 Mean % CV (4.0-12.0) 18.4 26.0 36.1 PPI Geometric 4.0 14.5
170 3680 Mean % CV (3.0-6.0) 16.9 37.4 36.8 Ratio 1.11 1.16
Fed/Fasted (1.01-1.22) (1.10-1.22) (90% CI) Ratio 1.02 1.06
PPI/Fasted (0.92-1.12) (1.01-1.12) (90% CI)
Example 6
[0319] U-CLL cells and M-CLL cells were treated with and without 10
ng/mL IL-4 for 24 hours in the presence or absence of 104
cerdulatinib Immunoblotting was used to protein expression among
the different treatments. FIGS. 9A and 9B shows that IL-4
significantly increases the protein expression of GABA1, FOXP1,
SOCS1, and SOCS3 while treatment with cerdulatinib suppresses this
effect. FIGS. 10A-10G, 11A-11G and 12A-12G show the fold changes of
the protein expression.
Example 7
[0320] The Dual SYK/JAK Inhibitor Cerdulatinib Demonstrates Rapid
and Durable Tumor Responses in a Phase 2 Study in Patients with
Relapsed/Refractory Follicular Lymphoma--as a Single Agent and in
Combination with Rituximab
[0321] Background:
[0322] Follicular B cell lymphoma (FL) is the most common indolent
lymphoma, currently managed in the front-line setting with
anti-CD20 monoclonal antibodies as a single agent or in combination
with chemotherapy (i.e. CHOP, bendamustine). Based on current
understanding of disease pathology, several targeted agents are
under investigation in the relapsed/refractory (r/r) setting,
underscored by the recent approvals of idelalisib, copanlisib
duvelisib, targeting B cell antigen receptor signaling via
inhibition of PI3K. Despite recent advances, there remains a need
for well-tolerated and efficacious therapeutic options for r/r FL
patients.
[0323] SYK is a key regulator of BCR signaling (upstream of BTK and
PI3K), and its inhibition using entospletinib has demonstrated
clinical activity in B cell malignancies (Sharman et al, 2013 and
2014; Walker et al, 2016). Importantly, FL growth may additionally
be supported by autocrine or micro-environmental derived cytokines.
Study of the FL tumor microenvironment suggests an important IL-4
signaling axis critical for survival. Compared with unaffected
nodes, lymph nodes from patients with FL have greater numbers of
follicular helper T cells that express high levels of IL-4 which
appears to support the tumor via JAK1/3 pathway activation
(Pangault et al, 2010).
[0324] Cerdulatinib is an oral, reversible ATP-competitive dual
inhibitor of SYK and JAK family kinases (JAK1, JAK3, and TYK2) for
the treatment of r/r FL, and previously reported a .about.45% ORR
in r/r FL when used as a single agent. Pre-clinical data also
suggest synergy with venetoclax, presumably a consequence of
cerdulatinib-mediated loss of MCL-1 expression and induction of BIM
by the tumors. Moreover, xenograft studies indicate that
cerdulatinib does not interfere with the anti-tumor activity of
rituximab, suggesting that these two agents may combine well
clinically to enhance anti-tumor activity. We report here updated
results from a phase 2a dose expansion study in which cerdulatinib
was evaluated as a single agent and initial results with
cerdulatinib in combination with rituximab in r/r FL.
[0325] Methods: This is a phase 2a dose expansion study was carried
out with cerdulatinib dosed 30 mg orally BID in patients with
relapsed/refractory (r/r) B cell lymphoma. Dose reductions were
permitted to a minimum of 15 mg BID. Responses of patients to the
cerdulatinib treatment and cerdulatinib rituximab combination
treatment were assessed by Lugano Classification criteria.
[0326] A total of 40 patients were enrolled in the single arm,
cerdulatinib treatment cohort and 11 patients were enrolled in the
cerdulatinib rituximab combination cohort. Median age was 64
(42-81) and median number of prior therapies was three (1-8). 50
(98%) patients had prior anti-CD20 therapy and 8 (16%) patients had
prior PI3K or BTK inhibitors. The most common adverse effects (AEs)
of any grade were diarrhea (47%), nausea (37%), lipase increase
(29%) and amylase increase (22%). Grade 3+ AEs occurring in more
than 5% patients are lipase increase (24%), diarrhea (12%), amylase
increase (10%), nausea (8%), hypertension (8%), and neutropenia
(6%). Grade 3+ infections occurred in 6 (12%) of patients. One
patient had Grade 5 multi-organ failure potentially related to
study drug. Amylase and lipase elevations generally were not
associated with abdominal pain or pancreatitis. The safety profile
in the combination cohort appeared to be similar to what is seen
with single-agent cerdulatinib.
[0327] Responses observed for both cohorts included: an ORR of 46%
(5 CRs and 13 PRs out of 40 patients) in the single arm cohort and
an ORR of 67% (4 PRs out of 6 patients) in the combination cohort.
Responses typically occurred after 2 cycles of treatment. Responses
had been durable in the single arm cohort and 10 patients have been
on drug for more than one year. All patients in the combination
cohort remained on drug (up to 6 months).
[0328] In summary, data from the phase 2a does expansion study
showed that the recommended cerdulatinib phase 2 dose of 30 mg BID
had good tolerability and efficacy in heavily pre-treated r/r FL.
The combination of cerdulatinib with rituximab was well tolerated
and has led to tumor reductions in all patients evaluated, with
both patients who achieved SD demonstrating more than 40% reduction
in baseline target tumors at the first re-scan.
[0329] The disclosure has been described broadly and generically
herein. Each of the narrower species and subgeneric groupings
falling within the generic disclosure also form part of the
disclosure. This includes the generic description with a proviso or
negative limitation removing any subject matter from the genus,
regardless of whether or not the excised material is specifically
recited herein.
[0330] All publications, patent applications, patents, and other
references mentioned herein are expressly incorporated by reference
in their entirety, to the same extent as if each were incorporated
by reference individually. In case of conflict, the present
specification, including definitions, will control.
[0331] It is to be understood that while the disclosure has been
described in conjunction with the above embodiments, that the
foregoing description and examples are intended to illustrate and
not limit the scope of the disclosure. Other aspects, advantages
and modifications within the scope of the disclosure will be
apparent to those skilled in the art to which the disclosure
pertains.
* * * * *