U.S. patent application number 16/229524 was filed with the patent office on 2019-05-02 for methods for cancer therapy.
The applicant listed for this patent is Millennium Pharmaceuticals, Inc.. Invention is credited to Neeraj Gupta, AI-MIN HUI, Richard Labotka, Guohui Liu, Karthik Venkatakrishnan.
Application Number | 20190125773 16/229524 |
Document ID | / |
Family ID | 54554652 |
Filed Date | 2019-05-02 |
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United States Patent
Application |
20190125773 |
Kind Code |
A1 |
HUI; AI-MIN ; et
al. |
May 2, 2019 |
METHODS FOR CANCER THERAPY
Abstract
The present disclosure relates to methods or dosing regimens
comprising a proteasome inhibitor of formula (I), or a
pharmaceutically acceptable salt thereof, ##STR00001## for treating
cancer, or preventing cancer recurrence or progression; wherein
ring A, Z.sup.1 and Z.sup.2 are as defined herein.
Inventors: |
HUI; AI-MIN; (Lexington,
MA) ; Labotka; Richard; (Des Plaines, IL) ;
Gupta; Neeraj; (Newton, MA) ; Venkatakrishnan;
Karthik; (Cambridge, MA) ; Liu; Guohui;
(Belmont, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Millennium Pharmaceuticals, Inc. |
Cambridge |
MA |
US |
|
|
Family ID: |
54554652 |
Appl. No.: |
16/229524 |
Filed: |
December 21, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14716761 |
May 19, 2015 |
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16229524 |
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62000991 |
May 20, 2014 |
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62019600 |
Jul 1, 2014 |
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62088154 |
Dec 5, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
A61K 38/07 20130101; A61K 38/05 20130101; A61K 9/4858 20130101;
A61K 31/353 20130101; A61K 9/4866 20130101; A61K 9/485 20130101;
A61K 31/407 20130101; A61K 31/145 20130101; A61K 31/454 20130101;
A61K 31/69 20130101; A61K 31/426 20130101; A61K 31/198 20130101;
A61K 38/06 20130101; A61K 31/69 20130101; A61K 2300/00 20130101;
A61K 38/05 20130101; A61K 2300/00 20130101; A61K 31/198 20130101;
A61K 2300/00 20130101; A61K 38/06 20130101; A61K 2300/00 20130101;
A61K 38/07 20130101; A61K 2300/00 20130101; A61K 31/145 20130101;
A61K 2300/00 20130101; A61K 31/353 20130101; A61K 2300/00 20130101;
A61K 31/407 20130101; A61K 2300/00 20130101; A61K 31/426 20130101;
A61K 2300/00 20130101; A61K 31/454 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/69 20060101
A61K031/69; A61K 31/454 20060101 A61K031/454; A61K 31/426 20060101
A61K031/426; A61K 31/407 20060101 A61K031/407; A61K 31/353 20060101
A61K031/353; A61K 31/198 20060101 A61K031/198; A61K 9/48 20060101
A61K009/48; A61K 38/07 20060101 A61K038/07; A61K 38/06 20060101
A61K038/06; A61K 38/05 20060101 A61K038/05; A61K 31/145 20060101
A61K031/145 |
Claims
1. A method for delaying or preventing cancer recurrence or
progression, comprising administering to a patient, who has
undergone a primary cancer therapy and who is in remission, a
single-agent maintenance therapy, wherein the single-agent consists
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, ##STR00013## on a dosing schedule comprising at least four
28-day treatment cycles, wherein the 28-day treatment cycle
comprises four consecutive weeks in which the compound of formula
(I), or pharmaceutically acceptable salt thereof, is administered
once a week for the first three weeks of the treatment cycle and
the compound of formula (I), or pharmaceutically acceptable salt
thereof, is not administered during the fourth week; wherein the
primary cancer therapy comprises an autologous stem cell
transplant, wherein ring A is ##STR00014## and Z.sup.1 and Z.sup.2
are each independently hydroxyl; or Z.sup.1 and Z.sup.2 together
form a cyclic boronic ester having 2-20 carbon atoms, and
optionally one or more heteroatoms selected from N, S, or O.
2. The method of claim 1, wherein the compound of formula (I), or
pharmaceutically acceptable salt thereof, is administered
orally.
3. The method of claim 1, wherein the compound of formula (I), or
pharmaceutically acceptable salt thereof, is administered on days
1, 8, and 15 of each treatment cycle.
4. The method of claim 1, wherein the dosing schedule comprises
about twenty-six treatment cycles.
5. The method of claim 4, wherein the compound of formula (I), or
pharmaceutically acceptable salt thereof, is administered at a
first dose for at least four treatment cycles, and a second dose in
the treatment cycles 5 through 26.
6. The method of claim 5, wherein the first dose is about 3.0 mg
and the second dose is about 4.0 mg.
7. The method of claim 5, wherein the first dose is about 3.0 mg,
and the second dose is about 3.0 mg.
8. The method of claim 5, wherein the first dose is about 2.3 mg,
and the second dose is about 3.0 mg.
9. The method of claim 5, wherein the first dose is about 2.3 mg,
and the second dose is about 2.3 mg.
10. The method of claim 5, wherein the first dose and the second
dose are the same.
11. The method of claim 1, wherein the compound of formula (I) is a
compound of formula (IV) ##STR00015## or an ester or a
pharmaceutically acceptable salt thereof.
12. The method of claim 11, wherein said compound of formula (IV)
is administered to the patient in a form of an ester, or a
pharmaceutically acceptable salt thereof.
13. The method of claim 12, wherein the ester is a compound of
formula (IIIa) ##STR00016## or a pharmaceutically acceptable salt
thereof.
14. The method of claim 13, wherein the compound of formula (IIIa)
is in a solid dosage form.
15. The method of claim 14, wherein the solid dosage form is
capsule.
16. The method of claim 15, wherein the capsule contains a mixture
of ixazomib citrate, microcrystalline cellulose, talc, and
magnesium stearate.
17. The method of claim 1, wherein the primary cancer therapy
comprises a proteasome inhibitor based regimen, or an
immunomodulating drug based regimen, or both.
18. (canceled)
19. The method of claim 1, wherein the primary cancer therapy
comprises a proteasome inhibitor based regimen, or an
immunomodulating drug based regimen, or both, followed by
autologous stem cell transplant.
20. The method of claim 1, wherein the primary cancer therapy
comprises a proteasome inhibitor based regimen, or an
immunomodulating drug based regimen, or both, followed by a
conditioning regimen comprising melphalan and autologous stem cell
transplant.
21. The method of claims 17, 19 or 20, wherein the proteasome
inhibitor based regimen comprises bortezomib, ixazomib,
carfilzomib, disulfiram, epigallocatechin-3-gallate, salinosporamid
A, ONX0912, CEP-18770, or Epoxomicin.
22. The method of claim 21, wherein the proteasome inhibitor based
regimen comprises bortezomib.
23. The method of claims 17, 19 or 20, wherein the immunomodulating
drug based regimen comprises lenalidomide or pomalidomide.
24. The method of claim 23, wherein the immunomodulating drug based
regimen comprises lenalidomide.
25. The method of claim 1, wherein the first 28-day treatment cycle
begins at least 75 days after autologous stem cell transplant.
26. The method of claim 1, wherein the first 28-day treatment cycle
begins prior to 115 days after autologous stem cell transplant.
27. The method of claim 1, wherein the cancer is multiple
myeloma.
28. The method of claim 1, wherein the cancer is multiple myeloma
or refractory multiple myeloma.
29. The method of claim 1, wherein the cancer is amyloidosis.
30. The method of claim 1, wherein the patient is an individual
diagnosed with multiple myeloma or refractory multiple myeloma.
31. The method of claim 1, wherein the method is a maintenance
therapy to prevent relapse or recurrence of multiple myeloma in the
patient who has undergone a primary cancer therapy.
32. The method of claim 1, wherein the method is a maintenance
therapy to prevent progression of multiple myeloma in the patient
who has undergone a primary cancer therapy.
33. The method of claim 31 or 32, wherein the patient has achieved
complete or partial clinical and hematolotic recovery following the
primary cancer therapy.
34. The method of claim 1, wherein the method is a maintenance
therapy for treating a patient at risk of developing or
experiencing a recurrence of a proteasome-mediated disorder.
35. The method of claim 1, wherein the method is a maintenance
therapy for treating a patient at risk of developing or
experiencing a recurrence of a cancer selected from multiple
myeloma.
36. A method for delaying or preventing cancer recurrence or
progression, comprising administering to a patient, who has
undergone a primary cancer therapy and who is in remission, a
single-agent maintenance therapy, wherein the single-agent consists
of a compound of formula (I), or a pharmaceutically acceptable salt
thereof, ##STR00017## on a dosing schedule comprising at least four
28-day treatment cycles, wherein the compound of formula (I), or
pharmaceutically acceptable salt thereof, is administered at a
first dose for the first four treatment cycles, and a second dose
for at least one treatment cycle after the first four treatment
cycles, wherein the second dose is different from the first dose;
wherein the 28-day treatment cycle comprises four consecutive weeks
in which the compound of formula (I), or pharmaceutically
acceptable salt thereof, is administered once a week for the first
three weeks of the treatment cycle and the compound of formula (I),
or pharmaceutically acceptable salt thereof, is not administered
during the fourth week; wherein the primary cancer therapy
comprises an autologous stem cell transplant; wherein ring A is
##STR00018## and Z.sup.1 and Z.sup.2 are each independently
hydroxyl; or Z.sup.1 and Z.sup.2 together form a cyclic boronic
ester having 2-20 carbon atoms, and optionally one or more
heteroatoms selected from N, S, or O.
37. The method of claim 36, wherein the compound of formula (I), or
pharmaceutically acceptable salt thereof, is administered
orally.
38. The method of claim 36, wherein the compound of formula (I), or
pharmaceutically acceptable salt thereof, is administered on days
1, 8, and 15 of each treatment cycle.
39. The method of claim 36, wherein the dosing schedule comprises
about twenty-six treatment cycles.
40. The method of claim 39, wherein the first dose is about 3.0 mg
and the second dose is about 4.0 mg.
41. The method of claim 40, wherein the first dose is about 2.3 mg,
and the second dose is about 3.0 mg.
42. The method of claim 36, wherein the compound of formula (I) is
a compound of formula (IV) ##STR00019## or an ester or a
pharmaceutically acceptable salt thereof.
43. The method of claim 42, wherein said compound of formula (IV)
is administered to the patient in a form of an ester, or a
pharmaceutically acceptable salt thereof.
44. The method of claim 43, wherein the ester is a compound of
formula (IIIa) ##STR00020## or a pharmaceutically acceptable salt
thereof.
45. The method of claim 44, wherein the compound of formula (IIIa)
is in a solid dosage form.
46. The method of claim 45, wherein the solid dosage form is
capsule.
47. The method of claim 46, wherein the capsule contains a mixture
of ixazomib citrate, microcrystalline cellulose, talc, and
magnesium stearate.
48. The method of claim 36, wherein the primary cancer therapy
comprises an autologous stem cell transplant.
49. The method of claim 36, wherein the first 28-day treatment
cycle begins at least 75 days after autologous stem cell
transplant.
50. The method of claim 36, wherein the first 28-day treatment
cycle begins prior to 115 days after autologous stem cell
transplant.
51. The method of claim 36, wherein the cancer is multiple
myeloma.
52. The method of claim 36, wherein the cancer is multiple myeloma
or refractory multiple myeloma.
53. The method of claim 36, wherein the patient is an individual
diagnosed with multiple myeloma or refractory multiple myeloma.
54. The method of claim 36, wherein the method is a maintenance
therapy to prevent relapse or recurrence of multiple myeloma in the
patient who has undergone a primary cancer therapy.
55. The method of claim 36, wherein the method is a maintenance
therapy to prevent progression of multiple myeloma in the patient
who has undergone a primary cancer therapy.
56. The method of claim 54 or 55, wherein the patient has achieved
complete or partial clinical and hematolotic recovery following the
primary cancer therapy.
57. The method of claim 36, wherein the method is a maintenance
therapy for treating a patient at risk of developing or
experiencing a recurrence of a proteasome-mediated disorder.
58. The method of claim 36, wherein the method is a maintenance
therapy for treating a patient at risk of developing or
experiencing a recurrence of a cancer selected from multiple
myeloma.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/000,991, filed May 20, 2014, U.S. Provisional
Application No. 62/019,600, filed Jul. 1, 2014 and U.S. Provisional
Application No. 62/088,154, filed Dec. 5, 2014. The entire contents
of the aforementioned applications are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present disclosure relates to methods or dosing regimens
comprising proteasome inhibitors of formula (I) for treating
cancer, or preventing cancer recurrence or progression.
BACKGROUND OF THE INVENTION
[0003] Cancer has a major impact on society in the United States
and across the world. Cancer is the second most common cause of
death in the US, exceeded only by heart disease, accounting for
nearly 1 of every 4 deaths. The National Cancer Institute estimates
that in 2015, approximately 1,658,370 new cases of cancer will be
diagnosed in the United States and 589,430 people will die from the
disease. Although medical advances have improved cancer survival
rates, there is a continuing need for new and more effective
treatment.
[0004] Multiple myeloma, a B-cell tumor of malignant plasma cells
within the bone marrow, remains incurable despite advances in novel
therapies with proteasome inhibitors (PIs), immunomodulating drugs
(IMiD), and stem cell transplant (SCT) therapy. Multiple myeloma is
characterized by the accumulation of plasma cells in the bone
marrow (and other organs) and can result in bone marrow failure,
bone destruction, hypercalcemia, and renal failure. It constitutes
approximately 1% of all reported neoplasms and approximately 13% of
hematologic cancers worldwide. In the Americas, Canada, and Western
European countries, approximately five to seven new cases of
multiple myeloma are diagnosed per 100,000 people each year.
Palumbo and Anderson, N Engl J Med 2011; 364(11):1046-60; Landgren
and Weiss, Leukemia 2009; 23(10):1691-7; Harousseau, et al., Annals
of Oncology 2008; 19 Suppl 2:ii55-7. Although less common in Asian
countries, incidences of multiple myeloma have increased almost
4-fold in the past 25 years and are characterized by younger age of
onset, more invasive disease, and a less favorable prognosis
(Huang, et al., Cancer 2007; 110(4):896-905; Qiu, et al., Clinical
Epidemiological Study on Multiple Myeloma in China (ASH Annual
Meeting Abstracts) 2008; 112(11):abstr 2723).
[0005] Multiple myeloma is sensitive to many cytotoxic drugs
including alkylating agents, anthracyclines, and corticosteroids
for both initial treatment and relapsed disease. Over the past
decade, significant achievements have been made in expanding
treatment options for multiple myeloma with novel therapies such as
thalidomide, bortezomib, and lenalidomide. These regimens have
extended progression-free survival (PFS) and/or time-to-progression
(TTP) (Palumbo, et al., Leukemia 2008; 22(2):414-23; Mateos, et
al., Journal of Clinical Oncology 2010; 28(13):2259-66; Gay, et
al., Haematologica 2010; 94:0507; Richardson, et al., Hematology
2007:317-23; Dimopoulos, et al., Leukemia 2009; 23(11):2147-52).
The introduction of novel therapies and the increased use of
high-dose therapy (HDT) significantly improved overall survival in
patients with newly diagnosed multiple myeloma (NDMM) who were
eligible for autologous stem cell transplant (ASCT) (Kumar, et al.,
Blood 2008; 111(5):2516-20; Brenner, et al., Blood 2008;
111(5):2521-6; Libby, et al., Declining myeloma mortality rates in
the United States following introduction of novel therapies In:
International Myeloma Workshop Paris, France; 2011).
[0006] Despite more therapeutic options, multiple myeloma remains
incurable, and patients with early stage cancer remain at risk for
relapse after their initial therapy. When patients relapse after
their initial therapy, they demonstrate variable responses to
subsequent treatments with decreasing likelihood and duration of
response (DOR). Patients become refractory to approved therapies
and ultimately are left with no alternative treatment options.
There is a need for new and better drugs and regimens which improve
patient survival rates and/or decrease recurrence of cancer
following completion of primary treatment. The methods of the
instant disclosure present cancer patients with new options.
SUMMARY OF THE INVENTION
[0007] The present disclosure provides methods or dosing regimens
for treating cancer, or preventing cancer recurrence or
progression. The methods or the dosage regimens comprise
administering to a patient, who has undergone a primary cancer
therapy, a compound of formula (I), or a pharmaceutically
acceptable salt thereof,
##STR00002##
on a dosing schedule comprising at least four 28-day treatment
cycles, wherein the 28-day treatment cycle comprises four
consecutive weeks in which the compound of formula (I), or a
pharmaceutically acceptable salt thereof, is administered once a
week for the first three weeks of the treatment cycle and the
compound of formula (I), or pharmaceutically acceptable salt
thereof, is not administered during the fourth week, wherein ring A
is
##STR00003##
and
[0008] Z.sup.1 and Z.sup.2 are each independently hydroxyl; or
Z.sup.1 and Z.sup.2 together form a cyclic boronic ester having
2-20 carbon atoms, and optionally one or more heteroatoms selected
from N, S, or O.
[0009] In certain aspects, the compound of formula (I), or a
pharmaceutically acceptable salt thereof, is administered
orally.
[0010] In certain aspects, the compound of formula (I), or a
pharmaceutically acceptable salt thereof, is administered on days
1, 8, and 15 of each treatment cycle.
[0011] In certain aspects, the dosing schedule comprises about
twenty-six treatment cycles.
[0012] In certain aspects, the compound of formula (I), or a
pharmaceutically acceptable salt thereof, is administered at a
first dose for at least four treatment cycles and a second dose for
treatment cycles 5 through 26.
[0013] In certain aspects, the first dose is from about 1.5 mg/week
to about 3.0 mg/week, and the second dose is from about 2.3 mg/week
to about 4.0 mg/week for each of 3 weeks out of a 4 week treatment
cycle.
[0014] In certain aspects, the first dose of this disclosure is
about 3.0 mg/week and the second dose is about 4.0 mg/week, or the
first dose is about 3.0 mg/week and the second dose is about 3.0
mg/week, or the first dose is about 2.3 mg/week and the second dose
is about 3.0 mg/week, or the first dose is about 2.3 mg/week and
the second is about 2.3 mg/week, or the first dose is about 1.5
mg/week and the second is about 2.3 mg/week, or the first dose is
about 1.5 mg/week and the second is about 1.5 mg/week for each of 3
weeks out of a 4 week treatment cycle. In certain aspects, the
first dose is about 3.0 mg/week and the second dose is about 4.0
mg/week for each of 3 weeks out of a 4 week treatment cycle
[0015] In certain aspects, the first dose and the second dose are
the same.
[0016] In certain aspects, the dosing schedule comprises up to
about twenty-six treatment cycles and the compound of formula (I),
or pharmaceutically acceptable salt thereof, is administered at
about 3.0 mg/week from the first treatment cycle up to the
twenty-sixth treatment cycle.
[0017] In certain aspects, the compound of formula (I) of this
disclosure is a compound of formula (IV)
##STR00004##
or an ester or a pharmaceutically acceptable salt thereof.
[0018] In certain aspects, the compound of formula (I) of this
disclosure is a compound of formula (IIIa)
##STR00005##
or a pharmaceutically acceptable salt thereof.
[0019] In certain aspects, the compound of formula (IV) is
administered in the form of an ester.
[0020] In certain aspects, the compound of formula (IV) is
administered in the form of the compound of formula (IIIa).
[0021] In certain aspects, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa), or a
pharmaceutically acceptable salt thereof, to treat cancer or
prevent cancer recurrence or progression, wherein the cancer is a
hematological malignancy.
[0022] In certain aspects, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa), or a
pharmaceutically acceptable salt thereof, to prevent progression of
cancer in a cancer patient who has undergone a primary cancer,
wherein the cancer is a hematological malignancy.
[0023] In certain aspects, the present disclosure provides
maintenance therapies to prevent relapse or recurrence of multiple
myeloma in a cancer patient who has undergone a primary cancer
therapy.
[0024] In certain aspects, the present disclosure provides
maintenance therapies to a cancer patient who has been diagnosed
with multiple myeloma or refractory multiple myeloma.
[0025] In certain aspects, the present disclosure provides
maintenance therapies to prevent progression of multiple myeloma in
a cancer patient who has undergone a primary cancer therapy.
[0026] In certain aspects, the present disclosure provides
maintenance therapies for treating a patient having, or at risk of
developing or experiencing a recurrence of, a proteasome-mediated
disorder.
[0027] In certain aspects, the present disclosure provides
maintenance therapies for treating a patient having, or at risk of
developing, or experiencing a recurrence of, a cancer selected from
multiple myeloma.
[0028] In certain aspects, the present disclosure provides capsules
comprising compound of formula (IIIa).
BRIEF DESCRIPTION OF FIGURES
[0029] FIG. 1 illustrates the results of exposure-response analyses
of safety and efficacy data from patients with relapsed, refractory
multiple myeloma enrolled in a phase 1 study.
[0030] FIG. 2 shows best overall response in 21 patients who
received ixazomib maintenance therapy (n=21). The numbers on the
bar refer to the percentage of the patients. Complete response (CR)
or better was reached in 52 percent of patients. Very good partial
response (VGPR) or better was reached in 71 percent of patients.
Forty-eight percent of patients improved their response during
maintenance, including two VGPR to near-CR (nCR), five VGPR to CR,
one VGPR to stringent complete response (sCR), and two CR to
sCR.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The present disclosure provides various methods for treating
cancer, or preventing cancer recurrence or progression. In the
first aspect, the disclosure provides administering to a cancer
patient a compound of formula (I), or a pharmaceutically acceptable
salt thereof. In another aspect, the disclosure provides a dosing
schedule of a compound of formula (I), or a pharmaceutically
acceptable salt thereof, as a maintenance therapy to a patient who
has undergone a primary cancer therapy and responded. In a further
aspect, the disclosure provides maintenance therapy comprising a
proteasome inhibitor of formula (IIIa), or a pharmaceutically
acceptable salt thereof, to improve and maintain response for
patients who have undergone a primary cancer therapy.
[0032] In another aspect, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa), or a
pharmaceutically acceptable salt thereof, to prevent patients from
cancer recurrence or progression.
[0033] In another aspect, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa), or a
pharmaceutically acceptable salt thereof, to prevent cancer
recurrence or progression.
[0034] In another aspect, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa), or a
pharmaceutically acceptable salt thereof, to treat cancer or
prevent cancer recurrence or progression, wherein the cancer is a
hematological malignancy.
[0035] In another aspect, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa), or a
pharmaceutically acceptable salt thereof, to treat, or prevent
recurrence or progression of relapsed multiple myeloma.
[0036] In another aspect, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa), or a
pharmaceutically acceptable salt thereof, to treat, or prevent
recurrence or progression of refractory multiple myeloma.
[0037] In another aspect, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa), or a
pharmaceutically acceptable salt thereof, to treat or prevent
recurrence or progression of newly diagnosed multiple myeloma.
[0038] In another aspect, the disclosure provides maintenance
therapy comprising a proteasome inhibitor of formula (IIIa) to
prevent progression of newly diagnosed multiple myeloma.
[0039] In another aspect, the disclosure provides pharmaceutical
compositions containing a proteasome inhibitor of formula (IIIa),
or a pharmaceutically acceptable salt thereof.
[0040] In certain embodiments, the cancer is a hematological
malignancy.
[0041] In certain embodiments, the hematological malignancy is
multiple myeloma, mantle cell lymphoma, follicular cell lymphoma,
T-cell lymphoma, peripheral T-cell lymphoma (PTCL), diffuse large
B-cell lymphoma (DLBCL), or Waldenstrom's Macroglobulinemia.
[0042] In certain embodiments, the hematological malignancy is
mantle cell lymphoma, follicular cell lymphoma, T-cell lymphoma,
peripheral T-cell lymphoma (PTCL), diffuse large B-cell lymphoma
(DLBCL), or Waldenstrom's Macroglobulinemia.
[0043] In certain embodiments, the hematological malignancy is
amyloidosis. In certain embodiments, the hematological malignancy
is systemic light chain amylodosis.
[0044] In certain embodiments, the cancer is newly diagnosed.
[0045] In certain embodiments, the cancer is relapsed.
[0046] In certain embodiments, the cancer is refractory.
[0047] In certain embodiments, the cancer is relapsed, or
refractory multiple myeloma.
[0048] In certain embodiments, the cancer is newly diagnosed
multiple myeloma.
[0049] 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 invention belongs.
Accordingly, the following terms are intended to have the following
meanings:
[0050] The term "maintenance therapy" refers to a therapeutic
regimen that is designed to help a primary treatment succeed. For
example, maintenance chemotherapy may be given to people who have a
cancer in remission in an effort to prevent or delay a relapse, to
reduce the likelihood of disease recurrence or progression.
Maintenance therapy can be provided for any length of time,
including extended time periods up to the life-span of the subject.
Maintenance therapy can be provided after initial therapy or in
conjunction with initial or additional therapies. Dosages used for
maintenance therapy can vary and can include low-intensity dosages
as compared to dosages used for other types of therapies, for
example, the primary therapy (i.e., the first line therapy, the
induction therapy).
[0051] The term "primary therapy" refers to the initial treatment
given to a patient based upon the diagnosis of the disease in the
patient. The diagnosis of the disease may be the first occurrence
of that disease in the patient, i.e., a newly diagnosed patient, or
a reoccurrence of the disease in a patient, i.e., a relapsed
patient. It is often part of a standard set of treatments,
optionally, primary therapy include autologous stem cell
transplant. When used by itself primary therapy is the one accepted
as the best treatment. If it doesn't cure the disease or it causes
severe side effects, other treatment may be added or used instead.
The term is also known to the person having ordinary skill in the
art as first-line therapy when referring to the initial treatment
of a newly diagnosed patient, or induction therapy, initial
therapy, or primary treatment, each of which can refer to the
initial treatment of a newly diagnosed patient or the initial
treatment of a relapsed patient.
[0052] The term "induction therapy" refers to the first phase of
treatment for cancer. The goal of induction therapy for multiple
myeloma is to reduce the number of plasma cells in the bone marrow
and the proteins that the plasma cells produce. Induction therapy
may comprise three-four weeks as one treatment cycle.
[0053] The term "autologous stem cell transplant" refers to stem
cells that are collected from an individual and given back to that
same individual. A stem cell transplant is a procedure that is used
in conjunction with high-dose chemotherapy, which is frequently
more effective than conventional chemotherapy in destroying myeloma
cells. Because high-dose chemotherapy also destroys normal
blood-producing stem cells in the bone marrow, these cells must be
replaced in order to restore blood cell production.
[0054] The term "low-intensity dose" refers to a reduced dose
regimen in comparison with the dose regimen in the primary therapy.
In certain embodiments, the proteasome inhibitor of formula (I) is
reduced to a dose that is less than, 20%, 30%, 40%, 50%, 60%, 70%,
of the dosing regimens in the primary therapies, for example the
5.5 mg dosage.
[0055] In certain embodiments, the reduced dosage is from about 3.0
mg to about 1.5 mg.
[0056] In certain embodiments, the reduced dosage is 3.0 mg, 2.3
mg, or 1.5 mg.
[0057] The term "survival" refers to the patient remaining alive,
and includes progression-free survival (PFS) and overall survival
(OS). Survival can be estimated by the Kaplan-Meier method, and any
differences in survival are computed using the stratified log-rank
test.
[0058] The term "progression-free survival (PFS)" refers to the
time from treatment (or randomization) to first disease progression
or death. For example it is the time that the patient remains
alive, without return of the cancer (e.g., for a defined period of
time such as about one month, two months, three months, three and a
half months, four months, five months, six months, seven months,
eight months, nine months, about one year, about two years, about
three years, about five years, about 10 years, about 15 years,
about 20 years, about 25 years, etc.) from initiation of treatment
or from initial diagnosis. Progression-free survival can be
assessed by Response Evaluation Criteria in Solid Tumors
(RECIST).
[0059] The term "overall survival" refers to the patient remaining
alive for a defined period of time (such as about one year, about
two years, about three years, about four years, about five years,
about 10 years, about 15 years, about 20 years, about 25 years,
etc.) from initiation of treatment or from initial diagnosis.
[0060] The term "proteasome-mediated disorder" refers to any
disorder, disease or condition which is caused or characterized by
an increase in proteasome expression or activity, or which requires
proteasome activity to sustain the condition. The term
"proteasome-mediated disorder" also includes any disorder, disease
or condition in which inhibition of proteasome activity is
beneficial.
[0061] For example, compounds and pharmaceutical compositions of
this disclosure are useful in treatment of disorders mediated via
proteins (e.g., NF.kappa.B, p27.sup.Kip, p21.sup.WAF/CIP1, p53)
which are regulated by proteasome activity such as cancer. As used
herein, the term "cancer" refers to a cellular disorder
characterized by uncontrolled or disregulated cell proliferation,
decreased cellular differentiation, inappropriate ability to invade
surrounding tissue, and/or ability to establish new growth at
ectopic sites. The term "cancer" includes, but is not limited to,
solid tumors and bloodborne tumors (hematologic malignancy). The
term "cancer" encompasses diseases of skin, tissues, organs, bone,
cartilage, blood, and vessels. The term "cancer" further
encompasses primary and metastatic cancers.
[0062] Non-limiting examples of hematologic malignancies include
amyloidosis, acute myeloid leukemia (AML); chronic myelogenous
leukemia (CML), including accelerated CML and CML blast phase
(CML-BP); acute lymphoblastic leukemia (ALL); chronic lymphocytic
leukemia (CLL); Hodgkin's disease (HD); non-Hodgkin's lymphoma
(NIL), including follicular lymphoma and mantle cell lymphoma;
B-cell lymphoma; T-cell lymphoma; multiple myeloma (MM);
Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),
including refractory anemia (RA), refractory anemia with ringed
siderblasts (RARS), (refractory anemia with excess blasts (RAEB),
and RAEB in transformation (RAEB-T); and myeloproliferative
syndromes.
[0063] The following pairs of phrases are interchangeable: a
compound of formula (I) and a proteasome inhibitor of formula (I),
a compound of formula (IIIa) and a proteasome inhibitor of formula
(IIIa); and a compound of formula (IV) and a proteasome inhibitor
of formula (IV).
[0064] For cancer therapy, efficacy may be measured by assessing
the duration of survival, duration of progression-free survival
(PFS), the response rates (RR) to treatments, duration of response,
and/or quality of life.
[0065] Examples of the immunomodulatory drugs (immunomodulating
drugs) are thalidomide analogues. Examples of immunomodulating
drugs include lenalidomide and pomalidomide.
[0066] Proteasome inhibitors are drugs that block the action of
proteasomes, cellular complexes that break down proteins, like the
p53 protein. Proteasome inhibitors are being studied in the
treatment of cancer, especially multiple myeloma. Examples of
proteasome inhibitors are bortezomib, carfilzomib, disulfiram,
epigallocatechin-3-gallate, salinosporamid A, ONX0912, CEP-18770,
and Epoxomicin.
[0067] Further examples of proteasome inhibitors are bortezomib,
ixazomib, carfilzomib, disulfiram, epigallocatechin-3-gallate,
salinosporamid A, ONX0912, CEP-18770, and Epoxoricin.
[0068] In certain embodiments, the proteasome inhibitor is
bortezomib.
[0069] In certain embodiments, the proteasome inhibitor is ixazomib
or ixazomib citrate.
[0070] In certain embodiments, the proteasome inhibitor is
carfilzomib.
[0071] The term "about" is used herein to mean approximately, in
the region of, roughly, or around. When the term "about" is used in
conjunction with a numerical range, it modifies that range by
extending the boundaries above and below the numerical values set
forth. In general, the term "about" is used herein to modify a
numerical value above and below the stated value by a variance of
10%.
[0072] The term "comprises" refers to "includes, but is not limited
to."
[0073] The term "pharmaceutically acceptable carrier" is used
herein to refer to a material that is compatible with a recipient
subject, preferably a mammal, more preferably a human, and is
suitable for delivering an active agent to the target site without
terminating the activity of the agent. The toxicity or adverse
effects, if any, associated with the carrier preferably are
commensurate with a reasonable risk/benefit ratio for the intended
use of the active agent.
[0074] The pharmaceutical compositions of this disclosure can be
manufactured by methods well known in the art such as conventional
granulating, mixing, dissolving, encapsulating, lyophilizing, or
emulsifying processes, among others. Compositions may be produced
in various forms, including granules, precipitates, particulates,
or powders.
[0075] The term "orally" refers to administering a composition that
is intended to be ingested. Examples of oral forms include, but are
not limited to, tablets, pills, capsules, powders, granules,
solutions or suspensions, and drops. Such forms may be swallowed
whole or may be in chewable form.
[0076] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active ingredient is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid;
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants
such as glycerol; d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate; h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents such as
phosphates or carbonates.
[0077] Solid compositions may also be employed as fillers in soft
and hard-filled gelatin capsules using such excipients as lactose
or milk sugar as well as high molecular weight polyethylene glycols
and the like. The solid dosage forms of tablets, dragees, capsules,
pills, and granules can be prepared with coatings and shells such
as enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions that can be used include
polymeric substances and waxes.
[0078] In solid dosage forms the active ingredients may be mixed
with at least one inert diluent such as sucrose, lactose or starch.
Such dosage forms may also comprise, as is normal practice,
additional substances other than inert diluents, e.g., tableting
lubricants and other tableting aids such a magnesium stearate and
microcrystalline cellulose. In the case of capsules, tablets and
pills, the dosage forms may also comprise buffering agents.
[0079] The active ingredients can also be in micro-encapsulated
form with one or more excipients as noted above.
[0080] The terms "boronate ester" and "boronic ester" are used
interchangeably and refer to a chemical compound containing a
--B(Z.sup.1)(Z.sup.2) moiety, wherein Z.sup.1 and Z.sup.2 together
form a cyclic boronic ester having 2-20 carbon atoms, and
optionally one or more heteroatoms selected from N, S, or O.
[0081] In certain embodiments, the proteasome inhibitor of formula
(I) refers to the following formula:
##STR00006##
or a pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof, wherein ring A is
##STR00007##
and Z.sup.1 and Z.sup.2 are each independently hydroxyl; or Z.sup.1
and Z.sup.2 together form a cyclic boronic ester having 2-20 carbon
atoms, and optionally one or more heteroatoms selected from N, S,
or O.
[0082] In certain embodiments, the proteasome inhibitor of formula
(I) is characterized by formula (Ia):
##STR00008##
or a pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof, wherein: Z.sup.1 and Z.sup.2 are each independently
hydroxyl; or Z.sup.1 and Z.sup.2 together form a cyclic boronic
ester having 2-20 carbon atoms, and optionally one or more
heteroatoms selected from N, S, or O.
[0083] In certain embodiments, the proteasome inhibitor of formula
(I) is characterized by formula (II):
##STR00009##
or a pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof, wherein: ring A is defined above; R.sup.1 and R.sup.2
independently is --(CH.sub.2).sub.p--CO.sub.2H; wherein one of
carboxylic acids optionally forms a further bond with the boron
atom; n is 0 or 1; and p is 0 or 1.
[0084] In certain embodiments, the proteasome inhibitor of formula
(I) is characterized by formula (III):
##STR00010##
or a pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof, wherein ring A is defined above.
[0085] In one embodiment, the proteasome inhibitor of formula (I)
is a compound of formula (IIIa):
##STR00011##
or a pharmaceutically acceptable salt, stereoisomeric or tautomeric
form thereof.
[0086] In one embodiment, the proteasome inhibitor of formula
(IIIa) is in a substantially crystalline form.
[0087] In one embodiment, proteasome inhibitor formula (I) is a
compound of formula (IV):
##STR00012##
or an ester or a pharmaceutically acceptable salt thereof.
[0088] Synthetic methods for the preparation of proteasome
inhibitor of formulas (I), (II), (III), (IIIa) and (IV) are well
known in the art, for example, described in U.S. Pat. Nos.
7,442,830, 7,687,662, 8,003,819, 8,530,694, and International
Patent Publication WO 2009/154737, which are hereby incorporated by
reference specifically and in their entirety.
[0089] The compound of formula (IV), also known as ixazormib, is a
peptide boronic acid developed by Millennium Pharmaceuticals, Inc.
Ixazomib is the biologically active molecule that potently,
reversibly, and selectively inhibits the proteasome. The compound
of formula (IIIa) is a citrate ester of ixazomib, referred to as
ixazomib citrate herein. Ixazomib citrate rapidly hydrolyzes to
ixazomib upon contact with either plasma or aqueous solutions. In
contrast to the first-in-class, small molecule proteasome inhibitor
bortezomib (VELCADE.RTM.), ixazomib demonstrates a faster
dissociation rate from the proteasome, possibly resulting in
enhanced tumor penetration, exhibits antitumor activity in a
broader range of tumor xenografts, and has more prolonged tissue
penetration.
[0090] Ixazomib preferentially binds the .beta.5 site of the 20S
proteasome with a concentration producing 50% inhibition
(IC.sub.50) of 3.4 nM. At higher concentrations, it also inhibits
the activity of the .beta.1 and .beta.2 sites. Ixazomib is
selective for the proteasome when tested against a panel of
proteases (IC.sub.50 values between 20 and 100 .mu.M), kinases
(IC.sub.50 values>10 .mu.M), and receptors (IC.sub.50
values>10 .mu.M). Ixazomib and bortezomib have different .beta.5
proteasome dissociation half-lives (t.sub.1/2), reflecting
differences in their on-off binding kinetics (the .beta.5
proteasome dissociation [t.sub.1/2] for ixazomib citrate and
bortezomib is 18 and 110 minutes, respectively). Kupperman E, et
al. Cancer Res 2010; 70:1970-1980.
[0091] Ixazomib has been evaluated in clinical studies that have
included patients with advanced solid tumors, lymphoma,
relapsed/refractory multiple myeloma (RRMM), and relapsed or
refractory light-chain (AL) amyloidosis and demonstrated early
signs of activity. Data suggest a favorable toxicity profile with
low rates of peripheral neuropathy (PN). Richardson P G, et al.
Blood 2014; 124:1038-1046. Kumar S K, et al. Blood 2014;
124:1047-1055. Ongoing studies continue to investigate both
single-agent ixazomib and ixazomib in combination with standard
treatments. Additional clinical studies are evaluating ixazomib in
combination with lenalidormide and dexamethasone (LenDex) versus
placebo/LenDex at an ixazomib dose of 4 mg weekly. The emerging
safety profile indicates that ixazomib is generally well tolerated.
Kumar S, et al. Blood 2012; 119:4375-4382. Richardson P G, et al.
Blood; 2010; 116:679-686. Jakubowiak A J, et al. Blood 2012;
120:1801-1809.
[0092] To select an appropriate dose for ixazomib maintenance
study, Applicant conducted exposure-response analyses of safety and
efficacy data from patients with relapsed, refractory multiple
myeloma enrolled in a phase I study of weekly single-agent
ixazomnib. The analysis was designed to yield initial estimates of
a biologically active exposure/dose range of ixazomib associated
with disease control and acceptable tolerability, thereby ensuring
adequate tolerability for long-term treatment while maintaining
drug exposures in the biologically active range. The methods and
results of these analyses are described below.
Exposure/Efficacy Analyses
[0093] Safety (S) and efficacy (E) data from patients enrolled in a
phase 1 study of weekly single-agent ixazomib in relapsed and
refractory multiple myeloma were used (N=44). The ixazonib dose
range investigated was 1-8.9 mg. The metric of exposure (Ex) was
AUC per day (derived from individual clearance values using
population pharmacokinetics) for both exposure logistic regression
analyses Ex/S and Ex/E. Ex/S analysis was done on seven adverse
events (AEs): non-hematologic (non-H) (fatigue, rash, peripheral
neuropathy, diarrhea) and hematologic (H) (anemia,
thrombocytopenia, neutropenia). The non-hematologic adverse events
data were categorized into grade .gtoreq.2 vs. grade .ltoreq.1
groups while hematologic adverse events data were grouped into
grade .gtoreq.3 vs. grade .ltoreq.2. The data were categorized in
this way as maintenance treatment should have a tolerable adverse
events profile and contribute to acceptable quality of life.
Different cut-offs were used for hematologic and non-hematologic
adverse events because grade 3 hematologic adverse events may have
less impact on quality of life and be more manageable than grade 2
non-hematologic adverse events such as diarrhea. For exposure
efficacy (Ex/E), data were categorized as: .gtoreq.stable disease
(SD) vs. progressive disease (PD). Clinical benefit rate including
SD achieved in relapsed or refractory patients may be a meaningful
predictor of expected response in a maintenance setting. The
logistic regression analyses were done using SPLUS software version
8.1.
[0094] Results of the logistic regression analyses indicated that
of the 7 evaluated AEs, statistically significant relationships to
Ex (p<0.05) were observed for 5 AEs (fatigue, rash, diarrhea,
thrombocytopenia, neutropenia) and clinical benefit rate
(.gtoreq.SD). At a starting dose of 3.0 mg weekly (54% of MTD), the
model predicts .about.33%.gtoreq.SD, and incidence of grade
.gtoreq.2 non-H AEs (rash 16%, diarrhea 19% and fatigue 19%) and
grade .gtoreq.3 H AEs (neutropenia 10%, thrombocytopenia 22%).
Further, the 3.0 mg dose is within the therapeutic range and
represents one dose level below the starting dose used in ongoing
phase 3 trials in relapsed, refractory and previously untreated
multiple myeloma patients.
[0095] FIG. 1 illustrates the relationship of patients' exposure to
response (clinical benefit and safety) of ixazomib dose. FIG. 1
indicates that a favorable benefit versus risk may be achieved at
weekly doses of 3.0 mg and 4.0 mg, below the maximum tolerated
dose. Therefore, in the maintenance therapy, patients may initiate
ixazomib at a once-weekly dose of 3.0 mg, increased to 4.0 mg if
acceptable tolerability is determined after four cycles, to provide
maximum clinical benefit.
[0096] Maintenance Therapy
[0097] Maintenance therapy is a long-duration therapy intended to
prolong the duration of a patient's response to the primary
treatment. Long-term maintenance therapy improves survival
outcomes, including progression-free survival and sometime overall
survival, in both the transplant and non-transplant settings.
However, agents for continuous therapy need to be convenient and
well tolerated. The balance of benefit versus risk is paramount in
the maintenance therapy. Requirements for a successful maintenance
therapy include good long-term tolerability and adherence (low
discontinuation rates due to toxicity and convenience of
administration), demonstration of clinical benefit either in
prolonging survival or improving quality of life without shortening
survival, and a favorable benefit to risk ratio. Although there is
emerging evidence for the clinical benefit of maintenance therapy
following stem cell transplant/therapy, a positive benefit and risk
balance is yet to be established in existing therapies. There are
to date no drugs approved for maintenance in patients with newly
diagnosed multiple myeloma and patients with relapsed, refractory
multiple myeloma.
[0098] In one embodiment, the maintenance therapy of this
disclosure comprises administering a compound of formula (IIIa)
(ixazomib citrate) to patients with newly diagnosed multiple
myeloma, wherein the patients have already undergone induction
therapy and a single autologous stem cell transplant.
[0099] In one embodiment, the maintenance therapy of this
disclosure comprises administering a compound of formula (IIIIa)
(ixazomib citrate) to patients with newly diagnosed multiple
myeloma, wherein the patients have already undergone induction
therapy and one or more autologous stem cell transplants.
[0100] In one embodiment, the maintenance therapy of this
disclosure comprises administering a compound of formula (IIIa)
(ixazomib citrate) to patients with newly diagnosed multiple
myeloma, wherein the patients have already undergone induction
therapy according to regional standard of care, followed by a
conditioning regimen containing high-dose therapy such as melphalan
(200 mg/m.sup.2) and a single autologous stem cell transplant.
Induction therapy must include proteasome inhibitor and/or
immunomodulating drugs-based regimens.
[0101] In certain embodiments, the induction therapy includes a
proteasome inhibitor, wherein the proteasome inhibitor is ixazomib
or ixazomib citrate.
[0102] In one embodiment, the maintenance therapy of this
disclosure comprises administering a compound of formula (IIIa)
(ixazomib citrate) to patients with newly diagnosed multiple
myeloma wherein the patients have already undergone induction
therapy and have not undergone autologous stem cell transplant.
[0103] In certain embodiments, patients who have achieved clinical
and hematologic recovery following induction therapy, high-dose
therapy, and autologous stem cell transplant will initiate
screening for the maintenance therapy eligibility no earlier than
75 days after transplant, complete screening within 15 days, and be
randomized no later than 115 days after transplant. Eligible
patients (those who have a documented complete response, very good
partial response, or partial response to induction therapy during
screening) may be treated with ixazomib maintenance therapy. The
stratification factors, induction regimen (proteasome inhibitors
without immunomodulating drugs, immunomodulating drugs without
proteasome inhibitors, or proteasome inhibitors and
immunomodulating drugs); pre-induction International Staging System
(ISS) (stage 1 vs. stage 2 or 3); and response after
transplantation, defined as the response following induction
therapy, high-dose therapy, and autologous stem cell transplant
measured during screening (complete response, very good partial
response, or partial response).
[0104] In certain embodiments, patients with newly diagnosed
multiple myeloma who have had a response (complete response, very
good partial response, or partial response) to induction therapy
followed by high-dose therapy and autologous stem cell transplant
may be treated with ixazorib maintenance therapy.
[0105] In certain embodiments, patients with newly diagnosed
multiple myeloma who have had a response (complete response, very
good partial response, or partial response) to induction therapy
followed by autologous stem cell transplant may be treated with
ixazomib maintenance therapy.
[0106] In certain embodiments, patients with newly diagnosed
multiple myeloma who have had a response (complete response, very
good partial response, or partial response) to induction therapy
and who have not undergone stem-cell transplant may be treated with
ixazomib maintenance therapy.
[0107] In certain embodiments, the maintenance therapy of this
disclosure comprises administering a compound of formula (IIIa)
(ixazomib citrate) to patients with a hematological malignancy
wherein the patients have already undergone induction therapy.
[0108] In certain embodiment, the maintenance therapy of this
disclosure comprises administering a compound of formula (IIIa)
(ixazomib citrate) to patients with a hematological malignancy,
wherein the patients have already undergone induction therapy and
one or more autologous stem cell transplants
[0109] In certain embodiment, the maintenance therapy of this
disclosure comprises administering a compound of formula (IIIa)
(ixazomib citrate) to patients with a hematological malignancy,
wherein the patients have already undergone induction therapy and
have not undergone autologous stem cell transplant.
[0110] In certain embodiments, the induction therapy comprises a
chemotherapeutic regimen. Examples of such chemotherapeutic regimen
include but are not limited to, CHOP (cyclophosphamide,
doxorubicin, vincristine, and prednisone), R-CHOP (rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone),
R-EPOCH (etoposide, rituximab, cyclophosphamide, doxorubicin,
vincristine, and prednisone), HyperCVAD (cyclophosphamide,
vincristine, doxorubicin, dexamethasone alternating with
methotrexate and cytarabine) with or without rituximab, or VAD
(vincristine, doxorubicin, dexamethasone).
[0111] In certain embodiments, the induction therapy comprises
proteasome inhibitor and/or immunomodulating drugs-based
regimens.
[0112] In certain embodiments, patients are administered with
ixazomib citrate capsule orally once-a-week for three consecutive
weeks followed by one week without the capsule. This four-week
(28-day) dosing regimen comprises one treatment cycle. In certain
embodiments, patients are administered ixazomib citrate capsules
once on days 1, 8, and 15 in a 28-day cycle.
[0113] In certain embodiments, the proteasome inhibitor of formula
(I), or a pharmaceutically acceptable salt thereof, is administered
at a first dose for at least four treatment cycles and a second
dose in the treatment cycles 5 through 26.
[0114] In one embodiment, the first dose strength of 3.0 mg/week of
ixazomib in the form of ixazomib citrate capsule will be used for
patients from the first treatment cycle through the fourth
treatment cycle. Upon evaluation of toxicities at the completion of
the fourth treatment cycle, patients will receive a second dose
strength of ixazomib at an increased dose strength of 4.0 mg/week
beginning with the fifth treatment cycle through the twenty-sixth
treatment cycle, and administered on the same schedule of the
treatment cycles 1-4 for the duration of the maintenance therapy,
to provide maximum possible clinical benefit for patients who
tolerated the first four cycles of treatment.
[0115] In one embodiment, the first dose strength of ixazomib in
the form of ixazomib citrate capsule will be used for patients
starting from the first treatment cycle. If the patient is
tolerating the first dose strength, the patient may receive a
second dose at an increased dose strength at any time upon
evaluation of toxicities after the first dose.
[0116] In one embodiment, the first dose strength of 3.0 mg/week of
ixazomib in the form of ixazomib citrate capsule will be used for
patients starting from the first treatment cycle. If the patient is
tolerating the 3.0 mg/week of dose strength, the patient may
receive a second dose at an increased dose strength of 4.0 mg/week
at any time upon evaluation of toxicities after the first dose.
[0117] In one embodiment, the first dose strength of 4.0 mg/week of
ixazomib in the form of ixazomib citrate capsule will be used for
patients starting from the first treatment cycle. If the patient is
tolerating the 4.0 mg/week of dose strength, the patient may
continue at the 4.0 mg/week dose strength.
[0118] In one embodiment, the first dose of 3.0 mg of ixazomib in
the form of ixazomib citrate capsule will be used for patients from
the first treatment cycle through the fourth treatment cycle. Upon
evaluation of toxicities at the completion of the fourth treatment
cycle, patients who would not tolerate the increased dose strength
will remain at the starting dose strength of 3.0 mg/week for the
fifth treatment cycle through the twenty-sixth treatment cycle, and
administered on the same schedule of the treatment cycles 1-4 for
the duration of the maintenance therapy.
[0119] In certain embodiments, patients experiencing adverse events
during any treatment cycle may continue in the maintenance therapy,
but may have ixazomib doses held or reduced by at least 1 dose
level. In certain embodiments, the reduced doses are from about 3.0
mg to about 1.5 mg. In certain embodiments, the reduced doses are
3.0 mg, 2.3 mg, and 2.5 mg.
[0120] The treatment period of the maintenance therapy is defined
as any time a patient is receiving the proteasome inhibitor of
formula (I) of this disclosure and will comprise 28-day treatment
cycles. In certain embodiments, patients will have treatment
assessments performed at regular treatment cycle intervals while
they are participating in the therapy: weekly (days 1, 8, and 15)
for the first cycle, twice a treatment cycle during the second
cycle (days 1 and 8), and then once a treatment cycle for the
remainder of their participation in the treatment period, until
they experience progressive disease or discontinue for alternate
reasons.
[0121] In certain embodiments, patients will be assessed for
disease response and progression, according to the International
Myeloma Working Group criteria, every cycle during the treatment
period and subsequently every four weeks during the
progression-free survival on maintenance therapy or before the next
line of therapy if discontinued before the progression follow-up
period until progressive disease. Following progressive disease,
patients will be followed in the overall survival follow-up period.
Patients will initially be followed every four weeks until
initiation of the next line of therapy by the treating physician.
All patients will then be followed every 12 weeks until death or
termination of the therapy. During the overall survival follow-up
period, patients and their treating physician will be contacted for
evaluation of the next line of therapy, Health-related quality of
life (only until initiation of the next line of therapy), disease
status, and survival. Health-related quality of life (HRQL) will be
evaluated through patient self-reported instruments, from
randomization to the time of initiation of the next line of
therapy. After progression and following initiation of the next
line of therapy, determination of disease response and progression
will be assessed by the treating physician according to
International Myeloma Working Group criteria.
[0122] In certain embodiments, adverse events will be assessed, and
laboratory values, vital signs, and electrocardiograms (ECGs) will
be obtained to evaluate the safety and tolerability of ixazomib.
Toxicity will be evaluated according to National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE), version
4.03, effective date 14 Jun. 2010.
[0123] In certain embodiments, therapeutic efficacy will be
measured. A measured change in the patient between an earlier time
point and a subsequent time point indicates that the maintenance
therapy is therapeutically effective.
[0124] In certain embodiments, the first point may be, for example,
prior to administration, after the first day of administration,
after the fifth day of administration, at the beginning of a
treatment cycle, at the end of a treatment cycle, etc. Regardless
of when the first time point is, the second time point is
subsequent to the first time point.
[0125] During the course of treatment, patient data may be
collected and used to assess the efficacy of treatment. The
relevant data include pharmacokinetic(s) data.
[0126] In certain embodiments, patients will receive maintenance
therapy for a maximum duration of approximately 24 months (26
cycles, to the nearest complete cycle), or until documented disease
progression (on the basis of the International Myeloma Working
Group criteria) or intolerable toxicities, whichever comes
first.
[0127] In certain embodiments, patients will receive maintenance
therapy for approximately 24 months. In certain embodiments,
patients will receive maintenance therapy until documented disease
progression (on the basis of the International Myeloma Working
Group criteriteria) or intolerable toxicities. In certain
embodiments, patients will receive maintenance therapy for as long
as it is clinically indicated (beyond 26 cycles).
[0128] In certain embodiments, patients who complete 24 months of
treatment cycles, clinical, laboratory, response, and
Health-related quality of life with an emphasis on tolerability and
symptom burden, as well as minimal residual disease assessments,
will be made. Following documented disease progression, subsequent
therapy will be determined by the treating physician.
[0129] In certain embodiments, adult patients age 18 years or older
with a confirmed diagnosis of multiple myeloma who have had a
response (complete response, very good partial response, or partial
response) to primary multiple myeloma therapy consisting of
standard of care induction, a conditioning regimen containing
high-dose melphalan (200 mg/m.sup.2), and single autologous stem
cell transplant will be eligible for the maintenance therapy.
[0130] In certain embodiments, patients who meet the following
criteria may receive the maintenance therapy: [0131] a. Adult male
or female patients 18 years or older with a confirmed diagnosis of
symptomatic multiple myeloma. [0132] b. Documented results of
cytogenetics/fluorescence in situ hybridization (FISH) obtained at
any time before transplant, and International Staging System
staging at the time of diagnosis if available. [0133] c. Underwent
standard of care induction therapy/primary therapy (the therapy
must include proteasome inhibitor and/or immunomodulating
drugs-based regimens as primary therapy for multiple myeloma),
followed by a single autologous stem cell transplant with a
high-dose melphalan (200 mg/m.sup.2) conditioning regimen, within
12 months of diagnosis. [0134] d. Started screening no earlier than
75 days after transplant, completed screening within 15 days, and
randomized no later than 115 days after transplant. [0135] e.
Patient may not receive post-autologous stem cell transplant
consolidation therapy. [0136] f. Response to autologous stem cell
transplant (partial response, very good partial response, complete
response/stringent complete response). [0137] g. Eastern
Cooperative Oncology Group performance status of 0 to 2.
[0138] In certain embodiments, patients who meet the following
criteria may receive the maintenance therapy: [0139] a. Adult male
or female patients 18 years or older with a confirmed diagnosis of
symptomatic newly diagnosed multiple myeloma according to standard
criteria. [0140] b. Completed six to 12 months (.+-.two weeks) of
initial therapy, during which the patient was treated to best
response, defined as the best response maintained for two cycles
after the M-protein nadir is reached. [0141] c. Documented major
response (partial response, very good partial response, complete
response according to the International Myeloma Working Group
(IMWG) uniform response criteria, version 2011, after the initial
therapy).
[0142] In certain embodiments, active ixazomib is provided to
patients in strengths of 4.0 mg, 3.0 mg, 2.3 mg, and 1.5 mg.
[0143] In certain embodiments, ixazomib is administrated to the
patients as ixazomib citrate in solid dose capsules.
[0144] In certain embodiments, ixazomib citrate capsules in the
maintenance therapy contain various dose strengths, including 0.5
mg, 2.3 mg, 3.0 mg, or 4.0 mg of ixazomib. The pharmaceutical
compositions containing ixazomib citrate and pharmaceutically
acceptable carriers of this disclosure can be manufactured by
methods well known in the art, for example, described in
International Patent Publication WO 2009/154737, which is hereby
incorporated by reference specifically and in their entirety.
[0145] In certain embodiments, the ixazomib citrate capsules
contain a mixture of ixazormib citrate, microcrystalline cellulose,
talc, and magnesium stearate.
[0146] Tables 1A, 1B, 1C and 2 provide certain embodiments of
ixazomib citrate capsules.
[0147] Dose strengths per capsule at the top of the Tables refer to
the equivalent of ixazomib when it is hydrolyzed from ixazomib
citrate upon contact with either plasma or aqueous solutions. For
example, a 0.5 mg capsule refers to a capsule that contains the
equivalent of 0.5 mg ixazomib per capsule. A 2.0 mg capsule refers
to a capsule that contains the equivalent of 2.0 mg ixazomib per
capsule. A 2.3 mg capsule refers to a capsule that contains the
equivalent of 2.3 mg ixazomib per capsule. A 3.0 mg capsule refers
to a capsule that contains the equivalent of 3.0 mg ixazomib per
capsule. A 4.0 mg capsule refers to a capsule that contains the
equivalent of 4.0 mg ixazomib per capsule. A 5.0 mg capsule refers
to a capsule that contains the equivalent of 5.0 mg ixazomib per
capsule.
TABLE-US-00001 TABLE 1A Composition of the 2.3 mg Ixazomib Citrate
Capsules Components mg per Capsule % per Capsule Ixazomib citrate
3.29* 4.71 Microcrystalline cellulose 65.66 93.79 Talc 0.70 1.00
Magnesium stearate 0.35 0.50 Total weight 70.00 100.00 *The amount
of ixazomib citrate is equivalent to 2.3 mg ixazomib.
TABLE-US-00002 TABLE 1B Composition of the 3.0 mg Ixazomib Citrate
Capsules Components mg per Capsule % per Capsule Ixazomib citrate
4.30* 6.14 Microcrystalline cellulose 64.65 92.36 Talc 0.70 1.00
Magnesium stearate 0.35 0.50 Total weight 70.00 100.00 *The amount
of ixazomib citrate is equivalent to 3.0 mg ixazomib.
TABLE-US-00003 TABLE 1C Composition of the 4.0 mg Ixazomib Citrate
Capsules Components mg per Capsule % per Capsule Ixazomib citrate
5.73* 5.0 Microcrystalline cellulose 107.5 93.5 Talc 1.15 1.00
Magnesium stearate 0.58 0.50 Total weight 115.00 100.00 *The amount
of ixazomib citrate is equivalent to 4.0 mg ixazomib.
TABLE-US-00004 TABLE 2 Compositions of 0.5 mg Ixazomib Citrate
Capsules Components mg per Capsule Ixazomib citrate 0.72*
Microcrystalline cellulose 102.70 Talc 1.05 Magnesium stearate 0.53
Total weight (mg) 105.00 *The amount of ixazomib citrate is
equivalent to 0.5 mg ixazomib.
[0148] In certain embodiments, a single first dose of ixazomib is
administrated orally to the patients weekly on days 1, 8, and 15
for three weeks, followed by one week without ixazomib in a 28-day
cycle. Following the first four cycles of the 28-day cycle therapy,
a second dose of ixazomib is administrated to the patients weekly
on days 1, 8, and 15 for cycle 5 through cycle 26.
[0149] In certain embodiments, the first dose of ixazomib is 3.0
mg; the second dose of ixazomib is 4.0 mg.
[0150] In certain embodiments, the first dose of ixazomib is 3.0
mg; the second dose of ixazomib is 3.0 mg.
[0151] In certain embodiments, the first dose of ixazomib is 2.3
mg; the second dose of ixazomib is 3.0 mg.
[0152] In certain embodiments, the first dose of ixazomib is 2.3
mg; the second dose of ixazomib is 2.3 mg.
[0153] In certain embodiments, the first dose of ixazomib is 1.5
mg; the second dose of ixazomib is 2.3 mg.
[0154] In certain embodiments, the first dose of ixazomib is 1.5
mg; the second dose of ixazomib is 1.5 mg.
[0155] In certain embodiments, the maintenance therapy is initially
given as a single, oral dose of 3.0 mg weekly on days 1, 8, and 15
for three weeks, followed by one week without ixazomib in a 28 day
cycle. Following the first four cycles of therapy, the dose will be
increased to 4.0 mg in cycle 5 through cycle 26 for patients
tolerating the drug.
[0156] In certain embodiments, a single 3.0 mg dose of ixazomib is
administrated orally to the patients weekly on days 1, 8, and 15
for 3 weeks, followed by one week without ixazomib in a 28-day
cycle. Following the first four cycles of the 28-day cycle therapy,
a second dose of 3.0 mg ixazomib is administrated to the patients
weekly on days 1, 8, and 15 for cycle 5 through cycle 26.
[0157] In certain embodiments, a single 1.5 mg dose of ixazomib is
administrated orally to the patients weekly on days 1, 8, and 15
for 3 weeks, followed by one week without ixazomib in a 28-day
cycle. Following the first four cycles of the 28-day cycle therapy,
a second dose of 2.3 mg ixazomib is administrated to the patients
weekly on days 1, 8, and 15 for cycle 5 through cycle 26.
[0158] Clinical Study of Oral Single-Agent Ixazomib Maintenance
Therapy
[0159] Twenty-one patients who completed the induction therapy
received ixazomib maintenance therapy. During the induction,
therapy, patients received 4.0 mg ixazomib weekly on days 1, 8, 15;
25.0 mg lenalidomide on days 1-21, and 40 mg dexamethasone weekly
on days 1, 8, 15, and 22, in a 28 day cycles.
[0160] These patients completed induction therapy and progressed to
the maintenance phase. Sixteen patients entered at 4.0 mg ixazob;
four patients entered at 4.0 mg ixazomib; four patients entered at
3.0 mg ixazorib; one patient entered at 2.4 mg ixazomib. The
patients receiving the maintenance therapy have the characteristics
shown in Table 3 and Table 4.
TABLE-US-00005 TABLE 3 Patient Patients receiving Characteristics
maintenance, n = 21 Median age, years (range) 68 (34-77) Age
.gtoreq.65 years, n (%) 12 (57) Age .gtoreq.75 years, n (%) 2 (10)
Male, n (%) 13 (62) White, n (%) 16 (76) ISS disease stage at
diagnosis, n (%) I 14 (67) II 7 (33) III 0 MM subtype, n (%) IgG 16
(76) IgA 3 (14) IgD 0 Light chain 2 (10) Median creatinine
clearance, ml/min 83.5
TABLE-US-00006 TABLE 4 Patients receiving Cytogenetics maintenance,
n = 21 Patients with cytogenetic assessment, N* 19
Conventional/karyotype 3 (16) Molecular/FISH 6 (32) Both 10 (53)
Unfavorable cytogenetics.sup..dagger., n (%) 3 (16) Type of
cytogenetic abnormality, n (%) del 13 (by metaphase cytogenetics) 2
(11) del 17 1 (5) t(4; 14) 0 t(14; 16) 1 (5) 1q amplification 0 No
sample collected for three patients. .sup..dagger.Unfavorable
cytogenics includes del 17, t(4; 14), t(14; 16), and 1q
amplification abnormalities detected by FISH or metaphase
cytogenics and del 13 detected by metaphase cytogenics.
[0161] During the maintenance therapy phase, the patients received
single agent ixazomib for a median of 19 treatment cycles (range
3-23), with a median treatment duration of 29.0 months (range
14.3-33.3). Table 5 shows the treatment exposure.
TABLE-US-00007 TABLE 5 Median cycles of ixazomib received, n
(range) Patients receiving at data cut-off maintenance, n = 21
Total (including induction and maintenance cycles) 31 (15-35)
Maintenance cycles 19 (3-23) Median treatment duration, months
(range) 29.0 (14.3-33.3) Maintenance duration, months (range) 19.8
(2.3-22.9) Mean relative dose intensity of ixazomib 92/95/89.5
overall/during induction/during maintenance, % Patients remaining
on ixazomib maintenance, n (%) 11 (52%)
[0162] FIG. 2 shows best overall response in 21 patients who
received ixazomib maintenance therapy (n=21).
[0163] The best response overall is: complete response (CR) or
better was reached in 52(%) percent of patients (11/21) and very
good partial response (VGPR) or better was reached in 71(%) percent
of patients (15/21).
[0164] Forty-eight percent (48%) of patients improved their
response during maintenance (10/21), including two VGPR to near-CR
(nCR) (2/10), five VGPR to CR (5/10), one VGPR to stringent
complete response (sCR) (1/10), and two CR to sCR (2/10). Median
duration of response was 21.65 months (range 6.7-31.18).
[0165] Fifty-two percent (52%) of patients (11/21) remained on
ixazomib maintenance after data cut-off of the study.
[0166] Median time to first response (.gtoreq.rapid response "PR")
was 0.99 months (range 0.92-5.78) and median time to best response
was 7.46 months (range 1.02-24.74). Mean ixazomib relative dose
intensity was 95 percent (95%) and 89.5 (89.5) percent in the
induction and maintenance phases, respectively.
[0167] All patients who received ixazornib maintenance were alive
after follow-up of 25.1-33.9 months.
* * * * *