U.S. patent application number 12/747167 was filed with the patent office on 2011-01-13 for methods of using (+)-1,4-dihydro-7-[(3s,4s)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox- o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid for treatment of antecedent hematologic disorders.
This patent application is currently assigned to SUNESIS PHARMACEUTICALS, INC. Invention is credited to Glenn Michelson.
Application Number | 20110008371 12/747167 |
Document ID | / |
Family ID | 40717006 |
Filed Date | 2011-01-13 |
United States Patent
Application |
20110008371 |
Kind Code |
A1 |
Michelson; Glenn |
January 13, 2011 |
METHODS OF USING
(+)-1,4-DIHYDRO-7-[(3S,4S)-3-METHOXY-4-(METHYLAMINO)-1-PYRROLIDINYL]-4-OX-
O-1-(2-THIAZOLYL)-1,8-NAPHTHYRIDINE-3-CARBOXYLIC ACID FOR TREATMENT
OF ANTECEDENT HEMATOLOGIC DISORDERS
Abstract
Methods of treating, preventing or managing antecedent
hematologic disorders, such as myelodysplastic syndrome, including
chronic myelomonocytic leukemia are disclosed. The methods
encompass the administration of SNS-595. Also provided are methods
of treatment using this compound with chemotherapy, radiation
therapy, hormonal therapy, biological therapy or immunotherapy. In
certain embodiments, the method of treatment comprise administering
SNS-595 in combination with cytarabine. Pharmaceutical compositions
and single unit dosage forms suitable for use in the methods are
also disclosed.
Inventors: |
Michelson; Glenn; (San
Francisco, CA) |
Correspondence
Address: |
JONES DAY
222 EAST 41ST ST
NEW YORK
NY
10017
US
|
Assignee: |
SUNESIS PHARMACEUTICALS,
INC
|
Family ID: |
40717006 |
Appl. No.: |
12/747167 |
Filed: |
December 10, 2008 |
PCT Filed: |
December 10, 2008 |
PCT NO: |
PCT/US08/13549 |
371 Date: |
September 9, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61007229 |
Dec 10, 2007 |
|
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Current U.S.
Class: |
424/174.1 ;
424/649; 514/171; 514/19.9; 514/249; 514/265.1; 514/27; 514/274;
514/300; 514/34; 514/49 |
Current CPC
Class: |
A61K 39/39558 20130101;
A61K 31/513 20130101; A61P 7/06 20180101; A61K 31/7068 20130101;
A61K 31/706 20130101; A61K 38/18 20130101; A61K 2039/505 20130101;
A61K 2039/54 20130101; A61K 38/19 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; C07D 471/04 20130101; A61K 31/513 20130101;
A61P 35/00 20180101; A61K 31/4375 20130101; A61P 35/02 20180101;
A61K 45/06 20130101; A61K 31/4375 20130101 |
Class at
Publication: |
424/174.1 ;
514/300; 514/27; 514/34; 514/19.9; 424/649; 514/265.1; 514/249;
514/49; 514/274; 514/171 |
International
Class: |
A61K 39/395 20060101
A61K039/395; A61K 31/4375 20060101 A61K031/4375; A61K 31/7048
20060101 A61K031/7048; A61K 31/704 20060101 A61K031/704; A61K 38/12
20060101 A61K038/12; A61K 33/24 20060101 A61K033/24; A61K 31/519
20060101 A61K031/519; A61K 31/7068 20060101 A61K031/7068; A61K
31/513 20060101 A61K031/513; A61K 31/58 20060101 A61K031/58; A61P
35/00 20060101 A61P035/00; A61P 35/02 20060101 A61P035/02; A61P
7/06 20060101 A61P007/06 |
Claims
1. A method of treating an antecedent hematological disorder
comprising administering to a mammal having the antecedent
hematologic disorder a therapeutically effective amount of an
enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid.
2. The method of claim 1, wherein the antecedent hematological
disorder is a myelodysplastic syndrome.
3. The method of claim 1, wherein the myelodysplastic syndrome is
characterized by ineffective blood cell production, progressive
cytopenia, risk of progression to acute leukemia or cellular marrow
with impaired morphology.
4. The method of claim 2, wherein the myelodysplastic syndrome is
selected from group consisting of refractory anemia, refractory
anemia with ringed sideroblasts, refractory anemia with excess
blasts, refractory anemia with excess blasts in transformation, and
chronic myelomonocytic leukemia.
5. The method of claim 2, wherein the myelodysplastic syndrome is
chronic myelomonocytic leukemia.
6. The method of claim 5, wherein the chronic myelomonocytic
leukemia is relapsed, refractory, or resistant to conventional
therapy.
7. The method of claim 1, further comprising administering a
therapeutically effective amount of a second active agent.
8. The method of claim 7, wherein the second active agent is a
therapeutic antibody that specifically binds to a cancer antigen,
anti-cancer agent, corticosteroid.
9. The method of claim 8, wherein the anti-cancer agent is an
alkylating agent, an anti-neoplastic antibiotic, an
anti-metabolite, a platinum coordination complex, a topoisomerase
II inhibitor, or radiation.
10. The method of claim 8, wherein the anti-cancer agent is
etoposide, daunomycin, actinomycin D, mitomycin C, cisplatin,
carboplatin, premetrexed, methotrexate, cytarabine, 5-fluorouracil,
wortmannin, geldanamycin, gemcitabine, or a combination
thereof.
11. The method of claim 10, wherein the anti-cancer agent is
cytarabine.
12. The method of claim 11, wherein the amount of cytarabine is
about 200 to about 400 mg/m.sup.2/day.
13. The method of claim 11, wherein the amount of cytarabine is
about 400 mg/m.sup.2/day.
14. The method of claim 11, wherein the amount of cytarabine is
about 10-50 mg/m.sup.2/day.
15. The method of claim 11, wherein the amount of cytarabine is
about 20 mg/m.sup.2/day.
16. The method of claim 11, wherein the amount of cytarabine is
about 10 mg/m.sup.2 twice per day.
17. The method of claim 11, wherein the amount of cytarabine is
administered subcutaneously for 10 days.
18. The method of claim 1, wherein the amount of enantiomerically
pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid administered
is from about 1 to about 150 mg/m.sup.2.
19. The method of claim 1, wherein the amount of enantiomerically
pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid administered
is from about 10 to about 120 mg/m.sup.2.
20. The method of claim 1, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered once a week.
21. The method of claim 20, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered at a dose of from about 10 to about 90 mg/m.sup.2.
22. The method of claim 21, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered once a week for three weeks.
23. The method of claim 1, wherein the amount of enantiomerically
pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid administered
is from about 40 to about 80 mg/m.sup.2 per week.
24. The method of claim 1, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered as an IV injection.
25. The method of claim 1, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered twice per week.
26. The method of claim 25, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid administered
twice per week is at a dose of from about 10 to about 40
mg/m.sup.2.
27. The method of claim 25, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered twice per week for two weeks.
28. The method any claim 1, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered from about 5 to about 60 mg/m.sup.2 twice per week,
for 2 weeks.
29. The method of claim 11, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered intravenously twice per week, and cytarabine is
intravenously administered continuously over a treatment cycle of 5
days.
30. The method of claim 29, wherein cytarabine is administered at
about 400 mg/m.sup.2/day.
31. The method of claim 29, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered on day 1 and day 4 of said treatment cycle of 5
days.
32. The method of claim 29, wherein the treatment cycle is repeated
at least once.
33. The method of claim 29, wherein the treatment cycle is repeated
at least two times.
34. The method of claim 29, wherein the treatment cycle is repeated
at least three times.
35. The method of claim 11, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered 8 to 16 hours after the start of at least one
cytarabine administration.
36. The method of claim 11, wherein the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered within 24 hours before or after the start of at least
one cytarabine administration.
37. The method of claim 11, wherein cytarabine is administered
immediately after administration of the enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid.
38. The method of claim 1, wherein the mammal is a human.
Description
1. RELATED APPLICATIONS
[0001] This application claims priority to U.S. provisional
application Ser. No. 61/007,229, filed Dec. 10, 2007, entitled
"Methods of using
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid for treatment
of antecedent hematologic disorders". The disclosure of the above
referenced application is incorporated by reference herein in its
entirety.
2. FIELD OF THE INVENTION
[0002] Provided herein are methods of treating, preventing or
managing antecedent hematologic disorders, including
myelodysplastic syndrome, with enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, which is
also known as SNS-595 or AG-7352.
[0003] Further provided is a combination therapy for treatment of
antecedent hematologic disorders comprising administering a
combination of
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-
-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and
cytarabine (Ara-C). Also provided are pharmaceutical compositions
and dosing regimens for the methods provided herein.
3. BACKGROUND OF THE INVENTION
[0004] Antecedent hematological disorders include the disorders
myelofibrosis, aplastic anemia, paroxysmal nocturnal
hemoglobinuria, polycythemia vera, and most commonly
myelodysplastic syndrome. Myelodysplastic syndrome (MDS) refers to
hematological conditions characterized by abnormalities in the
production of one or more of the cellular components of blood (red
cells, white cells (other than lymphocytes) and platelets (or their
progenitor cells, megakaryocytes). MDS possesses a variable risk of
progression to acute leukemia, resulting from ineffective blood
cell production. The Merck Manual 953 (17th ed. 1999) and List et
al., 1990, J. Clin. Oncol. 8:1424. Myelodysplastic syndromes (MDS)
may be classified into several subtypes according to various
systems of classification.
[0005] According to the French-American-British classification
system, MDS may be classified according to the respective
percentages of peripheral blasts and bone marrow blasts of the
patient. See e.g., Bennett et al., Br. J. Haematol. 51:189-199
(1982); and Bennett et al., Br. J. Haematol. 87:746-754 (1994).
Patients with MDS are classified as having one of five subtypes of
disease: refractory anemia (RA); RA with ringed sideroblasts
(RARS); RA with excess of blasts (RAEB); RAEB in transformation
(RAEB-T); and chronic myelomonocytic leukemia (CMML).
Myelodysplastic syndromes are generally indolent, with patients'
blood counts remaining relatively stable over at least several
months. With a moderate degree of variability, RAEB patients (those
with 5% to 20% marrow blasts) and those with RAEB-T (20% to 30%
marrow blasts) generally have a relatively poor prognosis, with a
median survival ranging from 5 to 12 months. In contrast, RA
patients (fewer than 5% blasts) or RARS patients (fewer than 5%
blasts plus more than 15% ringed sideroblasts) have a median
survival of approximately 3 to 6 years. The proportion of these
individuals whose disease transforms to AML ranges from 5% to 15%
in the low-risk RA/RARS group to 40% to 50% in the relatively
high-risk RAEB/RAEB-T group. The FAB classification categorizes
patients with more than 30% marrow blasts as having AML.
[0006] The subtype CMML can have 5-20% bone marrow blasts with a
monocytosis of 1000/dL or more. It may be associated with
splenomegaly. This subtype overlaps with a myeloproliferative
disorder and may have an intermediate clinical course. It is
differentiated from the classic chronic myelocytic leukemia (CML)
that is characterized by a negative Ph chromosome.
[0007] MDS can also be classified according to the World Health
Organization's (WHO) proposed system of classification. See, e.g.
Brunning et al., Pathology and Genetics of Haematopoietic and
Lymphoid Tissues, Lyon:IARC Press: 61-73 (2001); Harris et al., J.
Clin. Oncol. 17:3835-3849 (1999); and Vardiman et al., Blood
100:2292-2302 (2002). MDS can be categorized under the WHO
classification system according to the following criteria:
[0008] Refractory anemia (RA) is characterized by anemia with no or
few blasts in the blood, and bone marrow displaying erythroid
dysplasia only, less than 5% blasts, and less than 15% ringed
sideroblasts.
[0009] Refractory cytopenia with multilineage dysplasia (RCMD) is
characterized by cytopenias with no or few blasts in the blood, and
bone marrow displaying dysplasia in greater than at least 10% of
cells in at least 2 myeloid cell lines, less than 5% blasts, at
least 15% ringed sideroblasts, and no Auer rods.
[0010] Refractory anemia with ringed sideroblasts (RARS) is
characterized by anemia with no or rare blasts in the blood, and
bone marrow displaying erythroid dysplasia only, less than 5%
blasts, and at least 15% ringed sideroblasts.
[0011] Refractory cytopenia with multilineage dysplasia and ringed
sideroblasts (RCMD-RS) is characterized by cytopenias with no or
few blasts in the blood, and bone marrow displaying dysplasia at
least 10% of cells in at least two myeloid cell lines, less than 5%
blasts, no Auer rods, and at least 15% ringed sideroblasts.
[0012] Refractory anemia with excess blasts-1 (RAEB-1) is
characterized by cytopenias with less than 5% blasts in the blood
with no Auer rods, and bone marrow displaying unilineage or
multilineage dysplasia, 5% to 9% blasts, and no Auer rods.
[0013] Refractory anemia with excess blasts-2 (RAEB-2) is
characterized by cytopenias with between 5-19% blasts in the blood,
and bone marrow displaying unilineage or multilineage dysplasia,
and 10% to 19% blasts.
[0014] Myelodysplastic Syndrome, unclassified (MDS-U), is
characterized by cytopenias with no or rare blasts in the blood and
no Auer rods, and bone marrow displaying unilineage dysplasia in
granulocytes or megakaryocytes, less than 5% blasts, and no Auer
rods.
[0015] MDS associated with isolated del (5q) is characterized by
anemia with less than 5% blasts in blood with normal or increased
platelets, and bone marrow displaying normal or increased
megakaryocytes with hypoloblated nuclei, less than 5% blasts, no
Auer rods, and an isolated 5q31-33 chromosomal deletion.
[0016] MDS can also be classified according to the International
Prognostic Scoring System. See, e.g. Greenberg et al., Blood
89:2079-2088 (1997); and Greenberg et al., Blood 91:1100 (1998).
Under IPSS scoring, prognostic values are assigned to 3 categories:
(1) percent marrow blasts (less than 5%=0; 5-10%=0.5; 11-20%=1.0;
and 21-30%=2.0); (2) karyotype (normal cytogenetics=0; some
chromosomal defects=0.5; complex, or chromosome 7 anomalies=1.5);
and (3) cytopenia (a score of 0 if one of the following criteria
are met: neutrophil count <1,800/mcL, platelets <100,000/mcL,
Hb <10 g/dL; a score of 0.5 if two of three criteria are met).
Risk is then determined based on the cumulative score of the 3
categories: "low" risk of MDS for an overall score of 0; "INT-1"
risk of MDS for a score of 0.5-1; "INT-2" risk of MDS for an
overall score of 1.5-2.0; and "high" risk of MDS for an overall
score of 2.5 or higher.
[0017] The most common cases of MDS are primary, or idiopathic.
However, a nonspecific history of exposure to indeterminable
chemicals or radiation 10-15 years prior to onset of disease may be
present in about 50% of patients. This relationship to pathogenesis
remains unproved. Compounds such as, but not limited to, benzene,
insecticides, weed killers, and fungicides are possible causes of
MDS. Goldberg H., et al., Cancer Res. 1990 Nov. 1; 50(21): 6876-81.
Secondary MDS describes development of MDS or acute leukemia after
known exposures to chemotherapy drugs that can cause bone marrow
damage. These drugs are associated with a high incidence of
chromosomal abnormalities following exposure and at the time of MDS
or acute leukemia diagnosis.
[0018] Further, MDS is associated with complications associated
with severe cytopenias. Other complications are development of
myelofibrosis, which can accelerate decline in blood counts and
increase transfusion requirements. Transformation to acute leukemia
accelerates the development of complications such as anemia,
bleeding, and infections.
[0019] MDS Treatments
[0020] The current treatment of MDS is based on the stage and the
mechanism of the disease that predominates the particular phase of
the disease process. Bone marrow transplantation has been used in
patients with poor prognosis or late-stage MDS. Epstein and Slease,
1985, Surg. Ann. 17:125. This type of therapy, however, is both
painful for donor and recipient, because of the involvement of
invasive procedures and can cause severe and even fatal
complications to the recipient, particularly with allogeneic
transplant and related Graft Versus Host Disease (GvHD) results.
Therefore, the risk of GvHD restricts the use of bone marrow
transplantation to patients with otherwise fatal diseases. Further,
as most patients are elderly and only a few young MDS patients will
have a matched donor, the use of bone marrow transplantation is
limited.
[0021] An alternative approach to therapy for MDS is the use of
hematopoietic growth factors or cytokines to stimulate blood cell
development in a recipient. Dexter, 1987, J. Cell Sci. 88:1; Moore,
1991, Annu. Rev. Immunol. 9:159; and Besa E. C., Med. Clin. North
Amer. 1992 May, 76(3): 599-617. The process of blood cell
formation, by which a small number of self-renewing stem cells give
rise to lineage specific progenitor cells that subsequently undergo
proliferation and differentiation to produce the mature circulating
blood cells has been shown to be at least in part regulated by
specific hormones. These hormones are collectively known as
hematopoietic growth factors. Metcalf, 1985, Science 229:16;
Dexter, 1987, J. Cell Sci. 88:1; Golde and Gasson, 1988, Scientific
American, July: 62; Tabbara and Robinson, 1991, Anti-Cancer Res.
11:81; Ogawa, 1989, Environ. Health Presp. 80:199; and Dexter,
1989, Br. Med. Bull. 45:337. The most well characterized growth
factors include erythropoietin (EPO), granulocyte macrophage colony
stimulating factor (GM-CSF), and granulocyte colony stimulating
factor (G-CSF). Apart from inducing proliferation and
differentiation of hematopoietic progenitor cells, such cytokines
have also been shown to activate a number of functions of mature
blood cells, including influencing the migration of mature
hematopoietic cells. Stanley et al., 1976, J. Exp. Med. 143:631;
Schrader et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78:323; Moore
et al., 1980, J. Immunol. 125:1302; Kurland et al., 1979, Proc.
Natl. Acad. Sci. U.S.A. 76:2326; Handman and Burgess, 1979, J.
Immunol. 122:1134; Vadas et al., 1983, Blood 61:1232; Vadas et al.,
1983, J. Immunol. 130:795; and Weibart et al., 1986, J. Immunol.
137:3584.
[0022] Unfortunately, hematopoietic growth factors have not proven
effective in many clinical settings. Clinical trials of MDS
patients treated with recombinant human GM-CSF and G-CSF have shown
that while these cytokines can restore granulocytopoiesis in
treated patients, their efficacy is restricted to the granulocyte
or monocyte lineage with little or no improvement in hemoglobin or
platelet counts. Schuster et al., 1990, Blood 76 (Suppl. 1):318a.
When such patients were treated with recombinant human EPO, a
sustained improvement in hemoglobin or decrease in transfusion
requirement was achieved in only less than 25% of patients. Besa et
al., 1990, Blood, 76 (Suppl. 1):133a; Hellstrom et al., 1990,
Blood, 76 (Suppl. 1):279a; Bowen et al, 1991, Br. J. Haematol.
77:419.
[0023] Therefore, there remains a need for safe and effective
methods of treating and managing antecedent hematological
disorders, including MDS.
4. SUMMARY OF THE INVENTION
[0024] Provided herein are methods of treating, preventing or
managing antecedent hematological disorders, including
myelofibrosis, aplastic anemia, paroxysmal nocturnal
hemoglobinuria, polycythemia vera, and myelodysplastic syndrome. In
one embodiment, methods are for treating, preventing or managing
myelodysplastic syndrome (MDS), including CMML. In certain
embodiments, provided herein are methods for treating, preventing
or managing CMML.
[0025] The methods comprise administering to a subject in need of
such treatment, prevention or management a therapeutically or
prophylactically effective amount of
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid. In some
embodiments,
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is used
alone, e.g., without other chemotherapeutics.
[0026] In another embodiment,
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered in combination with a therapy, e.g., another
pharmaceutical agent with activity against cancer or its symptoms.
Examples of therapies within the scope of the methods include, but
are not limited to, surgery, chemotherapy, radiation therapy,
hormonal therapy, biological therapy, immunotherapy, and
combinations thereof. It should be noted that the combinations
encompass simultaneous as well as sequential administration.
[0027] In a particular embodiment, the combination therapy
comprises administering
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and
cytarabine.
[0028] Also provided are dosing regimens, dosing schedules and
methods of using SNS-595 in combination with cytarabine.
[0029] The methods provided include the administration of SNS-595
in combination with 5-1500 mg/m.sup.2 of cytarabine. For example,
one embodiment includes continuous daily administration of
cytarabine at a dose of 200-400 mg/m.sup.2. The administration of
cytarabine can be made by intravenous infusion, intravenous push,
bolus injection or subcutaneous injection. In one embodiment, the
administration of cytarabine is daily, e.g., for 5 days, while the
administration of SNS-595 occurs once or twice per week. As
discussed herein, the administration of SNS-595 and cytarabine as
set forth above in a week is considered a weekly cycle. The methods
contemplate performing one weekly cycle, waiting a period of one
week to several weeks where neither cytarabine nor SNS-595 is
given, then repeating a weekly cycle. The methods also contemplate
repeating the weekly cycles continuously, for example, for 4 weeks
or 28 days. In addition, the methods contemplate repeating the
cycle for several cycles, waiting a period of a week to several
weeks where neither cytarabine nor SNS-595 is given, then repeating
one or more cycles. Finally, the methods provide administration of
a SNS-595/cytarabine weekly cycle followed by a cycle of only
cytarabine or SNS-595.
[0030] Also provided are methods where the daily cytarabine
administration is at a dose of 5-50 mg/m.sup.2 and where the
SNS-595 is administered once a week or twice a week. For example,
cytarabine may be administered daily for 10 days, and SNS-595 may
be administered on a schedule of once a week for three weeks, or
twice a week for two weeks.
[0031] Also provided are pharmaceutical compositions, single unit
dosage forms, and dosing regimens which comprise
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, and a
second, or additional, active agent. Second active agents include
specific drugs or therapy, or combinations thereof, i.e.
"cocktails."
5. DETAILED DESCRIPTION OF THE INVENTION
[0032] Provided herein are methods of treating, managing, or
preventing antecedent hematologic disorders comprising
administering to a mammal in need of such treatment, management or
prevention a therapeutically or prophylactically effective amount
of
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid alone, or in
combination with another chemotherapeutic agent such as cytarabine.
In one embodiment, the methods encompass treating, preventing or
managing antecedent hematological disorders (AHD). In one
embodiment, the antecedent hematological disorder is CMML.
[0033] In other embodiments,
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
administered in combination with another drug (i.e. a "second
active agent") or another therapy for treating, managing, or
preventing cancer. Second active agents include small molecules and
large molecules (e.g., proteins and antibodies), examples of which
are provided herein, as well as stem cells or cord blood. Methods
or therapies that can be used in combination with the
administration of
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid include, but
are not limited to, surgery, blood transfusions, immunotherapy,
biological therapy, radiation therapy, and other non-drug based
therapies presently used to treat, prevent or manage cancer.
[0034] In one embodiment, the combination therapy comprises
administering
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and
cytarabine. Specific doses and dosing regimens for the combination
therapy are provided below.
[0035] Also provided are pharmaceutical compositions (e.g., single
unit dosage forms) that can be used in methods disclosed herein. In
one embodiment, pharmaceutical compositions comprise
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and a second
active agent.
DEFINITIONS
[0036] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art. All patents, applications, published
applications and other publications are incorporated by reference
in their entirety. If there are a plurality of definitions for a
term herein, those in this section prevail unless stated
otherwise.
[0037] As used herein, enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is
substantially free from
(-)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolid-
inyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid
(i.e., in enantiomeric excess). In other words, the "(+)" form of
1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-oxo-1--
(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid is substantially
free from the "(-)" form of the compound and is, thus, in
enantiomeric excess of the "(-)" form. The term "enantiomerically
pure" or "pure enantiomer" denotes that the compound comprises more
than 75% by weight, more than 80% by weight, more than 85% by
weight, more than 90% by weight, more than 91% by weight, more than
92% by weight, more than 93% by weight, more than 94% by weight,
more than 95% by weight, more than 96% by weight, or more than 97%
by weight of the enantiomer.
[0038] As used herein and unless otherwise indicated, the term
"enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid" refers to at
least about 80% by weight
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and at most
about 20% by weight
(-)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, at least
about 90% by weight
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolid-
inyl]-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and
at most about 10% by weight the (-)-enantiomer, at least about 95%
by weight
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and at most
about 5% by weight the (-)-enantiomer, at least about 97% by weight
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid and at most
about 3% by weight (-)-enantiomer.
[0039] As used herein, administration of
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-methylamino-1-pyrrolidinyl]-4-oxo--
1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid includes
administration of
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-methylamino-1-pyrrolidinyl]-4-oxo--
1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, as well as any
ionic form, salts, solvates, e.g., hydrate, or other forms of that
compound, including mixtures thereof. Thus, compositions comprising
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-methylamino-1-pyrrolidinyl]-4-oxo--
1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid may include
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-methylamino-1-pyrrolidinyl]-4-oxo--
1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid or an ionic
form thereof, salt, solvate, e.g., hydrate, or other form of the
compound.
[0040] As used herein, "subject" is an animal, typically a mammal,
including a human, such as a human patient.
[0041] As used herein, the term "antecedent hematological
disorders" includes the disorders myelofibrosis, aplastic anemia,
paroxysmal nocturnal hemoglobinuria, polycythemia vera, and
myelodysplastic syndrome.
[0042] The term "myelodysplastic syndrome" refers to hematological
conditions characterized by abnormalities in the production of one
or more of the cellular components of blood (red cells, white cells
(other than lymphocytes) and platelets (or their progenitor cells,
megakaryocytes), and include the following disorders: refractory
anemia (RA); RA with ringed sideroblasts (RARS); RA with excess of
blasts (RAEB); RAEB in transformation (RAEB-T); and CMML.
[0043] As used herein, "chronic myelomonocytic leukemia" or "CMML"
refers to a clonal disorder of a bone marrow stem cell, wherein an
abundance of myelocytes and monocytes (immature white blood cells)
are made in the bone marrow resulting in the crowding out of normal
blood cells, such as other white blood cells, red blood cells, and
platelets. In certain embodiments, CMML is refractory to and/or
relapsed from prior therapy.
[0044] As used herein and unless otherwise indicated, the terms
"treat," "treating" and "treatment" refer to alleviating or
reducing the severity of a symptom associated with the disease or
condition being treated.
[0045] As used herein, unless otherwise specified, the term
"preventing" includes but is not limited to, inhibition or the
averting of symptoms associated with antecedent hematologic
disorders, including MDS. The symptoms associated with antecedent
hematologic disorder include, but are not limited to, anemia,
thrombocytopenia, neutropenia, cytopenia, bicytopenia (two
deficient cell lines), and pancytopenia (three deficient cell
lines).
[0046] As used herein and unless otherwise indicated, the term
"managing" encompasses preventing the recurrence of antecedent
hematologic disorders, including MDS, in a patient who had suffered
from antecedent hematologic disorders, lengthening the time a
patient who had suffered from antecedent hematologic disorders
remains in remission, and/or preventing the occurrence of
antecedent hematologic disorders in patients at risk of suffering
from antecedent hematologic disorders.
[0047] As used herein and unless otherwise indicated, the term
"pharmaceutically acceptable salt" includes, but is not limited to,
salts of acidic or basic groups that can be present in the
compounds provided herein. Under certain acidic conditions, the
compounds can form a variety of salts with various inorganic and
organic acids. The acids that can be used to prepare
pharmaceutically acceptable salts of such basic compounds are those
that form salts comprising pharmacologically acceptable anions
including, but not limited to, acetate, benzenesulfonate, benzoate,
bicarbonate, bitartrate, bromide, calcium edetate, camsylate,
carbonate, chloride, bromide, iodide, citrate, dihydrochloride,
edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate,
malate, maleate, mandelate, mesylate, methylsulfate, muscate,
napsylate, nitrate, panthothenate, phosphate/diphosphate,
polygalacturonate, salicylate, stearate, succinate, sulfate,
tannate, tartrate, teoclate, triethiodide and pamoate. Under
certain basic conditions, the compounds can form base salts with
various pharmacologically acceptable cations. Non-limiting examples
of such salts include alkali metal or alkaline earth metal salts
and, particularly, calcium, magnesium, sodium, lithium, zinc,
potassium and iron salts.
[0048] As used herein and unless otherwise indicated, the term
"hydrate" means a compound provided herein, or a salt thereof, that
further includes a stoichiometric or non-stoichiometric amount of
water bound by non-covalent intermolecular forces.
[0049] As used herein and unless otherwise indicated, the term
"solvate" means a solvate formed from the association of one or
more solvent molecules to a compound provided herein. The term
"solvate" includes hydrates (e.g., mono-hydrate, dihydrate,
trihydrate, tetrahydrate and the like).
[0050] As used herein, and unless otherwise specified, the terms
"therapeutically effective amount" and "effective amount" of a
compound refer to an amount sufficient to provide a therapeutic
benefit in the treatment, prevention and/or management of a
disease, to delay or minimize one or more symptoms associated with
the disease or disorder to be treated. The terms "therapeutically
effective amount" and "effective amount" can encompass an amount
that improves overall therapy, reduces or avoids symptoms or causes
of disease or disorder, or enhances the therapeutic efficacy of
another therapeutic agent.
[0051] The terms "co-administration" and "in combination with"
include the administration of two therapeutic agents (for example,
SNS-595 and another anti-cancer agent) either simultaneously,
concurrently or sequentially with no specific time limits. In one
embodiment, both agents are present in the cell or in the patient's
body at the same time or exert their biological or therapeutic
effect at the same time. In one embodiment, the two therapeutic
agents are in the same composition or unit dosage form. In another
embodiment, the two therapeutic agents are in separate compositions
or unit dosage forms.
[0052] The term "the supportive care agent" refers to any substance
that treats, prevents or manages an adverse effect associated with
SNS-595 treatment.
[0053] The term "biological therapy" refers to administration of
biological therapeutics such as cord blood, stem cells, growth
factors and the like.
[0054] The term "about," as used herein, unless otherwise
indicated, refers to a value that is no more than approximately 10%
above or below the value being modified by the term.
[0055] SNS-595
[0056] The compound for use in the methods provided herein,
including the combination therapy, and in compositions provided
herein is enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid, which is
also known as SNS-595 or AG-7352. The name assigned by the United
States Adopted Names Council (USANC) to the compound is
"voreloxin". SNS-595 has the following chemical structure:
##STR00001##
[0057] In certain embodiments, pharmaceutically acceptable salts,
solvates, hydrates or prodrugs of SNS-595 are used in the methods
and compositions provided herein.
[0058] SNS-595 can be prepared by methods known to one of skill in
the art, for example, according to the preparation procedure for
Example C-1 of U.S. Pat. No. 5,817,669, entitled "Compounds,
processes for the preparation thereof and anti-tumor agents,"
issued Oct. 6, 1998, and in Japanese Patent Application No. Hei
10-173986, to Chikugi et al., which are incorporated herein by
reference in their entireties. Certain exemplary pharmaceutical
compositions comprising SNS-595 and methods of using the same are
described in U.S. Patent Application Pub. Nos. 2005/0203120;
2005/0215583; 2006/0025437; 2006/0063795 and 2006/0247267, which
are incorporated herein by reference in their entireties.
[0059] Second Active Agents
[0060] In the methods and compositions provided herein, SNS-595 can
be used with or combined with other pharmacologically active
compounds ("second active agents"). Without being limited by any
theory, it is believed that certain combinations work
synergistically in the treatment of particular antecedent
hematologic disorders. The methods also encompass the use of
SNS-595 in a manner to alleviate, reduce or avoid adverse effects
associated with certain second active agents. Also provided are
methods, wherein the second active agents are used in the manner to
alleviate, reduce or avoid adverse or unwanted effects associated
with SNS-595, including dose limiting toxicity.
[0061] One or more second active ingredients or agents can be used
together with SNS-595 in the methods and compositions provided
herein. Second active agents can be large molecules (e.g.,
proteins) or small molecules (e.g., synthetic inorganic,
organometallic, or organic molecules).
[0062] Examples of large molecule active agents include, but are
not limited to, hematopoietic growth factors, cytokines, and
monoclonal and polyclonal antibodies, particularly, therapeutic
antibodies to cancer antigens. Typical large molecule active agents
are biological molecules, such as naturally occurring or synthetic
or recombinant proteins. Proteins that are particularly useful in
the methods and compositions provided herein include proteins that
stimulate the survival and/or proliferation of hematopoietic
precursor cells and immunologically active poietic cells in vitro
or in vivo. Other useful proteins stimulate the division and
differentiation of committed erythroid progenitors in cells in
vitro or in vivo. Particular proteins include, but are not limited
to: interleukins, such as IL-2 (including recombinant IL-II
("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-18; interferons,
such as interferon alfa-2a, interferon alfa-2b, interferon alfa-n1,
interferon alfa-n3, interferon beta-I a, and interferon gamma-I b;
G-CSF and GM-CSF; and EPO.
[0063] Also provided for use in combination with SNS-595 are
native, naturally occurring, and recombinant proteins. Further
encompassed are mutants and derivatives (e.g., modified forms) of
naturally occurring proteins that exhibit, in vivo, at least some
of the pharmacological activity of the proteins upon which they are
based. Examples of mutants include, but are not limited to,
proteins that have one or more amino acid residues that differ from
the corresponding residues in the naturally occurring forms of the
proteins. Also encompassed by the term "mutants" are proteins that
lack carbohydrate moieties normally present in their naturally
occurring forms (e.g., nonglycosylated forms). Examples of
derivatives include, but are not limited to, pegylated derivatives
and fusion proteins, such as proteins formed by fusing IgG1- or
IgG3-derived proteins to the protein of interest or an active
portion thereof. See, e.g., Penichet, M. L. and Morrison, S. L., J.
Immunol. Methods 248:91-101 (2001).
[0064] Antibodies that can be used in combination with SNS-595
include monoclonal and polyclonal antibodies. Examples of
antibodies include, but are not limited to, trastuzumab (e.g.,
Herceptin.RTM.), rituximab (e.g., Rituxan.RTM.), bevacizumab (e.g.,
Avastin.RTM.), pertuzumab (e.g., Omnitarg.RTM.), tositumomab (e.g.,
Bexxar.RTM.), edrecolomab (e.g., Panorex.RTM.), CD20 antibodies
such as ibritumomab tiuxetan (e.g., Zevalin.RTM.)+.sup.111In or
.sup.90Yt or ofatumumab; CD23 antibodies such as lumiliximab; CD33
antibodies such as gemtuzumab ozogamicin (Mylotarg.RTM.) or
lintuzumab; CD52 antibodies such as alemtuzumab (e.g.,
Campath.RTM.); CD80 antibodies such as galiximab; and G250. SNS-595
can also be combined with, or used in combination with,
anti-TNF-.alpha. antibodies such as infliximab (e.g.,
Remicade.RTM.) or adalimumab (e.g., Humira.RTM.), anti-IL-2
antibodies such as daclizumab (dacliximab, e.g., Zenapax.RTM.),
and/or anti-EGFR antibodies, such as cetuximab (e.g., Erbitux.RTM.)
or panitumumab (e.g., Vectibix.RTM.).
[0065] Large molecule active agents may be administered in the form
of anti-cancer vaccines. For example, vaccines that secrete, or
cause the secretion of, cytokines such as IL-2, G-CSF, and GM-CSF
can be used in the methods and pharmaceutical compositions
provided. See, e.g., Emens, L. A., et al., Curr. Opinion Mol. Ther.
3(1):77-84 (2001).
[0066] Second active agents that are small molecules can also be
used to alleviate adverse effects associated with the
administration of SNS-595. However, like some large molecules, many
are believed to be capable of providing a synergistic effect when
administered with (e.g., before, after or simultaneously) SNS-595.
Examples of small molecule second active agents include, but are
not limited to, anti-cancer agents, antibiotics, immunosuppressive
agents, and steroids. Examples of chemotherapeutic anticancer
agents that may be used as second active agents in combination with
SNS-595 include, but are not limited to, alkylating agents (e.g.,
mechlorethamine, chlorambucil, cyclophosphamide, melphalan,
ifosfamide), antimetabolites (e.g., methotrexate), purine
antagonists and pyrimidine antagonists (e.g., 6-mercaptopurine,
5-fluorouracil, cytarabine, capecitabine, decitabine, gemcitabine),
spindle poisons (e.g., vinblastine, vincristine, vinorelbine,
paclitaxel), podophyllotoxins (e.g., etoposide, irinotecan,
topotecan), antibiotics (e.g., doxorubicin, daunorubicin,
bleomycin, mitomycin), nitrosoureas (e.g., carmustine, lomustine),
inorganic ions (e.g., platinum complexes such as cisplatin,
carboplatin), enzymes (e.g., asparaginase), hormones (e.g.,
tamoxifen, leuprolide, flutamide, and megestrol), EGFR (Her1,
ErbB-1) inhibitors (e.g., gefitinib), antibodies (e.g., rituximab),
IMIDs (e.g., thalidomide, lenalidomide), various targeted agents
(e.g., HDAC inhibitors such as vorinostat), Bcl-2 inhibitors, VEGF
inhibitors); proteasome inhibitors (e.g., bortezomib) and
dexamethasone.
[0067] Examples of anti-cancer agents to be used within the methods
or compositions described herein include, but are not limited to:
acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; alitretinoin (e.g., Panretin.RTM.); altretamine
(hexamethylmelamine; e.g., Hexylen.RTM.); ambomycin; ametantrone
acetate; aminoglutethimide (e.g., Cytadren.RTM.); amonafide malate
(e.g., Xanafide.RTM.); amsacrine; anastrozole (e.g.,
Arimidex.RTM.); anthramycin; asparaginase (e.g., Kidrolase.RTM.,
Elspar.RTM.); asperlin; azacitidine (e.g., Vidaza.RTM.); azetepa;
azotomycin; batimastat; benzodepa; bexarotene (e.g.,
Targetin.RTM.); bicalutamide (e.g., Casodex.RTM.); bisantrene
hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate
(e.g., Blenoxane.RTM.); bortezomib (e.g., Velcade.RTM.); brequinar
sodium; bropirimine; busulfan (e.g., Busulfex.RTM., Myleran.RTM.);
cactinomycin; calusterone; capecitabine (e.g., Xeloda.RTM.);
caracemide; carbetimer; carmustine (e.g., BiCNU.RTM.); carmustine
implant (e.g., Gliadel.RTM. wafer); carubicin hydrochloride;
carboplatin (e.g., Paraplatin.RTM.); carzelesin; cedefingol;
celecoxib (COX-2 inhibitor, e.g., Celebrex.RTM.); chlorambucil
(e.g., Leukeran.RTM.); cirolemycin; cisplatin (e.g.,
Platinol.RTM.); cladribine (e.g., Leustatin.RTM.); clofarabine;
cloretazine; crisnatol, crisnatol mesylate; cyclophosphamide (e.g.,
Cytoxan.RTM., Neosar.RTM.); 4-hydroperoxycyclophosphamide;
dacarbazine (e.g., DTIC-Dome.RTM.); dactinomycin (e.g.,
Cosmegen.RTM.); dasatanib (e.g., Sprycel.RTM.); daunorubicin
hydrochloride (e.g., Cerubidine.RTM.), liposomal daunorubicin
citrate (e.g., DaunoXome.RTM.); decitabine (e.g., Dacogen.RTM.);
denileukin diftitox (e.g., Ontak.RTM.); dexormaplatin; dezaguanine,
dezaguanine mesylate; diaziquone; doxorubicin, doxorubicin
hydrochloride (e.g., Adriamycin.RTM.), liposomal doxorubicin
hydrochloride (e.g., Doxil.RTM.); droloxifene, droloxifene citrate;
dromostanolone propionate; duazomycin; edatrexate; eflornithine,
eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate;
epipropidine; epirubicin hydrochloride (e.g., Ellence.RTM.);
erbulozole; erlotinib (e.g., Tarceva.RTM.); esorubicin
hydrochloride; estramustine, estramustine phosphate sodium (e.g.,
Emcyt.RTM.), estramustine analogues; etanidazole; etoposide (VP-16;
e.g., Toposar.RTM.), etoposide phosphate (e.g., Etopophos.RTM.);
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine (e.g., FUDR.RTM.); fludarabine, fludarabine phosphate
(Fludara.RTM.); fluorocitabine; 5-fluorouracil (e.g.,
Adrucil.RTM.); flutamide (e.g., Eulexin.RTM.); fosquidone;
fostriecin, fostriecin sodium; gefitinib (e.g., Iressa.RTM.);
gemcitabine hydrochloride (e.g., Gemzar.RTM.); goserelin acetate
(Zoladex.RTM.); hydroxyurea (e.g., Droxia.RTM., Hydrea.RTM.);
idarubicin, idarubicin hydrochloride (e.g., Idamycin.RTM.);
ifosfamide (e.g., Ifex.RTM.); ilmofosine; iproplatin; irinotecan
(CPT-11, camptothecin-11), irinotecan hydrochloride (e.g.,
Camptosar.RTM.); lanreotide, lanreotide acetate; lapatinib (e.g.,
Tykerb.RTM.); lenalidomide (e.g., Revlimid.RTM.); letrozole (e.g.,
Femara.RTM.); leuprolide acetate (e.g., Eligard.RTM., Viadur.RTM.);
liarozole, liarozole hydrochloride; lometrexol, lometrexol sodium;
lomustine (e.g., CeeNu.RTM.); losoxantrone, losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine (nitrogen
mustard, mustine), mechlorethamine hydrochloride (e.g.,
Mustargen.RTM.); megestrol acetate (e.g., Megace.RTM.);
melengestrol acetate; melphalan (e.g., Alkeran.RTM.); menogaril;
mercaptopurine (e.g., Purinethol.RTM.); methotrexate sodium (e.g.,
Rheumatrex.RTM.); metoprine; meturedepa; mitindomide; mitocarcin;
mitocromin; mitogillin; mitomalcin; mitomycin (Mutamycin.RTM.),
mitomycin analogues; mitosper; mitotane; mitoxantrone, mitoxantrone
hydrochloride (e.g., Novantrone.RTM.); mycophenolic acid;
nelarabine (Arranon.RTM.); nocodazole; nogalamycin; ormaplatin;
oxisuran; paclitaxel (e.g., Taxol.RTM.); paclitaxel protein-bound
(e.g., Abraxane.RTM.); pegaspargase (PEG-L-asparaginase; e.g.,
Oncaspar.RTM.); peliomycin; pemetrexed (e.g., Alimta.RTM.);
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride (e.g., Matulane.RTM.); puromycin; puromycin
hydrochloride; pyrazofurin; R-roscovitine (seliciclib); riboprine;
safingol; safingol hydrochloride; semustine; simtrazene; sorafenib
(e.g., Nexavar.RTM.); sparfosate sodium; sparsomycin;
spirogermanium hydrochloride; spiromustine; spiroplatin;
streptonigrin; streptozocin (e.g., Zanosar.RTM.); sulofenur;
sunitinib malate (e.g., Sutent.RTM.); talisomycin; tecogalan
sodium; tegafur; teloxantrone hydrochloride; temoporfin;
temozolomide (e.g., Temodar.RTM.); teniposide (e.g., Vumon.RTM.);
teroxirone; testolactone; thalidomide (e.g., Thalomid.RTM.);
thiamiprine; thioguanidine; 6-thioguanine; thiotepa (e.g.,
Thioplex.RTM.); tiazofurin; tipifarnib (e.g., Zarnestra.RTM.);
tirapazamine; topotecan (e.g., Hycamtin.RTM.); toremifene,
toremifene citrate (e.g., Fareston.RTM.); trestolone acetate;
triciribine, triciribine phosphate; trimetrexate, trimetrexate
glucuronate; triptorelin; troxacitabine (e.g., Troxatyl.RTM.);
tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;
verteporfin; vinblastine sulfate (e.g., Velban.RTM.); vincristine
(leurocristine) sulfate (e.g., Vincasar.RTM.); vindesine, vindesine
sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine
sulfate; vinorelbine tartrate (e.g., Navelbine.RTM.); vinrosidine
sulfate; vinzolidine sulfate; vorinostat (e.g., Zolinza.RTM.);
vorozole; zeniplatin; zinostatin, zinostatin stimalamer; and
zorubicin (rubidazone) hydrochloride.
[0068] Other anti-cancer drugs to be included within the methods or
comprising include, but are not limited to:
20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone
acetate; acylfulvene, (hydroxymethyl)acylfulvene; adecypenol;
ALL-TK antagonists; ambamustine; amidox; amifostine; aminolevulinic
acid; amrubicin; anagrelide (e.g., Agrylin.RTM.); andrographolide;
angiogenesis inhibitors; antagonist D; antagonist G; antarelix;
anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic
carcinoma; antiestrogen; antineoplaston; antisense
oligonucleotides; aphidicolin glycinate; apoptosis gene modulators;
apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine
deaminase; arsenic trioxide (e.g., Trisenox.RTM.); asulacrine;
atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin
3; azasetron; azatoxin; azatyrosine; baccatin III derivatives;
balanol; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;
beta lactam derivatives; beta-alethine; betaclamycin B; betulinic
acid; bFGF inhibitor; bisantrene; bisaziridinylspermine; bisnafide;
bistratene A; brefeldin A or its prodrug breflate; budotitane;
buthionine sulfoximine; calcipotriol; calphostin C; camptothecin
derivatives (e.g., irinotecan); carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor; casein kinase inhibitors; castanospermine; cecropin B;
cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;
cis-porphyrin; clarithromycin (e.g., Biaxin.RTM.); clomifene
analogues; clotrimazole; collismycin A; collismycin B;
combretastatin A4, combretastatin analogues; conagenin;
crambescidin 816; cryptophycin 8; cryptophycin A derivatives;
curacin A; cyclopentanthraquinones; cycloplatam; cypemycin;
cytolytic factor; cytostatin; dehydrodidemnin B; deslorelin;
dexamethasone (e.g., Decadron.RTM.); dexifosfamide; dexrazoxane;
dexverapamil; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenyl;
docetaxel (e.g., Taxotere.RTM.); docosanol; doxifluridine;
duocarmycin SA; ebselen; ecomustine; edelfosine; elemene; emitefur;
epristeride; estrogen agonists; estrogen antagonists; exemestane
(e.g., Aromasin.RTM.); fadrozole; filgrastim; finasteride;
flavopiridol (alvocidib); flezelastine; fluasterone;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine;
ganciclovir; ganirelix; gelatinase inhibitors; glutathione
inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide;
hypericin; ibandronic acid; idoxifene; idramantone; ilomastat;
imatinib mesylate (e.g., Gleevec.RTM.); imiquimod (e.g.,
Aldara.RTM.), and other cytokine inducers; immunostimulant
peptides; insulin-like growth factor-1 receptor inhibitor;
interferon agonists; interferons such as interferon alpha (e.g.,
Intron.RTM. A); pegylated interferon alfa-2b (e.g., PegInton.RTM.);
interleukins such as IL-2 (aldesleukin, e.g., Proleukin.RTM.);
iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; jasplakinolide; kahalalide F;
lamellarin-N triacetate; leinamycin; lenograstim; lentinan sulfate;
leptolstatin; leukemia inhibiting factor; leukocyte alpha
interferon; leuprolide+estrogen+progesterone; leuprorelin;
levamisole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lonidamine; loxoribine; lurtotecan;
lutetium texaphyrin; lysofylline; lytic peptides; maitansine;
mannostatin A; marimastat; maspin; matrilysin inhibitors; matrix
metalloproteinase inhibitors; merbarone; meterelin; methioninase;
metoclopramide; MIF inhibitor; mifepristone (e.g., Mifepre.RTM.);
miltefosine; mirimostim; mitoguazone; mitolactol; mitonafide;
mitotoxin fibroblast growth factor-saporin; mofarotene; human
chorionic gonadotrophin; monophosphoryl lipid A+mycobacterium cell
wall sk; mopidamol; mustard anticancer agent; mycaperoxide B;
mycobacterial cell wall extract; myriaporone; N-acetyldinaline;
N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic acid; nilutamide (e.g.,
Nilandron.RTM.); nisamycin; nitric oxide modulators; nitroxide
antioxidants (e.g., tempol); nitrullyn; oblimersen
(Genasense.RTM.); O6-benzylguanine; octreotide (e.g.,
Sandostatin.RTM.); octreotide acetate (e.g., Sandostatin LAR.RTM.);
okicenone; oligonucleotides; onapristone; oracin; osaterone;
oxaliplatin (e.g., Eloxatin.RTM.); oxaunomycin; paclitaxel
analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin;
panaxytriol; panomifene; parabactin; pazelliptine; peldesine;
pentosan polysulfate sodium; pentostatin (e.g., Nipent.RTM.);
pentrozole; perflubron; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
plasminogen activator inhibitor; platinum-triamine complex; propyl
bis-acridone; prostaglandin J2; proteasome inhibitors; protein
A-based immune modulator; protein kinase C inhibitors, including
microalgal PKC inhibitors; protein tyrosine phosphatase inhibitors;
purine nucleoside phosphorylase inhibitors; purpurins;
pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene
conjugate; raf antagonists; raltitrexed (e.g., Tomudex.RTM.); ras
farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP
inhibitor; retelliptine demethylated; rhenium (.sup.186Re)
rhizoxin; ribozymes; RII retinamide; rohitukine; romurtide;
roquinimex; rubiginone B1; ruboxyl; saintopin; SarCNU; sarcophytol
A; Sdi 1 mimetics; senescence derived inhibitor 1; sense
oligonucleotides; signal transduction inhibitors; sizofuran;
sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol;
somatomedin binding protein; sonermin; sparfosic acid; spicamycin
D; splenopentin; spongistatin 1; squalamine; steroids (e.g.,
prednisone, prednisolone); stipiamide; stromelysin inhibitors;
sulfinosine; sulindac; superactive vasoactive intestinal peptide
antagonist; suradista; suramin; swainsonine; tallimustine;
tamoxifen, tamoxifen citrate (e.g., Nolvadex.RTM.), tamoxifen
methiodide; tauromustine; tazarotene; tellurapyrylium; telomerase
inhibitors; tetrachlorodecaoxide; tetrazomine; thaliblastine;
thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin;
thymopoietin receptor agonist; thymotrinan; thyroid stimulating
hormone; tin ethyl etiopurpurin; titanocene bichloride; topsentin;
translation inhibitors; tretinoin (all-trans retinoic acid, e.g.,
Vesanoid.RTM.); triacetyluridine; turosteride; tyrosine kinase
inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital
sinus-derived growth inhibitory factor; urokinase receptor
antagonists; variolin B; velaresol; veramine; verdins; vinxaltine;
vitaxin; zanoterone; and zilascorb.
[0069] Specific second active agents useful in the methods or
compositions include, but are not limited to, rituximab, oblimersen
(Genasense.RTM.), infliximab (Remicade.RTM.), docetaxel, celecoxib,
melphalan, dexamethasone (Decadron.RTM.), steroids, gemcitabine,
cisplatinum, temozolomide, etoposide, cyclophosphamide,
temozolomide (Temodar.RTM.), carboplatin, procarbazine, gliadel,
tamoxifen, topotecan, methotrexate, paclitaxel (Taxol.RTM.),
taxotere, 5-fluorouracil, leucovorin, irinotecan, capecitabine
(Xeloda.RTM.), CPT-11, interferon alpha, pegylated interferon alpha
(e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa,
fludarabine, carboplatin, liposomal daunorubicin, cytarabine,
vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic
acid, palmitronate, biaxin, busulphan, prednisone, bisphosphonate,
arsenic trioxide, vincristine, doxorubicin (Doxil.RTM.),
ganciclovir, adriamycin, estramustine sodium phosphate
(Emcyt.RTM.), sulindac, and etoposide.
[0070] In certain embodiments, the first active agent is SNS-595
and the second active agent is etoposide, daunomycin, actinomycin
D, mitomycin C, cisplatin, carboplatin, premetrexed, methotrexate,
cytarabine, 5-fluorouracil, wortmannin, geldanamycin, gemcitabine
or a combination thereof.
[0071] In certain embodiments, the second active agent is an
antileukemic nucleoside, such as cytarabine and/or decitabine
and/or troxacitabine. In some embodiments, the nucleoside is
cytarabine. In certain embodiments, cytarabine can be administered
simultaneously or sequentially with SNS-595. In certain
embodiments, SNS-595 and cytarabine are used in combination methods
that may also include the use of one or more other therapies
including, but not limited to, other anti-cancer agents,
anti-emetics and the like. In other embodiments, the second active
agent is a supportive care agent, such as an antiemetic agent or a
myeloid growth factor. Specific antiemetic agents include, but are
not limited to, phenothiazines, butyrophenones, benzodiazapines,
corticosteroids, serotonin antagonists, cannabinoids, and NK1
receptor antagonists. Examples of phenothiazine antiemetic agents
include, but are not limited to, prochlorperazine and
trimethobenzamide. Examples of butyrophenone antiemetic agents
include, but are not limited to, haloperidol. Examples of
benzodiazapine antiemetic agents include, but are not limited to,
lorazepam. Examples of corticosteroid antiemetic agents include,
but are not limited to, dexamethasone. Examples of serotonin
receptor (5-HT3 receptor) antagonist antiemetic agents include, but
are not limited to, dolasetron mesylate (e.g., Anzemet.RTM.),
granisetron (e.g., Kytril.RTM.), itasetron, ondansetron (e.g.,
Zofran.RTM.), palonosetron (e.g., Aloxi.RTM.) ramosetron,
tropisetron (e.g., Navoban.RTM.), batanopride, dazopride,
renzapride. Examples of cannabinoid antiemetic agents include, but
are not limited to, dronabinol. Examples of NK1 receptor
antagonists include, but are not limited to, aprepitant (e.g.,
Emend.RTM.).
[0072] Other supportive care agents include myeloid growth factors
that stimulate erythropoiesis or other hematopoietic processes,
such as epoetin alfa (e.g., Epogen.RTM., Procrit.RTM.); G-CSF and
recombinant forms such as filgrastim (e.g., Neupogen.RTM.),
pegfilgrastim (e.g., Neulasta.RTM.), and lenofilgrastim;
darbepoetin alfa (e.g., Aranesp.RTM.); and GM-CSF and recombinant
forms such as sargramostim (e.g., Leukine.RTM.) or molgramostim
(e.g., Leucomax.RTM.). Recombinant and mutated forms of GM-CSF can
be prepared as described in U.S. Pat. Nos. 5,391,485; 5,393,870;
and 5,229,496; the entireties of which are incorporated herein by
reference. Recombinant and mutated forms of G-CSF can be prepared
as described in U.S. Pat. Nos. 4,810,643; 4,999,291; 5,528,823; and
5,580,755; the entireties of which are incorporated herein by
reference.
[0073] Other supportive care agents include chemoprotectant agents
such as amifostine (e.g., Ethyol.RTM.), dexrazoxane (e.g.,
Zinecard.RTM.), leucovorin (folinic acid), and mesna (e.g.,
Mesnex.RTM.); thrombopoeitic growth factors such as interleukin-11
(IL-11, oprelvekin, e.g., Neumega.RTM.); bisphosphonates such as
pamidronate disodium (e.g., Aredia.RTM.), etidronate disodium
(e.g., Didronel.RTM.) and zoledronic acid (e.g., Zometa.RTM.); and
TNF antagonists, such as infliximab (e.g., Remicade.RTM.).
[0074] In certain embodiments of the methods provided herein, use
of a second active agent in combination with SNS-595 may be
modified or delayed during or shortly following administration of
SNS-595 as deemed appropriate by the practitioner of skill in the
art. In certain embodiments, subjects being administered SNS-595
alone or in combination with other therapies may receive supportive
care including antiemetics, myeloid growth factors, and
transfusions of platelets, when appropriate.
[0075] In some embodiments, subjects being administered SNS-595 may
be administered a growth factor as a second active agent according
to the judgment of the practitioner of skill in the art. In some
embodiments, provided is administration of SNS-595 in combination
with erythropoietin or darbepoetin. Again, the method includes the
use of these agents with the addition of others such as cytarabine.
In certain embodiments, administration of erythropoietin or
darbepoetin is delayed during administration of SNS-595, cytarabine
or both. In certain embodiments, erythropoietin or darbepoetin is
administered during administration of SNS-595, for instance when
the subject presents anemia or severe anemia. In some embodiments,
administration of prophylactic GM-CSF, sargramostim, molgramostim,
G-CSF, filgrastim, or pegfilgrastim is delayed during one or more
administrations of SNS-595. In certain embodiments, administration
of prophylactic GM-CSF, sargramostim, molgramostim, G-CSF,
filgrastim, or pegfilgrastim is permitted after administration of
SNS-595, for instance, in a subject experiencing neutropenia or
recurrent neutropenia. In certain embodiments, a myeloid growth
factor may be administered in combination with SNS-595, for
instance in a subject with a serious neutropenic complications,
such as tissue infection, sepsis syndrome, or fungal infection, or
at the discretion of the skilled practitioner.
[0076] In certain embodiments, administration of SNS-595 is
performed in combination with one or more supportive care
treatment(s) to mitigate or prevent tumor lysis syndrome or its
component symptoms. Treatments suitable for preventing or
mitigating TLS (or any of the symptoms thereof, including
hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and
acute renal failure), include, for example, allopurinol (e.g.,
Zyloprim.RTM.), rasburicase (e.g., Elitek.RTM.), and sodium
polystyrene sulfonate (e.g., Kayexalate.RTM.). Leukapheresis may be
performed, for example, up to 72 hours after the first treatment
with SNS-595.
[0077] Doses and dosing regimens of SNS-595 together with other
active moieties and combinations thereof should depend on the
specific indication being treated, the age and condition of a
patient, and the severity of adverse effects, and may be adjusted
accordingly by those of skill in the art. Examples of conventional
doses and dosing regimens for other active moieties can be found,
for example, in Physicians' Desk Reference, and will require
adaptation for use in the methods provided herein.
[0078] Methods of Treatment and Prevention
[0079] The methods provided herein encompass treating, preventing,
or managing antecedent hematological disorders in a subject, for
example, myelodysplastic syndromes, including refractory anemia
(RA), RA with ringed sideroblasts (RARS), RA with excess blasts
(RAEB), RAEB in transformation (RAEB-T), and CMML. In some
embodiments, the myelodysplastic syndrome is refractory anemia
(RA). In some embodiments, the myelodysplastic syndrome is
refractory anemia with ringed sideroblasts (RARS). In some
embodiments, the myelodysplastic syndrome is refractory anemia with
excess blasts (RAEB). In some embodiments, the myelodysplastic
syndrome is refractory anemia in transformation (RAEB-T). In some
embodiments, the myelodysplastic syndrome is CMML.
[0080] In certain embodiments, myelodysplastic syndrome or MDS is
characterized by one or more of the following: ineffective blood
cell production, progressive cytopenias, risk of progression to
acute leukemia or cellular marrow with impaired morphology and
maturation (dysmyelopoiesis). The symptoms associated with MDS
include, but are not limited to, anemia, thrombocytopenia,
neutropenia, cytopenia, bicytopenia (two deficient cell types), and
pancytopenia (three deficient cell types).
[0081] In certain embodiments, the method of treating, preventing,
or managing MDS comprises the step of administering to the subject
a therapeutically effective amount of an enantiomerically pure
(+)-1,4-dihydro-7-[(3S,4S)-3-methoxy-4-(methylamino)-1-pyrrolidinyl]-4-ox-
o-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acid (SNS-595). In
certain embodiments, the method of treating MDS encompasses
administration of the compound after the onset of symptoms of MDS.
In certain embodiments, the method of preventing MDS encompasses
administration prior to the onset of symptoms, particularly to
patients at risk of MDS.
[0082] Further provided are methods of treating or preventing
patients with primary and secondary MDS. The methods further
encompass treating patients who have been previously treated for
MDS, as well as those who have not previously been treated for MDS.
Because patients with MDS have heterogeneous clinical
manifestations and varying clinical outcomes, it has become
apparent that staging the patients according to their prognosis and
approaching therapy depending on the severity and stage is
necessary. The methods and compositions provided herein are useful
in various stages of treatments for patients with one or more types
of MDS including, but not limited to, refractory anemia (RA), RA
with ringed sideroblasts (RARS), RA with excess blasts (RAEB), RAEB
in transformation (RAEB-T), or CMML. In one embodiment, the methods
encompass treating patients diagnosed using the IPSS for MDS
discussed above. Greenberg et al., Blood 1997 (89):2079-88.
[0083] In some embodiments, the methods comprise administering to
the subject a therapeutically effective amount of SNS-595 in
combination with a therapeutically effective amount of a second
active agent. In some embodiments, the second active agent is a
therapeutic antibody to a cancer antigen, a hematopoietic growth
factor, a cytokine, an anti-cancer agent, an antibiotic, a cox-2
inhibitor, an immunomodulatory agent, an immunosuppressive agent, a
corticosteroid, or a pharmacologically active mutant or derivative
thereof. In other embodiments, the second active agent is an
alkylating agent, an anti-neoplastic antibiotic, an
anti-metabolite, a platinum coordination complex, a topoisomerase
II inhibitor or poison, a CDK inhibitor, an aurora kinase
inhibitor, or radiation. In other embodiments, the second active
agent is etoposide, daunomycin, actinomycin D, mitomycin C,
cisplatin, carboplatin, premetrexed, methotrexate, cytarabine,
5-Fu, wortmannin, geldanamycin, gemcitabine or a combination
thereof. In a particular embodiment, the second active agent is
cytarabine, which may be administered as cytarabine (e.g.,
Cytosar.RTM.), cytarabine liposomal (e.g., DepoCyt.RTM.),
cytarabine ocfosfate, or other formulations of the active
moiety.
[0084] In some embodiments, the methods provided herein encompass
treating preventing or managing CMML in a subject. The methods
comprise the step of administering to the subject an amount of
SNS-595 effective to treat, prevent or manage CMML. In some
embodiments, the methods comprise the step of administering to the
subject SNS-595 in combination with a second active agent in
amounts effective to treat, prevent or manage CMML. In a particular
embodiment, the second active agent is cytarabine.
[0085] 5.1.1 Subjects
[0086] In certain embodiments of the methods provided herein, the
subject is an animal, preferably a mammal, more preferably a
non-human primate. In particular embodiments, the subject is a
human. The subject can be a male or female subject.
[0087] Particularly, subjects for the methods provided herein
include patients suffering from antecedent hematological disorders,
such as myelofibrosis, aplastic anemia, paroxysmal nocturnal
hemoglobinuria, polycythemia vera, or myelodysplastic syndrome. The
methods are particularly useful in the treatment of subjects
afflicted with a myelodysplastic syndrome, including the disorders:
refractory anemia (RA); refractory anemia with ring sideroblasts
(RARS); refractory anemia with excess of blasts (RAEB); and CMML.
In a particular embodiment, the subject suffers from CMML. In
certain embodiments, CMML is refractory to and/or relapsed from
prior therapy.
[0088] In some embodiments, the subject is treated according to the
methods provided herein following a diagnosis of MDS according to
any diagnostic criteria known to the skilled practitioner of the
art. In some embodiments, the subject has been diagnosed with MDS
according to the French-American-British (FAB) classification
system. In a particular embodiment, the subject has been diagnosed
with CMML under the FAB classification system. In some embodiments,
the subject has been diagnosed with MDS according to the WHO
proposed system of MDS classification. In some embodiments, the
subject has been determined to be at risk for MDS according to the
International Prognostic Scoring System (IPSS) for myelodysplastic
syndrome. In a particular embodiment, the subject has a score of
INT-2 or higher according to the IPSS scoring system.
[0089] In certain embodiments, the methods provided herein
encompass the treatment of subjects who have not been previously
treated for leukemia. In some embodiments, the subject has not
undergone allogeneic bone marrow transplantation. In some
embodiments, the subject has not undergone a stem cell
transplantation. In some embodiments, the subject has not received
hydroxyurea treatment. In some embodiments, the subject has not
been treated with any investigational products for leukemia. In
some embodiments, the subject has not been treated with systemic
glucocorticoids.
[0090] In other embodiments, the methods encompass treating
subjects who have been previously treated or are currently being
treated for leukemia. For example, the subject may have been
previously treated or are currently being treated with a standard
treatment regimen for leukemia. In some embodiments, the subject
has undergone autologous bone marrow transplantation or stem cell
transplantation. In some embodiments, the bone marrow or stem cell
transplantation occurred at least 3 months prior to treatment
according to the methods provided herein. In some embodiments, the
subject has undergone hydroxyurea treatment. In some embodiments,
the hydroxyurea treatment occurred no later than 24 hours prior to
treatment according to the methods provided herein. In some
embodiments, the subject has undergone treatment with one or more
of the following drugs: 5-azacytidine (Vidaza.RTM.), decitabine and
lenalidomide (Revlimi.RTM.). In some embodiments, the subject has
undergone prior induction or consolidation therapy with cytarabine.
In some embodiments, the subject has undergone treatment with
systemic glucocorticosteroids. In some embodiments, the
glucocorticosteroid treatment occurred no later 24 hours prior to
treatment according to the methods described herein. In other
embodiments, the methods encompass treating subjects who have been
previously treated for cancer, but are non-responsive (i.e., their
conditions may be refractory and/or resistant) to standard
therapies. For example, the subject may have been treated with an
anticancer agent such as alemtuzumab; azacitabine; bortezomib;
cyclophosphamide; cytarabine; decitabine; dexamethasone;
doxorubicin; pegylated doxorubicin; liposomal doxorubicin;
fludarabine; galiximab; lenalinomide; melphalan; prednisone;
rituximab; thalidomide; or vincristine, or with a combination of
anticancer agents such as fludarabine and alemtuzumab; fludarabine
and cyclophosphamide; fludarabine, cyclophosphamide, and rituximab;
fludarabine and rituximab; cyclophosphamide, vincristine, and
prednisone; cyclophosphamide, vincristine, prednisone, and
rituximab; melphalan and prednisone; melphalan, prednisone and
thalidomide; or other combinations of such agents. The subject may
have been treated with any standard leukemia treatment regimen
known to the practitioner of skill in the art.
[0091] In some embodiments, the subject has not previously
undergone treatment with SNS-595. In some embodiments, the subject
has not previously undergone treatment with cytarabine. In some
embodiments, the subject has not previously undergone treatment
with SNS-595 in combination with a second active agent. In some
embodiments, the subject has not previously undergone treatment
with SNS-595 in combination with cytarabine. In other embodiments,
the subject has previously undergone treatment with SNS-595. In
some embodiments, the subject has previously undergone treatment
with cytarabine. In some embodiments, the subject has previously
undergone treatment with SNS-595 in combination with a second
active agent. In some embodiments, the subject has previously
undergone treatment with SNS-595 in combination with
cytarabine.
[0092] Also encompassed are methods of treating a subject
regardless of the subject's age, although some diseases or
disorders are more common in certain age groups. In some
embodiments, the subject is at least 18 years old. In some
embodiments, the subject is more than 18, 25, 35, 40, 45, 50, 55,
65, 70, 75, 80 or 85 years old. In one embodiment, the subject is
more than 80 years old. In other embodiments, the subject is less
than 65 years old. In some embodiments, the subject is less than 18
years old. In some embodiments, the subject is less than 18, 15,
12, 10, 9, 8 or 7 years old.
[0093] In some embodiments, the methods find use in subjects at
least 50 years of age, although younger subjects could benefit from
the method as well. In other embodiments, the subjects are at least
55, at least 60, at least 65, and at least 70 years of age. In
another embodiment, the subjects have adverse cytogenetics.
"Adverse cytogenetics" is defined as any nondiploid karyotype, or
greater than or equal to 3 chromosomal abnormalities. In another
embodiment, the subjects are at least 60 years of age and have
adverse cytogenetics. In another embodiment, the subjects are 60-65
years of age and have adverse cytogenetics. In another embodiment,
the subjects are 65-70 years of age and have adverse cytogenetics.
In some embodiments, subjects in this paragraph are administered a
low dose of cytarabine as described herein.
[0094] In certain embodiments, the subject treated has no history
of myocardial infarction within three months of treatment according
to the methods provided herein. In some embodiments, the subject
has no history of cerebrovascular accident or transient ischemic
attack within three months of treatment according to the methods
provided herein. In some embodiments, the subject has suffered no
thromboembolic event, including deep vein thrombosis or pulmonary
embolus, within 28 days of treatment according to the methods
provided herein. In other embodiments, the subject has not
experienced or is not experiencing uncontrolled disseminated
intravascular coagulation.
[0095] Because subjects with antecedent hematologic disorders, such
as MDS, have heterogeneous clinical manifestations and varying
clinical outcomes, the treatment given to a patient may vary,
depending on his/her prognosis. The skilled clinician will be able
to readily determine without undue experimentation specific
secondary agents, types of surgery, and types of non-drug based
standard therapies that can be effectively used to treat an
individual subject according to the invention.
[0096] 5.1.2 Combination Therapy with a Second Active Agent
[0097] In certain embodiments, the methods provided herein comprise
administering SNS-595 in combination with one or more second active
agents, and/or in combination with radiation therapy, blood
transfusions, or surgery. The administration of SNS-595 and the
second active agents to a patient can occur simultaneously or
sequentially by the same or different routes of administration. The
suitability of a particular route of administration employed for a
particular active agent will depend on the active agent itself
(e.g., whether it can be administered orally without decomposing
prior to entering the blood stream) and the disease being treated.
Recommended routes of administration for the second active agents
are known to those of ordinary skill in the art. See, e.g.,
Physicians' Desk Reference, 1755-1760 (56.sup.th ed., 2002).
[0098] In one embodiment, the second active agent is administered
intravenously or subcutaneously and once or twice daily in an
amount of from about 1 to about 1,500 mg/m.sup.2, from about 5 to
about 1,500 mg/m.sup.2, from about 1 to about 1,000 mg, from about
5 to about 500 mg, from about 10 to about 375 mg, or from about 50
to about 200 mg.
[0099] The second active agent may be administered simultaneously,
at essentially the same time, or sequentially with SNS-595. If such
administration is conducted sequentially, second active agent may
be administered before or after administration of SNS-595. In some
embodiments, the second active agent is administered before
administration of SNS-595. In some embodiments, the second active
agent is administered simultaneously with administration of
SNS-595. In some embodiments, the second active agent is
administered after the administration of SNS-595. SNS-595 and the
second active agent need not be administered by means of the same
vehicle. In some embodiments, the second active agent and SNS-595
are administered in different vehicles. In embodiments of the
methods described herein where delivery of SNS-595 and the second
active agent are both by an intravenous route of administration,
administration of each component of the combination need not be
administered in the same IV line. In some embodiments, SNS-595 is
administered in a different IV line than the second active agent.
The second active agent may be administered one or more times, and
the number of administrations of each component of the combination
may be the same or different. In addition, SNS-595 and the second
active agent need not be administered at the same site.
[0100] In other embodiments, provided herein are methods of
treating, preventing and/or managing antecedent hematologic
disorders, which comprise administering SNS-595 in conjunction with
(e.g., before, during, or after) conventional therapy including,
but not limited to, surgery, immunotherapy, biological therapy,
radiation therapy, or other non-drug based therapy presently used
to treat, prevent or manage cancer. Without being limited by
theory, it is believed that SNS-595 may provide additive or
synergistic effects when given concurrently with other anti-cancer
therapy.
[0101] In one embodiment, SNS-595 can be administered in an amount
of from about 1 to about 150 mg/m.sup.2, about 1 to about 120
mg/m.sup.2, about 1 to about 100 mg/m.sup.2, about 1 to about 75
mg/m.sup.2, about 1 to about 60 mg/m.sup.2, about 1 to about 50
mg/m.sup.2, alone, or in combination with a second active agent
disclosed herein, prior to, during, or after the use of
conventional therapy. In another specific embodiment, SNS-595 is
administered at a dose of about 5 to about 50 mg/m.sup.2 or about
10 to about 40 mg/m.sup.2, or about 10 to about 90 mg/m.sup.2.
[0102] In another embodiment, the methods provided herein comprise:
a) administering to a patient in need thereof, a dose of about
1-150 mg/m.sup.2 of SNS-595 and b) administering a therapeutically
effective amount of a supportive care agent. Such support care
agents are known in the art, for example, see, U.S. Application
Publication No. 2006/0025437, which is incorporated by reference in
its entirety.
[0103] In certain embodiments, the combination dosing of SNS-595
and cytarabine is used together as well with supportive care agents
or other auxillary therapies. While not intending to be bound by
any particular theory of operation, it is believed that SNS-595 and
cytarabine can act synergistically in the methods provided herein.
Exemplary dosing schedules for the combination dosing of SNS-595
and cytarabine are provided below.
[0104] Pharmaceutical Compositions and Dosage Forms
[0105] The methods provided herein use pharmaceutical compositions
containing SNS-595 and pharmaceutically acceptable carriers, such
as diluents or adjuvants, or in combination with other active
ingredient, such as another anti-cancer agent. In clinical practice
SNS-595 may be administered by any conventional route, including
but not limited to orally, parenterally, rectally or by inhalation
(e.g., in the form of aerosols). In one embodiment, SNS-595 is
administered by an IV injection.
[0106] The compositions for parenteral administration can be
emulsions or sterile solutions. Use may be made, as solvent or
vehicle, of propylene glycol, a polyethylene glycol, vegetable
oils, in particular olive oil, or injectable organic esters, for
example, ethyl oleate. These compositions can also contain
adjuvants, in particular wetting, isotonizing, emulsifying,
dispersing and stabilizing agents. Sterilization can be carried out
in several ways, for example, using a bacteriological filter, by
radiation or by heating. They can also be prepared in the form of
sterile solid compositions which can be dissolved at the time of
use in sterile water or any other injectable sterile medium.
[0107] The compositions can also be aerosols. For use in the form
of liquid aerosols, the compositions can be stable sterile
solutions or solid compositions dissolved at the time of use in
apyrogenic sterile water, in saline or any other pharmaceutically
acceptable vehicle. For use in the form of dry aerosols intended to
be directly inhaled, the active principle is finely divided and
combined with a water-soluble solid diluent or vehicle, for example
dextran, mannitol or lactose.
[0108] Pharmaceutical compositions can be used in the preparation
of individual, single unit dosage forms. Pharmaceutical
compositions and dosage forms comprise SNS-595 and one or more
excipients.
[0109] Pharmaceutical compositions and dosage forms can also
comprise one or more additional active ingredients. Examples of
optional second, or additional, active ingredients are disclosed
herein.
[0110] In certain embodiments, a composition provided herein is a
pharmaceutical composition or a single unit dosage form.
Pharmaceutical compositions and single unit dosage forms provided
herein comprise a prophylactically or therapeutically effective
amount of SNS-595, and typically one or more pharmaceutically
acceptable carriers or excipients. The term "carrier" refers to a
diluent, adjuvant (e.g., Freund's adjuvant (complete and
incomplete)), excipient, or vehicle with which the therapeutic is
administered. Such pharmaceutical carriers can be sterile liquids,
such as water and oils, including those of petroleum, animal,
vegetable or synthetic origin, such as peanut oil, soybean oil,
mineral oil, sesame oil and the like. In certain embodiments, water
is a carrier when the pharmaceutical composition is administered
intravenously. Saline solutions and aqueous dextrose and glycerol
solutions can also be employed as liquid carriers, particularly for
injectable solutions. Examples of suitable pharmaceutical carriers
are described in Remington: The Science and Practice of Pharmacy,
21st edition, Lippincott, Williams and Wilkins, Baltimore, Md.
(2005), the contents of which are hereby incorporated by reference
in their entirety.
[0111] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well-known
to those skilled in the art of pharmacy, and non limiting examples
of suitable excipients include starch, glucose, lactose, sucrose,
gelatin, malt, rice, flour, chalk, silica gel, sodium stearate,
glycerol monostearate, talc, sodium chloride, dried skim milk,
glycerol, propylene, glycol, water, ethanol and the like. Whether a
particular excipient is suitable for incorporation into a
pharmaceutical composition or dosage form depends on a variety of
factors well known in the art including, but not limited to, the
way in which the dosage form will be administered to a subject and
the specific active ingredients in the dosage form. The composition
or single unit dosage form, if desired, can also contain minor
amounts of wetting or emulsifying agents, or pH buffering
agents.
[0112] Further provided herein are pharmaceutical compositions and
dosage forms that comprise one or more compounds that reduce the
rate by which an active ingredient will decompose. Such compounds,
which are referred to herein as "stabilizers," include, but are not
limited to, antioxidants such as ascorbic acid, pH buffers, or salt
buffers.
[0113] The pharmaceutical compositions and single unit dosage forms
can take the form of solutions, suspensions, emulsion, powders and
the like. Such compositions and dosage forms will contain a
prophylactically or therapeutically effective amount of a
prophylactic or therapeutic agent, in certain embodiments, in
purified form, together with a suitable amount of carrier so as to
provide the form for proper administration to the subject. The
formulation should suit the mode of administration. In one
embodiment, the pharmaceutical compositions or single unit dosage
forms are sterile and in suitable form for administration to a
subject, such as a mammalian subject, such an animal subject, or in
particular a human subject.
[0114] A pharmaceutical composition provided herein is formulated
to be compatible with its intended route of administration.
Examples of routes of administration include, but are not limited
to, parenteral, e.g., intravenous, intradermal, subcutaneous,
intramuscular, subcutaneous, inhalation, intranasal, transdermal,
topical, transmucosal, intra-tumoral, intra-synovial and rectal
administration. In a specific embodiment, the composition is
formulated in accordance with routine procedures as a
pharmaceutical composition adapted for intravenous, subcutaneous,
intramuscular, intranasal or topical administration to human
beings. In one embodiment, a pharmaceutical composition is
formulated in accordance with routine procedures for subcutaneous
administration to human beings. Typically, compositions for
intravenous administration are solutions in sterile isotonic
aqueous buffer. Where necessary, the composition may also include a
solubilizing agent and a local anesthetic such as lignocaine to
ease pain at the site of the injection.
[0115] Examples of dosage forms include, but are not limited to:
liquid dosage forms suitable for parenteral administration to a
subject; and sterile solids (e.g., crystalline or amorphous solids)
that can be reconstituted to provide liquid dosage forms suitable
for parenteral administration to a subject.
[0116] The composition, shape, and type of dosage forms provided
herein will typically vary depending on their use. For example, a
dosage form used in the initial treatment of disease may contain
larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the maintenance treatment of
the same infection. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease
or disorder. These and other ways in which specific dosage forms
encompassed herein will vary from one another will be readily
apparent to those skilled in the art. See, e.g., Remington: The
Science and Practice of Pharmacy, referenced hereinabove.
[0117] Generally, the ingredients of compositions provided herein
are supplied either separately or mixed together in unit dosage
form, for example, as a dry lyophilized powder or water free
concentrate in a hermetically sealed container such as an ampoule
or sachette indicating the quantity of active agent. Where the
composition is to be administered by infusion, it can be dispensed
with an infusion bottle containing sterile pharmaceutical grade
water or saline. Where the composition is administered by
injection, an ampoule of sterile water for injection or saline can
be provided so that the ingredients may be mixed prior to
administration.
[0118] Typical dosage forms provided herein comprise SNS-595 within
the range of about 1 mg to about 150 mg per vial. Particular dosage
forms provided herein have about 1, 3, 6, 9, 10, 12, 13.5, 15, 18,
19, 21, 24, 25, 27, 30, 38, 45, 50, 60, 63, 70, 75, 80, 85, 90, 95,
100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or 150 mg of
SNS-595 per vial.
[0119] 5.5.1 Parenteral Dosage Forms
[0120] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0121] Suitable vehicles that can be used to provide parenteral
dosage forms are well known to those skilled in the art. Examples
include, but are not limited to: Water for Injection USP; aqueous
vehicles such as, but not limited to, Sodium Chloride Injection,
Ringer's Injection, Dextrose Injection, Dextrose and Sodium
Chloride Injection, and Lactated Ringer's injection; water-miscible
vehicles such as, but not limited to, ethyl alcohol, polyethylene
glycol, and polypropylene glycol; and non-aqueous vehicles such as,
but not limited to, corn oil, cottonseed oil, peanut oil, sesame
oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
[0122] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms. For example, cyclodextrin and its
derivatives can be used to increase the solubility of active
ingredients. See, e.g., U.S. Pat. No. 5,134,127, which is
incorporated herein by reference.
[0123] 5.6 Exemplary Dosages
[0124] The methods of treating, preventing or managing antecedent
hematologic disorders, such as MDS, that are provided herein
comprise administering to a patient SNS-595, alone or in
combination with a second active agent. Doses of SNS-595 (and other
agents) may be defined on the basis of body surface area. Body
surface area (BSA) calculations can be calculated, for example, by
means of the Mosteller formula wherein:
BSA(m.sup.2)=square root of
[(height(cm).times.weight(kg)/3600].
The administered dose of SNS-595 (and other agents) can be
expressed in units other than as mg/m.sup.2. For example, doses can
be expressed as mg/kg. One of ordinary skill in the art would
readily know how to convert doses from mg/m.sup.2 to mg/kg for a
human subject, given the height and weight of the subject.
[0125] In one embodiment, SNS-595 can be administered orally or
intravenously and in single or divided daily doses in an amount of
about 1 mg/m.sup.2 to about 150 mg/m.sup.2 (i.e. about 1-150
mg/m.sup.2). Certain exemplary doses per day include about 10, 15,
18, 21, 24, 25, 27, 30, 35, 40, 45, 48, 50, 55, 60, 63, 70, 72, 75,
80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145 or
150 mg/m.sup.2.
[0126] In another embodiment, the methods of comprise administering
a dose of about 10-120 mg/m.sup.2 of SNS-595. In another
embodiment, the methods of comprise administering a dose of about
10-110 mg/m.sup.2 of SNS-595. In another embodiment, the dose is
about 15-100 mg/m.sup.2. In another embodiment, the dose is about
30-75 mg/m.sup.2. In another embodiment, the dose is about 40-80
mg/m.sup.2. In another embodiment, the dose is about 50-90
mg/m.sup.2. In another embodiment, the dose is about 15-80
mg/m.sup.2.
[0127] In another embodiment the dose of SNS-595 is about 20-30
mg/m.sup.2. In another embodiment the dose is about 25-35
mg/m.sup.2. In another embodiment the dose is about 40-50
mg/m.sup.2. In another embodiment the dose is about 45-55
mg/m.sup.2. In another embodiment the dose is about 50-60
mg/m.sup.2. In another embodiment the dose is about 55-65
mg/m.sup.2. In another embodiment the dose is about 60-70
mg/m.sup.2. In another embodiment the dose is about 65-75
mg/m.sup.2. In another embodiment the dose is about 70-80
mg/m.sup.2. In another embodiment the dose is about 75-85
mg/m.sup.2. In another embodiment the dose is about 80-90
mg/m.sup.2. In another embodiment the dose is about 85-95
mg/m.sup.2. In another embodiment the dose is about 90-100
mg/m.sup.2. In another embodiment the dose is about 100-110
mg/m.sup.2. In another embodiment the dose is about 110-120
mg/m.sup.2. In another embodiment the dose is about 120-130
mg/m.sup.2. In another embodiment the dose is about 130-140
mg/m.sup.2. In another embodiment the dose is about 140-150
mg/m.sup.2.
[0128] In another embodiment, the dose of SNS-595 is 15 mg/m.sup.2,
16 mg/m.sup.2, 17 mg/m.sup.2, 18 mg/m.sup.2, 19 mg/m.sup.2, 20
mg/m.sup.2, 21 mg/m.sup.2, 22 mg/m.sup.2, 23 mg/m.sup.2, 24
mg/m.sup.2, 25 mg/m.sup.2, 26 mg/m.sup.2, 27 mg/m.sup.2, 28
mg/m.sup.2, 29 mg/m.sup.2, 30 mg/m.sup.2, 31 mg/m.sup.2, 32
mg/m.sup.2, 33 mg/m.sup.2, 34 mg/m.sup.2, 35 mg/m.sup.2, 36
mg/m.sup.2, 37 mg/m.sup.2, 38 mg/m.sup.2, 39 mg/m.sup.2, 40
mg/m.sup.2, 41 mg/m.sup.2, 42 mg/m.sup.2, 43 mg/m.sup.2, 44
mg/m.sup.2, 45 mg/m.sup.2, 46 mg/m.sup.2, 47 mg/m.sup.2, 48
mg/m.sup.2, 49 mg/m.sup.2, 50 mg/m.sup.2, 51 mg/m.sup.2, 52
mg/m.sup.2, 53 mg/m.sup.2, 54 mg/m.sup.2, 55 mg/m.sup.2, 56
mg/m.sup.2, 57 mg/m.sup.2, 58 mg/m.sup.2, 59 mg/m.sup.2, 60
mg/m.sup.2, 61 mg/m.sup.2, 62 mg/m.sup.2, 63 mg/m.sup.2, 64
mg/m.sup.2, 65 mg/m.sup.2, 66 mg/m.sup.2, 67 mg/m.sup.2, 68
mg/m.sup.2, 69 mg/m.sup.2, 70 mg/m.sup.2, 71 mg/m.sup.2, 72
mg/m.sup.2, 73 mg/m.sup.2, 74 mg/m.sup.2, 75 mg/m.sup.2, 76
mg/m.sup.2, 77 mg/m.sup.2, 78 mg/m.sup.2, 79 mg/m.sup.2, 80
mg/m.sup.2, 81 mg/m.sup.2, 82 mg/m.sup.2, 83 mg/m.sup.2, 84
mg/m.sup.2, 85 mg/m.sup.2, 86 mg/m.sup.2, 87 mg/m.sup.2, 88
mg/m.sup.2, 89 mg/m.sup.2, 90 mg/m.sup.2, 91 mg/m.sup.2, 92
mg/m.sup.2, 93 mg/m.sup.2, 94 mg/m.sup.2, 95 mg/m.sup.2, 96
mg/m.sup.2, 97 mg/m.sup.2, 98 mg/m.sup.2, 99 mg/m.sup.2, 100
mg/m.sup.2, 110 mg/m.sup.2, 111 mg/m.sup.2, 112 mg/m.sup.2, 113
mg/m.sup.2, 114 mg/m.sup.2, 115 mg/m.sup.2, 116 mg/m.sup.2, 117
mg/m.sup.2, 118 mg/m.sup.2, 119 mg/m.sup.2, 120 mg/m.sup.2, 121
mg/m.sup.2, 122 mg/m.sup.2, 123 mg/m.sup.2, 124 mg/m.sup.2, 125
mg/m.sup.2, 126 mg/m.sup.2, 127 mg/m.sup.2, 128 mg/m.sup.2, 129
mg/m.sup.2, 130 mg/m.sup.2, 131 mg/m.sup.2, 132 mg/m.sup.2, 133
mg/m.sup.2, 134 mg/m.sup.2, 135 mg/m.sup.2, 136 mg/m.sup.2, 137
mg/m.sup.2, 138 mg/m.sup.2, 139 mg/m.sup.2, 140 mg/m.sup.2, 141
mg/m.sup.2, 142 mg/m.sup.2, 143 mg/m.sup.2, 144 mg/m.sup.2, 145
mg/m.sup.2, 146 mg/m.sup.2, 147 mg/m.sup.2, 148 mg/m.sup.2, 149
mg/m.sup.2, or 150 mg/m.sup.2.
[0129] The administered dose of SNS-595 can be delivered as a
single dose (e.g. a single bolus IV injection) or over a 24-hour
period (e.g., continuous infusion over time or divided bolus doses
over time) and is repeated until the patient experiences stable
disease or regression, or until the patient experiences disease
progression or unacceptable toxicity. Stable disease or lack
thereof is determined by methods known in the art, such as
evaluation of patient symptoms, physical examination and other
commonly accepted evaluation modalities.
[0130] In certain embodiments, SNS-595 is cyclically administered
to a patient. Cycling therapy involves the administration of an
active agent for a period of time, followed by a rest for a period
of time, and repeating this sequential administration. Cycling
therapy can reduce the development of resistance to one or more of
the therapies, avoid or reduce the side effects of one of the
therapies, and/or improves the efficacy of the treatment.
[0131] In one embodiment, the methods provided herein comprise: i)
administering a dose of about 10-120 mg/m.sup.2 of SNS-595 to a
mammal; ii) waiting a period of at least one day where the mammal
is not administered any SNS-595; iii) administering another dose of
about 10-120 mg/m.sup.2 of SNS-595 to the mammal. Optionally, the
method comprises repeating steps ii)-iii) once, twice, or a
plurality of times.
[0132] In one embodiment, the methods provided herein comprise: i)
administering a dose of about 10-90 mg/m.sup.2 of SNS-595 to a
mammal; ii) waiting a period of at least one day where the mammal
is not administered any SNS-595; iii) administering another dose of
about 10-90 mg/m.sup.2 of SNS-595 to the mammal. Optionally, the
method comprises repeating steps ii)-iii) once, twice, or a
plurality of times.
[0133] In one embodiment, the methods provided herein comprise: i)
administering a dose of about 10-40 mg/m.sup.2 of SNS-595 to a
mammal; ii) waiting a period of at least one day where the mammal
is not administered any SNS-595; iii) administering another dose of
about 10-40 mg/m.sup.2 of SNS-595 to the mammal. Optionally, the
method comprises repeating steps ii)-iii) once, twice, or a
plurality of times.
[0134] In another embodiment, the dose of SNS-595 is about 10-150
mg/m.sup.2 once per week. In another embodiment, the dose is about
10 mg/m.sup.2, 15 mg/m.sup.2, 20 mg/m.sup.2, 25 mg/m.sup.2, 30
mg/m.sup.2, 35 mg/m.sup.2, 40 mg/m.sup.2, 45 mg/m.sup.2, 50
mg/m.sup.2, 55 mg/m.sup.2, 60 mg/m.sup.2, 65 mg/m.sup.2, 70
mg/m.sup.2, 72 mg/m.sup.2, 75 mg/m.sup.2, 80 mg/m.sup.2, 85
mg/m.sup.2, 90 mg/m.sup.2, 95 mg/m.sup.2, 100 mg/m.sup.2, 105
mg/m.sup.2, 110 mg/m.sup.2, 115 mg/m.sup.2, or 120 mg/m.sup.2, once
per week. In another embodiment, the dose is about 72 mg/m.sup.2
once per week.
[0135] In another embodiment, the dose of SNS-595 is about 1-75
mg/m.sup.2 twice per week. In another embodiment, the dose is about
5 mg/m.sup.2, 7.5 mg/m.sup.2, 10 mg/m.sup.2, 12.5 mg/m.sup.2, 15
mg/m.sup.2, 17.5 mg/m.sup.2, 20 mg/m.sup.2, 22.5 mg/m.sup.2, 25
mg/m.sup.2, 27.5 mg/m.sup.2, 30 mg/m.sup.2, 32.5 mg/m.sup.2, 35
mg/m.sup.2, 37.5 mg/m.sup.2, 40 mg/m.sup.2, 42.5 mg/m.sup.2, 45
mg/m.sup.2, 47.5 mg/m.sup.2, 50 mg/m.sup.2, 52.5 mg/m.sup.2, 55
mg/m.sup.2, 57.5 mg/m.sup.2, or 60 mg/m.sup.2, twice per week. In
another embodiment, the dose is about 40 mg/m.sup.2 twice per
week.
[0136] 5.1.3 Exemplary Dosages: Combination Dosing of SNS-595 and
Cytarabine
[0137] In certain embodiments, the methods provided herein comprise
administering SNS-595 in combination with cytarabine. Cytarabine
can be administered either prior to, concurrently with, or
subsequent to administration of SNS-595. In some embodiments,
cytarabine can be administered subcutaneously or intravenously. In
certain embodiments, cytarabine is administered subcutaneously. In
certain embodiments, cytarabine is administered intravenously. In
one embodiment, the dose of cytarabine is about 5 mg/m.sup.2 to
about 1500 mg/m.sup.2, about 5 mg/m.sup.2 to about 50 mg/m.sup.2,
about 25 mg/m.sup.2 to 1000 mg/m.sup.2, 50 mg/m.sup.2 to 600
mg/m.sup.2 and 200 to 400 mg/m.sup.2. In another embodiment, the
dose of cytarabine is about 200 mg/m.sup.2, 300 mg/m.sup.2 or 400
mg/m.sup.2. In another embodiment, the dose of cytarabine is about
400 mg/m.sup.2. Cytarabine can be administered continuously, by
bolus injection, or by divided bolus injections over a particular
time period such as, for example, one day.
[0138] In another embodiment the dose of cytarabine is about 50-100
mg/m.sup.2. In another embodiment the dose of cytarabine is about
100-150 mg/m.sup.2. In another embodiment the dose of cytarabine is
about 150-200 mg/m.sup.2. In another embodiment the dose of
cytarabine is about 200-250 mg/m.sup.2. In another embodiment the
dose of cytarabine is about 250-300 mg/m.sup.2. In another
embodiment the dose of cytarabine is about 350-400 mg/m.sup.2. In
another embodiment the dose of cytarabine is about 400-450
mg/m.sup.2. In another embodiment the dose of cytarabine is about
450-500 mg/m.sup.2. In another embodiment the dose of cytarabine is
about 500-550 mg/m.sup.2. In another embodiment the dose of
cytarabine is about 550-600 mg/m.sup.2.
[0139] In some embodiments, treatment of antecedent hematologic
disorders in a subject in need thereof with a combination of
SNS-595 and cytarabine comprises dosing the subject with about
1-150 mg/m.sup.2 of SNS-595 and about 100-500 mg/m.sup.2 of
cytarabine. In certain embodiments, the subject is dosed with 10
mg/m.sup.2 SNS-595 and 400 mg/m.sup.2 of cytarabine; 18 mg/m.sup.2
SNS-595 and 400 mg/m.sup.2 of cytarabine; 30 mg/m.sup.2 SNS-595 and
400 mg/m.sup.2 of cytarabine; 45 mg/m.sup.2 SNS-595 and 400
mg/m.sup.2 of cytarabine; 63 mg/m.sup.2 SNS-595 and 400 mg/m.sup.2
of cytarabine; 70 mg/m.sup.2 SNS-595 and 400 mg/m.sup.2 of
cytarabine; 72 mg/m.sup.2 SNS-595 and 400 mg/m.sup.2 of cytarabine;
75 mg/m.sup.2 SNS-595 and 400 mg/m.sup.2 of cytarabine; 80
mg/m.sup.2 SNS-595 and 400 mg/m.sup.2 of cytarabine; 90 mg/m.sup.2
SNS-595 and 400 mg/m.sup.2 of cytarabine; 100 mg/m.sup.2 SNS-595
and 400 mg/m.sup.2 of cytarabine; 110 mg/m.sup.2 SNS-595 and 400
mg/m.sup.2 of cytarabine; 120 mg/m.sup.2 SNS-595 and 400 mg/m.sup.2
of cytarabine; 130 mg/m.sup.2 SNS-595 and 400 mg/m.sup.2 of
cytarabine; 140 mg/m.sup.2 SNS-595 and 400 mg/m.sup.2 of
cytarabine; or 150 mg/m.sup.2 SNS-595 and 400 mg/m.sup.2 of
cytarabine. In some embodiments, the subject is dosed with about 10
mg/m.sup.2 of SNS-595 and about 400 mg/m.sup.2 of cytarabine. In
some embodiments, the subject is dosed with about 20 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 30 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 45 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 60 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 70 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 72 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 75 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 80 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 90 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 100 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 110 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 120 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 130 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 140 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 150 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine.
[0140] In certain embodiments, the subject is dosed with 10
mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of cytarabine; 18 mg/m.sup.2
SNS-595 and 200 mg/m.sup.2 of cytarabine; 30 mg/m.sup.2 SNS-595 and
200 mg/m.sup.2 of cytarabine; 45 mg/m.sup.2 SNS-595 and 200
mg/m.sup.2 of cytarabine; 63 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2
of cytarabine; 70 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of
cytarabine; 72 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of cytarabine;
75 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of cytarabine; 80
mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of cytarabine; 90 mg/m.sup.2
SNS-595 and 200 mg/m.sup.2 of cytarabine; 100 mg/m.sup.2 SNS-595
and 200 mg/m.sup.2 of cytarabine; 100 mg/m.sup.2 SNS-595 and 200
mg/m.sup.2 of cytarabine; 110 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2
of cytarabine; 120 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of
cytarabine; 130 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of
cytarabine; 140 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of
cytarabine; or 150 mg/m.sup.2 SNS-595 and 200 mg/m.sup.2 of
cytarabine. In some embodiments, the subject is dosed with about 10
mg/m.sup.2 of SNS-595 and about 200 mg/m.sup.2 of cytarabine. In
some embodiments, the subject is dosed with about 20 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 30 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 45 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 60 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 70 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 72 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 75 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 80 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 90 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 100 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 110 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 120 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 130 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 140 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine. In some
embodiments, the subject is dosed with about 150 mg/m.sup.2 of
SNS-595 and about 200 mg/m.sup.2 of cytarabine.
[0141] In other embodiments, the exemplary combination dosages of
SNS-595 and cytarabine provided herein comprise the total weekly
dosage of SNS-595, and the total daily dosage of cytarabine,
respectively. For example, where a subject treated by the methods
provided herein with a combination dose of about 70 mg/m.sup.2 of
SNS-595 and about 400 mg/m.sup.2 of cytarabine, the subject is
treated a total weekly dose of about 70 mg/m.sup.2 SNS-595, and a
daily dose of about 400 mg/m.sup.2 of cytarabine over the course of
seven days.
[0142] In certain embodiments, the method of treating, preventing
or managing an antecedent hematologic disorders in a subject in
need thereof comprises administering a total dosage of about 10-120
mg/m.sup.2 SNS-595, in combination with a continuous intravenous
dose of about 50-600 mg/m.sup.2/day cytarabine over a 5-day period,
wherein the 5-day period comprises a treatment cycle. In some
embodiments, the method comprises administering a total dosage of
about 10-120 mg/m.sup.2 SNS-595 in combination with a continuous
intravenous dose of about 200-400 mg/m.sup.2/day cytarabine over a
5-day period, wherein the 5-day period comprises a treatment cycle.
In certain embodiments, the methods of treating, preventing or
managing an antecedent hematologic disorder in a subject in need
thereof comprise administering a total dosage of about 10-40
mg/m.sup.2 SNS-595, in combination with a continuous intravenous
dose of about 50-600 mg/m.sup.2/day cytarabine over a 5-day period,
wherein the 5-day period comprises a treatment cycle. In some
embodiments, the method comprises administering a total dosage of
about 20-40 mg/m.sup.2 SNS-595 in combination with a continuous
intravenous dose of about 200-400 mg/m.sup.2/day cytarabine over a
5-day period, wherein the 5-day period comprises a treatment cycle.
In some embodiments, the method comprises administering a total
dosage of about 10, 20, 30 or 40 mg/m.sup.2 SNS-595 in combination
with a continuous intravenous dose of about 200, 300 or 400
mg/m.sup.2/day cytarabine over a 5-day period, wherein the 5-day
period comprises a treatment cycle. In some embodiments, the method
comprises administering a total dosage of about 40-80 mg/m.sup.2
SNS-595 in combination with a continuous intravenous dose of about
400 mg/m.sup.2/day cytarabine over a 5-day period, wherein the
5-day period comprises a treatment cycle. In some embodiments, the
method comprises administering a total dosage of about 70
mg/m.sup.2 SNS-595 in combination with a continuous intravenous
dose of about 400 mg/m.sup.2/day cytarabine over a 5-day period,
wherein the 5-day period comprises a treatment cycle. In some
embodiments, the treatment cycle is repeated at least once. In some
embodiments, the treatment cycle is repeated at least twice. In
some embodiments, the treatment cycle is repeated at least three
times. In some embodiments, the treatment cycle is repeated at
least four times.
[0143] In certain embodiments, the methods of treating, preventing,
or managing antecedent hematological disorders in a subject in need
thereof comprises administering a total weekly amount of about
10-120 mg/m.sup.2 SNS-595 in combination with a total daily amount
of about 10-50 mg/m.sup.2 cytarabine.
[0144] In one embodiment, the doses of cytarabine used are about
5-25 mg/m.sup.2. Such doses are referred to herein as low dose
cytarabine for use in certain antecedent hematologic disorders and
in certain patient populations. In another embodiment the doses of
cytarabine used are about 5-25 mg/m.sup.2 twice a day. In another
embodiment, the doses of cytarabine used are about 5-25 mg/m.sup.2
twice a day for 10 days. In another embodiment the cytarabine is
administered subcutaneously (SC). In another embodiment, the dose
is about 10-20 mg/m.sup.2 cytarabine twice a day. In another
embodiment the cytarabine dose is about 10 mg/m.sup.2 SC twice a
day for 10 days. In another embodiment, the cytarabine dose is
about 15 mg/m.sup.2 SC twice a day for 10 days. In another
embodiment, the cytarabine dose is about 20 mg/m.sup.2 SC twice a
day for 10 days.
[0145] In another embodiment, the dose of cytarabine is 10-40
mg/m.sup.2 once a day. In another embodiment, the dose of
cytarabine is 10-40 mg/m.sup.2 once a day for 10 days. In another
embodiment the dose is administered subcutaneously. In another
embodiment, the dose is from 15-30 mg/m.sup.2 cytarabine. In
another embodiment the cytarabine dose is 20 mg/m.sup.2 SC once per
day. In another embodiment, the cytarabine dose is 20 mg/m.sup.2 SC
once per day for 10 days.
[0146] SNS-595 schedules that can be used in combination with
cytarabine at a total daily cytarabine dose of 10-50 mg/m.sup.2
(administered as a continuous infusion, single bolus, or divided
boluses), include, for example, SNS-595 administered once per week
for three weeks (Day 1, 8, and 15) and SNS-595 administered twice
per week for two weeks (Days 1, 4, 8, and 11). In certain
embodiments, doses of SNS-595 are about 10-90 mg/m.sup.2 for the
once a week for three weeks schedule and about 10-50 mg/m.sup.2 for
the twice per week for two weeks schedule. In one embodiment, the
daily cytarabine doses are administered for 10 days starting on the
same day as (i.e. within 24 hours of) the initiation of the SNS-595
dose.
[0147] Duration (interval) between repeated administrations of the
schedules can range from about 1 week to 8 weeks after the end of
the schedule (e.g., after Day 15 or Day 11 respectively). In
another embodiment, the interval is from 3 weeks to 6 weeks. In
another embodiment, the interval is from 4 weeks to 6 weeks. In
another embodiment, the interval is measured from Day 21 or Day 14,
for the once a week for three weeks and twice a week for two week
schedules, respectively
[0148] 5.1.4 Exemplary Dosing Schedules of SNS-595 and
Cytarabine
[0149] In the embodiments of the present invention, SNS-595 and
cytarabine can be administered according to any schedule deemed
suitable by a practitioner of skill in the art. Provided in this
section are exemplary dosing schedules of SNS-595 in combination
with cytarabine that can be practiced within the present
invention.
[0150] In certain embodiments, SNS-595 and cytarabine are
administered in cycles. In certain embodiments, SNS-595 and
cytarabine are administered in at least one cycle. In certain
embodiments, SNS-595 and cytarabine are administered in at least
two cycles. In certain embodiments, SNS-595 and cytarabine are
administered in at least three cycles. In certain embodiments,
SNS-595 and cytarabine are administered in at least four cycles. In
certain embodiments each cycle is at least 28 days.
[0151] In a cycle, SNS-595 and cytarabine are administered in
combination. In certain embodiments, SNS-595 is administered in two
doses three days apart, i.e. on days 1 and 4 of a cycle. In certain
embodiments, cytarabine is administered by continuous intravenous
infusion for five days. In certain embodiments, cytarabine is
administered by continuous IV infusion on days 1 through 5 of a
cycle. In certain embodiments, SNS-595 is administered in two doses
three days apart, i.e. on days 1 and 4 of a cycle, and cytarabine
is administered by continuous intravenous infusion for five
days.
[0152] In certain embodiments, as discussed above, the initial dose
of SNS-595 is administered before the administration of cytarabine.
In certain embodiments, the initial dose of SNS-595 is administered
immediately before the administration of cytarabine. In certain
embodiments, administration of cytarabine is initiated 1, 2, 3, 4,
8, 12, 16, 24, or 32 hours following administration of SNS-595, for
instance, 1, 2, 3, 4, 8, 12, 16, 24, or 32 hours following
completion of the administration of SNS-595. In certain
embodiments, administration of cytarabine is initiated about 8
hours following administration of SNS-595, for instance, 8 hours
following administration of SNS-595.
[0153] In certain embodiments, provided is an assessment of the
subject within a cycle. For instance, in certain embodiments, the
subject is assessed for safety and/or efficacy of the therapy by
any of the techniques described above. In certain embodiments, the
subject is assessed 12-16 days following the initial administration
of SNS-595 in the cycle (i.e. the subject is assessed on days 13,
14, 15, 16 or 17 of the cycle). In certain embodiments, the subject
is assessed 14 days following initial administration of SNS-595 in
the cycle (i.e. on day 15 of the cycle).
[0154] In certain embodiments, the subject is administered a
following cycle of therapy based on an evaluation of the assessment
by a practitioner of skill in the art. For instance, in certain
embodiments, after a first cycle of therapy (Cycle 1), a subject
can be administered a second cycle of therapy (Cycle 2) if bone
marrow blasts are reduced with greater than 5% of blasts are
observed in the marrow. In certain embodiments, therapy can be
discontinued after the first cycle (Cycle 1) if the subject
presents progressive disease.
[0155] In certain embodiments, after the second cycle of therapy
(Cycle 2; Reinduction), a subject can be administered a third cycle
of therapy (Cycle 3) if the subject presents morphologic complete
remission ("CR"; >1000 neutrophils per microliter and
>100,000 platelets per microliter of serum, and <5% bone
marrow blasts). In certain embodiments, after a second cycle of
therapy (Cycle 2), a subject can be administered a third cycle of
therapy (Cycle 3) if the subject presents morphologic complete
remission without platelet recovery ("CRp"; >1000 neutrophils
per microliter, .ltoreq.100,000 platelets per microliter of serum,
and <5% bone marrow blasts). In certain embodiments, after a
second cycle of therapy (Cycle 2), a subject can be administered a
third cycle of therapy (Cycle 3) if the subject presents
morphologic complete remission without incomplete blood count
recovery ("CRi"; .ltoreq.1000 neutrophils per microliter,
.ltoreq.100,000 platelets per microliter of serum, and <5% bone
marrow blasts). In certain embodiments, therapy can be discontinued
after the first cycle (Cycle 1) if the subject presents progressive
disease. In certain embodiments, therapy can be discontinued after
the second cycle (Cycle 2) if the subject presents >5% bone
marrow blasts.
[0156] In certain embodiments, after the third cycle of therapy
(Cycle 3), a subject can be administered a fourth cycle of therapy
(Cycle 4) if the subject presents peripheral blood CR (i.e. bone
marrow need not be assessed). In certain embodiments, after a third
cycle of therapy (Cycle 3), a subject can be administered a fourth
cycle of therapy (Cycle 4) if the subject presents peripheral blood
CRp (i.e. bone marrow need not be assessed). In certain
embodiments, after a third cycle of therapy (Cycle 3), a subject
can be administered a fourth cycle of therapy (Cycle 4) if the
subject presents peripheral blood Cri (i.e. bone marrow need not be
assessed). In certain embodiments, therapy can be discontinued
after the third cycle (Cycle 3) if the subject presents progressive
disease.
[0157] In certain embodiments, a subject can be administered Cycle
3 following Cycle 1. For instance, a subject proceeds from Cycle 1
to Cycle 3 if the subject presents CR, CRp, or CRi following Cycle
1.
[0158] In certain embodiments, Cycle 2 is initiated n more than 14
days following the assessment of Cycle 1 (Induction).
[0159] In certain embodiments, Cycle 3 is initiated 27 days to 83
days following the initiation of treatment in the previous Cycle
(i.e. on day 28 to day 84 of the previous Cycle). As discussed
above, in certain embodiments, Cycle 3 follows Cycle 1. In certain
embodiments, Cycle 3 follows Cycle 2.
[0160] In certain embodiments, Cycle 4 is initiated at least 27
days following the initiation of treatment Cycle 3, i.e. on day 28
of Cycle 3.
[0161] In certain embodiments, the dose of SNS-595 is constant in
each cycle of the therapy. In certain embodiments, the dose of
cytarabine is constant in each cycle of the therapy. In certain
embodiments, the dose of cytarabine is can be reduced from one
Cycle to a second Cycle. For instance, in certain embodiments, in
Cycle 1 cytarabine can be administered at 400 mg/m.sup.2 while in
Cycles 2-4 cytarabine can be administered at 200 mg/m.sup.2. In
certain embodiments, in Cycles 1-2 cytarabine can be administered
at 400 mg/m.sup.2 while in Cycles 2-4 cytarabine can be
administered at 200 mg/m.sup.2. In certain embodiments, in Cycles
1-3 cytarabine can be administered at 400 mg/m.sup.2 while in Cycle
4 cytarabine can be administered at 200 mg/m.sup.2. In certain
embodiments, in Cycles 1-4 cytarabine can be administered at 400
mg/m.sup.2. Such dose reductions are administered according to the
judgment of a practitioner of skill in the art, for instance, if a
subject presents one or more dose limiting toxicities described
herein.
[0162] In certain embodiments, therapy can continue beyond Cycle 4
according to the assessment described above. Patients can continue
to be monitored for remission according to the assessment following
therapy according to the judgment of the practitioner of skill.
6. EXAMPLES
[0163] Certain embodiments of the invention are illustrated by the
following non-limiting examples.
Example 1
Pharmaceutical Composition Suitable for Injection or Intravenous
Infusion
[0164] Acidic compositions (<pH 4) provided the appropriate
balance of increased solubility of SNS-595 and desirable
pharmaceutical properties (e.g., increased patient comfort by
causing less irritation at the delivery site). An illustrative
example of a suitable composition comprises: 10 mg SNS-595 per mL
of aqueous solution of 4.5% sorbitol that is adjusted to pH 2.5
with methanesulfonic acid. One protocol for making such a solution
includes the following for making a 100 mg/10 mL presentation: 100
mg of SNS-595 and 450 mg D-sorbitol are added to distilled water;
the volume is brought up to a volume of 10 mL; and the pH of the
resulting solution is adjusted to 2.5 with methanesulfonic acid.
The resulting composition is also suitable for lyophilization. The
lyophilized form is then reconstituted with sterile water to the
appropriate concentration prior to use.
Example 2
Clinical Study: Treatment with SNS-595
[0165] A caucasian female patient (81 years old) with MDS that had
transformed to refractory CMML was enrolled in this study. The
patient was diagnosed about 26 months prior to the study and was
given 8 cycles of azacitadine (Vidaza.RTM.) about 10 months prior
to the study. She was then treated with mitoxantrone+VP 16 for 1
cycle, about 4 months prior to the study. The disease had
progressed to AML prior to treatment with SNS-595.
[0166] The treatment with SNS-595 was started at 72 mg/m.sup.2
(once per week for three weeks, as slow IV push).
[0167] The patient had initial marrow blast count of 39%. The
following observations were noted on days 15 and 35.
TABLE-US-00001 Peripheral White blood cell Absolute neutrophil
Blasts (WBC) count count (ANC) Day 15 No blasts 600 94 Around Day
35 33% 16000 (was 7000 but 3139 patient had Necrotizing fasciitis
(NF) infection)
[0168] The data demonstrates that, although the patient ultimately
had progressive disease, the treatment showed clinical benefit with
reduction in splenomegaly and blast counts.
Example 3
Clinical Study: Treatment with SNS-595
[0169] A black/African-American male patient (58 years old) with
relapsed CMML (transformed to AML) was enrolled. The patient was
diagnosed about 17 months prior to the study, was treated with 1
cycle of a Southwest Oncology Group (SWOG) regimen after diagnosis.
He was given 4 cycles of azacitidine (Vidaza.RTM.) about 14 months
prior to the study and 1 cycle of decitabine, about 6 months before
the study.
[0170] The treatment with SNS-595 was started at 50 mg/m.sup.2
(twice a week, as slow IV push). The patient showed initial marrow
at baseline 20% blasts.
[0171] Post Cycle 1: marrow showed 8% blasts
[0172] Post Cycle 2: marrow showed 1% with 4% circulating
blasts.
[0173] Post Cycle 3: there was 8% circulating blasts.
[0174] Post Cycle 4: there was 12% circulating blasts.
[0175] At the time of undergoing treatment with third cycle of
SNS-595, the patient's absolute neutrophil count (ANC) was
1600.
[0176] The data demonstrates that the treatment showed clinical
benefit (i.e. hematological improvement) with reduction in blast
counts.
Example 4
Clinical Study: Treatment of Acute Leukemia with SNS-595
[0177] The safety and efficacy of SNS-595 were investigated in two
dose-escalating studies. As demonstrated below, SNS-595 provides
good safety profiles and evidence of clinical activity as measured
by complete responses (CR) and decreases in leukemic blasts in
pateints with advanced or refractory acute leukemias.
[0178] In the study, total of 49 patients were enrolled, Arm A
(SNS-595 was administered as a weekly.times.3): 25 patients and Arm
B (SNS-595 was administered twice weekly.times.2 bolus): 24
patients. Thirty-one patients were male and 18 patients female,
with a median age of 65 years. Diagnoses included AML (43
patients), ALL (4 patients), and 1 patient each with acute
lymphoblastic leukemia and acute biphenotypic leukemia. Most
patients had relapsed/refractory leukemia from prior therapy
(median 3 prior regimens (range 1-7)).
[0179] SNS-595 was administered as a slow IV push on days 1, 8, 15
(Arm A) or days 1, 4, 8, 11 (Arm B). Minimum cycle length was 42
days for Arm A and 39 days for Arm B, respectively. Additional
cycles were permitted if patients achieved stable disease or
better. The starting dose of SNS-595 was 18 mg/m.sup.2 weekly on
Arm A, and 9 mg/m.sup.2 twice weekly on Arm B. The dose was
escalated by cohort.
[0180] Pharmakokinetic analyses for SNS-595 were performed during
cycle 1. Pre- and post-dose bone marrow aspirates were obtained
from a subset of patients to assess biomarkers.
[0181] The results provided herein are for dose escalation to 90
mg/m.sup.2/day on Arm A. Three dose-limiting toxicities (DLTs) were
observed on Arm A-G4 myelosuppression at the 27 mg/m.sup.2 weekly
dose (also had progressive disease), prolonged myelosuppression at
the 50 mg/m.sup.2 weekly dose, and bowel obstruction at the 72
mg/m.sup.2 weekly dose. Non-dose-limiting toxicities (non-DLTs)
included nausea/vomiting and diarrhea; drug-related G3 & 4
events were limited to stomatitis (3 pateints) and diarrhea (1
patient).
[0182] On Arm B, dose-limiting toxicity (DLT) of Grade (G) 3
mucositis was observed in 3 patients at the 50 mg/m.sup.2 dose
level. At 40 mg/m.sup.2, two patients out of 11 exhibited G3
mucositis.
[0183] Blast reduction (>95%) and response was associated with
time above a threshold concentration of SNS-595. Following
administration of SNS-595, evidence of DNA-damage induced by
SNS-595 was detected. Clinical activity--reductions in marrow
blasts to .ltoreq.5%--was noted at doses at or above 50 mg/m.sup.2
(5 patients in Arm A) and 40 mg/m.sup.2 (1 patient in Arm B).
Complete Responses (CR) have been observed at the 50 mg/m.sup.2
dose level (Arm A, 1 patient) and at the 40 mg/m.sup.2 level (Arm
B, 1 patient). A third patient with AML and splenomegaly achieved
partial response at the 50 mg/m.sup.2 dose level (Arm B) and had G3
mucositis. In addition, 1 patient with AML and splenomegaly (at 72
mg/m.sup.2, Arm A) achieved clinical benefit with reduction in
splenomegaly and blast counts.
[0184] This study demonstrates that SNS-595 is well-tolerated in
patients with advanced leukemias, with preliminary signs of
clinical activity as measured by complete responses (CR) and
decreases in leukemic blasts.
[0185] The embodiments described above are intended to be merely
exemplary, and those skilled in the art will recognize, or will be
able to ascertain using no more than routine experimentation,
numerous equivalents of specific compounds, materials, and
procedures. All such equivalents are considered to be within the
scope of the invention and are encompassed by the appended
claims.
* * * * *